Pleura >

Malignant Mesothelioma

Synonyms: Diffuse Mesothelioma

Definition

Malignant tumor of the pleura with a mesothelial origin.

Clinical Features

  • Usually older adults1
  • Sometimes familial clustering2
  • Typically:
    • chest pain
    • pleural effusion
    • lower half of a hemithorax initially
    • spread to rest of pleural cavity later

Spread and Metastases

  • Typically contiguous spread and perhaps implantation to:
    • entire pleural space
    • both pleurae
    • interlobular septa
    • pericardium
    • chest wall
    • diaphragm
    • peritoneum3
  • Extension into subpleural lung common
  • May be intraparenchymal spread,4 but nodular masses within lung parenchyma favor primary lung cancer with prominent pleural spread
  • Distant metastases:
    • generally late disease if at all5
    • prominent hilar and supraclavicular lymphadenopathy at presentation favor carcinoma over mesothelioma

Gross Pathology

  • Usually multiple gray or white ill-defined nodules in a diffusely thickened pleura (Figs 1 and 2
    Malignant mesothelioma growing as multiple nodules on the parietal pleura.

    Fig. 1: Malignant mesothelioma growing as multiple nodules on the parietal pleura.

    Classical pattern of spread of advanced pleural mesothelioma. (Courtesy of Dr RA Cooke, Brisbane, Australia; from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology. Edinburgh, Churchill Livingstone, 2004).

    Fig. 2: Classical pattern of spread of advanced pleural mesothelioma. (Courtesy of Dr RA Cooke, Brisbane, Australia; from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology. Edinburgh, Churchill Livingstone, 2004).

    )
  • Rarely localized pleural mass9
  • Almost always pleural effusion

Histopathology

  • Neoplastic formations may form:
    • papillae (Fig. 3
      Malignant pleural mesothelioma with a predominantly papillary pattern of growth.

      Fig. 3: Malignant pleural mesothelioma with a predominantly papillary pattern of growth.

      )
    • pseudoacini
    • solid nests10
  • Cytoplasm:
    • abundant
    • acidophilic
  • Features in favor of malignancy:
    • infiltration of deep tissues
    • obvious cytologic atypia
    • prominent cell groupings
    • necrosis11

Special Stains and Immunohistochemistry

  • Usually produce large amounts of hyaluronic acid:
    • demonstrated with:
      • Alcian blue:
      • nearly always mucicarmine negative
  • Glycogen usually absent:
    • exceptions are glycogen-rich mesotheliomas15
  • Markers:
  • C-kit (CD117) usually not expressed26
  • Overexpression p53:
    • ≈ 50% malignant mesotheliomas regardless of relationship to asbestos exposure27

Diagnosis

Variants

Spindle Cell or Sarcomatoid Mesothelioma
Desmoplastic Mesothelioma
  • Subtype of spindle cell malignant mesothelioma
  • Abundant deposition of fibrous tissue41
  • Main differential diagnosis:
    • more cellular types of solitary fibrous tumors of pleura (some malignant)
    • desmoplastic mesothelioma favored by positivity for:
      • keratin
      • WT-1
  • Ultrastructurally:
    • evidence of rudimentary epithelial differentiation42
  • Also distinguish from areas of dense inflammatory fibrosis43
    • differential diagnosis largely based on appearance of proliferating cells in routinely stained sections44
    • features favoring malignancy:
      • nuclear atypia
      • necrosis
      • well-developed fascicular, storiform, or other complex tissue patterns
      • infiltration of adjacent tissues44,45
  • Conservative approach in dubious cases
Deciduoid Mesothelioma
  • Large tumor cells with abundant ground glass cytoplasm that simulate decidual cells
  • First described in abdominal cavity of young women
  • Also:
    • pleural cavity
    • older age group
    • both sexes48,49
Malignant Mesothelioma with Squamous Differentiation
Small Cell Variant
  • Most immunoreactive for:
    • keratin
    • neuron-specific enolase
    • occasionally Leu 752

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Malignant Mesothelioma

(View full diagnosis)
(View full diagnosis)
(View full diagnosis)


Reactive Mesothelial Hyperplasia

  • Associated with inflammatory or neoplastic diseases of underlying lung
  • Sometimes no apparent cause53–55
  • Must be distinguished from early malignant mesothelioma
  • Diagnosis of ‘mesothelioma in situ'56 (i.e. in absence of detectable invasion) should be made:
    • only if clearcut cytologic aberrations
    • with great caution
  • Generally conservative approach indicated:
    • if lesion is a mesothelioma usually apparent in a few months11
  • No immunomarkers discriminate reactive proliferation from neoplastic mesothelioma:
    • EMA and p53 stains:
      • more often positive in mesothelioma than in reactive conditions
    • desmin:
      • less often positive in mesothelioma than in reactive conditions57
    • exceptions limit diagnostic use58,59

Metastatic Carcinoma

Staging/grading

Primary Tumor (T)

.
*

T3 describes locally advanced but potentially resectable tumor.

**

T4 describes locally advanced, technically unresectable tumor.

TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
T1Tumor involves ipsilateral parietal pleura, with or without focal involvement of visceral pleura
T1aTumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura. No involvement of visceral pleura
T1bTumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura, with focal involvement of visceral pleura
T2Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: confluent visceral pleural tumor (including fissure), invasion of diaphragmatic muscle, invasion of lung parenchyma
T3*Tumor involves any of the ipsilateral pleural surfaces, with at least one of the following: invasion of endothoracic fascia, invasion into mediastinal fat, solitary focus of tumor invading soft tissues of the chest wall, nontransmural involvement of pericardium
T4**Tumor involves any of the ipsilateral pleural surfaces, with at least one of the following: diffuse or multifocal invasion of soft tissues of chest wall, any involvement of rib, invasion through diaphragm to peritoneum, invasion of any mediastinal organ(s), direct extension to contralateral pleura, invasion into spine, extension to internal surface of pericardium, pericardial effusion with positive cytology, invasion of myocardium, invasion of brachial plexus

Regional Lymph Nodes (N)

.
NXRegional lymph nodes cannot be assessed
N0No regional lymph node metastases
N1Metastases in ipsilateral bronchopulmonary and/or hilar lymph node(s)
N2Metastases in subcarinal lymph node(s) and/or ipsilateral internal mammary or mediastinal lymph node(s)
N3Metastases in contralateral mediastinal, internal mammary, or hilar lymph node(s) and/or ipsilateral or contralateral supraclavicular or scalene lymph node(s)

Distant Metastasis (M)

.
MXDistant metastases cannot be assessed
M0No distant metastasis
M1Distant metastasis

Stage Grouping

.
Stage IT1N0M0
Stage IAT1aN0M0
Stage IBT1bN0M0
Stage IIT2N0M0
Stage IIIT1, T2N1M0
T1, T2N2M0
T3N0, N1, N2M0
Stage IVT4Any NM0
Any TN3M0
Any TAny NM1

References

1 Kane MJ, Chahinian P, Holland JF. Malignant mesothelioma in young adults. Cancer. 1990;65:1449–1455.

2 Dawson A, Gibbs A, Browne K, Pooley F, Griffiths M. Familial mesothelioma. Details of 17 cases with histopathologic findings and mineral analysis. Cancer. 1992;70:1183–1187.

3 Brenner J, Sordillo PP, Magill GB, Golbey RB. Malignant mesothelioma of the pleura. Review of 123 patients. Cancer. 1982;49:2431–2435.

4 Nind NR, Attanoos RL, Gibbs AR. Unusual intraparenchymal growth patterns of malignant pleural mesotheliom. Histopathology. 2003;42:150–155.

5 Nauta RJ, Osteen RT, Antman KH, Koster JK. Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized. Ann Thorac Surg. 1982;34:66–70.

6 Lloreta J, Serrano S. Pleural mesothelioma presenting as an axillary lymph node metastasis with anemone cell appearance. Ultrastruct Pathol. 1994;18:293–298.

7 Sussman J, Rosai J. Lymph node metastasis as the initial manifestation of malignant mesothelioma. Report of six cases. Am J Surg Pathol. 1990;14:819–828.

8 Zanconati F, DelConte A, Bonifacio-Gori D, Falconieri G. Metastatic pleural mesothelioma presenting with solitary involvement of the tongue. Int J Surg Pathol. 2003;11:51–55.

9 Crotty TB, Myers JL, Katzenstein AL, Tazelaar HD, Swensen SJ, Churg A. Localized malignant mesothelioma. A clinicopathologic and flow cytometric study. Am J Surg Pathol. 1994;18:357–363.

10 Attanoos RL, Gibbs AR. Pathology of malignant mesothelioma. Histopathology. 1997;30:403–418.

11 McCaughey WTE, Al-Jabi M. Differentiation of serosal hyperplasia and neoplasia in biopsies. Part 1. Pathol Annu. 1986;21:271–293.

12 Kannerstein M, Churg J, Magner D. Histochemistry in the diagnosis of malignant mesothelioma. Ann Clin Lab Sci. 1973;3:207–211.

13 Kwee WS, Veldhuizen RW, Golding RP, Mullink H, Stam J, Donner R, et al. 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]. 1982;397:287–299.

14 Azumi N, Underhill CB, Kagan E, Sheibani K. A novel biotinylated probe specific for hyaluronate. Its diagnostic value in diffuse malignant mesothelioma. Am J Surg Pathol. 1992;16:116–121.

15 Ordonez NG. Immunohistochemical diagnosis of epithelioid mesotheliomas: a clinical review of old markers, new markers. Hum Pathol. 2002;33:953–967.

16 Di Muzio M, Spoletini L, Strizzi L, Vianale G, Fontana V, Orenga MA, et al. Prognostic significance of presence and reduplication of basal lamina in malignant pleural mesothelioma. Hum Pathol. 2000;31:1341–1345.

17 Jasani B, Edwards RE, Thomas ND, Gibbs AR. The use of vimentin antibodies in the diagnosis of malignant mesothelioma. Virchows Arch [A]. 1985;406:441–448.

18 Kallianpur AR, Carstens PHB, Liotta LA, Frey KP, Siegal GP. Immunoreactivity in malignant mesotheliomas with antibodies to basement membrane components and their receptors. Mod Pathol. 1990;3:11–18.

19 Rasmusser OO, Larsen KE. S-100 protein in malignant mesotheliomas. Acta Pathol Microbiol Immunol Scand (A). 1985;93:199–201.

20 Ordonez NG, Mackay B. Glycogen-rich mesothelioma. Ultrastruct Pathol. 2000;23:401–406.

21 Amin KM, Litzky LA, Smythe WR, Mooney AM, Morris JM, Mews DJY, et al. Wilms’ tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma. Am J Pathol. 1995;146:344–356.

22 Collins C, Ordonez N, Schaffer R, Cook C, Xie S, Granger J, et al. Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma. Am J Pathol. 1992;141:827–833.

23 Oates J, Edwards C. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma. Histopathology. 2000;36:341–347.

24 Hurlimann J. Desmin and neural marker expression in mesothelial cells and mesotheliomas. Hum Pathol. 1994;25:753–757.

25 Okamoto H, Matsuno Y, Noguchi M, Morinaga S, Fujioka Y, Tsuchiya R, et al. Malignant pleural mesothelioma producing human chorionic gonadotropin. Report of two cases. Am J Surg Pathol. 1992;16:969–974.

26 Horvai AE, Li L, Xu Z, Kramer MJ, Jablons DM, Treseler PA. c-Kit is not expressed in malignant mesothelioma. Mod Pathol. 2003;16:818–822.

27 Mayall F, Goddard H, Gibbs A. The frequency of p53 immunostaining in asbestos-associated and non-asbestos-associated mesotheliomas. Histopathology. 1993;22:383–386.

28 Hammar SP, Bockus DE, Remington FL, Rohrbach KA. Mucin-positive epithelial mesotheliomas: a histochemical, immunohistochemical, and ultrastructural comparison with mucin-producing pulmonary adenocarcinomas. Ultrastruct Pathol. 1996;20:293–325.

29 MacDougall D, Wang S, Zidar B. Mucin-positive epithelial mesothelioma. Arch Pathol Lab Med. 1992;116:874–879.

30 Mayall F, Goddard H, Gibbs A. The frequency of p53 immunostaining in asbestos-associated and non-asbestos-associated mesotheliomas. Histopathology. 1993;22:383–386.

31 Ordóñez NG. The immunohistochemical diagnosis of mesothelioma. Am J Surg Pathol. 2003;27:1031–1051.

32 Ordóñez NG. Value of E-cadherin and N-cadherin immunostaining in the diagnosis of mesothelioma. Hum Pathol. 2003;34:749–755.

33 Ordóñez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003;27:1418–1428.

34 Lewis RJ, Sisler GE, Mackenzie JW. Diffuse, mixed malignant pleural mesothelioma. Ann Thorac Surg. 1981;31:53–60.

35 Ratzer ER, Pool JL, Melamed MR. Pleural mesotheliomas. Clinical experiences with thirty-seven patients. Am J Roentgenol Radium Ther Nucl Med. 1967;99:863–880.

36 Donna A, Betta PG, Bianchi V, Ribotta M, Bellingeri D, Robutti F, et al. A new insight into the histogenesis of “mesodermomas” – malignant mesotheliomas. Histopathology. 1991;19:239–244.

37 Yousem SA, Hochholzer L. Malignant mesotheliomas with osseous and cartilaginous differentiation. Arch Pathol Lab Med. 1987;111:62–66.

38 Lucas DR, Pass HI, Madan SK, Adsay NV, Wali A, Tabaczka P, et al. Sarcomatoid mesothelioma and its histological mimics: a comparative immunohistochemical study. Histopathology. 2003;42:270–279.

39 Montag AG, Pinkus GS, Corson JM. Keratin protein immunoreactivity of sarcomatoid and mixed types of diffuse malignant mesothelioma. An immunoperoxidase study of 30 cases. Hum Pathol. 1988;19:336–342.

40 Kung ITM, Thallas V, Spencer EJ, Wilson SM. Expression of muscle actins in diffuse mesotheliomas. Hum Pathol. 1995;26:565–570.

41 Cantin R, Al-Jabi M, McCaughey WTE. Desmoplastic diffuse mesothelioma. Am J Surg Pathol. 1982;6:215–222.

42 Klima M, Bossart MI. Sarcomatous type of malignant mesothelioma. Ultrastruct Pathol. 1983;4:349–358.

43 Epstein JI, Budin RE. Keratin and epithelial membrane antigen immunoreactivity in nonneoplastic fibrous pleural lesions. Implications for the diagnosis of desmoplastic mesothelioma. Hum Pathol. 1986;17:514–519.

44 Mangano WE, Cagle PT, Churg A, Vollmer RT, Roggli VL. 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;110:191–199.

45 McCaughey WTE, Al-Jabi M. Differentiation of serosal hyperplasia and neoplasia in biopsies. Part 1. Pathol Annu. 1986;21:271–293.

46 Khalidi HS, Medeiros LJ, Battibora H. Lymphohistiocytoid mesothelioma: an often misdiagnosed variant of sarcomatoid malignant mesothelioma. Am J Clin Pathol. 2000;113:649–654.

47 Galateau-Salle F, Vigaud JM, Burke I, Launoy G, Abdalsamad I, Brambilla E, et al. Lymphohistiocytoid mesothelioma, a series of 21 cases. Mod Pathol. 2003;16:307A.

48 Shanks JH, Harris M, Banerjee SS, Eyden BP, Joglekar VM, Nicol A, et al. Mesotheliomas with deciduoid morphology: a morphologic spectrum and a variant not confined to young females. Am J Surg Pathol. 2000;24:285–294.

49 Shia J, Erlandson RA, Klimstra DS. Deciduoid mesothelioma: a report of five cases and literature review. Ultrastruct Pathol. 2003;26:355–363.

50 Hillerdal G, Berg J. Malignant mesothelioma secondary to chronic inflammation and old scars. Two new cases and review of the literature. Cancer. 1985;55:1968–1972.

51 Moran CA, Suster S. Primary mucoepidermoid carcinoma of the pleura. A clinicopathologic study of two cases. Am J Clin Pathol. 2003;120:381–385.

52 Mayall FG, Gibbs AR. The histology and immunohistochemistry of small cell mesothelioma. Histopathology. 1992;20:47–52.

53 Hansen RM, Caya JG, Clowry LJ, Anderson T. Benign mesothelial proliferation with effusion. Clinicopathologic entity that may mimic malignancy. Am J Med. 1984;77:887–892.

54 Suzuki Y. Diagnostic criteria for human diffuse malignant mesothelioma. Acta Pathol Jpn. 1992;42:767–786.

55 Yokoi T, Mark EJ. Atypical mesothelial hyperplasia associated with bronchogenic carcinoma. Hum Pathol. 1991;22:695–699.

56 Whitaker D, Henderson D, Shilkin K. The concept of mesothelioma in situ: Implications for diagnosis and histogenesis. Semin Diagn Pathol. 1992;9:151–161.

57 Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use of desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology. 2003;43:231–238.

58 Cagle PT, Brown RW, Lebovitz RM. p53 immunostaining in the differentiation of reactive processes from malignancy in pleural biopsy specimens. Hum Pathol. 1994;25:443–448.

59 Walts AE, Said JW, Koeffler HP. Is immunoreactivity for p53 useful in distiguishing benign from malignant effusions? Localization of p53 gene product in benign mesothelial and adenocarcinoma cells. Mod Pathol. 1994;7:462–468.

60 Shah IA, Salvatore JR, Kummet T, Gani OS, Wheeler LA. Pseudomesotheliomatous carcinomas involving pleura and peritoneum: a clinicopathologic and immunohistochemical study of three cases. Ann Diagn Pathol. 1999;3:148–159.

61 Otis CN, Carter D, Cole S, Battifora H. Immunohistochemical evaluation of pleural mesothelioma and pulmonary adenocarcinoma. A bi-institutional study of 47 cases. Am J Surg Pathol. 1987;11:445–456.

62 Oury TD, Hammar SP, Roggli VL. Ultrastructural features of diffuse malignant mesotheliomas. Hum Pathol. 1999;29:1382–1392.

63 Burns TR, Greenberg SD, Mace ML, Johnson EH. Ultrastructural diagnosis of epithelial malignant mesothelioma. Cancer. 1985;56:2036–2040.

64 Dardick I, Jabi M, McCaughey WTE, Deodhare S, van Nostrand AWP, Srigley JR. Diffuse epithelial mesothelioma. A review of the ultrastructural spectrum. Ultrastruct Pathol. 1987;11:503–533.

65 Suzuki Y, Churg J, Kannerstein M. Ultrastructure of human malignant diffuse mesothelioma. Am J Pathol. 1976;85:241–252.

66 Warhol MJ, Corson JM. An ultrastructural comparison of mesotheliomas with adenocarcinomas of the lung and breast. Hum Pathol. 1985;16:50–55.

67 Miettinen M, Sarlomo-Rikala M. Expression of calretinin, thrombomudulin, keratin 5, and mesothelin in lung carcinomas of different types. Am J Surg Pathol. 2003;27:150–158.

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

69 Kondi-Paphitis A, Addis BJ. Secretory component in pulmonary adenocarcinoma and mesothelioma. Histopathology. 1986;10:1279–1287.

70 Riera JR, Astengo-Osuna C, Longmate JA, Battifora H. The immunohistochemcial diagnostic panel for epithelial mesothelioma: a reevaluation after heat-induced epitope retrieval. Am J Surg Pathol. 1998;21:1309–1419.

71 Ruitenbeek T, Gouw AS, Poppema S. Immunocytology of body cavity fluids. MOC-31, a monoclonal antibody discriminating between mesothelial and epithelial cells. Arch Pathol Lab Med. 1994;118:265–269.

72 Sheibani K, Shin SS, Kezirian J, Weiss LM. BER-EP4 antibody as a discriminant in the differential diagnosis of malignant mesothelioma versus adenocarcinoma. Am J Surg Pathol. 1991;15:79–84.

73 Szpak CA, Johnston WW, Roggli V, Kolbeck J, Lottich C, Vollmer R, et al. The diagnostic distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by monoclonal antibody (B72.3). Am J Pathol. 1986;122:252–260.

74 Wick MR, Loy T, Mills SE, Legier JF, Manivel JC. Malignant epithelioid pleural mesothelioma versus peripheral pulmonary adenocarcinoma. A histochemical, ultrastructural, and immunohistological study of 103 cases. Hum Pathol. 1990;21:759–766.

75 Osborn M, Pelling N, Walker MM, Fisher C, Nicholson AG. The value of “mesothelium-associated” antibodies in distinguishing between metastatic renal cell carcinomas and mesotheliomas. Histopathology. 2002;41:301–307.

76 Kawai T, Suzuki M, Torikata C, Suzuki Y. Expression of blood group-related antigens and helix pomatia agglutinin in malignant pleural mesothelioma and pulmonary adenocarcinoma. Hum Pathol. 1991;22:118–124.

77 el-Naggar AK, Ordonez NG, Garnsey L, Batsakis JG. Epithelioid pleural mesotheliomas and pulmonary adenocarcinomas. A comparative DNA flow cytometric study. Hum Pathol. 1991;22:972–978.

78 Esteban J, Sheibani K. DNA ploidy analysis of pleural mesotheliomas. Its usefulness for their distinction from lung adenocarcinomas. Mod Pathol. 1992;5:625–630.

79 Aisner J, Wiernik PH. Chemotherapy in the treatment of malignant mesothelioma. Semin Oncol. 1981;8:335–343.

80 Klima M, Spjut HJ, Seybold WD. Diffuse malignant mesothelioma. Am J Clin Pathol. 1976;65:583–600.

81 Wanebo HJ, Martini N, Melamed MR, Hilaris B, Beattie EJ. Pleural mesothelioma. Cancer. 1976;38:2481–2488.

82 Law MR, Gregor A, Hodson ME, Bloom HJG, Turner-Warwick M. Malignant mesothelioma of the pleura. A study of 52 treated and 64 untreated patients. Thorax. 1984;39:255–259.

83 Legha SS, Muggia FM. Pleural mesothelioma. Clinical features and therapeutic implications. Ann Intern Med. 1977;87:613–621.

84 Ratzer ER, Pool JL, Melamed MR. Pleural mesotheliomas. Clinical experiences with 37 patients. Am J Roentgenol Radium Ther Nucl Med. 1967;99:863–880.

85 Vogelzang NJ, Schultz SM, Iannucci AM, Kennedy BJ. Malignant mesothelioma. The University of Minnesota experience. Cancer. 1984;53:377–383.

86 Curran D, Sahmoud T, Therasse P, Van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer Experience. J Clin Oncol. 1998;16:145–152.

87 Law MR, Hodson ME, Heard B. Malignant mesothelioma of the pleura. Relation between histological type and clinical behaviour. Thorax. 1982;37:810–815.

Last updated: 12 Mar 2006

Malignant Mesothelioma

Back to top