Epithelioid mesothelioma versus primary pulmonary adenocarcinoma

Markers positive in adenocarcinoma but negative in mesothelioma have now been supplemented with a range of markers positive in mesothelioma and negative in adenocarcinoma. Generally, a panel should contain members of both groups. The following panels have been recommended, based on studies of panels of markers:

Reference

Summary17

sensitivity

specificity

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

34bE12

O

O

44-3A6

O

Amylase

O

AUA1

O

B72.3

A,=1 (positive in adenocarcinoma; recommended as a first-line marker with BerEP4 or MOC1 as alternatives)

80%

91%

1

O

1

1

2

O

O

O

O

=1

=1

BerEP4

A,=1 (positive in adenocarcinoma; recommended as a first-line marker with B72.3 or MOC1 as alternatives)

80%

88%

1

1

O

1

=1

1

O

2

O

1

O

2

=1

=1

Ber-H2

O

BG-8

A,2 (positive in adenocarcinoma; recommended as a second-line marker)

88%

89%

1

2

Blood-group related antigens A, B &H

3

BMA-120

O

Ca 125

O

O

Ca 19.9

A,2 (positive in adenocarcinoma; recommended as a second-line marker)

56%

99.5%

1

2

Calretinin

M,1 (positive in epithelioid mesothelioma; recommended as a first-line marker)

80%

86%

O

O

O

1

1

1

O

=1

O

2

1

=1

Cam 5.2

O

CD 44H

O

O

CD44S

M,O (positive in epithelioid mesothelioma, but not recommended)

66%

61%

O

CD138

A (positive in adenocarcinoma: not of proven value as a marker)

55%

92%

CEA

A,1 (positive in adenocarcinoma; recommended as a first-line marker)

84%

97.5%

1

4

1

1

1

1

1

O

O

1

1

=1

O

O

2

1

=1

CK4

O

CK5/6

M,=1 (positive in epithelioid mesothelioma; recommended as a first-line marker with WT1 as an alternative)

80%

83%

O

1

2

=1

=1

CK7

O

O

CK8

O

CK8/18/19

O

CK10

O

CK13

O

CK13/16

O

CK14

O

CK16

O

CK18

O

O

CK19

O

CK20

O

D2-40

M,=1 (positive in epithelioid mesothelioma; recommended as a first-line marker with podoplanin as an alternative; more studies are needed.)

=1

Desmin

O

O

E-cadherin

A,O (positive in adenocarcinoma, but not recommended)

89%

66%

1

1

O

EMA

A,O (positive in adenocarcinoma, but not recommended)

O

O

O

1

O

O

O

HBME-1

M,O (positive in epithelioid mesothelioma, but not recommended)

78%

51%

O

O

O

2

O

O

1

O

O

O

HEA125

2

O

HMFG-2

2

IOB3

1

LeuM1

A,2 (positive in adenocarcinoma; recommended as a second-line marker)

67%

93%

2

O

O

1

2

O

O

O

1

1

O

O

O

2

2

mesothelin

M,2 (positive in epithelioid mesothelioma; recommended as a second-line marker)

97%

53%

2

MNF116

O

MOC-31

A,=1 (positive in adenocarcinoma; recommended as a first-line marker with B72.3 or BerEP4 as alternatives)

91%

88%

=1

O

1

O

1

=1

=1

N-cadherin

M,O (positive in epithelioid mesothelioma, but not recommended)

77%

65%

2

O

p-170gp

O

p53

O

PDGFR-beta

O

PLAP

O

Podoplanin

M,=1 (positive in epithelioid mesothelioma; recommended as a first-line marker with D2-40 as an alternative; more studies are needed.)

=1

Secretory component

O

Sialosyl-TN

2

SP-A

O

SM3

O

thrombomodulin

M,2 (positive in epithelioid mesothelioma; recommended as a second-line marker)

62%

81%

O

1

O

O

2

1

O

O

2

2

TTF-1

A,2 (positive in adenocarcinoma; recommended as a second-line marker)

75%

100%

1

2

vimentin

M,O (positive in mesothelioma, but not recommended)

66%

72%

O

O

O

O

O

O

1

1

O

O

O

O

WT1

M,=1 (positive in epithelioid mesothelioma; recommended as a first-line marker with CK5/6 as an alternative)

76%

97%

1

=1

=1

A: preferentially stains adenocarcinoma, M: preferentially stains (epithelioid) mesothelioma, 1: first line marker, 2: second line marker, 3: third line marker, etc, =1: two or more markers are equally recommended as alternative first line markers, O: studied but not recommended.

Most studies have been of mesothelioma versus pulmonary adenocarcinoma. Some metastatic carcinomas, such as renal cell carcinoma, pose particular problems. The differentiation of peritoneal mesothelioma from ovarian serous tumours possess specific problems.

The following is a summary of the usual patterns of immunoreactivity in different types of mesothelioma:

cytokeratins vimentin EMA, HMFG-2 CEA LeuM1 (CD 15) B72.3 (TAG-72) BerEP4 CK5/6 HHF35 thrombo- modulin E cad- herin N cad- herin low MW high MW m e s o t h e l i o m a epithelial tubulopapillary, glandular, histiocytoid, adenoid cystic, signet ring + 30% 75% (cell membrane staining) <15% (focal, low-intensity, associated with mucicarmine positivity) rare cases focally positive rare cases focally positive <20% focally, rarely diffusely, positive + - + -  + solid poorly differentiated + ± rarely positive - - - -   -   sarcomatoid   + (most) + rarely positive - - - - ± ±   mixed each component as above anaplastic   rarely positive ± + rarely positive - - - -   ±   transitional   + ± + rarely positive - - + +   -   desmoplastic   + ± + - - + + +   ±   small cell       + (most)                   pulmonary adenocarcinoma + 17% to 46% + cytoplasmic (bronchoalveolar carcinoma may show a membrane pattern) + variably reported as 50% to 95% of cases positive variably reported as 20% to 86% positive 87% positive ±   8% positive + - co-expression is less common than for mesothelioma      See also: TTF-1 is positive in most adenocarcinomas but negative in mesothelioma.  CD56 is more often positive in mesothelioma than in non small cell lung carcinoma Calretinin is usually positive in mesothelioma and negative in adenocarcinoma. HBME-1 is of low specificity for mesothelioma,  MOC-31 is usually expressed by adenocarcinomas, but is usually negative in mesotheliomas. MNF116 positivity in fibrous cells is reported to be more frequent in mesothelioma than in adenocarcinoma Sialosyl-TN CD 44H. Ca 19.9 mesothelin is of limited value References 1 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. 2 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. 3 Skov, B. G., A. F. Lauritzen, et al. (1994). "Differentiation of adenocarcinoma of the lung and malignant mesothelioma: predictive value and reproducibility of immunoreactive antibodies." Histopathology 25(5): 431-7. 4 Kortsik, C. S., P. Werner, et al. (1995). "Immunocytochemical characterization of malignant mesothelioma and carcinoma metastatic to the pleura: IOB3--a new tumor marker." Lung 173(2): 79-87. 5 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. 6 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. 7 Chenard-Neu, M. P., A. Kabou, et al. (1998). "[Immunohistochemistry in the differential diagnosis of mesothelioma and adenocarcinoma. Evaluation of 5 new antibodies and 6 traditional antibodies]." Ann Pathol 18(6): 460-5. 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 Leers, M. P., M. M. Aarts, et al. (1998). "E-cadherin and calretinin: a useful combination of immunochemical markers for differentiation between mesothelioma and metastatic adenocarcinoma." Histopathology 32(3): 209-16. 10 Brockstedt, U., M. Gulyas, et al. (2000). "An optimized battery of eight antibodies that can distinguish most cases of epithelial mesothelioma from adenocarcinoma." Am J Clin Pathol 114(2): 203-9. 11 Comin, C. E., L. Novelli, et al. (2001). "Calretinin, thrombomodulin, CEA, and CD15: a useful combination of immunohistochemical markers for differentiating pleural epithelial mesothelioma from peripheral pulmonary adenocarcinoma." Hum Pathol 32(5): 529-36. 12 Oates, J. and C. Edwards (2000). "HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma." Histopathology 36(4): 341-7. 13 Carella, R., G. Deleonardi, et al. (2001). "Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma: a study with logistic regression analysis." Am J Surg Pathol 25(1): 43-50. 14 Gonzalez-Lois, C., C. Ballestin, et al. (2001). "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 38(6): 528-34. 15 Roberts, F., McCall, A. E., Burnett, R. A. Malignant mesothelioma: a comparison of biopsy and postmortem material by light microscopy and immunohistochemistry. J Clin Pathol 2001;54:766-70. 16 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. 17 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. 18 Ordonez NG. Immunohistochemical diagnosis of epithelioid mesothelioma: an update. Arch Pathol Lab Med 2005; 129:1407-14 Dail and Hammar, 2nd ed., p 1516-1526   This page last revised 7.8.06. ©SMUHT/PW Bishop