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V. Roggli



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    MTE20 - Pathology of Mesothelioma (ID 64)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE20.1 - Pathology of Mesothelioma (ID 617)

      07:00 - 08:00  |  Author(s): V. Roggli

      • Abstract
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      Abstract
      Malignant mesothelioma is an uncommon malignancy that may involve the pleura, peritoneum or pericardium. Mesothelioma may assume a variety of histological appearances ranging from epithelial to sarcomatoid to mixed. Because of its histologic similarity to a variety of other malignancies and because other malignancies may metastasize to serosal membranes, the diagnosis of mesothelioma may be challenging. A variety of immunohistochemical stains have been developed to aid in the distinction between mesothelioma and other malignancies with which it may be confused. It is currently recommended that at least two positive (mesothelial) and two negative (carcinomatous) markers should be used. The differential diagnosis may differ depending on the particular histologic pattern under consideration and the location of the tumor. This will in turn affect what immunohistochemical panel is chosen. It is also recommended that the markers used should have a specificity and sensitivity of at least 80%. For epithelial pleural mesothelioma, the main differential diagnostic consideration is adenocarcinoma of the lung. For such cases the author uses a panel of four positive markers and two negative markers. Positive markers include calretinin, cytokeratins 5/6, WT-1 and D2-40. Negative markers include carcinoembryonic antigen (CEA) and TTF-1. The author has used this panel since 2004 and has had experience with more than 500 mesotheliomas to date. Epithelial pleural mesotheliomas were positive for calretinin in 98% of cases, and this was the most sensitive mesothelial marker. Cytokeratins 5/6 and D2-40 were each positive in 92% of cases, and WT-1 was positive in 91% (nuclear staining only counted). For the negative markers, pCEA was positive in 10% and TTF-1 in 0.5% (nuclear staining only counted). More recently we have used mCEA and thus far have not identified any positive cases. We have seen some cases where mesothelioma was confused with squamous cell carcinoma. Cytokeratins 5/6 are not useful in this scenario since nearly all squamous cell carcinomas are positive for this marker. Similarly, TTF-1 is not useful since squamous cell carcinomas are expected to be negative. For this differential diagnosis, WT-1 and p63 (or p40) are a good pair of nuclear markers to use. Biphasic pleural mesotheliomas are more poorly differentiated so it is not surprising that one often observes a drop-out of one or more of the positive mesothelial markers in these tumors. We find calretinin positivity in 92% with positive staining for D2-40 in 83%. The corresponding values for WT-1 and cytokeratins 5/6 are 80% and 78%, respectively. CEA was positive in only 4% and none was positive for TTF-1. If one grades the intensity of staining, the epithelial tumors show higher scores on average than the biphasic. Peritoneal mesotheliomas usually involve a different set of diagnostic considerations. Since lung cancer is unlikely to be in the differential, TTF-1 has limited usefulness in this setting. Similarly, many of the tumors in the abdomen with which mesothelioma may be confused are negative for CEA. Therefore our panel for peritoneal tumors includes the same four positive markers noted above, and we substitute B72.3 and BerEP4 as negative markers. Epithelial peritoneal mesotheliomas are positive for calretinin in 98% of cases, identical to pleurals. Positive staining for WT-1 and D240 is seen in 91% of cases, and 89% are positive for cytokeratins 5/6. BerEP4 was focally positive in 9% of peritoneal mesotheliomas but B72.3 was uniformly negative. For biphasic peritoneal mesothelioma, calretinin is positive in 80% and cytokeratins 5/6 positive in 75%. Only 60% were positive for D2-40 and 50% for WT-1. None of the biphasic peritoneal cases was positive for B72.3 or BerEP4. Peritoneal mesotheliomas in women present a special diagnostic problem since many of the malignancies involving the peritoneal cavity in women stain for one or more of the mesothelial specific markers. For this reason, we add estrogen and progesterone receptor immunohistochemical staining to the panel for peritoneal mesothelioma in women. Strong diffuse nuclear staining for these markers would favor a diagnosis of ovarian carcinoma over mesothelioma. Also, histochemical staining for PASD is useful in this setting. We also use a broad spectrum cytokeratin marker in our panel, with cytokeratins positive in 100% of our epithelial or biphasic pleural and peritoneal mesotheliomas. The intensity of staining for these broad spectrum cytokeratins was a little greater for epithelial as compared to biphasic mesotheliomas. Complete absence of staining for cytokeratins in an epithelioid serosal based malignancy should alert the pathologist to the possibility of melanoma, lymphoma or epithelioid hemangioendothelioma and appropriate follow-up immunostains examined to rule out these considerations. Sarcomatoid mesotheliomas account for 16.5% of our cases, and these are the least differentiated form. This is reflected in their immunohistochemical profile, which is typically negative for mesothelial specific markers. For example, in 76 cases of sarcomatoid mesothelioma, we found positivity for calretinin in only 47% and D2-40 in 55%. The other two markers we use in the sarcomatoid panel are vimentin (95%) and broad spectrum cytokeratins (92%). Vimentin is important as an antigenic preservation marker: if vimentin is negative in a sarcomatoid tumor, then one should suspect poor tissue preservation with less concern for a negative keratin stain. Strong diffuse staining for cytokeratins is the most useful marker for sarcomatoid mesotheliomas. However, sarcomatoid carcinomas may be similarly positive, so one should pay close attention to the gross distribution of tumor in these cases. Although diffuse and moderate to strong staining for cytokeratins was seen in more than 70% of our sarcomatoid mesotheliomas, it should be noted that focal staining or less intense staining may also be seen in some cases. REFERENCES: Husain AN, Colby T, Ordonez N, et al. Guidelines for pathologic diagnosis of mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 137: 647, 2013. Klebe S, Brownlee NA, Mahar A, et al. Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases. Mod Pathol 23: 470, 2010. Churg A, Cagle PT, Roggli VL. Tumors of the Serosal Membranes, AFIP Atlas of Tumor Pathology, Series IV, Fascicle 3, American Registry of Pathology: Washington, DC, 2006.

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