Hemangiopericytoma (HPC) was originally described in 1942 as a soft tissue neoplasm thought to arise from pericytes, the cells that form the walls of capillaries and post-capillary venules. Pathologically, HPC was defined by a distinctive “staghorn” branching pattern of vasculature [35]. While the term “hemangiopericytoma” is still used by neuropathologists, general consensus is that the tumors traditionally been called HPCs are actually quite heterogeneous. Previously, these tumors were classified separately as meningeal solitary fibrous tumors (SFTs) and hemangiopericytoma. The most recent WHO classification of central nervous system tumors, however, has grouped these tumors into a single entity named solitary fibrous tumor/hemangiopericytoma (SFT/HPC). [36]. Most of these tumors can be identified by STAT6 nuclear expression, which is detectable by immunohistochemistry [36]. In reviewing the literature on this topic, one may find the terms CNS HPC or intracranial HPC used to describe SFT/HPC of the CNS.

Solitary fibrous tumors have 3 typical primary locations: pleura, meninges, and extrathoracic soft tissue [37]. Most (80%) of pleural-based SFTs are benign. Pleural-based SFTs generally occur in the 5th–7th decade of life, occur equally in men and women, and have no clear risk factors. These tumors may cause symptoms characteristic of pleural irritation (pleuritic pain, cough, dyspnea) and have also been associated with paraneoplastic osteoarthropathy and paraneoplastic hypoglycemia [37–39]. Extrathoracic soft tissue SFTs also tend to occur in the 5th decade of life and occur equally in both genders. They generally present as painlessly enlarging soft tissue masses that may be asymptomatic until they cause compression of adjacent structures.

SFT/HPC represents 2–3% of all meningeal tumors and <1% of all intracranial tumors [40, 41]. These tumors generally occur in those aged 40–50 and have been suggested to have a gender distribution that is dependent on age. In a recent systematic review of over 500 patients with SFT/HPC, it was found that below age 45, the tumors were more common in men, while above age 45, they were more common in women [40]. The most common symptoms associated with intracranial HPC include headache and upper/lower limb weakness [42]. SFT/HPCs generally grow slowly although they can cause great morbidity due to their highly vascular and invasive nature. They often appear similar to a benign meningioma on radiographic studies, making preoperative diagnosis of HPC difficult.

Surgical resection is the most important component of management of all SFTs/HPCs. Multiple studies have demonstrated statistically significant improved overall survival in patients with SFT/HPC who had complete resection rather than incomplete resection [40]. The role of radiation therapy in management of intracranial HPC has been debated. Although the review by Ghose and colleagues showed a statistically improved survival when adjuvant radiation therapy was added to surgical resection [40], multiple other studies have been unable to show a survival benefit with addition of adjuvant radiation [43, 44]. Adjuvant radiation may play a role in decreasing local recurrence and improving time to local recurrence [41, 42, 45]. Adjuvant chemotherapy is not a standard component of management of localized soft tissue/pleural-based SFTs; however, response to chemotherapy (particularly doxorubicin) appears to be better in these tumors than in SFT/HPC [46]. There has been interest in using temozolomide and VEGF inhibitors in SFT/HPC with evidence showing response to this combination in small numbers of patients. However, a controlled, prospective trial is lacking [47].

SFT/HPCs tend to have high local recurrence rate but can also cause extracranial metastases. Although complete resection of the primary SFT/HPC improves overall survival, complete resection appears to have no impact on controlling rates of distant metastasis [40, 48]. The pattern of development of extracranial metastases requires long-term follow-up and awareness on the part of the provider as metastases can develop years after the primary tumor (typically 5–8 years but up to 20 years). Typical extracranial metastatic sites include bone, lung, and liver [37, 49, 50].

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that is morphologically similar to other small round cell tumors but is specifically characterized by features of skeletal muscle including histological identification of cross-striations. This tumor is the most common soft tissue tumor of childhood but accounts for only 3–4% of pediatric cancers overall [51]. The majority of cases are diagnosed in children under the age of 6 with a slight male predominance and higher incidence in African Americans compared to Caucasians. Histologically, these tumors are classified as either embryonal or alveolar. Embryonal RMS is more commonly found in the head and neck or urinary tract, while alveolar-type RMS is more commonly found in the extremities [52]. No clear risk factors for RMS have been identified although there is an association with higher incidence with neurofibromatosis, Li–Fraumeni syndrome, Beckwith–Wiedemann syndrome, and Costello syndrome [53–56]. Despite the association with these syndromes, sporadic cases of RMS are most common. Rhabdomyosarcomas often present as areas of swelling either in the head and neck region or in the extremities with variable degrees of pain.

Primary intracranial RMS is very rare. Most CNS involvement with RMS occurs as a result of intracranial extension of tumors that occur in the head and neck (in areas such as the orbit, paranasal sinuses, middle ear, infratemporal fossa) rather than by lymphatic spread [57]. As in other sarcomas, brain metastases occur uncommonly with systemic RMS. The most common sites of metastases for RMS include bone marrow and lungs [57]. If brain metastases do occur, they generally develop with or after pulmonary metastases [58]. Neurologic symptoms associated with intracranial RMS, whether primary or metastatic, are largely dependent on the site of the tumor and can include headache, visual disturbance, papilledema, or proptosis with orbital tumors and nasal discharge due to sinus obstruction [52, 59]. Direct extension from these locations can result in leptomeningeal disease [60, 61].

Treatment of RMS generally involves use of combined modality therapy under guidelines developed by cooperative groups such as the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (formerly known as the Intergroup Rhabdomyosarcoma Study Group or IRSG). The use of multimodality therapy has been crucial in the improvement of survival rates in RMS in children [62]. Treatment decisions are based largely on a prognostic stratification system with the knowledge that prognosis of RMS is highly dependent on site of presentation. For example, a SEER database review of 558 cases of head and neck RMS reported from 1973 to 2007 showed 5-year survival rates of 49, 70, and 84% for parameningeal sites, non-parameningeal non-orbital sites, and orbital tumors, respectively [63]. Prognosis in adults is generally worse than in children, and studies have demonstrated that results of treatment are most favorable when adults are treated using pediatric clinical trial protocols (often enroll patients up to age 50) [64]. RMS tends to be quite radiosensitive, and radiation therapy has been a critical component of management of parameningeal primary tumors as well as metastatic intracranial disease [65]. Chemotherapy regimens for systemic RMS including vincristine, doxorubicin, and cyclophosphamide have limited utility for intracranial disease due to lack of blood-brain barrier penetration [64]. Once a patient develops cerebral metastases, survival is very short. In a series of over 400 pediatric patients with RMS, 2% of patients were found to have brain metastases and median survival was 2.7 months after diagnosis of brain metastases despite aggressive therapy [66].

Leiomyosarcomas are soft tissue sarcomas that occur most commonly in the retroperitoneum, GI tract, uterus, and skin [67]. Primary CNS leiomyosarcoma is a very rare entity that has been reported more frequently in the HIV/AIDS era due to an association between development of leiomyosarcoma and EBV infection [68]. A similar rise in incidence has been seen in patients with solid organ transplant due to immunosuppression although the absolute incidence of primary CNS leiomyosarcoma remains very low [67]. Primary CNS leiomyosarcomas have been described from ages 4 to 72 years with no clear gender predominance [69–72]. Risk factors for development include immunosuppression as well as prior CNS radiation exposure [73]. As with other intracranial sarcomas, symptoms correlate with location of tumor and can include headache, motor deficits, and seizures. The prognosis of primary CNS leiomyosarcoma is poor with the longest reported overall survival of 32 months [69, 71, 74]. The approach to treatment of primary CNS leiomyosarcoma is not standardized due to the small number of cases; however, a multimodality approach utilizing surgical resection, radiation therapy, and chemotherapy is typically advocated [72]. Doxorubicin is the typical first-line chemotherapy for systemic leiomyosarcoma although dacarbazine, gemcitabine, and docetaxel are all reported to be active agents for leiomyosarcoma [23, 75]. It is unknown what the optimal chemotherapy regimen for CNS leiomyosarcoma is and outcome data are sparse.

Metastatic disease to the CNS from a systemic leiomyosarcoma is also very rare. To date, only 16 cases of CNS metastases from uterine leiomyosarcoma have been reported [67]. When CNS metastases do occur, they are generally found supratentorially with reports of involvement of the frontal and parietal lobes [76]. Treatment of brain metastases may include surgical resection, if feasible, though most commonly includes radiation, either whole-brain radiation therapy or stereotactic radiosurgery [77]. Prognosis once a patient develops CNS metastases from systemic leiomyosarcoma is also very poor and likely measured in months [67].

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are soft tissue sarcomas that arise from peripheral nerves. They can arise from any component of the nerve sheath including Schwann cells, fibroblasts, and perineural cells [78]. These tumors occur in approximately 0.001% of the general population but affect individuals with neurofibromatosis type 1 (NF1) at a higher rate with a 5–10% lifetime risk [79]. There is also a weak association with neurofibromatosis type 2 (NF2) [80]. Previous radiation exposure is an additional risk factor with approximately 10% of MPNSTs occurring in patients who have had prior radiation [81, 82]. MPNSTs occur in men and women with equal distribution and can occur at any age with a mean age of 40 years [83, 84]. The age of onset tends to be younger in patients with NF1. Intracranial MPNSTs are more common in men and are less likely to be associated with NF1 [83]. MPNSTs tend to occur most commonly in the extremities at sites of major nerve trunks like the sciatic nerve [78]. These tumors can also occur in the trunk or head and neck. Involvement of cranial nerves or intraosseous nerves is rare but can cause important neurologic symptoms including cranial nerve palsies and spinal cord compression [85, 86].

The presentation of MPNST commonly includes evidence of a painful enlarging mass. As these tumors originate from nerve sheaths, other common presenting symptoms are those of nerve compression including motor deficit or paresthesias in the innervated region of the particular nerve affected [78]. Intracranial involvement may occur with cranial nerves (primarily centered around the cerebellopontine angle but can also be intraventricular or intraparenchymal [87]. Presenting symptoms can be non-specific such as headache or dizziness. Other patients present with more specific signs of cranial nerve palsy. Karami and colleagues reported a case of MPNST of the vestibulocochlear nerve and brain stem in a young woman who presented with dizziness, headache, ataxia, and sudden unilateral hearing loss with hemifacial paralysis [85].

MPNSTs are generally aggressive tumors with high rates of local recurrent and metastasis via hematogenous spread. A review from 2014 reported a recurrence rate of MPNSTs as high as 40% with approximately two-thirds of patients experiencing metastatic spread (most commonly to lungs and bone) [78]. They also reported a poorer prognosis associated with larger tumors (variably defined as either greater than 5 cm or 7 cm depending on the series), those with higher histologic grade and those associated with NF1. Prognosis of intracranial MPNST also appears to be worse than extracranial disease with one review reporting 5-year overall survival of 14% [87].

Treatment of both extracranial and intracranial MPNSTs is focused on maximal safe surgical resection. These tumors have limited sensitivity to chemotherapy and radiation so the role of adjuvant therapy is unclear. Adjuvant radiation may improve local control rates although there is no clear survival benefit [88, 89]. A 2013 review of all reported cases (n = 61) of intracranial MPNST showed that nearly equal numbers of patients received partial resection and gross total resection. The majority of patients in this review received radiation after surgery, while very few (4 of 61) received chemotherapy [87]. Survival seems to be improved with adjuvant radiation therapy regardless of surgical results (partial or gross total resection) as the irradiated patients had a mean survival of 30 months with a 5-year survival of 30%, while unirradiated patients had a mean survival of 8.6 months with no survivors at 5 years. Notably, this study included 5 patients with history of NF1, and these patients were found to have survival from time of diagnosis of 3–5 months.

Osteosarcoma is the most frequently occurring primary malignant tumor of bone [90] although it is rare overall and accounts for approximately 1% of all cancers in the USA annually [91]. It has a bimodal distribution in incidence with peaks occurring in adolescence and again at age over 65 [91]. In both adolescents and adults, males are more commonly affected than females. In children, African Americans are more commonly affected than whites; however, in adults, whites are more commonly affected than other races [91]. Predisposing factors include prior radiation and Paget’s disease. Several genetic conditions also predispose to the development of osteosarcoma including hereditary retinoblastoma, Li-Fraumeni syndrome, and Rothmund–Thomson syndrome [92]. Typical sites of primary osteosarcoma include femur, tibia, humerus, and pelvis. Osteosarcomas usually present with bone pain. Osteosarcomas of the vertebral column and skull bones are rare. When the tumor involves the spine, presenting symptoms can include those of spinal cord compression. One case of primary osteosarcoma of the lamina of L2 presented with painless paraplegia in a young woman [93].

Osteosarcoma typically has a hematogenous route of spread with common metastatic sites including lung and other bones [94]. CNS metastasis of osteosarcoma is uncommon, occurring in only 2–6% of cases [95]. Pulmonary metastasis usually precedes CNS metastasis. A case report described an orbital metastasis of osteosarcoma in an eight-year-old girl, which presented as severe, progressive ptosis with associated visual disturbance after a minor orbital injury [96]. On evaluation, this patient was found to have a primary tumor of femur without pulmonary metastasis. A recent review of 55 cases of metastatic osteosarcoma involving the CNS showed that brain metastases have occurred throughout the cerebrum (with the frontal lobe being most common) and cerebellum in addition to the bones of the skull [90]. Treatment of these patients included a combination of surgical resection, whole-brain radiation therapy, or stereotactic radiosurgery. Chemotherapy may be used for osteosarcoma of the central nervous system; however, given the small number of cases reported in the literature, there is no consensus on optimal regimen to use. In a review of 19 cases of primary meningeal osteosarcoma, use of “standard osteosarcoma chemotherapy” was described [97]. Typical osteosarcoma regimens include doxorubicin with high-dose methotrexate and cisplatin [98]. Both methotrexate and cisplatin have known ability to penetrate the blood-brain barrier so are reasonable choices for treatment of CNS metastases [99]. Other agents used in osteosarcoma include ifosfamide and etoposide which also have been known to cross the blood-brain barrier [98, 99]. The overall mean survival for patients following diagnosis of brain metastases was 18.4 ± 30.4 months, highlighting the variability in clinical course [90].

Ewing’s sarcoma accounts for approximately 6% of all childhood malignancies with peak incidence from age 10–15 years [100, 101]. Unlike osteosarcoma, Ewing’s sarcoma rarely affects adults. Any bone can be affected; however, the femur, pelvis, and axial skeleton are most commonly involved [102]. The most common presenting symptom of Ewing’s sarcoma is pain, which is typically progressive. The pain can often be exacerbated by activity and tends to be worse at night [103]. Up to 80% of patients have subclinical metastatic disease at the time of presentation [104]. Ewing’s sarcoma has been known to metastasize to the CNS in 32–56% of cases with less than 2% of these cases comprising brain metastases [105]. More commonly, direct extension of tumor from location in bony elements of the spine causes CNS involvement. Symptoms of spine involvement can include back pain, radiculopathy, lower extremity weakness, or paresthesias. A recent review of 40 cases of Ewing’s sarcoma brain metastases showed that the parietal lobe was most commonly affected followed by the frontal lobe, then the temporal/occipital lobes [90]. Management of primary Ewing’s sarcoma is generally treated with multimodality therapy including chemotherapy, radiation, and surgical resection. In the review referenced above, management of Ewing’s sarcoma brain metastases included surgical resection (25%), whole-brain radiation therapy (70%), stereotactic radiosurgery (18%), and conservative management (17%). The overall survival of these patients was 7.1 months (±7.7 months, range 0–24 months) after detection of metastatic disease to the brain [90].

Typical first-line chemotherapy regimens for Ewing’s sarcoma include agents such as cyclophosphamide, doxorubicin, vincristine, etoposide, and ifosfamide [98]. Of these agents, etoposide and ifosfamide are known to be active in the CNS and this 5-drug regimen has been used previously in a case of primary intraspinal intradural extraosseous Ewing’s sarcoma [99, 106]. Other chemotherapy regimens used for systemic recurrence of Ewing’s sarcoma including cyclophosphamide/topotecan, irinotecan/temozolomide, and gemcitabine have also been used in cases of CNS involvement by Ewing’s sarcoma [107]. In a study of 18 children with CNS involvement by sarcoma (10 had Ewing’s sarcoma), survival from time of CNS involvement until death, or last follow-up was similar between those receiving CNS-directed therapy (radiation/surgical resection) and chemotherapy, ranging from 2 to 6 months [107].

Gliosarcoma is a rare primary brain tumor composed of a combination of malignant glial cells and mesenchymal elements. The mesenchymal elements of the tumor can show fibrosarcomatous, pleomorphic sarcomatous, leiomyosarcomatous, or osteosarcomatous patterns [108]. These tumors represent approximately 2% of glioblastomas (GBM) [109] and are molecularly identical to GBM with presumed sarcomatous metaplasia. They occur more commonly in men with typical age of onset in the 5th−6th decade of life [110, 111]. Gliosarcomas are most often found in the temporal lobe [111] and can present with symptoms such as headache and motor weakness [110]. These tumors have a similar clinical pattern of behavior as GBM overall although they have a unique propensity to metastasize extracranially. Involvement of the lungs, pancreas, bone marrow, and liver has all been reported with gliosarcoma [110, 112, 113]. Typical GBMs do not spread hematogenously but rather spread via the cerebrospinal fluid with resulting metastasis throughout the neuraxis [114–116]. Gliosarcomas also metastasize to other locations within the neuraxis as evidenced in the report of an intramedullary cervical spinal cord metastasis from a temporal lobe primary gliosarcoma by [117]. Prognosis for both glioblastoma and gliosarcoma is poor with overall survival on the order of months. In a 2009 review of all cases of glioblastoma and gliosarcoma reported in the SEER database of the US National Cancer Institute from 1988 to 2004, overall survival was slightly worse for gliosarcoma [118]. As this tumor is very rare, there is no standardized approach to treatment; however, surgical resection and radiation have been used [118]. Typically, these tumors are managed similarly to GBM and are generally included in GBM clinical trials.

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that arise from the interstitial cells of Cajal [119]. They commonly originate in the stomach and small intestine although they can occur throughout the GI tract or in extraintestinal sites such as the omentum or retroperitoneum [120–122]. GISTs account for up to 3% of all GI neoplasms and 5–7% of all sarcomas [123, 124]. Common presenting symptoms include abdominal pain, vomiting, anorexia, or bowel obstruction [122]. These tumors commonly metastasize, and up to one half of patients will have distant metastases at the time of diagnosis [125]. Common metastatic sites include the liver, peritoneum, and lung. CNS metastases are very rare although there have been reports of brain parenchymal lesions in both children and adults [122, 126]. Symptoms reported with intracranial space occupying metastases include headache, weakness, and vomiting [122, 126]. There has also been a report of metastatic GIST involving the thoracic and lumbar spine which resulted in bilateral scapular tightness/pain and low back pain [125].

GISTs have traditionally been resistant to chemotherapy and radiation therapy [127]. Surgical resection is the treatment of choice for primary GIST [128]. Advances in treatment for relapsed or advanced disease occurred with the introduction of molecularly targeted therapy, specifically imatinib mesylate a small molecule kinase inhibitor. Lower concentrations of imatinib are achieved in the central nervous systems of both mice and humans [129, 130], which correlates with clinical observations of imatinib being ineffective in treatment of CNS metastases. Surgical resection has been utilized for management of intracranial or spinal metastases [119, 122, 125, 126].

Traditionally, sarcomas have been divided into groups based on site of origin and histopathologic features. More recently, effort has been directed to separating sarcomas into different categories based on their genetic characteristics. Some sarcomas are characterized by discrete genetic changes that may serve as the target for therapy, such as the 11:22 translocation seen in Ewing’s sarcoma [1]. Other sarcomas are characterized by complex genetic changes that are not as easily targetable, such as leiomyosarcoma or undifferentiated pleomorphic sarcoma [1]. Identification of specific genetic targets or discovery of particular cellular pathways implicated in oncogenesis has opened the door for new drug development and testing of existing drugs in sarcoma with the hope of improving clinical outcomes.

Cellular pathways involved in angiogenesis have been an area of interest for drug development in sarcoma. Pazopanib is an angiogenesis inhibitor that targets VEGF receptors 1–3, PDGF receptor α/β, and c-kit that has recently been approved for use in patients with advanced soft tissue sarcomas who have received prior chemotherapy [1]. In the phase III PALETTE (pazopanib for metastatic soft tissue sarcoma) study, an improvement in progression-free survival was found for pazopanib compared to placebo (4.6 months vs. 1.6 months, respectively) with no difference in overall survival in the setting of advanced soft tissue sarcoma [131]. While no data exist for the use of pazopanib in sarcomas involving the CNS, there is a report of renal cell carcinoma brain metastases that were responsive to pazopanib [132]. This suggests that pazopanib may be helpful for intracranial disease. In this case report, the patient received whole-brain radiation therapy prior to pazopanib so it is unclear whether the drug has CNS activity on its own or whether the effect of radiation was necessary to allow CNS activity. In either case, pazopanib may have a role in treatment of sarcoma with CNS involvement. Although not FDA approved, agents including temozolomide/bevacizumab and sunitinib, which also have anti-angiogenic activity, have activity in small numbers of patients with hemangiopericytoma/solitary fibrous tumor extraskeletal myxoid chondrosarcoma and may be considered for off-label use with CNS involvement [47, 133, 134].