Reactive mesothelium versus malignant mesothelioma
This differential may be extremely difficult, especially on small biopsies.
Immunohistochemistry
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reactive mesothelium
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malignant mesothelioma
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comment
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Desmin
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83%(
8/10staining generally strong and diffuse2, 8/103,
34/40(In 26 cases, desmin stained more than 75% of cells with high intensity, in 5 cases ~50% of cells with moderate intensity and in 3 cases less than 25% of cells with low intensity. Exfoliated reactive mesothelial cells stained.)21)
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28% (
10/45biphasic: 10/19, epithelioid 0/13, sarcomatoid; 0/131,
9/16epithelioid; 8/13, biphasic; 1/3. Staining was only focal.2,
4/3827 predominantly epithelioid, 4 predominantly spindle, 7 biphasic. Desmin positive in epithelioid component in 4/38 and in spindle cell component in 12/383 ),
18/40(12/26 epithelioid, 4/10 sarcomatoid, 2/4 biphasic)16,
21/43(14/34 epithelioid, 5/7 sarcomatoid, 0/1 mixed and 1/1 lymphohistiocytoid mesotheliomas)17,
6/60(all 60 cases were of epithelioid type. In all six cases, staining was cytoplasmic. In two cases, more than 75% of cells stained intensely: in four cases staining was less than 25% of cells and of low intensity. Exfoliated malignant mesothelial cells were negative.)21
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Appears to be useful.
Examine epithelial component: desmin is less useful in distinguishing reactive from neoplastic spindle cell mesothelial proliferations
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EMA
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15% (3/734, 5/205, 2/126 6/117,
8/40(8 cases showed moderate staining of less than 25% of cells.)21)
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75% (103/1414,
30/31diffuse linear membrane, stronger in epithelioid areas5, 10/126, 76/1127,
48/60(staining was strong and membranous. In 39 cases, more than 75% of cells stained. In 9 cases less than 25% of cells stained but the staining was strong.)21)
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Appears to be useful.
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p53
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9% (0/208, 0/209, 0/4010, 0/1311, 0/2012, 0/136,
13/20(occasional nuclei positive)5, 9/117),
1/7(This was a study of the differentiation of desmoplastic mesothelioma from fibrous pleurisy: the difference in staining for p53 was not significant.)20, 0/4021
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59% (14/208,
21/47epithelioid; 10/16, biphasic; 9/19, sarcomatoid; 2/12. Some small biopsies shows very intense staining.9, 9/3610, 19/4011, 30/3512, 5/126, 30/315, 78/1127),
8/15(This was a study of the differentiation of desmoplastic mesothelioma from fibrous pleurisy: the difference in staining for p53 was not significant.)20,
27/60(In only 2 cases did more than 75% of mesothelial cells show nuclear staining. In 20 cases, less than 25% of cells were positive.)21
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May be useful.
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bcl-2
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0/4413, 0/205, 0/1521
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5/6213, 0/315, 0/1521
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Does not appear to be useful
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p-glycoprotein, p170
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3% (0/3514, 2/117, 0/1521)
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45% (31/3314, 37/1067, 2/1521)
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Background staining may make interpretation difficult
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PDGF receptor b
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13% (0/3515, 2/117,
6/15(Two cases showed strong staining of more than 75% of cells, two cases showed moderate staining of 26-75% of cells and two cases showed low intensity staining of less than 25% of cells.)21)
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38% (15/3315, 31/1127,
15/15(9 cases showed strong staining of more than 75% of cells; 6 cases showed strong staining of 26-75% of cells)21)
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Probably not useful
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Telomerase reverse transcriptase
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0/318
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67/6818
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Needs the study of more cases of reactive proliferation
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GLUT-1
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0/4026
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48/48(36/36 epithelioid, 11/11 biphasic, 1/1 sarcomatoid)26
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Sensitivities and specificities have been calculated in a review paper19:
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p53
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EMA
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bcl-2
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p170
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desmin
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number of studies
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105,6,7,8,9,10,11,12,20
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54,5,6,7,21
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35,13,21
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37,14,21
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32,3,21
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staining in mesothelioma
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positive
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positive
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positive
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positive
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negative
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Sensitivity for mesothelioma
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epithelioid
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61% of 236 cases
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77% of 296 cases
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3% of 76 cases
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58% of 100 cases
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81% of 73 cases
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biphasic
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41% of 34 cases
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73% of 26 cases
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4% of 22 cases
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56% of 16 cases
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2 of 3 cases
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sarcomatoid
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54% of 39 cases
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25% of 20 cases
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10% of 10 cases
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17% of 18 cases
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not classified
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59% of 32 cases
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83% of 12 cases
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89% of 38 cases
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overall
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58% of 341 cases
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74% of 354 cases
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4% of 108 cases
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52% of 134 cases
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83% of 114 cases
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staining in benign pleural disease
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negative
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negative
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negative
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negative
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positive
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Specificity for mesothelioma
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91% of 218 cases
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89% of 167 cases
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100% of 93 cases
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97% of 61 cases
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83% of 60 cases
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Proliferation markers MCM2 and Ki67 may be helpful22:
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Reference 22
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MCM2
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Ki67
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Median
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Interquartile range
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Median
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Interquartile range
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Reactive mesothelial hyperplasia (n=18)
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0.225
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0.150-0.250
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0.100
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0.030-0.130
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Reactive pleural fibrosis (n=15)
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0.230
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0.110-0.380
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0.170
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0.055-0.285
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Epithelioid mesothelioma (n=14)
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0.330
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0.205-0.465
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0.150
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0.085-0.250
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0.320
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0.320-0.530
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0.200
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0.200-0.265
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Sarcomatoid mesothelioma (n=10)
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non-hot spot
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0.265
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0.225-0.360
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0.215
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0.165-0.280
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hot spot
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0.525
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0.410-0.595
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0.285
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0.200-0.440
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A MCM2 labelling index >0.32 identifies epithelioid malignant mesothelioma with 100% specificity and 87.% sensitivity (14/16 cases) in the distinction from reactive mesothelial proliferation. .
AgNORs have been studied but are difficult to assess in paraffin sections.
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Mesothelioma
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Benign pleural disease
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n
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AgNOR count
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n
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AgNOR count
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Ayres23
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epithelioid
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10
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5.4
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10
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1.75
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biphasic
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5
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4.9
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sarcomatoid
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5
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7.5
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undifferentiated
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5
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5.0
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Bethwaite24
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10
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5.1
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11
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3.7
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Soosay25
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7
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3.7
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9
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1.9
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Wolanski4
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80
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6.1
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26
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5.0
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See also the use of immunohistochemistry in effusion cytology.
References
1 Mayall, F. G., Goddard, H., Gibbs, A. R. Intermediate filament expression in mesotheliomas: leiomyoid mesotheliomas are not uncommon. Histopathology 1992;21:453-7.
2 Hurlimann, J. Desmin and neural marker expression in mesothelial cells and mesotheliomas. Hum Pathol 1994;25:753-7.
3 Scoones DJ, Richman PI. Expression of desmin and smooth msucle actin in mesothelial hyperplasia and mesothelioma. J Pathol 1993;169SL188A (abstract).
4 Wolanski, K. D., Whitaker, D., Shilkin, K. B., Henderson, D. W. The use of epithelial membrane antigen and silver-stained nucleolar organizer regions testing in the differential diagnosis of mesothelioma from benign reactive mesothelioses. Cancer 1998;82:583-90.
5 Cury, P. M., Butcher, D. N., Corrin, B., Nicholson, A. G. The use of histological and immunohistochemical markers to distinguish pleural malignant mesothelioma and in situ mesothelioma from reactive mesothelial hyperplasia and reactive pleural fibrosis. J Pathol 1999;189:251-7.
6 Casalots J, Tarroch X, Forcada P et al. Utility of epithelial membrane antigen and p53 in the differential diagnosis of benign reactive processes from malingnacy in pleural biopsy specimens. Virchows Archives 1999;435:286 (abstract).
7 Roberts, F., Harper, C. M., Downie, I., Burnett, R. A. Immunohistochemical analysis still has a limited role in the diagnosis of malignant mesothelioma. A study of thirteen antibodies. Am J Clin Pathol 2001;116:253-62.
8 Kafiri, G., Thomas, D. M., Shepherd, N. A., Krausz, T., Lane, D. P., Hall, P. A. p53 expression is common in malignant mesothelioma. Histopathology 1992;21:331-4.
9 Mayall, F. G., Goddard, H., Gibbs, A. R. p53 immunostaining in the distinction between benign and malignant mesothelial proliferations using formalin-fixed paraffin sections. J Pathol 1992;168:377-81.
10 Ramael, M., Lemmens, G., Eerdekens, C., Buysse, C., Deblier, I., Jacobs, W., van Marck, E. Immunoreactivity for p53 protein in malignant mesothelioma and non- neoplastic mesothelium. J Pathol 1992;168:371-5.
11 Cagle, P.T., Brown, R.W. and Lebovitz, R.M. p53 immunostaining in the differentiation of reactive processes from malignancy in pleural biopsy specimens. Hum Pathol 1994;25:443-8.
12 Esposito, V., Baldi, A., De Luca, A., Claudio, P.P., Signoriello, G., Bolognese, A., Centonze, P., Giordano, G.G., Caputi, M., Baldi, F. and Giordano, A. p53 immunostaining in differential diagnosis of pleural mesothelial proliferations. Anticancer Res 1997;17:733-6.
13 Segers, K., Ramael, M., Singh, S.K., Weyler, J., Van Meerbeeck, J., Vermeire, P. and Van Marck, E. Immunoreactivity for bcl-2 protein in malignant mesothelioma and non- neoplastic mesothelium. Virchows Arch 1994;424:631-4.
14 Ramael, M., van den Bossche, J., Buysse, C., van Meerbeeck, J., Segers, K., Vermeire, P. and van Marck, E. Immunoreactivity for P-170 glycoprotein in malignant mesothelioma and in non-neoplastic mesothelium of the pleura using the murine monoclonal antibody JSB-1. J Pathol 1992;167:5-8.
15 Ramael, M., Buysse, C., van den Bossche, J., Segers, K. and van Marck, E. Immunoreactivity for the beta chain of the platelet-derived growth factor receptor in malignant mesothelioma and non-neoplastic mesothelium. J Pathol 1992;167:1-4.
16 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.
17 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.
18 Kumaki, F., Kawai, T., Churg, A., Galateau-Salle, F. B., Hasleton, P., Henderson, D., Roggli, V., Travis, W. D., Cagle, P. T., Ferrans, V. J. Expression of Telomerase Reverse Transcriptase (TERT) in Malignant Mesotheliomas. Am J Surg Pathol 2002; 26:365-370
19 King J, Thatcher N, Pickering C, et al. Sensitivity and specificity of immunohistochemical antibodies used to distinguish between benign and malignant pleural disease: a systematic review of published reports. Histopathology 2006; 49:561-8
20 Mangano WE, Cagle PT, Churg A, et al. The diagnosis of desmoplastic malignant mesothelioma and its distinction from fibrous pleurisy: a histologic and immunohistochemical analysis of 31 cases including p53 immunostaining. Am J Clin Pathol 1998; 110:191-9
21 Attanoos RL, Griffin A,Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology 2003; 43:231-8
22 Sington JD, Morris LS, Nicholson AG, et al. Assessment of cell cycle state may facilitate the histopathological diagnosis of malignant mesothelioma. Histopathology 2003; 42:498-502
23 Ayres JG, Crocker JG,Skilbeck NQ. Differentiation of malignant from normal and reactive mesothelial cells by the argyrophil technique for nucleolar organiser region associated proteins. Thorax 1988; 43:366-70
24 Bethwaite PB, Delahunt B, Holloway LJ, et al. Comparison of silver-staining nucleolar organizer region (AgNOR) counts and proliferating cell nuclear antigen (PCNA) expression in reactive mesothelial hyperplasia and malignant mesothelioma. Pathology 1995; 27:1-4
25 Soosay GN, Griffiths M, Papadaki L, et al. The differential diagnosis of epithelial-type mesothelioma from adenocarcinoma and reactive mesothelial proliferation. J Pathol 1991; 163:299-305
26 Kato Y, Tsuta K, Seki K, et al. Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma. Mod Pathol 2007; 20:215-20
This page last revised 29.4.2007.
©SMUHT/PW Bishop