An otherwise healthy 53-year-old man presented with a 3-month history of right-sided chest pain associated with cough and fatigue. The patient smoked cigarettes and had occupational exposure to asbestos resulting from his work as a pipe fitter. A chest radiograph revealed diffuse right-sided pleural thickening and basilar opacities (Figure 1; arrow demonstrates area of pleural thickening). After thoracoscopic surgery failed to establish a diagnosis, a decortication and pleurectomy was performed. The specimen consisted of an aggregate of soft, gelatinous, pink-yellow tissue. Histologic examination showed a biphasic malignant neoplasm, with epithelioid and sarcomatous elements. The epithelioid component featured tubulo-glandular architecture, composed of cuboidal cells with monomorphic round nuclei (Figure 2). The sarcomatous component featured pleomorphic, plump spindle cells with prominent mitoses (Figure 3). Desmoplastic tumor foci were also identified, exhibiting a patternless pattern of growth (Figure 4, a). In addition, there were conspicuous areas of fibromyxoid stroma and foci of osteo-cartilaginous differentiation (Figure 4, b). Immunohistochemical studies demonstrated diffuse, strong staining for vimentin and broad-spectrum cytokeratins in both epithelial and sarcomatous foci. Staining for both calretinin and cytokeratin 5/6 was limited to the epithelial component. There was no evidence of immunoreactivity for carcinoembryonic antigen, thyroid transcription factor-1, or monoclonal antibody BerEP4.
What is your diagnosis?
Pathologic Diagnosis: Malignant (Diffuse) Pleural Mesothelioma, Biphasic Variant, With Heterologous Differentiation
Mesothelioma is a malignant neoplasm arising from the serosal membranes lining the pleural, pericardial, and peritoneal cavities. Relatively rare tumors, the incidence of mesothelioma in North America is estimated to be between 10 and 15 cases per million persons per year for men, with a much lower incidence in women.1 Mesothelioma is strongly associated with occupational and paraoccupational exposure to asbestos, although the mechanism remains incompletely understood. Recent investigations suggesting a causative or contributory role for simian virus 40 remain highly controversial.
Malignant mesothelioma is characterized by a broad range of microscopic appearances, both across the entire disease entity and often within individual tumors. The World Health Organization recognizes 4 major histologic subtypes of malignant mesothelioma: epithelial, sarcomatoid, desmoplastic biphasic, and a separate category encompassing a variety of less common patterns that may feature the presence of heterologous elements.2 Such heterologous differentiation includes patterns resembling leiomyosarcoma, malignant fibrous histiocytoma, chondro- and osteogenic sarcoma, and muscle-like differentiation. Osteo-cartilaginous differentiation, as featured in the current case, is quite uncommon. Such differentiation has been described in isolated case reports and in small series.3,4
The diagnosis of mesothelioma requires correlation of the gross distribution of the tumor with the histologic, histochemical, and immunohistochemical features of the tumor. Pleural mesothelioma often encases the lung, forming a circumferential rind of tumor with extension along fissures and interlobular septa. Parenchymal lung masses may appear in late-stage disease. The immunohistochemical markers with greatest specificity for mesothelial differentiation include calretinin, cytokeratin 5/6, and thrombomodulin. The expression of these markers is generally limited to the epithelial mesothelioma, wherein they find their greatest utility in securing the diagnosis.5,6 Epithelial mesothelioma must be distinguished from pseudomesotheliomatous adenocarcinoma or adenocarcinoma metastatic to the serosal membranes. Such tumors are typically negative for calretinin but are generally positive for carcinoembryonic antigen, CD15, BerEP4, and B72.3.6 A panel of such antibodies is required to secure the diagnosis of epithelial mesothelioma, as an antibody with 100% specificity for mesothelium has not yet been discovered.
Despite radical surgery and tumor debulking, the prognosis for malignant mesothelioma remains dismal, with survival generally measured in weeks to months. Although sarcomatoid and desmoplastic variants tend to be more aggressive than epithelial mesotheliomas,7 there is no definitive evidence that heterologous differentiation significantly worsens the prognosis. It is important to be aware of the capacity of mesothelioma to demonstrate heterologous differentiation, both in terms of understanding the biology of mesothelial neoplasia and to avoid a misdiagnosis of sarcoma involving the serosal membranes.
References
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