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A 69-year-old woman presented with a large anterior mediastinal mass. Grossly, the mass was 1150 g, 16.5 x 15.0 x 10.0 cm. Sectioning revealed a well-circumscribed, encapsulated tumor with tan-pink to grey, focally nodular, hemorrhagic, cystic, and necrotic cut surfaces, which was adherent to, but did not invade the left lung parenchyma.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 8, Spindle cell thymoma (WHO type A).
Criteria for Diagnosis and Comments:
Sections demonstrate an encapsulated, cellular tumor with a prominent hemangiopericytoma-like vascular pattern. The tumor has areas of solid growth alternating with cyst-like areas, composed of dilated, irregular vascular channels filled with proteinaceous fluid, which are surrounded by tumor cells. The tumor cells are fairly monomorphic, with plump, oval nuclei with finely stippled chromatin. In some areas, the neoplastic cells are spindled and display more elongated nuclei. The tumor cells are admixed with few, small, mature lymphocytes and lack mitotic activity. Immunohistochemical stains show strong positivity of the spindle cells for CK19 and cytokeratin AE1/AE3. The spindle cells are negative for smooth muscle actin, vimentin, desmin, CD34, and S100 protein. The small lymphocytes stain positive for CD45, CD3 and CD45RO. A few rare lymphocytes also label with CD1a and CD99. These features are diagnostic of spindle cell thymoma, corresponding to WHO type A.
The differential diagnosis for spindle cell tumors of the mediastinum includes both primary epithelial and mesenchymal lesions. Epithelial tumors with rather bland spindled morphology, such as spindle cell thymoma (WHO type A) and the spindle cell variant of thymic carcinoid tumor, may be mistaken histologically for mesenchymal tumors, such as solitary fibrous tumor, peripheral nerve sheath tumors and synovial sarcoma. Spindle cell tumors with high grade cytology are less commonly seen in the mediastinum, but include carcinosarcoma, sarcomatoid carcinoma, a variety of primary mediastinal sarcomas and metastatic malignant melanoma.
The current case demonstrates a prominent hemangiopericytoma-like vascular pattern – a well-recognized pattern in several primary mediastinal tumors, namely thymomas and solitary fibrous tumors. In addition to the branching “staghorn” vessel pattern, spindle cell thymomas (WHO type A) may also exhibit a storiform growth pattern, mimicking solitary fibrous tumor. Immunohistochemistry and/or electron microscopy, demonstrating cytokeratin positivity and/or desmosomes and tonofilaments, respectively, are needed in histologically difficult cases to identify the epithelial origin of a thymoma. Conversely, solitary fibrous tumors display immunoreactivity for CD34 and lack epithelial differentiation markers. Clinical history may also assist in this differential, as thymomas may be seen in association with myasthenia gravis, hypogammaglobulinemia, and erythroid hypoplasia. Of course, the hemangiopericytomatous vascular pattern is not unique to these two entities, as other tumors described in the mediastinum, including synovial sarcoma and peripheral nerve sheath tumors, may display such a pattern.
According to the most recent WHO classification (2004), the current case corresponds to a type A thymoma. Type A thymomas are characterized by a predominance of cytologically bland epithelial cells with ovoid to spindle nuclei and very few mature lymphocytes. Type B thymomas are characterized by a neoplastic epithelial component made up of round, plump cells with round to oval nuclei, scant chromatin pattern and prominent eosinophilic nucleoli. The latter are further subdivided into three types: B1, characterized by a predominance of immature cortical thymocytes containing few, scattered neoplastic epithelial cells; B2, characterized by a near equal admixture of epithelial cells and lymphocytes; and B3, in which there is a predominance of epithelial cells displaying mild to moderate atypia admixed with a minor component of lymphocytes. Mixed thymomas, containing foci of both type A and type B thymomas, are categorized as type AB thymomas. Thymic carcinomas (formerly type C) are classified separately.
It remains controversial whether histologic subtyping of thymomas can predict biologic behavior of these tumors. Because many studies have established the status of tumor invasiveness (i.e., clinical staging) as the most important prognostic factor in predicting biologic behavior for these tumors, it is critically important that they are extensively sampled and studied for capsular invasion, if invasion is not grossly documented. All histologic subtypes can exhibit invasion; thus, regardless of morphology, all thymomas should be regarded as neoplasms capable of local spread and metastasis.
Thymic carcinomas are rare and comprise a heterogeneous group of malignant thymic epithelial neoplasms that are characterized by significant cytologic atypia and complete loss of organotypical features of thymic differentiation, mimicking carcinomas seen in other locations. The WHO recognizes several morphologic variants, including squamous cell, basaloid, mucoepidermoid, clear cell, papillary, sarcomatoid, lymphoepithelioma-like, and undifferentiated carcinomas. The majority of thymic carcinomas behave aggressively. The present case could raise the possibility of a sarcomatoid (spindle cell) variant of thymic carcinoma; however, it lacked the degree of cytologic atypia and mitotic activity observed in such tumors. Again, it is important to remember that histologically bland thymic epithelial tumors such as spindle cell thymoma may also behave aggressively despite their morphology when they are invasive.
Neuroendocrine tumors are also a consideration in the differential diagnosis. The majority of these tumors show similar cytologic and architectural features as their lung counterpart, and are characterized by a “neuroendocrine” or “organoid” pattern of growth composed of round, spindle or polygonal cells with stippled chromatin pattern and focal rosette formation. In a mediastinal location, it is common for these tumors to exhibit necrosis, increased mitotic activity, and lymphovascular invasion. As such, thymic carcinoids behave more aggressively, frequently invading locally and metastasizing. A rare variant, spindle cell thymic carcinoid, may histologically mimic spindle cell thymoma, but can be distinguished either immunohistochemically by chromogranin, synaptophysin, and/or neuron-specific enolase positivity and/or by the ultrastructural demonstration of dense-core neurosecretory granules. This distinction is important as spindle cell thymic carcinoids behave more aggressively than most spindle cell thymomas.
Synovial sarcoma has been reported as a primary neoplasm in the mediastinum, with identical histology as in other sites. The tumor may be either monophasic and primarily composed of spindle cells, or biphasic, composed of an admixture of epithelial and spindle cells. The monophasic spindle cell variant will often display a “staghorn” vascular pattern. Monophasic synovial sarcoma is characterized by the uniformity of its cell population, with oval nuclei with dense chromatin pattern and variable mitotic activity. Immunohistochemically it expresses keratin, EMA, vimentin, bcl-2 and calponin positivity. Definitive diagnosis in equivocal cases requires cytogenetic studies, as over ninety percent of synovial sarcomas have a characteristic translocation, t(X;18).
Neurogenic tumors, such as schwannomas and neurofibromas, are more commonly encountered in the posterior mediastinum. While these tumors may be spindled and cytologically bland, they will strongly express S100 protein and will usually be negative for cytokeratins.