Differentiating Sarcomas from Mesotheliomas

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Differentiating Sarcomas from Mesotheliomas 35 Differentiating Sarcomas from Mesotheliomas Oliver Kim and Thomas Krausz Despite the abundant literature data on the topic, the diagnosis of malignant mesothelioma remains challenging. Its frequent phenotypic heterogeneity and diverse architectural patterns underline the capac- ity of mesothelioma to mimic other neoplasms, notably adenocarci- noma and sarcomas. Immunohistochemical markers facilitate solving differential diagnostic problems; however, in some cases, a definitive diagnosis of malignant mesothelioma is still a challenge. The pleura or other serosal surfaces can be involved by a number of neoplastic conditions, ranging from benign to malignant. Furthermore, meta- static neoplasms commonly involve these sites. Although malignant mesothelioma is a relatively uncommon tumor, it is the most common primary malignancy of the pleura and can develop at other sites, including the peritoneum, pericardium, and tunica vaginalis (1). Histologically, the major subtypes of malignant mesothelioma are epithelioid, sarcomatoid, and mixed. Therefore, the differential diag- nosis varies according to histologic type. Correlation between clinical, radiographic, and pathologic findings is critical to make a correct diagnosis. Although distinguishing mesothelioma from an adenocarcinoma is the more common problem, differentiating either a metastatic or primary sarcoma from a malignant mesothelioma can have important therapeutic consequences. Primary mesenchymal tumors, primarily solitary fibrous tumors and sarcomas, of the pleura and other serosal membranes are rare (1). Most sarcomatous tumors of the pleura are manifestations of either a metastatic sarcoma or a sarcomatoid mesothelioma. In addition, sarcomas arising from the chest wall or lung can also involve the pleura. Both primary and metastatic sarco- mas can mimic the characteristic clinical, radiologic, and pathologic findings of a malignant mesothelioma. Distinguishing sarcomatoid mesothelioma from morphologically similar sarcomas is a diagnostic challenge. This chapter outlines a practical approach in distinguishing mesothelioma from sarcomas. 527 528 Chapter 35 Differentiating Sarcomas from Mesotheliomas Sarcoma Versus Malignant Mesothelioma: General Differential Diagnostic Considerations The pathologic features of sarcomatoid mesothelioma are not entirely specific and often overlap with other primary and secondary serosal- based sarcomas and spindle cell carcinomas. Furthermore, depending on the degree of collagen deposition (desmoplastic mesothelioma), a more frequent problem is distinguishing sarcomatoid mesothelioma from benign fibrous pleurisy. The growth pattern of sarcomatoid mesothelioma is diverse. It may be storiform with similarity to the so- called malignant fibrous histiocytoma. The tumor cells may display a fibrosarcoma-like appearance with long fascicles exhibiting a herring- bone pattern. Leiomyoid differentiation has been described in which the cells have oval, elongated nuclei, eosinophilic cytoplasm, and coexpress actin and desmin (2,3). In addition, heterologous elements, including osteoid (4), chondroid (4), and rhabdomyoblastic differenti- ation (5), rarely can be identified. Depending on the histologic features present, diagnostic considerations can include fibrosarcoma, so-called malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (6), rhabdomyosarcoma, leiomyosarcoma (7), synovial sarcoma (8), angiosarcoma (9–11), liposarcoma (12), malignant solitary fibrous tumor (13–15), and chondrosarcoma (16), all of which have been reported to arise primarily in the pleura. Metastatic neoplasms, includ- ing sarcomatoid carcinoma, malignant melanoma, and thymoma, have all been documented and should be diagnostic considerations (17). Gastrointestinal stromal tumor (GIST), either as a metastasis or an extraintestinal primary, can also histologically resemble a sarcomatoid mesothelioma. C-KIT immunoreactivity defines this tumor, and is negative in mesotheliomas. Cytokeratin expression is most useful in distinguishing most sarcomas from sarcomatoid mesothelioma. Characteristically, nearly all mesotheliomas of epithelioid, sarcomatoid, or mixed type exhibit strong cytokeratin expression (18,19). Both low and high molecular weight cytokeratins are detectable in most mesotheliomas, especially low molecular weight cytokeratins. Although cytokeratin can be utilized to distinguish sarcomatoid mesothelioma from most sarcomas, there are a few caveats. First, inves- tigators have reported variable immunoreactivity with cytokeratins. Although all epithelioid mesotheliomas express cytokeratin, the per- centage of sarcomatoid mesotheliomas reported in the literature to express cytokeratin is variable. Some investigators have detected cytokeratins in 100% of their sarcomatoid mesothelioma cases exam- ined (18,19). In contrast, others failed to detect cytokeratins in up to 40% of sarcomatoid mesotheliomas (4,5,13,20–24). In our experience, all cases of sarcomatoid mesothelioma exhibit immunoreactivity with cytokeratin antibody CAM 5.2. Thus, these results stress the importance of utilizing, in addition to cytokeratins, a panel of other immunomarkers. O. Kim and T. Krausz 529 Second, cytokeratin expression can also be occasionally seen in sar- comas (25,26), including monophasic synovial sarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and leiomyosarcoma. But cytokeratin immunoreactivity seen in these sarcomas is usually focal. Monophasic synovial sarcomas tend to express either or both cytoker- atins 7 and 19, whereas malignant peripheral nerve sheath tumors do not (27). Malignant melanoma can metastasize to the pleura and sim- ulate a mesothelioma. Rare melanomas are keratin-positive (28,29) but typically express S-100 and HMB-45 antigen. Third, cytokeratin does not discriminate sarcomatoid mesothelioma from metastatic sarcomatoid carcinoma, primary pleural thymoma, pseudomesotheliomatous carcinoma of lung, or even metastatic epithe- lioid sarcoma. Cytokeratin immunoreactivity is typically strong in all of these tumors. In these cases, positivity with any of the mesothelial- specific markers or absence of carcinoma markers would favor sarcomatoid mesothelioma. However, many of the allegedly specific mesothelial markers have cross-reactivity with other tumors, especially metastatic carcinoma. Hence, the importance of utilizing a broad panel of carcinoma and mesothelial markers is emphasized, in addition to obtaining clinical history. Of important note, thymomas can rarely occur in the pleura without evidence of an associated mediastinal tumor (30). They may occur as a localized tumor or, more rarely, as a diffuse pleural thickening mimicking a mesothelioma (30–32). Histo- logically, they may be confused with a sarcomatoid mesothelioma with a lymphocytic infiltrate or a lymphohistiocytoid mesothelioma. The neoplastic cells exhibit strong cytokeratin immunoreactivity. As opposed to mesotheliomas, which can have a mixed population of plasma cells and T and B lymphocytes, thymomas contain a popula- tion of precursor T lymphocytes, commonly coexpressing CD1, CD2, CD3, CD99 (MIC-2) (33), bcl-2 (34), and terminal deoxynucleotidyl transferase (35) antigens. Epithelioid sarcoma, both the conventional and proximal variant, can metastasize to the lung and pleura and be difficult to differentiate from the epithelioid mesothelioma. They typi- cally exhibit strong immunoreactivity to both low and high molecular weight keratins. Although the conventional or distal variant of epithe- lioid sarcoma tends to occur in young adults, the proximal variant occurs in the older age group. Thus, epithelioid sarcoma should be con- sidered in the differential diagnosis. The differentiating factor would be the strong positivity for CD34 in a high percentage of epithelioid sarcomas, for which mesotheliomas are negative. Ultrastructural features of sarcomatoid mesothelioma are non- specific and overlap with those of fibroblasts (5,36). The tumor cells contain variable amounts of rough endoplasmic reticulum, Golgi appa- ratus, intermediate filaments, and extracellular collagen. Occasionally, the tumor cells exhibit actin filaments in the cell periphery, resembling myofibroblasts. Epithelial differentiation can also be identified on occa- sion, which includes the presence of intercellular junctions, rare surface microvilli, aggregates of tonofilaments, and incomplete formation of basal lamina. Differentiation of sarcomatoid mesotheliomas from other 530 Chapter 35 Differentiating Sarcomas from Mesotheliomas sarcomatoid neoplasms can be made by the presence of specific ultra- structural components in other tumors that are typically lacking in mesotheliomas. Thus, the diagnosis continues to rely on a multimodal approach incorporating clinical history, gross and microscopic features, immunohistochemistry, and electron microscopy to arrive at a defini- tive diagnosis. Synovial Sarcoma Versus Malignant Mesothelioma Synovial sarcoma is a rare tumor most commonly found in the soft tissues of the extremities but other sites, including the head and neck (37–39), mediastinum (40–42), lung (43–48), heart (49), esophagus (50), and vulva (51), have also been reported. There have been reports of synovial sarcoma arising in the pleural cavity (8,52,53). The rarity of this tumor at this site makes it a potentially overlooked diagnosis, espe- cially since the histologic characteristics of synovial sarcoma can closely resemble malignant mesothelioma. Both tumors can present with either purely sarcomatoid or mixed
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