Uncommon brain tumors

INTRODUCTION — Brain tumors are a diverse group of neoplasms arising from different cells within the central nervous system (CNS) or from systemic tumors that have metastasized to the CNS. The World Health Organization (WHO) classification of tumors of the CNS recognizes more than 100 tumor types in 13 different categories [1]. The most common of these include the diffuse gliomas and meningiomas, as well as metastatic lesions from extracranial tumors. The 2021 revision of the WHO classification introduced a number of important classification changes and new tumor subtypes. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

The clinical manifestations of brain tumors are determined by the anatomic location, rate of growth, and histology of the specific tumor. Although symptoms, imaging characteristics, and demographic features may suggest a specific tumor type, definitive diagnosis requires biopsy and, in many instances, molecular studies for confirmation. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

For the rare brain tumors reviewed here, information about the clinical and imaging manifestations, natural history, and management is based on case reports and small series. Our recommendations regarding treatment are necessarily extrapolated from these limited data and the general principles of brain tumor management. More detailed discussions of other tumor types are presented separately.

GLIONEURONAL AND NEURONAL TUMORS — Glioneuronal and neuronal tumors are a diverse group of tumors that usually occur in children and young adults and are characterized by a variable degree of neuronal and glial differentiation (table 1). Most are indolent and associated with good outcomes with surgery alone.

Ganglioglioma and gangliocytoma — Gangliogliomas and gangliocytomas comprise a spectrum of World Health Organization (WHO) grade 1 tumors characterized by a dysplastic (abnormal-appearing) neuronal population.

●Clinical features – Gangliogliomas and gangliocytomas typically occur in children and young adults; the average age in most series is approximately 20 years [2-5]. They can occur anywhere in the neuraxis, but most are supratentorial and located in the temporal lobes. Seizures are the most common presenting symptom, and long-standing epilepsy is frequent. Gangliogliomas can be an incidental finding when temporal lobectomies are performed to treat epilepsy [6].

●Imaging – On magnetic resonance imaging (MRI), these tumors are hyperintense on T2-weighted images (image 1) [7]. One-half of cases have cysts and approximately one-third have calcifications [8]. Contrast enhancement varies from none to marked and may be solid or rim enhancing.

●Pathology and genetics – Gangliogliomas are composed of dysplastic neuronal cells accompanied by neoplastic glial cells. By contrast, in gangliocytomas, large, well-differentiated neurons are the sole neoplastic component.

Up to 60 percent of gangliogliomas harbor a BRAF V600E mutation, which has been associated with higher risk for recurrence after standard therapy in pediatric low-grade gliomas [9-12]. The mutant protein is found primarily in the neuronal cells [9]. Midline gangliogliomas may harbor mutations in both H3F3A K27M and BRAF V600E in both the glial and neuronal components [13]. More rarely, tumors harbor oncogenic fusions involving genes such as neurotrophic receptor tyrosine kinase (NTRK), which are mutually exclusive with BRAF alterations, and which may be therapeutically relevant [14,15].

Mutations in isocitrate dehydrogenase type 1 (IDH1), when found in tumors histologically appearing like gangliogliomas, strongly support the alternate diagnosis of diffuse glioma and are associated with an older age at diagnosis, a greater risk of recurrence, and a poorer prognosis [1,16]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'IDH1/IDH2 mutation'.)

●Treatment and prognosis – The initial management is surgical resection. As grade I tumors, gangliogliomas are associated with excellent long-term survival and low recurrence rates after gross total resection. In a literature review of over 400 gangliogliomas reported in the literature from 1978 to 2007, 10-year local control and overall survival rates were 89 and 95 percent, respectively, for the 188 patients who underwent gross total resection alone at the time of diagnosis [17].

Local control and overall survival rates are lower in patients who undergo subtotal resection, although prognosis is still good. In the same literature review, among 193 patients who underwent subtotal resection, 10-year local control ranged from 52 to 65 percent, and 10-year overall survival ranged from 62 to 74 percent [17]. Receipt of radiation therapy after subtotal resection was associated with improved local control (65 versus 52 percent at 10 years) but not overall survival on subgroup analysis. Aside from subtotal resection, factors associated with increased risk of recurrence/progression include older age (eg, >30 or 40 years), nontemporal tumor location, and, at least in historical studies, high-grade/anaplastic pathologic features [12,17,18]. The last factor requires validation in contemporary studies that include tumors diagnosed according to the 2021 WHO classification, since molecular testing on such tumors may lead to reclassification as an alternative tumor type [1,19]. Historically, recurrent anaplastic ganglioglioma has been associated with an aggressive clinical course and often death despite management with radiation and chemotherapy [12].

Treatment decisions in patients with residual tumor after maximal safe resection should be individualized, and all tumors should undergo molecular testing to identify targetable mutations such as BRAF V600E or NTRK fusions. Evidence is insufficient to support a uniform recommendation for adjuvant therapy after subtotal resection rather than a watch-and-wait approach. However, selected patients with symptomatic or bulky residual disease are reasonably treated with adjuvant therapy. For gangliogliomas, options include radiation therapy (in older children and adults), chemotherapy (for younger children without a targetable mutation), and targeted therapy (if applicable).

In most children with BRAF V600E-mutant tumors who require further treatment beyond surgery due to symptomatic residual disease or tumor progression, we suggest targeted therapy with BRAF and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibition (eg, dabrafenib and trametinib) as a first-line option. Targeted therapy achieves better response rates and progression-free survival than chemotherapy in this setting [20] and, although not compared directly with radiation therapy, has the advantage of avoiding or at least delaying the long-term neurologic and cognitive consequences of radiation, which are of particular concern in younger patients. Adults with recurrent/progressive BRAF V600E-mutant tumors are also candidates for BRAF/MEK inhibition, although radiation therapy remains a standard approach and the durability of targeted therapy responses requires further study.

Supporting evidence for BRAF/MEK inhibition in pediatric low-grade glioma includes results of a multicenter, randomized, open-label phase 2 trial of dabrafenib plus trametinib versus chemotherapy (carboplatin plus vincristine) in 110 children aged 1 to 17 years with measurable, BRAF V600E-mutant low-grade glioma selected for first-line therapy based on symptoms and/or clinical or radiographic progression after surgery [20]. The most common tumor types were pilocytic astrocytoma (30 percent), ganglioglioma (29 percent), and low-grade glioma not otherwise specified (19 percent). With a median follow-up of 19 months, the dabrafenib/trametinib group had an improved overall response rate (47 versus 11 percent; median response duration, 20.3 months) and median progression-free survival (20.1 versus 7.4 months; hazard ratio [HR] 0.31, 95% CI 0.17-0.55) compared with chemotherapy. Grade 3 or higher adverse events were less frequent with targeted therapy (47 versus 97 percent). Overall survival data are not yet mature, with all but one patient alive at last follow-up.

Based on these and other data, the combination of dabrafenib plus trametinib is specifically approved by the US Food and Drug Administration (FDA) for BRAF V600E-mutant low-grade glioma in children one year of age and older [21,22]. The combination also has tissue-agnostic approval in patients ≥1 year of age with unresectable or metastatic BRAF V600E-mutant solid tumors that have progressed on previous treatment.

For tumors with an NTRK fusion detected [23], the NTRK inhibitors entrectinib and larotrectinib may be an option and are approved by the FDA in children and adults with tumors with an NTRK fusion that have failed prior standard therapies or are nonresectable. (See "Management of recurrent high-grade gliomas", section on 'Genotype-directed therapies'.)

Desmoplastic infantile astrocytoma/ganglioglioma — Desmoplastic infantile astrocytoma and desmoplastic infantile ganglioglioma were initially thought to occur only in the first two years of life but have subsequently been reported in patients as old as 25 years of age. Infants often present with megalocephaly and bulging, tense fontanelles [19]. Tumors tend to be very large size and located in the cerebral hemispheres [24]. They usually have both solid and cystic components and distinct hypointensity on T2-weighted MRI [25].

Pathologically, they are WHO grade 1 tumors that feature dual astrocytic and ganglionic differentiation, prominent desmoplastic stroma, and activation of the mitogen-activated protein kinase (MAPK) pathway, most commonly by mutation or fusion involving BRAF or RAF1 [1].

Treatment consists of surgery, with chemotherapy in cases of incomplete resection. Most studies indicate that gross total resection results in long-term survival. Radiation therapy is usually considered only when other options have been exhausted. Rare cases of late recurrence with malignant transformation have been reported [26].

Dysembryoplastic neuroepithelial tumor — Dysembryoplastic neuroepithelial tumors (DNTs) are cortical WHO grade 1 glioneuronal tumors with distinct multinodular histopathology.

●Clinical features – DNTs are slow-growing, supratentorial masses. They typically occur in children and young adults with a long-standing history of intractable focal epilepsy. Patients with DNTs generally have minimal or no neurologic signs other than seizures. Rare histologically defined DNTs in the septum pellucidum are now classified separately as myxoid glioneuronal tumors [27]. (See 'Myxoid glioneuronal tumor' below.)

●Imaging – On MRI, DNTs are T1 hypointense and T2 hyperintense (image 2). The lesions are based in and focally expand the cortex, sometimes extending into the white matter. Gadolinium enhancement is variable, occurring in less than one-half of cases; enhancement is patchy and multifocal rather than diffuse [28,29]. There is sometimes skull molding adjacent to the lesions due to slow tumor growth.

●Pathology and genetics – Key pathologic features of DNTs include the presence of entrapped cortical neurons, foci of dysplastic cortical organization, a multinodular architecture with components resembling astrocytoma or oligodendroglioma, and a columnar structure oriented perpendicular to the cortical surface. DNTs are distinguished from diffuse gliomas and other low-grade brain tumors by histologic and molecular features.

Fibroblast growth factor receptor 1 (FGFR1) gene alterations are observed in 40 to 60 percent of DNTs [30,31]. BRAF V600E mutations have been reported in up to 50 percent of DNTs, although some of these tumors may be reclassified as ganglioglioma or MAPK pathway-altered low-grade gliomas with complete histomolecular analysis [1]. Neither IDH1 nor IDH2 mutations are consistent with DNT, and the presence of either suggests a diffuse glioma, as does codeletion of 1p and 19q.

●Treatment and prognosis – Surgery is indicated for refractory seizures, but lesions in eloquent cortex are best observed, if possible. Most patients are seizure free at least initially following surgery [32,33]. However, the incidence of seizures appears to increase with longer duration of follow-up. This was illustrated by a series of 26 children, in which 62 percent remained seizure free at a median follow-up of 4.3 years [34]. The main risk factors for recurrent seizures were age >10 years and longer duration of epilepsy (>2 years) prior to surgery. Rarely, tumor recurrence or even malignant transformation may occur [35].

Papillary glioneuronal tumor — Papillary glioneuronal tumors are rare WHO grade 1 tumors that occur primarily in young adults, with a median age at diagnosis of 16 years (range 6 to 54 years) [1,36,37]. They occur in the cerebral hemispheres, often adjacent to the lateral ventricles, and may present with headaches, seizures, or rarely hemorrhage [38,39].

MRI features are similar to other glioneuronal tumors. Most lesions have cystic and enhancing, solid components that are iso- to hyperintense on T2-weighted images. Calcification may also be observed.

Pathology consists of biphasic astrocytic and neuronal differentiation and a distinctive pseudopapillary architectural pattern. The molecular hallmark is protein kinase C alpha (PRKCA) gene fusion, mainly solute carrier family 44 member 1 (SLC44A1)-PRKCA, with resultant MAPK signaling dysregulation [40-42].

In most cases, papillary glioneuronal tumors are curable by surgical resection. Rare recurrent or progressive papillary glioneuronal tumors have been reported, typically in association with an elevated Ki-67 index (>5 percent) [1].

Rosette-forming glioneuronal tumor — Rosette-forming glioneuronal tumors are rare, slow-growing WHO grade 1 lesions primarily affecting young adults. They usually occur in the fourth ventricle but can also be seen in the supratentorial ventricular system, cerebellum, pineal region, optic chiasm, spinal cord, septum pellucidum, and brain parenchyma [1,43].

Tumors in the fourth ventricle typically present with hydrocephalus and therefore headaches, as well as ataxia and nystagmus. On MRI, they are heterogeneous, cystic, or multiloculated lesions with enhancing areas. They are T1 dark or isointense [44]. In some cases, they invade cerebellar or brainstem parenchyma.

The defining histopathologic feature is a mixed population of neurocytes organized in pseudorosettes and pilocytic astrocytes. Unlike pilocytic astrocytomas, rosette-forming glioneuronal tumors do not harbor alterations in BRAF; some harbor mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), FGFR1, and/or neurofibromin 1 (NF1) [45,46].

These tumors appear to be curable by surgical resection in the majority of cases, although rare cases of tumor dissemination throughout the ventricular system have been described.

Myxoid glioneuronal tumor — Myxoid glioneuronal tumor is a newly designated tumor as of the 2021 revision of the WHO classification [1]. It is a rare WHO grade 1 glioneuronal tumor usually located in the septum pellucidum, corpus callosum, or periventricular white matter. Most would have been previously classified as DNTs or rosette-forming glioneuronal tumors.

Most reported cases are in children and young adults, often presenting with increased intracranial pressure and hydrocephalus [27,47]. On MRI, they are usually well circumscribed, T2 hyperintense, and nonenhancing. Leptomeningeal dissemination at the time of presentation has been described.

Histologically, the tumor is characterized by oligodendrocyte-like cells embedded in a myxoid stroma [1]. The molecular hallmark is mutations in platelet-derived growth factor receptor alpha (PDGFRA) [27]. They have a distinct yet closely related deoxyribonucleic acid (DNA) methylation profile with cortical DNTs.

The primary management is surgical, including cerebrospinal fluid (CSF) diversion as necessary.

Diffuse leptomeningeal glioneuronal tumor — Diffuse leptomeningeal glioneuronal tumor is a primary leptomeningeal neoplasm characterized by predominant and widespread leptomeningeal growth, oligodendrocyte-like cytology, and, in a subset of cases, evidence of neuronal differentiation.

Based on the largest published series of 36 patients, the median age at diagnosis is 5 years (range 5 months to 45 years) [48]. Most patients present acutely with signs and symptoms of increased intracranial pressure due to hydrocephalus, cranial neuropathies, and other leptomeningeal signs.

MRI shows widespread leptomeningeal enhancement and thickening, often most prominent along the spinal cord, posterior fossa, and brainstem (image 3). Intraparenchymal and intramedullary enhancing nodules can also be seen. CSF cytology is often negative despite high protein levels, and diagnosis usually requires meningeal biopsy. However, in one reported case, CSF study of cell-free DNA was used to make a diagnosis when leptomeningeal biopsy had been inconclusive [49]. Histopathologically, tumor cells usually have low-grade features, but a WHO grade has not yet been assigned [1].

The genetic landscape of these tumors often includes concurrent BRAF-KIAA1549 gene fusion and either 1p deletion or 1p/19q codeletion, in the absence of mutations in IDH [50]. Less commonly reported abnormalities include H3 K27M histone gene alterations and FGFR1 mutations [51].

Optimal treatment is unknown, and these tumors can have a relatively indolent course. Due to the young age at which many patients are diagnosed, chemotherapy is often attempted before radiation. In a series of 36 patients with a median follow-up of five years, median survival was not yet reached; of the nine patients who died, survival ranged from less than a year to 21 years after first biopsy (median 3 years) [48]. Mitotic activity, Ki67 >4 percent, and microvascular proliferation were associated with worse survival. Other studies have identified gain of chromosome arm 1q as an adverse prognostic factor [52].

Multinodular and vacuolating neuronal tumor — Multinodular and vacuolating neuronal tumor is a WHO grade 1 tumor composed of nodules of monomorphic neuronal elements in a fibrillar background. They are primarily encountered as epileptogenic lesions in the temporal or parietal lobes. The appearance on MRI may be highly characteristic, with subcortical clusters of nonenhancing, T2-hyperintense nodules within the deep cortical ribbon and subcortical white matter [53].

The pathogenesis involves MAPK pathway activation and genetic alterations, most commonly MAP2K1 exon 2 variants [19,54]. Non-V600E BRAF alterations and FGFR2 fusions have been described.

Surgery is curative, and long-term stability without intervention is also possible [53].

Dysplastic cerebellar gangliocytoma — Dysplastic cerebellar gangliocytoma, also known as Lhermitte-Duclos disease, is an extremely rare entity characterized by loss of normal cerebellar cortical architecture and focal thickening of the folia. It is not clear whether dysplastic cerebellar gangliocytoma is a neoplastic or hamartomatous tumor of the cerebellar cortex; if neoplastic, it corresponds to WHO grade 1. Histologically, there is reduced cerebellar white matter and presence of abnormal hypertrophic ganglion cells that are reminiscent of Purkinje cells.

●Clinical features – Dysplastic gangliocytoma of the cerebellum is typically seen in young and middle-aged adults, although the disease has been diagnosed in patients as young as 3 years and as old as 70 years. Cerebellar symptoms may be present for a number of years prior to establishing the diagnosis, and obstructive hydrocephalus is common. The lesion arises in the cerebellar hemispheres, with rare extension into the vermis. An association with developmental disabilities including macrocephaly and intellectual disability is not uncommon.

●Imaging – On MRI, dysplastic cerebellar gangliocytoma is characterized by enlarged cerebellar folia with distorted architecture and variable cystic change (image 4). The lesion is typically nonenhancing and T1 hypointense, and T2-weighted images are characterized by a laminar pattern of alternating high and low signal. The mass is well circumscribed and distinct from the surrounding tissue. In rare cases it enhances with contrast, which may represent venous proliferation in the outer portions of the cerebellar cortex and prominent draining veins [55-57].

●Pathology and genetics – Histologically, there is reduced cerebellar white matter and presence of abnormal hypertrophic ganglion cells that are reminiscent of Purkinje cells.

Dysplastic gangliocytoma of the cerebellum can be familial or sporadic. Molecular studies in patients with dysplastic gangliocytoma of the cerebellum suggest a high frequency of abnormalities in the phosphatase and tensin homolog (PTEN)/AKT pathway, a major regulator of cell growth [58]. As such, this tumor has been linked to Cowden syndrome, an autosomal dominantly inherited condition characterized by multiple hamartomatous growths; an increased incidence of breast, uterine, and thyroid cancer; and germline mutations in the PTEN gene.

Most adults, but not children, with dysplastic gangliocytoma have PTEN germline mutations [59]. Dysplastic gangliocytoma of the cerebellum is a major criterion for Cowden syndrome in revised diagnostic criteria, and the National Comprehensive Cancer Network considers its presence to be an indication for genetic testing for Cowden syndrome (table 2). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cowden syndrome'.)

●Treatment – Treatment of dysplastic gangliocytoma of the cerebellum is surgical resection; a few reported cases have recurred after apparent gross total resection. Inhibition of the phosphoinositide 3-kinase (PI3K)/PTEN/AKT pathway with rapamycin was effective in one case of an infant with severe, symptomatic bilateral dysplastic gangliocytoma [60].

Because of the association with Cowden syndrome in adults, clinicians should exclude concomitant malignancies (particularly breast and genitourinary cancers) and refer patients for genetic testing for Cowden syndrome [58,61]. (See "Overview of hereditary breast and ovarian cancer syndromes".)

Central and extraventricular neurocytoma — Central neurocytomas are well-differentiated WHO grade 2 tumors that constitute approximately one-half of all intraventricular lesions in adults [62]. Similar tumors have occasionally been identified in the brain parenchyma or spinal cord, in which case they are referred to as extraventricular neurocytomas [63,64].

●Clinical features – The mean age at diagnosis in patients with central neurocytoma is 29 years [65]. Most patients present with symptoms of increased intracranial pressure due to hydrocephalus. Visual disturbances and impaired cognitive function may also be present. Focal neurologic deficits are uncommon. A few patients have presented with intraventricular hemorrhage.

Most central neurocytomas are multicystic and calcified, with a broad-based attachment to the superolateral wall of the ventricle. They are typically found in the lateral or third ventricle, attached to the septum pellucidum or ventricular wall at the foramen of Monro. They do not usually occur in the occipital or temporal horns. Despite their usual intraventricular location, leptomeningeal dissemination is extremely rare [66].

●Imaging – The typical computed tomography (CT) appearance is that of a heterogeneous, hyperdense intraventricular mass with moderate contrast enhancement (image 5). On MRI, they are slightly hyperintense on T1-weighted images; the appearance on T2-weighted images is somewhat more variable. They usually enhance with gadolinium. Both central and extraventricular neurocytomas may be difficult to distinguish from more common lesions like high-grade gliomas on MRI [67,68].

●Pathology and genetics – Neurocytomas are considered neuroectodermal tumors with predominant neuronal differentiation. They characteristically stain diffusely positive for synaptophysin, and most are immunoreactive for NeuN. Recurrent genetic alterations have not been identified in central neurocytomas [69]. A characteristic alteration in extraventricular neurocytoma is the FGFR1-transforming acidic coiled-coil containing protein 1 (TACC1) fusion [70].

●Treatment and prognosis – The optimal treatment is complete surgical resection. Even subtotal resection may be associated with prolonged survival, since these tumors usually regrow slowly. The prognosis appears to be better in patients with typical neurocytomas (ie, a growth fraction <3 percent, as measured by the MIB-1 monoclonal antibody) [71-73], and adjuvant radiation therapy or stereotactic radiosurgery may be useful for patients with an incomplete resection or atypical histology [74-76].

Recurrent or progressive tumors are typically treated with focal radiation [77]. At least one report suggests that recurrent central neurocytomas may be responsive to systemic chemotherapy [62].

The outcomes and prognostic factors associated with the treatment of central neurocytoma are illustrated by the results of treatment in a retrospective series of 45 patients treated over a 35-year period using surgery, radiation therapy, and/or chemotherapy [72]. The 10-year survival and local control rates were better for those with typical neurocytomas compared with atypical lesions (90 versus 63 percent and 74 versus 46 percent, respectively). Postoperative radiation therapy improved local control at 10 years (75 versus 51 percent without postoperative radiation therapy), but this did not translate into an overall survival benefit. A multicenter study of 71 cases, which included an immunohistochemical assessment of tumors, found that extent of surgery was the sole prognostic marker. However, the study may have had an insufficient number of cases to identify a MIB-1 index prognostic threshold [78].

Cerebellar liponeurocytoma — Cerebellar liponeurocytomas are WHO grade 2 posterior fossa tumors, with an average age at diagnosis of approximately 50 years [79].

CT demonstrates well-demarcated lesions that are hypo- or isodense and have moderate heterogeneous enhancement. MRI demonstrates T1 hypointensity of the tumor, heterogeneous T2 hyperintensity, and heterogeneous enhancement with gadolinium.

Tumors contain mature adipose tissue and various other cell types, including some degree of neuronal differentiation. Gene profiling has provided evidence that cerebellar liponeurocytomas are a distinct clinical entity, more closely related to neurocytoma than to medulloblastoma [80]. Overexpression of fatty acid binding protein 4 (FAB4) may help distinguish these tumors from medulloblastoma [81].

Only approximately 40 cases have been reported, and the optimal treatment and the overall prognosis are difficult to estimate. Cerebellar liponeurocytomas appear to have a relatively protracted natural history [82,83]. On this basis, management with surgery has been recommended, with additional surgery or radiation therapy if disease recurs. However, a more aggressive natural history has been observed in some cases [84].

Jugulotympanic paraganglioma — Jugulotympanic paragangliomas, previously known as glomus jugulare or glomus tympanicum tumors, are highly vascular, typically benign tumors that arise from paraganglia tissue, usually of parasympathetic origin. Approximately one-third arise in the setting of an inherited syndrome, for which genetic testing is available. Paragangliomas of the head and neck are discussed separately. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

CIRCUMSCRIBED ASTROCYTIC GLIOMAS — Circumscribed astrocytic tumors such as pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA) tend to have a more indolent natural history compared with low-grade diffuse gliomas (table 3). Surgery is a cornerstone of management [19].

Diffuse astrocytic and oligodendroglial tumors in adults and children are reviewed separately. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Adult-type diffuse gliomas'.)

Pilocytic astrocytoma

●Clinical features – Pilocytic astrocytomas (World Health Organization [WHO] grade 1) are the most common gliomas in children, with a median age at diagnosis of eight years [85]. They are circumscribed tumors that frequently arise in the cerebellum and present with signs and symptoms of mass effect, obstructive hydrocephalus, and increased intracranial pressure. Other common locations include the optic pathway and midline structures (eg, hypothalamus, thalamus, brainstem, spinal cord).

Approximately 25 percent of pilocytic astrocytomas occur after the age of 20 years, more commonly in the cerebral hemispheres than cerebellum [86]. Leptomeningeal dissemination occurs rarely, most often in association with infantile or hypothalamic presentations [87-89].

●Imaging – On MRI, pilocytic astrocytomas are usually hyperintense on T2-weighted images and have variable T1 signal. In the posterior fossa and cerebral hemispheres, most pilocytic astrocytomas appear as a well-demarcated, expansile mass consisting of an enhancing mural nodule with a surrounding cyst (image 6). Tumors in the brainstem or optic apparatus may be solid or cystic, with variable enhancement patterns [90]. Surrounding edema is mild or absent. For tumors in the posterior fossa in children, the degree of T2 hyperintensity associated with the solid portion of the tumor helps to distinguish pilocytic astrocytoma from medulloblastoma [91].

●Pathology and genetics – Pilocytic astrocytomas typically have a biphasic appearance, with compact areas of bipolar cells and Rosenthal fibers alternating with loose and myxoid regions with oligodendrocyte-like cells (picture 1) [1]. Microcystic change and calcifications are common. Some tumors with prominent anaplasia are now classified as high-grade astrocytoma with piloid features. (See 'High-grade astrocytoma with piloid features' below.)

Most tumors harbor alterations that affect mitogen-activated protein kinase (MAPK) pathway signaling [92]. The single most common alteration is BRAF-KIAA fusion, which is observed in approximately 60 percent of tumors [1]. Other alterations include neurofibromin 1 (NF1) mutations (mostly germline in patients with NF1), BRAF V600E point mutations (5 to 10 percent), BRAF fusions with genes other than KIAA, fibroblast growth factor receptor 1 (FGFR1) mutations, and neurotrophic receptor tyrosine kinase (NTRK) gene fusions [93]. Pilocytic astrocytomas do not harbor mutations in isocitrate dehydrogenase (IDH) and usually have retained ATRX expression; loss of ATRX should prompt consideration of high-grade astrocytoma with piloid features [19].

●Treatment – Pilocytic astrocytomas are circumscribed tumors, and they are usually curable if completely resected. Malignant transformation of pilocytic astrocytomas occurs in less than 5 percent of cases [94,95].

Surgical resection is the standard initial approach, and the goal is complete resection and relief of hydrocephalus, if present. Further management is individualized based on molecular tumor characteristics.

•In the absence of a targetable molecular mutation, even if resection is incomplete, radiation therapy and chemotherapy are usually withheld until there is evidence of tumor growth. Radiation therapy at the time of diagnosis may be required for such patients in whom surgery is not feasible [19]. Radiation therapy is also used to treat progressive disease following surgical resection. When radiation therapy is recommended, an involved field fractionated course to 54 Gy is most commonly used. The combination of bevacizumab and irinotecan was well tolerated and showed some evidence of activity in a small single-arm study that included 16 children with recurrent pilocytic astrocytoma [96,97].

•In patients with symptomatic or recurrent/progressive tumors harboring an activating BRAF V600E mutation, BRAF plus MAPK kinase (MEK) inhibitor therapy (eg, dabrafenib plus trametinib; vemurafenib plus cobimetinib) has emerged as a preferred first-line therapy over chemotherapy [20,86,98-100]. Dabrafenib plus trametinib has been approved by the US Food and Drug Administration (FDA) for such patients based on results from a randomized phase 2 trial of dabrafenib plus trametinib versus chemotherapy in children with BRAF V600E-mutant low-grade gliomas [20], as discussed above. (See 'Ganglioglioma and gangliocytoma' above.)

●Prognosis – Pilocytic astrocytomas have a much better prognosis than diffuse astrocytomas and oligodendrogliomas [101-106]. With complete surgical resection, pilocytic astrocytomas are curable. Even incomplete tumor resection is often associated with prolonged survival. As an example, in a series of 361 pediatric patients with low-grade gliomas treated at a single institution over a 22-year period, 63 percent of patients had pilocytic astrocytoma [106]. The 10- and 20-year overall survival rates for the entire series were 87 and 82 percent, respectively. However, a substantial number of long-term survivors did experience adverse outcomes including, for example, intellectual impairment, endocrine abnormalities, hearing loss, and blindness.

Long-term outcomes are less favorable in adult patients [85]. Based on retrospective studies, the recurrence rate after gross total resection in adults approaches 30 percent [107]. In a population-based study of 865 adults (>20 years) with pilocytic astrocytoma in the Surveillance, Epidemiology, and End Results (SEER) database, cancer-specific five-year survival rates were 92, 79, and 64 percent for patients ages 20 to 39, 40 to 59, and >60 years, respectively [108].

High-grade astrocytoma with piloid features — High-grade astrocytoma with piloid features is a circumscribed astrocytoma with a distinct DNA methylation profile that separates it from other tumors that may have similar histologic features, such as pilocytic astrocytoma or glioblastoma [1]. The tumor was first designated in the 2021 WHO classification, and robust data on clinical features, biologic behavior, and prognosis are not yet available. In a series of 83 such tumors, most tumors were cerebellar (74 percent), followed by supratentorial (17 percent) and spinal (7 percent) [109]. The median age at presentation was 41.5 years. Imaging usually shows a solid mass with variable contrast enhancement and surrounding edema.

Histologic features vary considerably and are not distinct enough to allow for diagnosis without molecular testing (specifically, methylation profiling) [1]. Many of these tumors may have been previously called anaplastic pilocytic astrocytomas. Morphology is usually high-grade piloid and/or glioblastoma-like, and the tumors can show infiltration of surrounding brain. The most common molecular alterations are homozygous deletion or mutation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B), MAPK pathway gene alterations (eg, KIAA1549-BRAF fusion), NF1 mutations (at least some of which are germline), and FGFR1 mutations.

The prognosis falls in between that of pilocytic astrocytoma and isocitrate dehydrogenase (IDH)-wildtype glioblastoma. Among 41 patients in a retrospective series of molecularly characterized tumors for which survival data were available, five-year survival was approximately 50 percent [109]. After maximal safe resection, adjuvant radiation therapy should be considered even in patients who have undergone complete resection [19].

Pleomorphic xanthoastrocytoma — Pleomorphic xanthoastrocytomas are rare circumscribed astrocytic tumors. They typically occur in the temporal lobe and cause seizures. On MRI, they often contain cystic components, enhancement, and surrounding edema [19].

Pleomorphic xanthoastrocytoma is characterized histologically by markedly pleomorphic cells, eosinophilic granular bodies, prominent reticulin deposition, and a superficial meningocerebral location. Those with low mitotic activity (<2.5 mitoses per mm²) correspond to WHO grade 2; grade 3 tumors have elevated mitotic activity and necrosis. The most common molecular alterations are CDKN2A/B deletions (>90 percent) and BRAF V600E mutations (60 to 80 percent).

Standard treatment consists of maximal safe resection. Postoperative radiation therapy is usually given for grade 3 tumors [19]. The prognosis is generally good, although recurrence rates are higher compared with some other circumscribed astrocytic tumors, and some tumors undergo malignant progression. For recurrent/refractory BRAF V600E-mutant tumors, dual inhibition of the BRAF and MAPK pathways has shown benefit, and the combination of dabrafenib and trametinib has tissue-agnostic approval from the FDA for patients ≥6 years of age in this setting [110-112]. (See 'Ganglioglioma and gangliocytoma' above.)

Subependymal giant cell astrocytoma — SEGAs are benign, slow-growing glial tumors seen in patients with tuberous sclerosis. SEGAs usually arise in the periventricular area. Although these tumors have been classified as astrocytomas, they are of mixed glioneuronal lineage and are more accurately called subependymal giant cell tumors (SGCTs). (See "Tuberous sclerosis complex: Clinical features", section on 'Brain lesions'.)

These tumors may be responsive to treatment with mechanistic target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus. The management of these tumors is discussed separately. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Brain tumor treatment'.)

Chordoid glioma — Chordoid glioma is a WHO grade 2 tumor that arises in the wall of the third ventricle. The tumor mostly occurs in adults, with a mean age of 46 years and a female-to-male ratio of 2:1. Because of their location in the third ventricle, they frequently present with symptoms of hydrocephalus, endocrine abnormalities, and/or visual field defects.

On MRI, chordoid gliomas are well demarcated from brain parenchyma but may invade the hypothalamus. The lesions are isointense on T1-weighted sequences and typically have a dense, homogenous enhancement pattern (image 7). They may be ovoid or multilobular.

On pathologic examination, there are cords and clusters of epithelioid cells that stain for glial antigens. A missense mutation in the protein kinase C alpha (PRKCA) gene is present in the majority of cases [113,114]. High-grade features are absent.

Gross total resection is curative, and there may be a role for fractionated radiotherapy or stereotactic radiosurgery in incompletely resected lesions [115]. Complications of the tumor and its treatment may include arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) and memory deficits.

Astroblastoma — Astroblastomas are rare glial tumors that possess overlapping astrocytic, ependymal, and other glial elements. Approximately 70 percent of histologically defined astroblastomas contain structural rearrangements in the MN1 proto-oncogene on chromosome 22, and MN1-altered astroblastoma is a newly defined tumor type as of the 2021 WHO classification [1].

●Clinical features – Astroblastomas usually occur in older children and young adults [116], although patients as old as 71 years have been described [117,118]. MN1-altered astroblastoma in particular appears to have a striking female predominance (39 of 41 patients in one series) and affects primarily children <15 years of age [119]. Astroblastomas occur predominantly in the cerebral hemispheres and often present with seizures.

●Imaging – On MRI, these are discrete, lobulated, supratentorial lesions with solid and cystic components. The solid component has been described as having a characteristic "bubbly" appearance on T2-weighted sequences [116,117]. T2 hypointensity is frequently noted, and contrast enhancement and calcification are variable.

●Pathology and genetics – Astroblastomas have features of both astrocytoma and ependymoma; unlike ependymoma, however, the majority stain positive for oligodendrocyte transcription factor 2 (OLIG2) [118]. The characteristic finding is diffuse, perivascular, astroblastic pseudorosettes. Low-grade and high-grade variants exist, and grade and mitotic index appear to correlate with prognosis [119].

MN1 fusions, most commonly MN1-BEN domain containing 2 (BEND2), are the defining molecular lesion in many astroblastomas, and these tumors have a distinct DNA methylation profile [1]. Fusions can be detected by fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), ribonucleic acid (RNA) sequencing, or next-generation DNA sequencing. Other histologically defined astroblastoma tumors harbor BRAF V600E mutations, which are mutually exclusive with MN1 alterations. Adults with astroblastoma may be less likely to harbor MN1 alterations [120].

●Treatment and prognosis – Gross total resection of a low-grade lesion frequently confers a long disease-free interval. For high-grade histologically defined astroblastomas, treatment has traditionally consisted of surgery, radiation therapy, and chemotherapy, although the effectiveness of adjuvant therapy is controversial. Patients diagnosed after 30 years of age appear to have worse overall survival compared with young patients [118].

CHOROID PLEXUS TUMORS — The choroid plexus is the neuroepithelial tissue that produces cerebrospinal fluid (CSF). Tumors arising in the choroid plexus are distributed in proportion to the density of this tissue, with approximately 50 percent occurring in the lateral ventricle, 40 percent in the fourth ventricle, 5 percent in the third ventricle, and 5 percent multifocal. In rare extraventricular cases, they presumably arise from a residual nest of embryonic tissue.

●Epidemiology – Choroid plexus tumors account for less than 1 percent of all intracranial tumors; in children under age one year, they account for 10 to 15 percent of intracranial tumors. Choroid plexus papillomas are benign and account for approximately 60 percent of these tumors [1].

●Clinical features – Headache is the most common symptom of choroid plexus tumors, reflecting increased intracranial pressure. Hydrocephalus can occur due to increased CSF production, obstruction of CSF flow, or subclinical bleeding that blocks CSF absorption by arachnoid granulations.

The median age at diagnosis is three years [121]. Age at presentation correlates with the location of the tumor. Lateral ventricle tumors are more common in children less than 10 years old, while the fourth ventricle tumors are distributed evenly up to age 50 years [122].

Choroid plexus papilloma — Choroid plexus papillomas histologically resemble normal choroid plexus and probably represent local hamartomatous overgrowths. They are classified as World Health Organization (WHO) grade 1 neoplasms. Tumors with increased mitotic activity (≥2 mitoses per 10 high-power fields [HPF]) are classified as atypical choroid plexus papillomas (WHO grade 2).

●Imaging – On CT scan, choroid plexus papillomas are often calcified and enhance with contrast; they may be difficult to differentiate from ependymomas, although the latter do not typically have significant calcification. MRI may reveal flow voids, reflecting tumor vascularity. The noncalcified parts of the papilloma are hypo- to isointense compared with parenchyma on T1-weighted images and hyperintense on T2-weighted images (image 8). Magnetic resonance angiography (MRA) may demonstrate enlarged choroidal arteries [123]. There are no MRI features that distinguish grade 1 from grade 2 papillomas.

●Pathology and genetics – Histologically, choroid plexus papillomas contain a uniform cell population, without significant cytologic atypia. The MIB-1 labeling index is less than 2 percent for grade 1 tumors, indicating a low growth fraction. Most exhibit apical microvilli and scatted cilia, which exhibit a microtubule configuration characteristic of neuroepithelial cells. Atypical choroid plexus papillomas are distinguished from grade 1 tumors primarily by a higher mitotic rate (≥2 mitoses per 10 HPF) [63]. Driver genetic alterations are largely absent; tumor protein p53 (TP53) alterations are more common in choroid plexus carcinomas, and telomerase reverse transcriptase (TERT) promoter mutations have been identified in a minority of papillomas, mostly in adults [124]. In some children, choroid plexus papillomas occur in association with Aicardi syndrome [125,126].

●Treatment and prognosis – Treatment for large or symptomatic choroid plexus papillomas is resection; small, asymptomatic suspected papillomas can be monitored conservatively without any treatment and only intervened upon if they enlarge. After complete resection, these tumors seldom recur. Even subtotally resected tumors usually have a benign course, although malignant transformation to choroid plexus carcinoma has been reported [127]. Adjuvant radiation therapy is not indicated but may be useful for recurrent tumors that are inoperable [128]. Leptomeningeal seeding may occur with histologically benign tumors [129].

The results of treatment are illustrated by a meta-analysis that included 353 patients with choroid plexus papillomas. Patients who underwent a gross total resection had a 10-year survival rate of 85 percent, compared with 56 percent in those managed with subtotal resections [130]. In another series of 23 patients with choroid plexus papilloma, median event-free survival was 7.6 years [121]. Two patients had recurrence requiring re-resection and adjuvant therapy.

Atypical choroid plexus papillomas recur at higher rates; in a series of 92 patients with choroid plexus tumors, the five-year event-free survival rate was 92 percent in patients with grade 1 tumors compared with 83 percent in patients with grade 2 tumors [131].

Choroid plexus carcinoma — Choroid plexus carcinomas are WHO grade 3 malignant epithelial neoplasms believed to arise from choroid plexus epithelium progenitor cells.

●Imaging – On imaging, choroid plexus carcinomas are more heterogeneous than choroid plexus papillomas due to areas of necrosis and parenchymal invasion (image 9). T2-hyperintense signal may be present in the surrounding white matter, suggesting vasogenic edema [132].

The differential diagnosis includes metastatic adenocarcinoma (especially in adults), teratoma (especially in young male patients), and medulloepithelioma (especially in infants). The presence of multifocal areas of tumor with normal-appearing choroid plexus is more likely to be metastatic disease rather than multifocal choroid plexus carcinoma [133].

●Pathology and genetics – Histologically, choroid plexus carcinomas are characterized by dense cellularity, mitoses, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of brain. Approximately 40 percent of choroid plexus carcinomas are a manifestation of Li-Fraumeni syndrome (LFS), which is due to mutations in the TP53 tumor suppressor gene. In a multi-institution study of 64 patients with either choroid plexus papillomas or carcinomas, germline mutations of TP53 were present in all cases of carcinoma in which LFS was diagnosed based upon clinical criteria [134]. By contrast, such germline mutations were absent in all those without LFS. (See "Li-Fraumeni syndrome".)

●Treatment and prognosis – The invasiveness of choroid plexus carcinomas typically precludes gross total surgical resection. Prognosis is poor, with a median survival of approximately 2.5 to 3 years [121,135]. The presence of a TP53 mutation by immunohistochemistry has been associated with worse outcomes [134,136-138].

There are no randomized trials assessing the role of chemotherapy or radiation therapy following surgical resection. Adjuvant radiation appears to be beneficial based on retrospective series, but many patients are too young to receive radiation safely [130,135,139]. A meta-analysis that included 347 patients with choroid plexus carcinoma reported in the literature observed an improved survival rate among those given multiagent chemotherapy after an incomplete resection (median survival 2.75 versus 0.58 years) [135].

Similarly, a review of the literature suggested that craniospinal irradiation (CSI) was associated with improved survival compared with more limited fields [140]. However, given the association of choroid plexus carcinomas and LFS, it is worthwhile to consider the potential risk of radiation-induced second malignancies in weighing the benefit of craniospinal radiation. Limited data suggest that multiagent intensive chemotherapy with autologous stem cell rescue with deferred radiation may be a reasonable strategy in young children [137].

EMBRYONAL TUMORS — Central nervous system (CNS) embryonal tumors are malignant, mostly World Health Organization (WHO) grade 4 tumors that affect primarily infants and young children. The most common tumors in this group are medulloblastomas (table 4); other rarer tumor types include embryonal tumor with multilayered rosettes (ETMR), atypical teratoid/rhabdoid tumor (ATRT), and CNS embryonal tumor not elsewhere classified (NEC)/not otherwise specified (NOS) (table 4).

Medulloblastoma — Medulloblastoma is the most common malignant brain tumor in children. These tumors are discussed separately. (See "Histopathology, genetics, and molecular groups of medulloblastoma" and "Clinical presentation, diagnosis, and risk stratification of medulloblastoma" and "Treatment and prognosis of medulloblastoma".)

Atypical teratoid/rhabdoid tumor — ATRTs are poorly differentiated rhabdoid tumors characterized molecularly by biallelic inactivation of SMARCB1 (also known as INI1) or rarely SMARCA4.

●Clinical features – CNS ATRTs are highly malignant, WHO grade 4 tumors primarily occurring in young children less than three years old [141]. Approximately two-thirds of ATRTs occur in the cerebellum, typically in the cerebellopontine angle, with invasion of surrounding structures. The remaining cases are supratentorial or multifocal.

Infants often present with lethargy and vomiting; older children may have symptoms due to involvement of cranial nerves IV, VI, or VII, such as head tilt, diplopia, or facial weakness. Hemiplegia and/or headaches may also be present [142-146].

●Imaging – ATRTs are usually hypointense on T1-weighted MRI and iso- or hypointense on T2-weighted images. They have heterogeneous enhancement and may have internal cystic areas or hemorrhage (image 10). Leptomeningeal disease may be suggested by linear and nodular enhancement along the meninges around the spinal cord and cauda equina. Imaging cannot reliably differentiate ATRTs from medulloblastoma or other embryonal tumors. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma", section on 'Differential diagnosis'.)

●Pathology and genetics – Histologically, ATRTs are characterized by rhabdoid cells and are similar to that of other small round blue cell tumors; up to 70 percent also contain fields typical of primitive neuroectodermal tumor (PNET) cells. Necrosis and a high rate of mitotic activity are common. Germ cell markers are negative.

Diagnosis of ATRT requires either loss of INI1 nuclear staining, which is indicative of biallelic inactivation of SMARCB1 on chromosome 22, or loss of BRG1 staining, which is indicative of SMARCA4 inactivation. In addition to these somatic mutations detected in tumor tissue, approximately one-third of patients harbor germline mutations in SMARCB1 [147-149] or, less commonly, SMARCA4 [150]. (See "Schwannomatoses related to genetic variants other than NF2", section on 'Pathogenesis'.)

With advanced molecular analysis, three main molecular subgroups have been identified, denoted as ATRT-TYR, ATRT-SHH, and ATRT-MYC [151]. ATRT-TYR tumors are characterized by tyrosinase (TYR) overexpression, upregulation of the melanosomal pathway, and young age at onset. ATRT-SHH tumors have overexpression of both sonic hedgehog signaling molecule (SHH) and the Notch pathway; further subtyping distinguishes between supratentorial and infratentorial location. The ATRT-MYC subgroup is characterized by elevated expression of the MYC oncogene as well as homeobox C (HOXC) cluster genes.

●Treatment and prognosis – Surgery, multiagent chemotherapy, and radiotherapy are indicated for the majority of patients [152], but decisions about use, timing, and fields of radiotherapy are individualized because of the young age of most patients at presentation [152-157]. The order and components of therapy are tailored to age, tumor location, and extent of disease [152]. Given the rarity of the disease and the complexity of treating infants and young children, participation in clinical trials is encouraged, and there is no consensus on the optimal chemotherapy regimen.

Targeted therapies are also under investigation in a myriad of early-phase trials, and a large number of compounds have potential therapeutic activity [158]. In particular, the aurora kinase A inhibitor, alisertib, showed significant antitumor activity in a case series of four children with recurrent or progressive ATRT [159].

The prognosis of ATRT is worse than that associated with medulloblastoma, with a median survival of 12 to 24 months and five-year overall survival of 30 to 40 percent [152-154,160,161]. Patients with germline mutations in SMARCB1 tend to be younger and may have worse survival compared with those with sporadic tumors, although evidence is conflicting [148,152,162]. Factors variably associated with improved prognosis include localized disease at the time of presentation and resection [146,163,164].

Embryonal tumor with multilayered rosettes — ETMRs are highly malignant pediatric tumors with varied embryonal histology but shared genetic alterations in the chromosome 19 microRNA cluster (C19MC) in approximately 90 percent of cases [63,165-167].

●Clinical features – ETMRs affect young children, with a median age of onset of approximately two to three years and a slight female predominance [133,168-178]. ETMRs most commonly arise in the supratentorial compartment, often in the frontal or parietotemporal lobes. Approximately 20 percent of tumors arise in the cerebellum, and approximately 20 percent involve the midline, brainstem, or rarely spinal cord [178]. Approximately one-quarter of patients have disseminated or metastatic disease at the time of presentation. Patients may present with signs and symptoms of increased intracranial pressure or focal neurologic signs.

●Imaging – On MRI, tumors are typically large, well-circumscribed masses that enhance after contrast administration. Internal cysts and calcification may be present. Their nonspecific appearance does not allow them to be distinguished from other malignant brain tumors radiographically.

●Pathology and genetics – Histopathologically, the characteristic C19MC gene alterations (a micro-RNA cluster) can be detected by fluorescence in situ hybridization (FISH). Immunohistochemical staining for LIN28A supports the diagnosis of ETMR but is not specific. Tumors previously labeled embryonal tumor with abundant neuropil and true rosettes (ETANTR) [168], ependymoblastoma [133,169-171], and medulloepithelioma [133,170,172-177] are all included in this group, provided they have evidence of C19MC amplification.

A hereditary predisposition due to germline mutations in DICER1 has been identified in a small subset of patients with ETMRs (<5 percent), exclusively in tumors lacking C19MC amplification but otherwise molecularly similar to other ETMRs [166].

●Treatment and prognosis – ETMRs are aggressive tumors associated with a poor prognosis and median survival of less than one year [178]. A combined-modality approach including maximal surgical resection plus high-dose chemotherapy and age-adapted radiation therapy may result in prolonged survival in some cases [171,179,180]. Molecular and preclinical data suggest that targeting of aberrant micro-RNA processing with topoisomerase 1 and poly(ADP-ribose) polymerase (PARP) inhibition may be an effective strategy [166].

CNS neuroblastoma, FOXR2-activated — CNS neuroblastoma with structural rearrangements in the forkhead box R2 (FOXR2) gene is a new entity as of the 2021 revision of the WHO classification [1]. It is estimated that this tumor represents approximately 10 percent of tumors previously classified as CNS PNET [179,181]. Most tumors involve the cerebral hemispheres and present in childhood. Epidemiologic and clinical data are otherwise thus far limited.

FOXR2-activated CNS neuroblastomas are embryonal tumors with varying degrees of neuroblastoma and/or neuronal differentiation [1]. They are WHO grade 4 tumors with sheets of poorly differentiated cells with high nuclear-to-cytoplasmic ratio, abundant mitotic activity, necrosis, and variable brain infiltration. Most cells strongly express OLIG2. FOXR2 alterations on chromosome Xp11 are often complex rearrangements detectable by next-generation sequencing. They have a distinct DNA methylation profile [181].

Like other CNS embryonal tumors, they have the potential for leptomeningeal dissemination and metastatic spread, and clinical staging includes brain and spine MRI as well as cerebrospinal fluid (CSF) sampling. Absent prospective data, treatment is based on historical experience with CNS PNETs and consists of a combined-modality approach including maximal surgical resection plus chemotherapy and/or radiation, depending on the age of the child [182].

CNS tumor with BCOR internal tandem duplication — CNS tumor with BCL6 corepressor (BCOR) internal tandem duplication is a new entity as of the 2021 revision of the WHO classification [1]. A WHO grade has not yet been assigned based on lack of sufficient clinicopathologic data.

The median age at presentation of reported patients is 3.5 years (range 0 to 22 years), and tumors tend to be very large and may involve multiple lobes and both hemispheres. Cerebellar, cerebral, basal ganglia, and spinal cord localization has been reported.

Pathologically, these are malignant CNS tumors characterized by uniform oval or spindle-shaped cells, a dense capillary network, and focal pseudorosette formation. The molecular hallmark is somatic heterozygous internal tandem duplication in the BCOR gene, which is thought to be an activating, gain-of-function oncogenic event. Of note, the same molecular alteration is also seen in a subset of extracranial tumors, including clear cell sarcomas of the kidney.

Like other CNS embryonal tumors, they have the potential for leptomeningeal dissemination and metastatic spread, and clinical staging includes brain and spine MRI as well as CSF sampling. Absent prospective data, treatment is based on historical experience with CNS PNETs and consists of a combined-modality approach including maximal surgical resection plus chemotherapy and/or radiation, depending on the age of the child. In a retrospective series of 24 molecular-confirmed tumors with survival data available, median survival was approximately six years, but follow-up time was variable and limited in most cases [183].

CNS embryonal tumor NEC/NOS — CNS embryonal tumor NEC/NOS is the designation for CNS tumors with embryonal histology and immunophenotype that lack a molecular signature of an alternative embryonal or glial tumor; some tumors previously called CNS PNET fall into this category [63].

The term "PNET" is retained in this section when the supporting evidence derives from studies predating changes in nomenclature, since a literature on CNS embryonal tumor NEC/NOS, which excludes tumors with C19MC amplification, FOXR2 activation, or other molecule identifiers, is not well developed and will continue to evolve as new genetic alterations are discovered. In a prospective Children's Oncology Group (COG) trial of CNS PNET enrolled from 2007 to 2013 in which 31 tumors in a nonpineal location were reanalyzed in 2017, 71 percent of tumors received an alternative diagnosis, most commonly high-grade glioma (n = 18; eg, H3 G34-mutant diffuse hemispheric glioma), FOXR2-activated neuroblastoma (n = 3), ATRT (n = 2), and ependymoma (n = 2) [179].

●Clinical features – CNS embryonal tumors NEC/NOS are quite rare, even among embryonal tumors. CNS PNETs were estimated to account for less than 5 percent of embryonal tumors. Most occur in infants and children, but adult cases are seen.

Older children typically have signs of increased intracranial pressure (eg, headache, nausea, vomiting), while infants present with lethargy, irritability, anorexia, and/or an enlarging head circumference. Other presenting symptoms can include seizures or focal deficits referable to the tumor location. Patients can also present with leptomeningeal dissemination, manifested by signs of cranial nerve palsies, encephalopathy, or spinal cord symptoms. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Clinical features'.)

●Imaging – CT imaging usually reveals a well-defined hemispheric mass, which commonly contains calcification and necrotic areas. Intratumoral hemorrhage may be present. MRI demonstrates heterogeneous enhancement with hypointense regions correlating to hemosiderin or calcification; T1-hyperintense regions correspond to hemorrhage and T2 bright regions reflect cystic components. There is a relative absence of peritumoral edema [170].

●Pathology and genetics – CNS embryonal tumors are malignant, highly cellular tumors composed of sheets of densely packed immature cells with a high nuclear-to-cytoplasmic ratio [1]. Mitotic activity is typically high. They correspond to a WHO grade of at least 3, but due to changes in nomenclature and heterogeneity within the subtype, distinction between grades 3 and 4 based on pathologic features grade is not yet possible. Molecular drivers have not yet been identified.

●Treatment and prognosis – Management of CNS PNET has traditionally included aggressive surgical resection followed immediately by radiation therapy to the neuraxis [184,185]. The results of this treatment approach were illustrated by a combined report of two prospective trials that included 63 children with PNETs [186]. Using a total dose to the neuraxis of 35.2 Gy and a boost of 20 Gy to the primary tumor site, the three-year progression-free survival was 49 percent in children who completed the planned course of therapy, compared with 7 percent in those with major deviations from their planned course of radiation therapy.

Adjuvant chemotherapy may further improve survival, but the optimal chemotherapy approach is not known. Chemotherapy regimens for PNETs have utilized chemotherapy agents similar to those for medulloblastomas and have been evaluated in a large trial with mixed patient populations [187]. (See "Treatment and prognosis of medulloblastoma".)

Management of infants and children ≤3 years of age, who are at high risk for severe neurologic impairment if their initial treatment includes craniospinal radiation therapy, is particularly challenging. Small studies utilizing prolonged multiagent induction chemotherapy have been disappointing, with five-year overall survival rates ranging from 15 to 30 percent [188-191]. High-dose chemotherapy regimens appear more promising, with one study reporting five-year event-free and overall survival rates of 39 and 49 percent, respectively, in 43 patients with CNS PNET or pineoblastoma [192].

Despite aggressive combined-modality treatment, recurrence is fairly common, often occurring in the early posttreatment phase. The reported three-year survival rate has ranged from 57 to 73 percent with regimens that include radiation [193,194]. These studies may underestimate overall survival, however; in the COG study in which methylation profiling was used to reclassify patients with PNET, five-year overall survival was 78 percent when PNETs/pineoblastomas were considered separately from tumors molecularly reclassified as high-grade glioma, ATRT, or ependymoma [179]. Children younger than three years have a worse prognosis.

The treatment of CNS embryonal tumor NEC/NOS in adults consists of a combination of surgery, craniospinal irradiation (CSI), and adjuvant chemotherapy, based upon the approach in older children and children with medulloblastoma.

MESENCHYMAL TUMORS — Mesenchymal, nonmeningothelial tumors originating in the central nervous system (CNS) represent a spectrum of benign and malignant tumors that arise more commonly in the meninges than the brain parenchyma (table 5). They are rare compared with mesenchymal tumors originating in extracranial bone and soft tissues. Collectively, these tumors make up <1 percent of all intracranial neoplasms and mostly occur in adults [63]; some of the more commonly seen tumors are reviewed here.

Solitary fibrous tumor — Solitary fibrous tumor (SFT) of the CNS is a fibroblastic dural-based tumor characterized by recurrent inversion of the long arm of chromosome 12 resulting in fusion of two genes, NGFI-A binding protein 2 (NAB2) and signal transducer and activator of transcription 6 (STAT6) [195,196]. SFT includes tumors that were previously called hemangiopericytoma prior to discovery of the unifying molecular alteration.

SFTs involving the head and neck (including the meninges) make up approximately 20 percent of SFTs, which more commonly involve the serosal membranes and soft tissues of the thoracic cavity and abdomen. (See "Solitary fibrous tumor", section on 'Anatomic distribution'.)

●Clinical features – CNS SFTs are rare, dural-based tumors accounting for less than 1 percent of all primary CNS tumors. The median age at diagnosis is 49 to 53 years [197,198]. The distribution within the CNS is similar to that of meningiomas, with 70 percent supratentorial, 15 percent in the posterior fossa, and 15 percent spinal. Intraventricular lesions have also been reported [199].

Presenting symptoms vary based on location and size and may include headache, focal deficits, or seizures. Extracranial metastatic disease can occur, most commonly in bone, lung, and liver [200].

●Imaging – CT imaging often reveals a hyperdense extra-axial mass lesion with focal areas of hypodensity; there is heterogeneous enhancement. Bone erosion can be detected, but hyperostosis usually does not occur. MRI demonstrates T1 and T2 isointensity with flow voids; there is heterogeneous gadolinium enhancement (image 11). In approximately one-half of cases there is a dural tail sign. There may also be a "corkscrew" vascular configuration. Peritumoral edema is often present. However, imaging features are nonspecific and do not reliably distinguish between SFT and meningioma.

●Pathology and genetics – SFTs are composed of spindled to ovoid monomorphic cells amidst hyalinized, thin-walled blood vessels. There is a wide histologic spectrum ranging from a hypocellular phenotype to highly cellular, patternless architecture [1]. Detection of STAT6 nuclear expression by immunohistochemistry or confirmation of NAB2-STAT6 fusion is recommended to confirm the diagnosis. Molecular pathogenesis of the NAB2-STAT6 fusion gene is discussed in more detail separately. (See "Solitary fibrous tumor", section on 'Molecular pathogenesis and molecular diagnostics'.)

CNS World Health Organization (WHO) grades 1 to 3 are assigned based on mitotic activity and necrosis, which correlate with prognosis [197,198]:

•WHO grade 1 – <2.5 mitoses/mm² (<5 mitoses/10 high-power fields [HPF])

•WHO grade 2 – ≥2.5 mitoses/mm² (≥5 mitoses/10 HPF) without necrosis

•WHO grade 3 – ≥2.5 mitoses/mm² (≥5 mitoses/10 HPF) with necrosis

Of note, this grading scheme for CNS SFT is new as of the 2021 revision of the WHO classification of CNS tumors, is based on retrospective data, and has not been validated prospectively as a means of making treatment decisions [1]. It also differs from risk stratification models used for extracranial SFT, which are discussed separately. (See "Solitary fibrous tumor", section on 'Risk stratification models'.)

●Treatment and prognosis – Initial management consists of maximal safe resection. Gross total resection is associated with improved recurrence-free survival compared with subtotal resection in most studies, but the risk of local recurrence as well as extracranial metastatic spread for SFTs is higher than that of meningioma, particularly for higher-grade tumors. Systemic staging is appropriate in most cases given the propensity for extracranial spread.

For grade 1 SFTs, the prognosis is generally good with surgical resection alone, with a five-year recurrence-free survival greater than 80 percent [197,198,201]. Recurrent tumors may be treated by reoperation, radiation therapy, or stereotactic radiosurgery and are associated with reduced survival [202-204]. Distant metastases have been documented even for grade 1 SFTs.

Higher-grade SFTs, including those previously diagnosed as hemangiopericytoma, are more biologically aggressive tumors, with 5- and 10-year recurrence-free survival estimates ranging from 50 to 80 percent and 30 to 60 percent, respectively [197,198,201]. Postoperative radiation is therefore suggested in most patients. In observational data consisting of case series, local control, disease-free survival, and overall survival rates appear to be greater when patients receive radiation therapy [205-208].

In selected cases of recurrent disease following radiation therapy, chemotherapy may be helpful [209]. Novel treatments including antiangiogenic therapies are being evaluated for extracranial SFT [210,211] and could also have a role for intracranial disease. One report described a significant radiographic and clinical response to pazopanib, a multitargeted receptor tyrosinase kinase inhibitor that inhibits angiogenesis, in two patients with recurrent meningeal SFT [212].

Fibrous histiocytoma — Fibrous histiocytomas are composed of atypical fibroblasts and histiocytes and may be either benign or malignant [213,214]. When they occur in the CNS, they may be attached to the dura or exist intraparenchymally.

Fibrous histiocytomas may present with headache, seizures, hemiparesis, or cranial neuropathy. On CT, primary intracranial malignant fibrous histiocytomas are large masses that sometimes include a cystic component representing previous hemorrhage or liquefied necrosis. Contrast enhancement is variable. MRI demonstrates a heterogeneous extra-axial mass with thick irregular enhancement. Areas of liquefied necrosis may cause an intense signal on T2, while low signal on T2 represents tumor matrix [215].

Benign fibrous histiocytomas (also called fibrous xanthoma or fibroxanthoma) can be managed with surgery alone. Treatment of malignant fibrous histiocytomas (also called undifferentiated pleomorphic sarcomas) has been unsatisfactory, despite the addition of radiation therapy and chemotherapy to surgery. This was illustrated by a review of 18 cases of malignant fibrous histiocytoma from the literature, in which the one- and two-year survival rates were 46 and 23 percent, respectively [216].

Sarcomas — A variety of types of sarcomas can involve the CNS; some arise directly in the meninges from mesenchymal cells and others present with direct extension from the skull base, cranial vault, or sinuses. Secondary involvement of the CNS by extracranial soft tissue sarcomas is also possible.

Symptoms depend upon the location and size of the tumor and can include headache, seizures, vomiting, somnolence, or spinal cord compression. On MRI, they are T1 hypointense and T2 hyperintense. Other imaging characteristics are dependent on the specific differentiation of the tumor.

Sarcomas may be differentiated along several lines, including fibrosarcoma (producing fibrous tissue), chondromas or chondrosarcomas (producing cartilage), leiomyosarcomas (producing smooth muscle), rhabdomyosarcoma (producing striated muscle), osteosarcoma (producing bone), liposarcoma (producing adipose tissue), or angiosarcomas (producing blood vessels). (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

Treatment includes gross total resection whenever possible, plus radiation therapy and chemotherapy. Even with aggressive treatment, five-year survival is low [217-219]. Because of the rarity of these tumors in the CNS, evaluation and management should ideally be carried out in a center with expertise in the management of sarcomas, including neurosurgical oncology, radiation oncology, and medical oncology.

●Fibrosarcoma – Fibrosarcomas are spindle cell tumors composed of malignant fibroblasts on a background of collagen. Approximately 40 cases of primary fibrosarcoma arising within the CNS have been reported. Primary fibrosarcomas are dural based or arise from infolding of the leptomeninges into the parenchyma.

Fibrosarcomas can present with symptoms of increased intracranial pressure, hemiparesis, seizures, and cranial neuropathies if located at the skull base. On MRI, they avidly enhance and may have changes that reflect foci of hemorrhage. CT scan may demonstrate bone destruction or invasion [214].

Primary fibrosarcomas are usually of high histologic grade and have a high rate of local recurrence. Treatment includes surgery and radiation therapy, with or without adjuvant chemotherapy. Despite aggressive therapy, the prognosis is poor [220]. This was illustrated by a series of nine patients with primary CNS fibrosarcomas who were treated with surgery and radiation therapy. Eight patients died with a median survival of 7.5 months, with local recurrence in eight patients and distant recurrence in six patients [221].

●Chondrosarcoma – Chondrosarcomas are malignant cartilaginous tumors that account for approximately 6 percent of skull base tumors. There are also case reports of chondrosarcomas arising in the brain parenchyma (image 12) [222]. (See "Chordoma and chondrosarcoma of the skull base".)

●Liposarcoma – Primary intracranial liposarcomas are extremely rare, malignant tumors. Liposarcomas range from well differentiated to pleomorphic, with the latter having the worst prognosis. Systemic liposarcomas have been documented to metastasize to the CNS, and this possibility should also be considered in a patient presenting with a CNS liposarcoma [223-225].

Primary CNS liposarcomas are treated with surgery, radiation therapy, and chemotherapy, based upon the approach used to treat extracranial lesions. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

Ewing sarcoma/primitive neuroectodermal tumor — Primary CNS Ewing sarcoma/peripheral primitive neuroectodermal tumors (PNETs) are rare lesions that involve the CNS by extension from dura, bone, or paraspinal soft tissue. The peak incidence is in adolescence.

On MRI, these tumors are well-circumscribed, lobular, homogeneously enhancing masses with broad dural attachments that may be indistinguishable from meningioma [226]. Histology is the same as non-CNS Ewing sarcoma and may in some cases be confused with CNS embryonal tumors. Therefore, molecular testing is recommended to confirm the presence of a characteristic rearrangement involving the EWSR1 gene on chromosome 22q12. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Molecular genetics'.)

Some Ewing-like sarcomas in the brain and elsewhere in the body harbor rearrangements in the capicua transcriptional repressor (CIC) gene, which are now recognized as a separate diagnostic entity (CIC-rearranged sarcomas) with a worse prognosis compared with Ewing sarcoma [1,227]. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Differential diagnosis'.)

Combined-modality treatment with surgery, radiation, and chemotherapy is rarely curative [228]. Local recurrence, cerebrospinal fluid (CSF) involvement, and systemic metastases are commonly observed.

Lipoma — Lipomas arise intracranially and along the spinal cord and may be either intra- or extra-axial. Intracranial lipomas make up 0.4 percent of intracranial tumors [63]. Lipomas are believed to be malformations rather than true tumors, resulting from abnormal persistence and differentiation of the meninx primitiva, a mesenchymal derivative of the neural crest [229].

Approximately half of lipomas in the CNS arise in the interhemispheric fissure and pericallosal region [230]. They can also arise in the quadrigeminal cistern, cerebellopontine angle, Sylvian fissure, pontomesencephalic junction, and choroid plexus [231]. Midline lipomas may be associated with varying degrees of brain malformations. Associated anomalies include agenesis of surrounding tissues, frontal bone defects or facial dysplasia, absent/tortuous blood vessels or aneurysms, unusual branching patterns of nerves, or cranial nerve absence or duplication [229]. Lumbosacral lipomas can occur in association with tethered cord syndrome.

Intracranial lipomas may present with symptoms or may be diagnosed incidentally. In one series, 14 patients presented with headache (seven), seizures (three), or symptoms due to a local mass (one). In the three remaining cases, the lipoma was diagnosed incidentally during evaluation following trauma [232].

On CT imaging, lipomas have the hypoattenuation of fat. MRI reveals homogeneous T1 hyperintensity, T2 hypo- or isointensity, and suppression of T1 hyperintensity on fat-saturated sequences (image 13). Lipomas typically do not enhance with gadolinium, and edema is not present around the lesions. Calcification is uncommon.

Lipomas are often asymptomatic. Surgical resection is not routinely indicated but should be considered in epileptic patients who do not respond to medical management [232]. Given the high vascularity of some lesions, there is a risk of adhesion to surrounding tissues.

Angiolipoma — Angiolipomas are benign mesenchymal tumors, containing mature adipocytes as well as abnormal vasculature. Angiolipomas may be either encapsulated (noninfiltrating) or nonencapsulated (infiltrating). Angiolipomas are more common in females and are most commonly diagnosed during the fifth decade.

Most angiolipomas occur in the spinal canal, usually in the thoracic level; almost all are epidural [233]. Angiolipomas typically present with back pain and symptoms of progressive spinal cord compression. Intracranial angiolipomas may bleed, causing a subarachnoid hemorrhage [234]. The imaging characteristics of angiolipomas are similar to those of lipoma. In addition, angiographic features may demonstrate the vascularity of the lesions [235].

Hibernoma — Hibernomas originate from brown adipose tissue, which resembles the special fat deposits of hibernating animals. Most of these rare tumors have been intradural extramedullary lesions, although at least one was intracranial [236,237].

The radiographic appearance of hibernomas is similar to that of lipomas or angiosarcomas, depending on the vascularity of the lesion. Surgical resection is believed to be adequate treatment; the tumors typically may be more easily separable from their surroundings than lipomas [236,237].

PRIMARY MELANOCYTIC LESIONS — The neural crest is the origin of the melanocytes that are found in the epidermis, as well as those that are normally present within the pia at the base of the brain (ventral medulla) and the upper cervical spinal cord. Proliferation of these cells can result in either diffuse or localized, benign or malignant conditions [133,238].

Somatic mutations of the G protein subunit alpha q (GNAQ) or GNA11 genes, most often involving codon 209 in both cases, are frequently identified in melanocytomas and less commonly in primary meningeal melanomas [63,239]. These render GNAQ or GNA11 constitutively active and suggest that their shared downstream pathways (eg, mitogen-activated protein kinase [MAPK] signaling) offer promising therapeutic targets in these tumors. The same mutation has been identified in the majority of patients with uveal melanoma. (See "The molecular biology of melanoma", section on 'Uveal melanomas'.)

BRAF mutations are uncommon in primary meningeal melanomas, and their presence may raise suspicion for metastasis [63].

Meningeal melanocytoma — Meningeal melanocytomas are well-differentiated low-grade tumors arising from leptomeningeal melanocytes, typically located in the cervical or thoracic spinal cord. They may be dural based or associated with nerve roots or spinal foramina. Posterior fossa and supratentorial lesions arising from the leptomeninges are less common [240]. They are localized, solid, and attached to the meninges. Melanocytomas do not involve the cortex.

Although meningeal melanocytomas are grossly and histologically similar to meningiomas, they are ultrastructurally similar to melanocytic tumors. These tumors should be considered in the differential diagnosis of lesions in the posterior fossa, spinal canal, or Meckel's cave. They tend to occur in the fourth and fifth decades.

Symptoms depend upon the location of the lesion [241,242]. Posterior fossa and spinal lesions typically present with cerebellar symptoms or myeloradiculopathy. Supratentorial lesions can present with seizures.

Imaging alone cannot definitively distinguish a meningeal melanocytoma from a meningioma. On CT, these tumors are often isodense with gray matter. On MRI, the tumors are iso- to hyperintense on both T1- and T2-weighted images, and they homogeneously enhance with gadolinium. Tumors containing abundant melanin appear hyperintense on T1-weighted images.

Although meningeal melanocytomas were originally considered benign, there is a significant decrease in survival in patients who undergo a subtotal resection, possibly due to a transformation to malignant melanoma [243]. In a small case series, cerebellopontine angle meningeal melanocytomas had a particularly high rate of recurrence [244]. The five-year survival may be as low as 42 percent in those undergoing subtotal resection without adjuvant radiation therapy [243].

Meningeal melanocytosis and melanomatosis — Meningeal melanocytosis is a diffuse proliferation of cytologically bland melanocytic cells in the subarachnoid space, whereas melanomatosis is a malignant primary central nervous system (CNS) melanoma spread throughout the subarachnoid space. Patients typically present with either hydrocephalus, seizures, or focal neurologic symptoms related to leptomeningeal disease. The age at presentation ranges from the newborn period to the second decade of life [245].

Both conditions are strongly linked to neurocutaneous melanosis, a rare disorder typically associated with giant congenital nevi. Approximately 25 percent of patients with meningeal melanocytosis have significant cutaneous lesions, and approximately 10 to 15 percent of children with giant congenital nevi develop symptomatic melanocytosis [1]. Both disorders carry a poor prognosis, even when histologic appearance is not malignant.

Meningeal melanoma — Primary malignant melanomas arising in the CNS typically occur in the fourth decade, and there is a secondary peak in incidence in the first decade. These melanomas are dural based, diffuse, and poorly circumscribed, and typically invade into the brain or spinal cord parenchyma.

Although it may be difficult to distinguish a primary melanoma from a metastatic lesion, primary CNS melanoma is typically associated with the meninges (image 14), while metastatic melanoma more commonly involves the parenchyma. Given the rarity of meningeal melanoma compared with metastatic cutaneous melanoma, a systemic evaluation with positron emission tomography (PET)/CT is appropriate whenever a meningeal melanoma is diagnosed.

Symptoms of primary malignant melanoma are often due to increased intracranial pressure. Other symptoms may include seizures, focal sensory or motor abnormalities, or cranial nerve palsies. On MRI, CNS melanomas are hyperintense on T1 and hypointense on T2; enhancement with gadolinium is present. Occasionally, imaging reveals hemorrhage. The presence of subarachnoid disease may facilitate the diagnosis by cerebrospinal fluid (CSF) cytology.

Histopathologically, areas of necrosis and hemorrhage may be present. Approximately one-third of tumors do not contain melanin; however, most contain melanosomes, and electron microscopy is helpful in establishing the diagnosis. A high mitotic rate and proliferative index (based upon MIB-1 labeling) are used to distinguish these lesions from meningeal melanocytomas.

Mutational analysis and methylation profiling is useful to help distinguish primary meningeal melanoma from metastatic cutaneous melanoma. Mutations in GNAQ or GNA11 in the absence of a uveal melanoma favor primary meningeal melanoma, whereas BRAF, NRAS, or telomerase reverse transcriptase (TERT) promoter mutations favor cutaneous melanoma that has metastasized [1].

Primary CNS melanomas are highly aggressive tumors. Management is surgical whenever possible, followed by adjuvant radiation; tumors are relatively radioresistant. Overall, the prognosis is poor, with most patients not surviving more than a year [133,241,246,247]. Immunotherapy should be considered on a case-by-case basis given successes in advanced cutaneous melanoma, although the safety and efficacy of these therapies in meningeal melanoma has not been established. (See "Overview of the management of advanced cutaneous melanoma" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

CYSTIC LESIONS — A variety of nonneoplastic lesions can simulate a brain tumor and can give rise to neurologic symptoms. These include epidermoid, dermoid, arachnoid, and colloid cysts.

Epidermoid cyst — Epidermoid cysts, also known as primary cholesteatomas, arise from epithelial cells that are retained during closure of the neural tube. These cysts grow by accumulating cholesterol and keratin from desquamation of the lining epithelium and can encase nearby nerves and arteries.

Epidermoid cysts usually occur within the basilar cisterns but only rarely occur within the cerebral parenchyma, ventricles, or brainstem [248]. A retrospective series of 10 patients seen over a 33-year period at a single institution found that six cases originated in the cerebellopontine angle and four in the petrous apex [249].

Involvement of multiple cranial nerves and the internal carotid artery is common. Epidermoid cysts can present with loss of hearing, tinnitus, headache, hemifacial spasm, or trigeminal neuralgia [250]. On rare occasions, aseptic meningitis occurs from cyst leakage.

Imaging studies (CT and MRI) demonstrate extra-axial lesions whose characteristics are similar to cerebrospinal fluid (CSF). Lesions can be confused with meningioma if a CT demonstrates some evidence of calcification or if hemorrhage into the cyst gives a homogeneous high density on noncontrast CT [251]. However, there is minimal to no enhancement. Epidermoid cysts differ from arachnoid cysts on diffusion-weighted imaging, with the diffusion coefficient images of epidermoid cysts similar to parenchyma, while those of arachnoid cysts approximate free water (image 15) [250].

Epidermoid cysts are managed with surgery. The cysts tend to grow along cranial nerves and tissue planes, which can make gross total resection of posterior fossa epidermoid cysts impossible. Resection can be associated with postoperative aseptic meningitis from cyst leakage; this generally responds to treatment with steroids [252,253]. Successful use of external beam fractionated radiation has been described for multiply recurrent and rapidly progressive cysts [254].

Subtotal resection is the primary risk factor for cyst recurrence, which can occur many years after the initial surgery [255,256]. In a meta-analysis of observational studies in 691 patients, the pooled rates of recurrence after gross total and subtotal resection were 3 and 21 percent, respectively [255].

Malignant transformation of epidermoid and dermoid cysts into squamous cell carcinoma can occur, either within an existing benign cyst or from a remnant of a previously resected lesion [257]. The development of a squamous cell carcinoma may be manifested by a rapid onset of symptoms, recurrence after a previous resection, or leptomeningeal carcinomatosis. In a review of 52 patients from the literature, the median survival was nine months [257].

Dermoid cyst — Like epidermoid cysts, dermoid cysts arise from epithelial cells that are retained during closure of the neural tube. In addition to squamous epithelium, dermoid cysts contain elements of retained hair, sweat, and sebaceous glands.

Intracranial dermoid cysts occur most frequently in the posterior fossa, especially the vermis, fourth ventricle, and suprasellar cistern. Cerebellar dermoid cysts are sometimes associated with dermal sinuses of the occiput, which can predispose to bacterial meningitis.

Dermoid cysts typically present with symptoms due to local mass effect. Spontaneous rupture of the cyst contents into the CSF is rare but can be fatal [258,259]. Headache (32 percent) and seizures (30 percent) were the most common symptoms associated with cyst rupture in a series of 44 cases identified from the literature [259].

Dermoid cysts are similar to lipomas on imaging. CT reveals hypodense lesions and MRI demonstrates T1 hyperintensity and variable signal on T2; the sebaceous material is T1 hyperintense, whereas other contents are hypointense (image 16). There is minimal contrast enhancement. Very occasionally, these cysts can appear like a thrombosed aneurysm with clot in different stages of organization [260].

Symptomatic dermoid cysts are treated with resection; incompletely resected cysts may gradually recur. Malignant transformation of dermoid cysts may occur and is associated with a poor prognosis [257]. (See 'Epidermoid cyst' above.)

Colloid cyst — Colloid cysts are a rare developmental malformation and not a true neoplasm. Colloid cysts are composed of an outer fibrous layer and an inner epithelium of ciliated or mucin-producing cells [252,261].

The vast majority of colloid cysts occur in the anterior third ventricle, between the forniceal columns in the roof of the third ventricle. Thus, even relatively small lesions may block the foramen of Monro, producing hydrocephalus.

They can occur at any age but usually become symptomatic in the third to the sixth decades. Although typically asymptomatic, colloid cysts can cause increased intracranial pressure and present with headache and papilledema [262]. The headaches are typically frontal, intermittent, severe, of short duration, and associated with nausea and vomiting. The headache can be relieved by lying down [263]. Occasionally, gait abnormalities may occur as a result of hydrocephalus. The classic clinical description of intermittent headaches and drop attacks occurs in only one-third of patients. Rarely, sudden death can occur from obstruction of the ventricular system.

Imaging demonstrates iso- or hyperdense lesions on noncontrast CT. On MRI they may be T2 hyperintense or have a hypointense core (image 17). They do not enhance.

Surgical excision is curative, although it may be technically difficult. Resection can be performed via open craniotomy or through an endoscopic approach [264]. For patients with hydrocephalus, a ventriculoperitoneal shunt may be necessary. Stereotactic aspiration of a cyst may be useful, although there is a rate of high recurrence [261]. Patients with small asymptomatic colloid cysts without evidence of hydrocephalus may be closely followed by serial examinations and neuroimaging studies.

Arachnoid cyst — Arachnoid cysts are collections of CSF within the arachnoid membranes, with the CSF secreted by arachnoid cells lining the cyst. The vast majority are asymptomatic, particularly when they are detected in adulthood.

Arachnoid cysts account for approximately 1 percent of intracranial masses. Based on retrospective review of over 60,000 consecutive brain MRIs, the prevalence of arachnoid cyst in children and adults is 2.6 and 1.4 percent, respectively [265,266]. It is estimated that 75 percent of symptomatic arachnoid cysts present in childhood.

The pathogenesis is not well characterized. While most are sporadic, rare familial forms have been described. Arachnoid cysts occur with increased frequency in certain neurogenetic syndromes, and emerging research suggests that even sporadic cysts may be caused by variants in genes involved in chromatin remodeling and transcriptional regulation [267,268].

Arachnoid cysts usually contain clear CSF with a normal cell count and protein. Hemorrhage into the cyst may cause xanthochromia. The mechanism of cyst enlargement over time is not well understood, but theories include passive diffusion of CSF into the cyst or progressive entrapment due to a ball valve effect [269,270].

Approximately one-half of arachnoid cysts arise in the Sylvian fissure, although they may occur in any part of the nervous system where there is arachnoid. Other common sites are the cerebral convexity, interhemispheric fissure, suprasellar cistern, quadrigeminal cistern, cerebellopontine angle, midline of the posterior fossa, and spine. Cysts in the Sylvian fissure are usually asymptomatic but can present with headache, seizure, and, less commonly, focal neurologic deficits. Subdural hematomas may occur following relatively minor head trauma.

Arachnoid cysts of the craniospinal junction are rare lesions, with less than 10 cases reported in the literature. Such cysts extend through the foramen magnum to the level of the upper spine [271].

One review of the presenting neurologic signs and symptoms in 45 pediatric patients (2 to 17 years old) found that headache was the primary symptom in 61 percent, while 31 percent had epilepsy [272]. Among those with seizures, 91 percent had cysts located in the left temporal region [272].

Cysts in other locations also have characteristic presentations. Suprasellar cysts usually cause obstructive hydrocephalus; occasionally cysts in this area cause visual and/or endocrine dysfunction. Quadrigeminal and posterior fossa cysts may cause brainstem symptoms as well as hydrocephalus.

Plain film imaging may reveal thinning of adjacent bone in long-standing lesions. CT demonstrates a CSF-isodense mass, unless there is concomitant infection or intracystic hemorrhage. Mass effect is mild, and there is no contrast enhancement. Similarly, on MRI, contents of the arachnoid cyst are isointense with CSF on all sequences and there is no enhancement (image 18).

The differential diagnosis of arachnoid cysts includes chronic subdural hygromas, infarcts, low-grade gliomas, gangliogliomas, epidermoid cysts, and cerebellar hemangioblastomas. Diffusion-weighted MRI sequences show no water diffusion restriction and can be useful in distinguishing arachnoid cysts from epidermoid cysts. In diffusion-weighted images, epidermoid cysts are hyperintense, and apparent diffusion coefficient (ADC) maps are hypointense because of their high keratin and cholesterol content and solid nature (image 15). By contrast, arachnoid cysts have no restriction to the free movement of water; therefore, the signal is similar to CSF and the opposite of epidermoid cysts [273,274].

Treatment depends on whether the cysts are symptomatic. Serial imaging and neurologic examinations are adequate in the vast majority of lesions that are asymptomatic. Surgery is indicated if there are symptoms of increased intracranial pressure, seizures, focal neurologic deficits, or cognitive impairment. Surgical options include craniotomy for partial or complete cystectomy, fenestration into the subarachnoid space, or cyst peritoneal shunting. Needle aspiration usually is of temporary benefit and is not a good long-term treatment option [252]. Patients with suprasellar arachnoid cysts should be monitored for secondary endocrine abnormalities [275].

SUMMARY

●Scope – The World Health Organization (WHO) classification of tumors of the central nervous system (CNS) recognizes more than 100 tumor types in 13 different categories. Although most brain tumors in adults are diffuse gliomas, meningiomas, or metastases, the cumulative total of less common brain tumors makes up a significant minority, especially in infants and children. (See 'Introduction' above.)

●Clinical presentation and diagnosis – The clinical manifestations of rare brain tumors are determined by the anatomic location, growth rate, and histology. Although symptoms, imaging characteristics, and demographic features may suggest a specific tumor type, definitive diagnosis of a brain tumor requires biopsy, typically obtained at the time of attempted resection. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

●Glioneuronal and neuronal tumors – This group of tumors is unified histologically by tumor cells with neuronal differentiation, either exclusively (for neuronal tumors) or together with glial differentiation (table 1). Many are low-grade, circumscribed, cortically based tumors that are associated with seizures.

BRAF alterations and oncogenic fusion events are common in certain subtypes, especially gangliogliomas and dysembryoplastic neuroepithelial tumors (DNTs). Surgery is curative in most cases. Targeted therapies are available for certain genotypes. (See 'Glioneuronal and neuronal tumors' above.)

●Circumscribed astrocytic gliomas – Circumscribed astrocytic gliomas are distinguished from diffuse gliomas by a localized growth pattern, with absent or minimal infiltration of surrounding brain parenchyma (table 3). Surgery is the primary therapy, although several tumors in this group have an increased risk for recurrence compared with glioneuronal tumors. (See 'Circumscribed astrocytic gliomas' above.)

●Choroid plexus tumors – Tumors arising from the choroid plexus range from low-grade, hamartomatous papillomas to malignant carcinomas of the choroid plexus. Choroid plexus carcinomas can be a manifestation of Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition syndrome caused by mutations in the tumor protein p53 (TP53) gene. (See 'Choroid plexus tumors' above.)

●Rare embryonal tumors – Embryonal tumors are highly malignant tumors of the CNS that affect infants and young children. Several rare tumors in this category are now genetically defined, including embryonal tumor with multilayered rosettes (ETMR), associated with alterations in the chromosome 19 microRNA cluster (C19MC), and atypical teratoid/rhabdoid tumor (ATRT), defined by inactivation of SMARCB1 or SMARCA4 (table 4). These tumors typically require multimodality therapy including surgery, radiation therapy (depending on patient age), and chemotherapy. (See 'Embryonal tumors' above.)

●Mesenchymal tumors – Mesenchymal, nonmeningothelial tumors originating in the CNS represent a spectrum of benign and malignant tumors that arise more commonly in the meninges than the brain parenchyma (table 5). Among the most common are CNS solitary fibrous tumors (SFTs), which are dural-based tumors often indistinguishable from meningioma by imaging. (See 'Solitary fibrous tumor' above.)

●Primary melanocytic lesions – Proliferation of melanocytes derived from the neural crest can result in a range of both diffuse and localized, benign and malignant melanocytic processes involving the leptomeninges. Molecular genetic analysis is increasingly useful to identify a primary CNS versus cutaneous origin. (See 'Primary melanocytic lesions' above.)

●Cystic lesions – A variety of nonneoplastic cystic lesions can simulate brain tumors and can give rise to neurologic symptoms due to mass effect. These include epidermoid, dermoid, arachnoid, and colloid cysts. (See 'Cystic lesions' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Andrew Norden, MD, who contributed to an earlier version of this topic review.