Mesenchymal neoplasms are a diverse group of benign and malignant tumors arising predominantly from the soft tissue (eg, muscle, fat, fascia, or fibroblasts). The central and peripheral nervous system may be directly affected by these tumors, in cases of primary tumors arising in the CNS or PNS, or they may be secondarily affected due to mass effect or metastases. To cover the broad spectrum of these tumors would be in excess of this article; instead, the focus will be directed on a subset of tumors as suggested by the latest edition of the WHO Classification of Tumors, Central Nervous System (5th edition) (19). However, caution must be taken to exclude the possibility of a systemic malignancy with secondary effects on the nervous system (05).
Solitary fibrous tumor. Solitary fibrous tumors are among the most frequent entities in the radiographic differential diagnosis of dural-based lesions. A fibroblastic neoplasm is defined by the presence of a NAB2::STAT6 fusion that results from inversion at 12q13 (04). These tumors are known for key histologic features, including spindled to ovoid cells haphazardly arranged in a “patternless pattern” with prominent staghorn-shaped vessels (02). The defining fusion can be interrogated using an immunohistochemical stain for STAT6. These were previously called hemangiopericytoma, but that term has fallen out of favor to maintain consistency with the non-CNS nomenclature.
Solitary fibrous tumors most frequently occur supratentorially as dural-based lesions at the skull base, parasagittal, or subfalcine locations. They may occur in spinal locations as well as in the cerebellopontine angle, pineal region, or sella, though these latter locations are less common (18).
Clinical presentation is based on anatomic site and mass effect on adjacent structures. Histologically, they are graded (CNS WHO grades 1, 2, or 3) based on mitotic activity and the presence of tumor necrosis, with higher-grade solitary fibrous tumors showing more aggressive clinical behavior. These tumors may recur locally or may metastasize throughout the CNS as well as outside the CNS (08; 16).
Hemangiomas and vascular malformations. Hemangiomas and vascular malformations are common vascular lesions of the CNS. Vascular malformations include arteriovenous malformations, cavernous malformations, and capillary telangiectasias. Hemangiomas, as in their visceral counterparts, are lobulated tumors composed of variably sized blood vessels with fibrous septations separating the lobules. They may be intraosseous (24). They are more common in the spinal region (often involving the bones of the vertebral column, preferentially in males, and preferentially thoracic or lumbar), and may cause compressive symptoms. They may occur sporadically or in PIK3CA-related overgrowth spectrum (17).
Arteriovenous malformations are fistulas between arteries and veins with intervening gliotic brain parenchyma. They may arise anywhere in the neuraxis, both intra-axial and extra-axial, and may present with acute hemorrhage. They show no sex or age predilection. Notable molecular features include KRAS or BRAF mutations (10).
In contrast to the arteriovenous malformation, cavernous malformations show cavernous vessels without intervening gliotic brain parenchyma. They favor the supratentorial compartment (30) and clinically tend to present with seizures, though acute hemorrhage is a possible presentation. They may be sporadic or familial (07).
Capillary telangiectasias are focal intraparenchymal aggregates of capillary-sized vessels without reactive changes in the adjacent brain parenchyma. They are more common in the pons and are frequently incidental (30).
Hemangioblastomas. Hemangioblastomas are vascular tumors composed of vacuolated stromal cells and reactive vascular cells. They may occur sporadically or syndromically as part of von Hippel-Lindau disease, and both may show mutations in the VHL gene (20). They typically arise in the cerebellum but may be found throughout the neuraxis, including the spinal cord (most frequently dorsal in location) or cauda equina. They are often well-circumscribed and may have solid and cystic components. Clinical symptoms often occur secondary to mass effect.
Von Hippel-Lindau-associated tumors tend to occur at younger ages than their sporadic counterparts. Correlation with clinical and radiographic findings, as well as family history is key for management (09; 23). When observed in von Hippel-Lindau disease, they may occur in a setting of other neoplasms, including renal cell cancer, pheochromocytomas, retinal angiomas, endolymphatic sac tumors, and pancreatic neuroendocrine tumors.
Rhabdomyosarcomas. Rhabdomyosarcomas are clinically aggressive malignant neoplasms of skeletal muscle differentiation. They arise throughout the neuraxis, are more common in children, and are rare. Clinically, they most often present secondary to local mass effect. They commonly show one of two histologic varieties, embryonal and alveolar. The former is characterized by rhabdomyoblastic cells in a loose myxoid matrix, whereas the latter shows primitive round cells separated by fibrous septae.
Embryonal rhabdomyosarcomas typically show somatic mutations in the RAS pathway (eg, KRAS, NRAS), whereas alveolar rhabdomyosarcomas often have either a PAX3::FOXO1 or PAX7::FOXO1 fusion. The PAX3::FOXO1 suggests a worse prognosis, as does alveolar rhabdomyosarcoma overall (25; 31).
Primary intracranial sarcoma, DICER1-mutant. Primary intracranial sarcoma, DICER1-mutant, may show histologic overlap with rhabdomyosarcomas, but it is molecularly and clinically a distinct entity. This tumor is defined by either a somatic or germline mutation in the DICER1 gene and has a distinct DNA methylation profile. The prognostic information in these cases is limited by small case numbers and an absence of long-term follow-up data. They typically arise supratentorially and present with mass effect (14).
Intracranial mesenchymal tumor, FET::CREB fusion-positive. Intracranial mesenchymal tumors, FET::CREB fusion-positive, are variably aggressive intracranial neoplasms. They are defined by the fusion of a FET RNA-binding protein family gene (eg, EWSR1) and a CREB family of transcription factors (eg, CREB1). They show a diverse morphologic spectrum and require confirmation of a FET::CREB fusion for diagnosis (26).
CIC-rearranged sarcoma. CIC-rearranged sarcoma is composed of small round blue cells arranged in sheets with molecular confirmation of the CIC gene fusion to one of several fusion partners, the most common being NUTM1. They are invariably aggressive and may arise anywhere in the neuraxis with associated mass effect on adjacent structures, which dictates their clinical presentation. They typically arise in adolescents but have been reported in all age groups (27; 29; 01).
Ewing sarcoma. like their systemic counterparts, Ewing sarcomas typically show an EWSR1::FLI1 fusion. They are a prototypic example of a small round blue cell tumor, and CNS primaries typically arise from the meninges. Osseous primaries may show local invasion of the CNS as well. They show a wide range in age of clinical presentation but typically occur in children and young adults (11).
Chordoma. Chordomas are notochordal tumors with a characteristic histopathologic appearance of chords of tumor cells separated by myxoid matrix. The tumor cells are large, clear, and show a vacuolated appearance (physaliphorous). They show positive staining for Brachyury and cytokeratin stains but may lose these in more dedifferentiated varieties (12). Classic anatomic sites include the lumbosacral spine and clivus (22).
Chondrosarcoma. Chondrosarcomas are a family of tumors with cartilaginous differentiation. A large proportion of intracranial chondrosarcomas harbor IDH1 or IDH2 mutations. In contrast to the above-described chordoma, these tumors lack brachyury and cytokeratin expression (21; 13).
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcomas are rare, malignant tumors showing a biphasic histologic finding of well-differentiated cartilage and poorly differentiated small round cells (06; 15). They almost invariably harbor a HEY1::NCOA2 fusion (28). Of note, spinal mesenchymal chondrosarcomas show a low rate of recurrence (03).
