Elsevier

Human Pathology

Volume 36, Issue 4, April 2005, Pages 372-380
Human Pathology

Original contribution
D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma

https://doi.org/10.1016/j.humpath.2005.01.019Get rights and content

Summary

Recent investigations have shown that podoplanin and the D2-40 monoclonal antibody, which reacts with an oncofetal antigen present in fetal germ cells, are highly reliable lymphatic endothelial markers. The observation that both of these markers are also expressed in normal and reactive mesothelial cells prompted an investigation into their potential value in the diagnosis of mesotheliomas. To determine whether podoplanin and D2-40 had any use in the diagnosis of these tumors, 40 mesotheliomas (29 epithelioid, 5 biphasic, and 6 sarcomatoid), 34 carcinomas of the lung (24 adenocarcinomas, 10 squamous carcinomas), 80 nonpulmonary adenocarcinomas (17 ovary, 10 breast, 10 colon, 10 kidney, 5 endometrium, 5 stomach, 5 pancreas, 5 prostate, 3 thyroid), 12 synovial sarcomas (6 biphasic and 6 monophasic), 5 angiosarcomas, and 2 adenomatoid tumors were immunostained with a monoclonal antibody to podoplanin and with the D2-40 antibody. Reactivity for both D2-40 and podoplanin was obtained in 25 (86%) of the 29 epithelioid mesotheliomas but in none of the carcinomas or sarcomatoid mesotheliomas. Positivity for D2-40 and podoplanin was also seen in the epithelioid components of 4 of 5 biphasic mesotheliomas and 4 of 6 synovial sarcomas, whereas the spindle cell components of these tumors were negative as were the monophasic synovial sarcomas. Two (40%) of the 5 angiosarcomas expressed these markers, thus confirming previous reports suggesting that some angiosarcomas may have lymphatic endothelial differentiation. Both of the adenomatoid tumors were also positive for D2-40 and podoplanin, a finding which provides further support for the mesothelial derivation of these tumors. It is concluded that, because of their high specificity and sensitivity for epithelioid mesotheliomas, D2-40 and podoplanin are very useful markers for the diagnosis of these tumors. When compared with the other markers that are currently available, in my opinion, they appear to be the best.

Introduction

Distinguishing epithelioid mesothelioma from adenocarcinoma involving the serosal membranes is a well-known problem in surgical pathology. Since the mid-1990s, however, the histological diagnosis of epithelioid mesothelioma has been greatly facilitated by the identification of markers that usually react with mesotheliomas, but not with adenocarcinomas [1], [2]. The most useful of the so-called positive mesothelioma markers are thrombomodulin (TM) [3], [4], [5], calretinin [6], [7], cytokeratin 5/6 [8], [9], and Wilms tumor protein 1 (WT1) [10], [11], [12]; however, because none of these markers is specific for mesothelioma, the immunohistochemical diagnosis of this tumor still depends on the use of batteries of markers that combine some of the positive mesothelioma markers with negative mesothelioma markers (ie, carcinoembryonic antigen, MOC-31, B72.3, CD15) that are commonly expressed in adenocarcinomas but not in mesotheliomas [1], [13].

Recent investigations have shown that podoplanin and the D2-40 monoclonal antibody, which recognizes an oncofetal antigen present in fetal germ cells, can be used as reliable lymphatic endothelial cell markers [14], [15]. Because of their high sensitivity and specificity for lymphatic endothelium, they can be used for evaluating lymphatic involvement by tumors on routinely fixed and processed tissue specimens [16], [17], [18]. Recently, I noticed that both of these markers are also expressed in normal and reactive mesothelial cells which prompted me to investigate their potential use in the diagnosis of mesotheliomas.

Section snippets

Materials and methods

The materials used in this study were obtained from the files of the Department of Pathology at the University of Texas MD Anderson Cancer Center and are listed in Table 1. It consisted of 40 unequivocal mesotheliomas (29 epithelioid, 6 sarcomatoid, 5 biphasic), 34 primary lung carcinomas (24 adenocarcinomas, 10 squamous carcinomas), and 80 nonpulmonary carcinomas which consisted of 17 nonmucinous carcinomas of the ovary (14 serous, 3 endometrioid), 5 endometrial adenocarcinomas, 5 pancreatic

Results

The immunohistochemical results are summarized in Table 1. Twenty-five (86%) of the 29 epithelioid mesotheliomas reacted with the D2-40 antibody. In 14 of these cases, the staining was graded as 4+, in 5 as 3+, and in 3 each as 2+ and 1+. In the better differentiated tumors and those exhibiting a papillary pattern, the reaction was characterized by a continuous, thick, membranous staining pattern along the apical cell membranes (Fig. 1A and B). In the solid and less differentiated tumors, the

Discussion

Although in many cases the diagnosis of mesothelioma can be made on routine hematoxylin and eosin–stained sections, in many others, the diagnosis can be difficult because one of the characteristics of these tumors is that they can present a wide range of morphological features and thus, they may be confused with a variety of carcinomas and sarcomas. When diagnostic difficulties arise, immunohistochemical studies have proven to be very useful in establishing the differential diagnosis. Until

Acknowledgment

The author wishes to thank Ms Janet Quiñones, Mr Mannie Steglich, and Ms Maria Grimberg-Siehien for their technical assistance and Ms Asuncion Moroi for her secretarial assistance.

References (38)

  • C. Doglioni et al.

    Calretinin: A novel immunocytochemical marker for mesothelioma

    Am J Surg Pathol

    (1996)
  • N.G. Ordóñez

    Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma

    Mod Pathol

    (1998)
  • 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)
  • K.M. Amin et al.

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

    Am J Pathol

    (1995)
  • 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)
  • 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)
  • N.G. Ordóñez

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

    Am J Surg Pathol

    (2003)
  • P. Birner et al.

    Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer

    Int J Cancer (Pred Oncol)

    (2001)
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