Fibromatoses are tumors characterized by infiltrative growth but with benign-appearing cellular features. Occurring at almost every site of the body, mediastinal fibromatoses have been reported. These tumors are often very aggressive locally, but rarely metastatic. Fibromatosis occurs in both childhood and adult life. Fibromatoses of adulthood can be superficial or deep, usually slow growing and painless. Abdominal fibromatosis or desmoid tumors are more common in women of childbearing age and may be associated with pregnancy. Histologically, cellular areas of the tumor show myofibroblastic spindle cell proliferation with monomorphic cells arranged in streaming pattern. No atypia or mitotic activity is noted (Fig. 10.6). Varying amounts of collagen can be identified with some tumors being predominantly collagenous. Recent genetic studies have identified Beta–catenin mutations as the genetic hallmark of fibromatosis. This results in the nuclear expression of Beta-catenin by immunohistochemistry, a finding that is extremely useful to distinguish this tumor from a hypertrophic scar [23–25]. Although this tumor has been managed in different ways including surgery, radiation, chemotherapy, hormonal therapy, etc., with limited success, novel therapies using targeted kinase inhibitors such as Sorafenib have recently shown some benefit [26].

Extrapleural solitary fibrous tumors (SFT) are uncommon tumors that occur in almost any organ site and affects equally men and women. In some circumstances of mediastinal SFTs it may be questionable if the tumor is arising from the pleura or if the tumor is truly extrapleural [7, 27]. Histologically, the tumors have a patternless architecture characterized by hypocellular and hypercellular areas associated with hemangiopericytoma-like branching vessels. The tumors are composed of ovoid to spindle-shaped cells with scant cytoplasm (Fig. 10.7). The criteria for malignancy are high mitotic count (>4 mitoses per 10 high power fields), high cellularity, pleomorphism and necrosis. All cases are immunoreactive for CD34. Recently, nuclear staining of STAT6 resulting from NAB2–STAT6 gene fusion has been shown to be a more specific marker for SFT [28, 29]. It is important to note that STAT6 positivity has also been reported in dedifferentiated liposarcomas. So in cases of lipomatous SFT that shows a component of adipose tissue, dedifferentiated liposarcoma may be one of the differential diagnoses [30]. In such circumstances, other stains for MDM2 and CDK4 might be helpful. It has been suggested that mediastinal SFTs more frequently show aggressive behavior compared to non-mediastinal SFTs [31].

Angiomatoid malignant fibrous histiocytoma is a rare, low-grade malignant mesenchymal neoplasm that affects mostly the extremities of children and young adults. It is believed to have a partially myoid phenotype. Histologically, it is characterized by the presence of a multinodular proliferation of eosinophilic, histiocytoid or myoid cells, pseudoangiomatoid spaces, thick fibrous capsule, and pericapsular lymphoplasmacytic infiltrate. Immunohistochemical results are most consistent with myofibroblastic differentiation with desmin positivity in half of the cases. The most frequent genetic abnormality is t(2;22) translocation resulting in the fusion of EWSR1 and CREB1 genes. Other variant fusions reported include FUS–ATF1 and EWSR1–ATF1 [7, 32].

This is a distinctive neoplasm characterized by bland spindle cells arranged in a whorling pattern and curvilinear vessels, which are associated with extensive areas of collagenized and myxoid zones. Cytological features include clusters of bland spindle and round/polygonal cells embedded in a collagenous and myxoid matrix along with dissociated, uniform, or slightly/moderately pleomorphic spindle cells, bare nuclei and fragments of collagen and myxoid tissue in varying proportions [33, 34]. At a molecular level, these lesions demonstrate FUS–CREB3L2 or FUS–CREB3L1 gene fusion [7, 35, 36].

Inflammatory myofibroblastic tumor (IMT) is a tumor composed of myofibroblastic spindle cells and a variably dense nonneoplastic inflammatory component. It has been reported in many sites, predominantly in young adults and children [37]. Bona fide mediastinal IMTs are rare with few cases reported [38–41]. They appear to arise mostly in young adults (range 13–72; median age 34) with a slight female predominance (male:female = 5:8). Histologically, IMT is an infiltrative tumor composed of myofibroblastic cells admixed with an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils. Multifocality is not uncommon in IMT. Cytoplasmic expression of ALK protein is detectable in about half of the cases and correlates well with presence of ALK gene rearrangements. Recent genetic studies have identified other genetic abnormalities in the ROS1, RET, and PDGFRB genes [42, 43]. The biological behavior of IMT is variable and recurrences are common, but distant metastasis is rare. Similar to non-mediastinal sites, treatment rests mainly on complete local excision. Patients with ALK-rearranged IMT are potential candidates for treatment with specific inhibitors.

Hemangiomas are common benign vascular neoplasms which can present in almost any body location and at any age. Mediastinal hemangioma may originate in the soft tissue of the mediastinum or may arise in the thymus. Tumor size can range from a few centimeters to 20 cm. They are characterized histologically by a proliferation of thin-walled vascular channels lined by bland endothelial cells. Both capillary and cavernous hemangioma subtypes can be seen. Associated histological features described include adipose metaplasia, fibrosis, smooth muscle overgrowth and inflammation [44]. Surgical resection is curative in most cases.

Epithelioid hemangioma, also known as angiolymphoid hyperplasia with eosinophilia, is a rare benign vascular lesion. Although the most common sites are the skin and subcutaneous tissue of the head and neck region, it can rarely be seen in the deep soft tissue. The histological sections show a central area of proliferating blood vessels surrounded by a cellular infiltrate composed of lymphoid cells and eosinophils. The vascular proliferation is lined by endothelial cells with an epithelioid or histiocytoid appearance [7]. Recent studies have identified FOS gene-related fusions in a subset of these tumors [45].

Lymphangiomas are benign cavernous vascular lesions composed of dilated lymphatic channels most common in early childhood; they have been associated with Turner syndrome. The most common sites of the cystic type are the neck, axilla, and groin, while the cavernous types are most common in the mouth, upper trunk, and limbs. Lymphangiomas are more commonly seen in the anterior mediastinum [46, 47]. Histologically, these lesions are characterized by the presence of thin-walled, lymphatic vessels of different sizes lined by flat endothelium and surrounded by a lymphocytic infiltrate.

Epithelioid hemangioendothelioma (EHE) is a vascular tumor with metastatic potential. This tumor is rare and can occur at any age and usually in the deep soft tissue of extremities. Mediastinal involvement has been reported [48]. It is characterized histologically by a cellular proliferation composed of short nests and strands of round epithelioid cells embedded in myxohyaline stroma. These cells show intracytoplasmic lumina containing erythrocytes. The cells are bland with little or no mitotic activity. No distinct vascular formation is identified (Fig. 10.8). Immunohistochemical studies for vascular markers such as CD31 and ERG are required to distinguish epithelioid vascular lesions from carcinomas [7]. Angiosarcomas demonstrate a higher degree of atypia than hemangioendotheliomas. A t(1;3)(p36.3;q25) has been described in EHE resulting in a fusion of WWTR1(3q25) and CAMTA1(1p36) genes, suggesting a possible role as diagnostic marker [49]. A subset of EHE has been shown to have the YAP1–TFE3 gene fusion. These cases show strong positivity of the TFE3 stain by immunohistochemistry [50].

Angiosarcomas are malignant tumors composed of cells with morphological and phenotypical features of endothelial cells. The most common sites for angiosarcomas of soft tissue are deep muscles of lower extremities, arm, trunk, and head and neck. Few cases have been reported in the mediastinum [51]. They have been associated with coagulopathies, patients with Klippel-Trenaunay and Maffucci syndromes, and following radiation for other malignancies. The most common morphologies include spindle and epithelioid cell morphologies. These morphologies can coexist and might show predominance of one subtype. The spindle cell morphology resembles fibrosarcoma or Kaposi sarcoma. The epithelioid cells are represented by large polygonal cells with a high N/C ratio and eosinophilic or amphophilic cytoplasm. The neoplastic cells form rudimentary vascular channels, which are irregular in shape and infiltrate soft tissue (Fig. 10.9). The main differential diagnosis of the spindle cell angiosarcomas is with other types of sarcomas, while the main differential diagnosis of epithelioid angiosarcoma is adenocarcinoma and other epithelioid malignant neoplasms. Immunohistochemical stains for vascular markers such as CD31 and ERG are helpful in achieving the correct diagnosis. Special care must be taken in the interpretation of cytokeratin in epithelioid angiosarcomas since these lesions can express keratin markers. Vascular markers must be part of the immunohistochemical panel to avoid a misdiagnosis [7]. No consistent recurrent chromosomal abnormality has been identified in angiosarcomas. KDR (VEGFR) mutations have been seen in a subset of angiosarcoma [52]. Amplification of MYC gene on 8q24 is seen in radiation-induced and lymphedema-associated angiosarcoma [53].

These benign smooth muscle tumors are frequently found in the uterus. They also occur in the gastrointestinal tract and the skin and subcutaneous tissue. Smooth muscle tumors of superficial origin often have a vascular component (angioleiomyomas) and present with pain. Primary mediastinal leiomyomas are extremely rare [54]. Tumors histologically show bland appearing smooth muscle bundles with no significant atypia, mitoses or necrosis. Degenerative changes such as sclerosis, hemorrhage, cystic change, and calcification can be present. Tumor cells are positive for SMA, Desmin and h-Caldesmon and are negative for S-100.

This malignant smooth muscle tumor is found in adulthood, most frequently in the retroperitoneum, but also in association with blood vessels such as the pulmonary artery or vena cava. They rarely occur in the mediastinum and can involve the posterior mediastinum [55, 56]. Malignant smooth muscle tumors are characterized by increased mitoses, cytologic atypia, and necrosis.

Low-grade leiomyosarcoma may be less cellular with nuclear atypia and coarse chromatin more difficult to identify. Cells may palisade similar to neurogenic tumors. It may not be possible to make a diagnosis of malignancy with accuracy in these cases, which may have to be considered suspicious for malignancy or labeled as atypical. High-grade leiomyosarcoma show significant pleomorphism with necrosis and markedly abnormal-appearing cells (Fig. 10.10). Leiomyosarcoma express SMA, Desmin and h-Caldesmon in a majority of cases. Genetically, soft tissue leiomyosarcomas have a complex karyotype with genomic instability [57].

Glomus tumors are uncommon and only rarely involve the mediastinum [58–61]. They are composed of cells that resemble the modified smooth muscle cells of a glomus body. Most of these tumors are present in the distal extremities, especially in subungual region, hand, wrist, and foot. They can occur in deep soft tissue or viscera and most malignant glomus tumors are present in these locations. Familial glomus tumors have been reported and have an autosomal dominant pattern of inheritance. Histologically, the tumors are composed of small uniform round cells with a round nuclei and amphophilic to lightly eosinophilic cytoplasm, arranged around vessels (Fig. 10.11). Each cell is surrounded by a basement membrane, which can be seen by PAS stain. The neoplastic cells are immunoreactive for SMA and h-Caldesmon, while negative for CD34, cytokeratin, and S-100. Occasionally, features of malignancy, such as increased cellularity with cytologic atypia, increased mitotic activity and necrosis may be appreciated [7]. Recent studies have shown gene fusions involving the miR143 and NOTCH genes [62].