Elsevier

Human Pathology

Volume 38, Issue 1, January 2007, Pages 1-16
Human Pathology

Progress in pathology
What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update

https://doi.org/10.1016/j.humpath.2006.08.010Get rights and content

Summary

Numerous immunohistochemical markers that can assist in the diagnosis of epithelioid mesotheliomas, some of which have only recently been recognized, are currently available. Because the various types of carcinomas express these markers differently, their selection for inclusion in a diagnostic panel can vary according to the differential diagnosis. This article provides a critical review of all of the information that is presently available on those markers that are believed to have the greatest potential for assisting in distinguishing between epithelioid mesotheliomas and those carcinomas with which they are most likely to be confused. Information is also provided regarding the panels of immunohistochemical markers that are, at present, recommended in these differential diagnoses.

Introduction

The diagnosis and management of mesotheliomas continue to be a major problem for both clinicians and pathologists. The accuracy of the histopathologic diagnosis of this malignancy is critical to the successful evaluation of clinical trials and is of paramount importance in the determination of a compensation settlement for those individuals with a history of asbestos exposure. Despite the existence of a large volume of literature on the pathology of mesotheliomas describing the histomorphology of these tumors, it is not always possible to reach a firm diagnosis by the study of routine histologic or cytologic light microscopic preparations. The inherent ability of the cells of the serosal membranes to alter their appearance and phenotype, as is frequently manifested in the tumors arising from these structures, and the occurrence of morphologic variants compound the difficulties encountered in diagnosing these neoplasms. An important characteristic of mesotheliomas is their ability to exhibit a broad range of cytomorphological features and to grow in a wide variety of histologic patterns. When presenting a tubular or papillary pattern, mesotheliomas can be confused with adenocarcinomas, and when they present a sarcomatoid morphology, they can often be confused with sarcomatoid carcinomas or sarcomas composed of spindle cells or having pleomorphic features. Of the various ancillary techniques that have been used in the differential diagnosis of mesotheliomas, immunohistochemistry has been recognized as having the most practical utility, especially when distinguishing epithelioid mesotheliomas from peripheral adenocarcinomas of the lung involving the pleura and from metastatic carcinomas arising from a distant organ, such as, the kidney. In the peritoneum, epithelioid mesotheliomas may resemble papillary peritoneal serous carcinomas or metastatic serous carcinomas of the ovary. Because an absolutely specific and sensitive marker for mesotheliomas has not yet been recognized, the immunohistochemical diagnosis of epithelioid mesotheliomas largely depends on the use of panels of markers that are frequently expressed in mesotheliomas (positive mesothelioma markers) combined with those that are commonly expressed in carcinomas (positive carcinoma markers). These panels, however, are continually changing as a result of the identification of new markers that could be useful in the differential diagnosis of these tumors and the publication of new information regarding the value of individual markers. The purpose of this article is to review the information available for those markers that have, for some time, been used in the diagnosis of epithelioid mesotheliomas and to determine their current diagnostic value when compared with markers that have recently become available. Particular emphasis will be placed on those newly recognized markers for which there is some evidence that they could be useful in distinguishing epithelioid mesotheliomas from the different types of carcinomas with which they may be confused. To facilitate the discussion of the markers and to make such a discussion easier for the reader to follow, the various markers have been subdivided into 3 groups: positive mesothelioma markers, positive carcinoma markers, and miscellaneous markers. It should be mentioned that the placement of some of these markers, especially those in the miscellaneous group, is somewhat arbitrary because, in some instances, various individual markers could also be regarded as either a positive mesothelioma marker or a positive carcinoma marker.

Section snippets

Positive mesothelioma markers

Markers that are commonly expressed in mesotheliomas, but not in carcinomas, have only relatively recently been recognized. A list of these markers, which are often referred to as positive mesothelioma markers, is shown in Table 1.

Positive carcinoma markers

Since the 1979 report by Wang et al [86] indicating that carcinoembryonic antigen (CEA) was a useful immunohistochemical marker in the diagnosis of mesotheliomas because it is frequently expressed in adenocarcinomas of the lung, but not in mesotheliomas, a large number of other positive carcinoma markers have been investigated (Table 2). Those that have the most value in the diagnosis of mesotheliomas will be briefly discussed.

Miscellaneous markers

A variety of miscellaneous markers are listed in Table 3, including some tissue-associated markers that, because of their restricted expression, have been found to be useful in distinguishing mesotheliomas from some types of carcinomas. Only those that are, at present, considered to be useful in the diagnosis of mesothelioma will be briefly discussed.

Conclusion and recommendations

From this review, it is concluded that, at present, several highly specific and sensitive markers are available that can be used in the diagnosis of epithelioid mesotheliomas; however, as previously stated, an absolutely specific and sensitive marker for mesothelioma has yet to be identified. Also, it is evident that the selection of the markers to be used in this diagnosis depends on a variety of factors, including the location and histologic pattern of the tumor, and the sex of the patient.

Acknowledgment

The author thanks Janet Quiñones, Kim-Anh Vu, and Mannie Steglich for technical assistance.

References (157)

  • N.G. Ordóñez

    Value of mesothelin immunostaining in the diagnosis of mesothelioma

    Mod Pathol

    (2003)
  • A. Wetterwald et al.

    Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes

    Bone

    (1996)
  • V. Schacht et al.

    Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors

    Am J Pathol

    (2005)
  • S. Breiteneder-Geleff et al.

    Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium

    Am J Pathol

    (1999)
  • H.J. Kahn et al.

    Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi's sarcoma and a subset of angiosarcomas

    Mod Pathol

    (2002)
  • N.G. Ordóñez

    Immunohistochemical diagnosis of epithelioid mesothelioma: a critical review of old markers, new markers

    Hum Pathol

    (2002)
  • H.P. Cathro et al.

    The utility of calretinin, inhibin, and WT1 immunohistochemical staining in the differential diagnosis of ovarian tumors

    Hum Pathol

    (2005)
  • G. Martignoni et al.

    Parvalbumin is constantly expressed in chromophobe renal carcinoma

    Mod Pathol

    (2001)
  • A. Lugli et al.

    Calretinin expression in human normal and neoplastic tissues: a tissue microarray analysis on 5233 tissue samples

    Hum Pathol

    (2003)
  • B.W. Robinson et al.

    Mesothelin-family proteins and diagnosis of mesothelioma

    Lancet

    (2003)
  • N.G. Ordóñez

    Value of the MOC-31 monoclonal antibody in differentiating epithelial pleural mesothelioma from lung adenocarcinoma

    Hum Pathol

    (1998)
  • M.R. Wick et al.

    Malignant epithelioid pleural mesothelioma versus peripheral pulmonary adenocarcinoma: a histochemical, ultrastructural, and immunohistologic study of 103 cases

    Hum Pathol

    (1990)
  • M.R. Wick et al.

    Placental-like alkaline phosphatase reactivity in human tumors: an immunohistochemical study of 520 cases

    Hum Pathol

    (1987)
  • N. Khoury et al.

    A comparative immunohistochemical study of peritoneal and ovarian serous tumors and mesotheliomas

    Hum Pathol

    (1990)
  • L.D. Truong et al.

    Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases

    Hum Pathol

    (1990)
  • N. Kimura et al.

    Podoplanin as a marker for mesothelioma

    Pathol Int

    (2005)
  • A. Sienko et al.

    D2-40 is a novel new marker of malignant mesothelioma (MM): tissue microarray study of 45 MM versus 409 lung carcinomas and primary non-mesothelial neoplasms of the pleura and chest wall

    Mod Pathol

    (2005)
  • C. Doglioni et al.

    Calretinin: a novel immunocytochemical marker for mesothelioma

    Am J Surg Pathol

    (1996)
  • M.C.P. Barberis et al.

    Calretinin: a selective marker of normal and neoplastic mesothelial cells in serous effusions

    Acta Cytol

    (1997)
  • M.P.G. Leers et al.

    E-cadherin and calretinin: a useful combination of immunochemical markers for differentiation between mesothelioma and metastatic adenocarcinoma

    Histopathology

    (1998)
  • N.G. Ordóñez

    Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas

    Am J Surg Pathol

    (1998)
  • N.G. Ordóñez

    Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma

    Mod Pathol

    (1998)
  • R. Carella et al.

    Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma: a study with logistic regression analysis

    Am J Surg Pathol

    (2001)
  • A.S. Abutaily et al.

    Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies

    J Clin Pathol

    (2002)
  • R.L. Attanoos et al.

    Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum

    Histopathology

    (2002)
  • N.G. Ordóñez

    The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma

    Am J Surg Pathol

    (2003)
  • J. Clover et al.

    Anti-cytokeratin 5/6: a positive marker for epithelioid mesothelioma

    Histopathology

    (1997)
  • N.G. Ordóñez

    Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma

    Am J Surg Pathol

    (1998)
  • O. Kaufmann et al.

    Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas

    Am J Clin Pathol

    (2001)
  • K.M. Amin et al.

    Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma

    Am J Pathol

    (1995)
  • S. Kumar-Singh et al.

    WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis

    J Pathol

    (1997)
  • J. Oates et al.

    HBME-1, MOC-31, WT1 and calretinin: as assessment of recently described markers for mesothelioma and adenocarcinoma

    Histopathology

    (2000)
  • C. Walker et al.

    Wilms' tumor suppressor gene expression in rat and human mesothelioma

    Cancer Res

    (1994)
  • N.G. Ordóñez

    Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma

    Am J Surg Pathol

    (2000)
  • M.R. Foster et al.

    Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas

    Arch Pathol Lab Med

    (2001)
  • M. Miettinen et al.

    Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma

    Am J Surg Pathol

    (2001)
  • C.L. Collins et al.

    Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma

    Am J Pathol

    (1992)
  • R.L. Attanoos et al.

    Mesothelioma-binding antibodies: thrombomodulin, OV 632 and HBME-1 and their use in the diagnosis of malignant mesothelioma

    Histopathology

    (1996)
  • N.G. Ordóñez

    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)
  • N.G. Ordóñez

    Value of thrombomodulin immunostaining in the diagnosis of mesothelioma

    Histopathology

    (1997)
  • Cited by (0)

    View full text