Overall, the most common mesenchymal lesions of the mediastinum are neural in origin, most of which are benign. Mediastinal schwannomas most commonly occur in the posterior mediastinum, as they arise from spinal nerves. The majority of schwannomas are solitary and sporadic. If a patient has multiple schwannomas, the possibility of type 2 neurofibromatosis or schwannomatosis should be considered.
Patients with type 2 neurofibromatosis typically present at a younger age and have bilateral vestibular nerve schwannomas. Type 2 neurofibromatosis is caused by a germline mutation of the NF2 gene on chromosome 22 and is inherited in an autosomal dominant fashion; so many patients will have a family history. Schwannomatosis is a disorder characterized by multiple schwannomas, mainly of the spine and peripheral nerves; it only rarely affects cranial nerves, although some patients also have meningiomas. Schwannomatosis is more commonly sporadic rather than familial and is not due to germline NF2 mutations. Instead, germline mutations in two other genes on chromosome 22, SMARCB1 (also known as INI1) and LZTR1, have been implicated in the pathogenesis of schwannomatosis. However, schwannomas due to schwannomatosis often have somatic mutation of both NF2 alleles.
Grossly, schwannomas are often encapsulated with a tan to yellow cut surface with focal hemorrhage. Larger tumors may have cystic degenerative changes and/or calcification. Histologically, schwannomas are composed of spindled Schwann cells, often with a biphasic alternating pattern of hypercellular (Antoni A) and more hypocellular (Antoni B) areas. Schwannomas may also show scattered cells with striking nuclear atypia (ancient change). Hyalinization of large blood vessels and hemosiderin deposition may also be seen. Rarely, benign glandular or epithelial elements may be present.
Cytologically, fine needle aspiration of schwannoma should consist only of Schwann cells. Schwann cells have wavy nuclei that may have rounded or pointed ends (so called “fish hook nuclei”). The cytoplasm is scant. Cell borders are indistinct, and the cells are set in a fibrillary matrix. The groups of cells are cohesive, so single cells are sparse and larger tissue fragments predominate. Nuclei have fine, evenly distributed chromatin and smooth nuclear contours. Nuclei usually lack nucleoli, although small inconspicuous nucleoli and intranuclear cytoplasmic inclusions may be seen. Nuclear palisading may be prominent, and sometimes Antoni A and B type areas can be distinguished on cytologic preparations. The nuclei in Antoni A areas are generally tightly packed and well organized, but the nuclei in Antoni B areas may have a more jumbled and less orderly appearance. Verocay bodies, characterized by tissue fragments with peripheral palisaded nuclei and a central f ibrillary area, are distinctive of schwannoma but are not always present. If degenerative changes are present, there can be random nuclear atypia and myxoid changes. Necrosis and mitotic activity should be absent in schwannoma. A recent paper by Chebib, et al. identified these five criteria capable of distinguishing schwannoma from other low grade spindle cell lesions on fine needle aspiration with a specificity of 97%: aspirates with many clusters of cells, few to no single cells, fibrillary stroma, nuclei with pointed tips, and anisonucleosis.
On small biopsies and cytology, the differential diagnosis includes a variety of spindle cell lesions. Among other neural lesions, neurofibroma and malignant peripheral nerve sheath tumor are worth considering. Schwannomas are composed only of Schwann cells, while neurofibromas contain a mixture of Schwann cells with fibroblasts, perineurial-like cells, and ropy collagen bundles, usually set in a myxoid stroma. In general, neurofibromas show more disarray of nuclei than schwannomas.
Although it may not be possible (or clinically necessary) to distinguish neurofibroma from schwannoma on FNA alone, a cell block can be helpful. Neurofibromas should not show the strong diffuse positive staining for S100 seen in schwannoma, but instead show patchy staining for S100 since Schwann cells are only one component of the lesion. The perineurial cells of neurofibroma stain with EMA.
The diagnosis of malignant peripheral nerve sheath tumor (MPNST) is challenging, as there is significant morphologic overlap with other varieties of sarcoma. The tumor cells may appear spindled, pleomorphic, or as a mixture of the two patterns. The nuclei may resemble those of schwannoma, with oval to pointed nuclei with wavy contours. The stroma may be fibrous or fibrillary. Necrosis and mitotic activity may not be prominent, but either feature should raise suspicion for malignancy.
Immunohistochemical staining for S100 is usually only patchy or weakly positive, unlike in schwannoma. In addition, knowledge of clinical history (of neurofibromatosis type 1 or of a pre-existing neurofibroma) is crucial when making this diagnosis. Although the cytomorphology has been studied, no single feature or constellation of features has emerged as specific for MPNST. Wakely, et al. noted that the smears from MPNST are usually very cellular with variably sized syncytial fragments of cells and many single cells. Most of the single cells were fairly uniform with oval shape and finely granular chromatin. They conclude that cytologic diagnosis of MPNST is difficult given the lack of specific features, but that in the appropriate clinical setting (i.e., knowledge of history of NF1 or history of recurrent or metastatic MPNST), the diagnosis can be made with greater certainty.
The differential diagnosis also includes leiomyoma. Leiomyomata are composed of bland spindle cells with oval to elongated, blunt-ended nuclei; smooth nuclear contours; and scant fibrillar cytoplasm. The cells are cohesive, so aspirates usually consist of larger groups of cells with rare single cells. The cell groups are usually arranged in fairly orderly fascicles. Mitotic figures and necrosis should not be seen, and their presence should raise concern for malignancy. Immunochemistry can assist in making this diagnosis, as leiomyomata are negative for S100 but positive for smooth muscle actin, h-caldesmon, and other smooth muscle markers.
Depending on the location of the lesion, gastrointestinal stromal tumor (GIST) may also be considered in the differential diagnosis. GISTs may have spindled or epithelioid morphology. Spindle cell GISTs have oval to elongated nuclei with blunt ends and a moderate amount of cytoplasm, while the cells of epithelioid GISTs are plumper with rounded nuclei and more abundant cytoplasm. In both the spindle cell and epithelioid types, the tumor cells are usually fairly bland and monotonous without significant nuclear pleomorphism and are arranged in cohesive clusters and groups. GISTs are more likely to have scattered single cells with bipolar cytoplasmic extensions than schwannomas. Mitotic figures and necrosis are rare in tumors with a low risk of progression. Immunochemistry is important in this diagnosis as well. GISTs are frequently positive for ckit, DOG-1, and CD34, while negative for S100 and smooth muscle actin. The immunoprofile of GIST may vary depending on location, so a panel approach to staining is wise.
Solitary fibrous tumor (SFT) may also enter the differential diagnosis, as it is composed of bland plump spindle cells. Cells of SFT have oval and blunt-ended nuclei with fragile cytoplasm. Smears are cellular, and the tumor cells are loosely cohesive. Cells may be arranged in tissue fragments with a randomly arranged nuclei embedded in a myxoid or collagenous stroma, although some tumors do have a high proportion of single cells. Mitotic figures and necrosis may also be seen. Distinguishing between benign and malignant SFT is extremely challenging on fine needle aspiration and small biopsy specimens, as the risk of malignant behavior correlates with infiltrative tumor margins, hypercellularity, necrosis, pleomorphism, and mitotic activity in excess of 4 mitotic figures per 10 high power fields. The characteristic staghorn vessels may be seen on cell block preparation. As there is morphologic overlap with other spindle cell lesions, confirmation with immunohistochemical stains is necessary. Nuclear staining for STAT-6 is very sensitive for the diagnosis of SFT. In addition, SFTs are often positive for CD34, CD99, and Bcl-2; and some tumors will have focal staining for epithelial membrane antigen (EMA), SMA, and S-100.