Original contributionD2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma
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.
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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)
Immunohistochemical diagnosis of epithelioid mesotheliomas: A critical review of old markers, new markers
Hum Pathol
(2002)- et al.
Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium
Am J Pathol
(1999) - 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) - et al.
A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors
Lab Invest
(2002) - et al.
Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma
Hum Pathol
(1993) Value of mesothelin immunostaining in the diagnosis of mesothelioma
Mod Pathol
(2003)In search of a positive immunohistochemical marker for mesothelioma: An update
Adv Anat Pathol
(1998)- et al.
Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma
Am J Pathol
(1992) 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)Value of thrombomodulin immunostaining in the diagnosis of mesothelioma
Histopathology
(1997)
Calretinin: A novel immunocytochemical marker for mesothelioma
Am J Surg Pathol
Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma
Mod Pathol
Anti-cytokeratin 5/6: A positive marker for epithelioid mesothelioma
Histopathology
Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma
Am J Surg Pathol
Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma
Am J Pathol
Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas
Arch Pathol Lab Med
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
The immunohistochemical diagnosis of mesothelioma: A comparative study of epithelioid mesothelioma and lung adenocarcinoma
Am J Surg Pathol
Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer
Int J Cancer (Pred Oncol)
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