Podoplanin Is a Useful Marker for Identifying Mesothelioma in Malignant Effusions Atef Hanna, M.D., Ph.D., 1 Yijun Pang, M.D., Ph.D., 1 Carlos W. M. Bedrossian, M.D., 2 Annika Dejmek, M.D., Ph.D., 3 and Claire W. Michael, M.D. 1 * The diagnosis of malignant mesothelioma in serosal effusions continues to be a major challenge because some of its cytomorphological features closely resemble adenocarcinomas. Immunohistochemistry is a valuable tool in the differentiation of epithelioid mesothelioma from metastatic adenocarcinomas. However, no single antibody has demonstrated absolute sensitiv- ity or specificity. In this study, we evaluated the value of immu- nostaining pattern for podoplanin to differentiate mesothelioma from adenocarcinomas of various origins. Cell blocks from previously collected paraffin-embedded cell blocks of 86 effusions (18 mesothelioma, 35 reactive mesothe- lium, 9 breast adenocarcinoma, 14 ovarian adenocarcinoma, and 10 lung adenocarcinoma) were retrieved from the file of the Department of Pathology at University of Michigan and Lund University in Sweden and were used for the study. Slides prepared from the cell blocks were stained for podoplanin. The percentage of immunostained cells was recorded as follows: 1+ (5–25%), 2+ (26–50%), and 3+ (>50%). A stain result involving <5% of cells was considered negative. The intensity of positive results was evaluated as strong, moderate, or weak. Podoplanin is expressed in 94% of malignant mesothelioma cases (17/18), 97% (30/31) of cases of reactive mesothelial, 0% of lung adenocarcinoma cases (0/9), 0% of breast adenocarci- noma (0/9), and 7% of ovarian adenocarcinoma (1/14). All posi- tive cases of malignant mesothelioma and reactive mesothelium showed strong membranous reactivity to podoplanin. The one positive case of ovarian adenocarcinoma showed a weak mem- branous podoplanin immunostaining. On the basis of our results and published data, we believe that membranous podoplanin immunoreactivity, in conjunction with calretinin, would be more specific than CK5/6 and WT-1 in differentiating epithelioid malignant mesothelioma from adeno- carcinoma of the lung, breast, and ovary. Diagn. Cytopathol. 2010;38:264–269. ' 2010 Wiley-Liss, Inc. Key Words: podoplanin; mesothelioma; malignant effusion Malignant pleural mesothelioma arises from the serosal surfaces of body cavities and is linked to asbestos expo- sure. It is relatively rare in frequency but with poor clini- cal outcomes mainly because of lack of effective treat- ment at present. 1,2 Therefore, accurate diagnosis of malig- nant mesothelioma and correctly differentiating it from other tumors is imperative for proper patient management. However, the diagnosis of malignant mesothelioma continues to be a major challenge because of its ability to exhibit a broad range of cytomorphological features and to grow in a wide variety of histologic patterns. The tumor cells can exhibit epithelial, sarcomatous, and bipha- sic differentiation. 3 Epithelial malignant mesothelioma is composed of epithelial cells arranged in tubules, papillary patterns, and many other histologic patterns that closely resemble adenocarcinomas. 4 The diagnosis of epithelioid mesothelioma in the cyto- logical specimens has been greatly facilitated by the use of immunohistochemistry in the cell blocks. There are several lines of evidence indicating that immunohisto- chemistry is a valuable tool in the differentiation of epi- thelioid mesothelioma from metastatic adenocarcinomas. 5 However, no single antibody has demonstrated absolute sensitivity or specificity. Therefore, it is a common prac- tice to use a panel of markers that combine those that are frequently expressed in mesothelioma with those that are commonly expressed in carcinomas. It has been shown that the antibody D2-40, originally raised against M2A protein expressed in germ cell tumors, recognizes podoplanin. 6 Podoplanin and D2-40 have recently been recognized to stain mesothelial cells. 7–9 Both markers are known to recognize lymphatic endothe- lium with high sensitivity and specificity. 10 Podoplanin is a sialoglycoprotein that was first recognized as the E11 1 Department of Pathology, University of Michigan, Ann Arbor, Michigan 2 Rush Presbyterian Hospital, Chicago, Illinois 3 Department of Laboratory Medicine, Division of Pathology, Malmo University Hospital, Lund University, Sweden *Correspondence to: Claire W. Michael, M.D., Professor Director, Cytopathology 1500 East Medical Center Drive, Room 2G332 UH, Box 0054, Ann Arbor, MI 48109-0054. E-mail: clairemi@med.umich.edu Received 16 November 2009; Accepted 20 December 2009 DOI 10.1002/dc.21340 Published online 9 February 2010 in Wiley InterScience (www. interscience.wiley.com). 264 Diagnostic Cytopathology, Vol 38, No 4 ' 2010 WILEY-LISS, INC.