Continuing Education Activity

Neuronal brain tumors are a diverse group of primary central nervous system tumors consisting of lesions with either a primarily neuronal background or a mixed glial and neuronal background, termed glioneuronal tumors. These are rare tumors most commonly associated with epilepsy, although other symptoms may also occur, such as headaches, focal neurological deficits, and acute hydrocephalus. This activity reviews the evaluation and treatment of neuronal brain tumors and highlights the role of the interprofessional team in evaluating and treating patients that are found to harbor these tumors.

Objectives:

• Identify the etiology of neuronal brain tumors.
• Describe the presentation of neuronal brain tumors.
• Review the evaluation and management of patients with neuronal brain tumors.
• Explain the importance of interprofessional discussion regarding the evaluation and management of patients with neuronal brain tumors.

Introduction

Neuronal brain tumors are an uncommon group of central nervous system tumors that arise from cells with neuronal differentiation. These tumors may be purely neuronal in origin or have mixed neuronal and glial components, which comprise a subset of glioneuronal tumors.[1] The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors includes 14 distinct tumors within this classification.

The purely neuronal group includes gangliocytoma, multinodular and vacuolating neuronal tumor (MVNT), dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), central neurocytoma, extraventricular neurocytoma, and cerebellar liponeurocytoma. The mixed glioneuronal group includes ganglioglioma, desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma (DIG/DIA), dysembryoplastic neuroepithelial tumor (DNET), diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), papillary glioneuronal tumor (PGT), rosette-forming glioneuronal tumor (RGNT), myxoid glioneuronal tumor (MGT), and diffuse leptomeningeal glioneuronal tumor (DLGNT). MVNT, DGONC, and MGT are newly classified entities in the WHO CNS tumor classification schema.

Although there are some exceptions, these tumors are mostly low-grade with minimal risk for an aggressive clinical course. They most commonly present with seizures, although other symptoms of space-occupying intracranial lesions such as headache, vomiting, papilledema, cerebellar dysfunction, and focal neurological deficit have also been described.[2][3] Many of these tumors are commonly found in the temporal lobe, which helps explain their predilection for causing seizures.[4] However, these tumors can be found in many locations throughout the supratentorial and infratentorial spaces.

Etiology

There is no specific etiology or risk factor related to the development of this diverse group of tumors. However, the current emphasis on molecular characterization of brain tumors provides new insight into the genetic aberrations that underlie their tumorigenesis. Specifically, there may be two main molecular subgroups involving mutations within different cellular regulation pathways. The first subgroup demonstrates mutation in the mitogen-activated protein kinase (MAPK) pathway, which is involved in cellular growth. Specifically, alterations to the proto-oncogene BRAF in the form of BRAF fusion and single nucleotide missense mutations are commonly found in these tumors, with the highest incidence in gangliocytoma and ganglioglioma, with 25% demonstrating fusion mutation and 13-56% demonstrating single nucleotide missense mutation.[5] They have also been described in DLGNT and isolated cases of MVNT.[6][7]

These are gain-of-function mutations that lead to unregulated cell growth. The second group demonstrates mutation in fibroblast growth factor (FGFR) genes, mostly FGFR-1, which is upstream from the MAPK pathway.[8][9][10] This appears to be especially common in DNETs but has also been identified in neurocytoma and RGNT.[11][12]  Interestingly, for the glioneuronal group, in particular, these molecular subgroups may help distinguish between tumor types. The BRAF mutation group tends to have a glial component most similar to astrocytes, while the FGFR group tends to have a glial component more similar to oligodendroglia.

MGTs are newly recognized lesions within the neuronal and glioneuronal tumor groups. They are similar to DNET but have a predilection for location in the septum pellucidum and are associated with mutation in the platelet-derived growth factor receptor (PDGFR) gene instead of FGFR.[13][14] This tumor was often previously described as “intraventricular DNET” or “DNET-like neoplasm of the septum pellucidum.”

PGNTs also demonstrate unique genetic aberrations among the neuronal and glioneuronal tumor groups. These often harbor a fusion aberration between solute carrier family 44 choline transporter 1 (SLC44A1) and protein kinase C alpha (PRKCA), creating SLC44A1-PRKCA.[15] Notably, PRKCA is involved in the MAPK signaling pathway.[16] However, these tumors are not found to have the BRAF mutations that other neuronal and glioneuronal tumors with mutations in the MAPK pathway are found to have.

Dysplastic cerebellar gangliocytoma, also referred to as Lhermitte-Duclos disease, represents a special case within this group of tumors because it is associated with Cowden syndrome, which is also referred to as phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome.[17] PTEN contributes to the mammalian target of the rapamycin (mTOR) pathway, which helps regulate the cell cycle. Wild-type PTEN downregulates the pathway, which reduces proliferation. Mutations in PTEN can lead to unregulated mTOR signaling, which results in tumorigenesis. Common findings in Cowden syndrome include macrocephaly, developmental delay, hemangiomas or other vascular lesions, thyroid hamartomas, breast hamartomas, ganglioneuromas of the kidney, uterine fibroids, various skin lesions including lipomas and keratoses, and dysplastic cerebellar gangliocytoma.

It is important to note that not all tumor samples are found to have the molecular aberrations noted above and that these do not represent all aberrations that have been associated with neuronal and glioneuronal tumors. There may be other mutations upstream from the signaling pathways noted above that contribute to their development. However, the rare nature of this group of tumors makes their molecular characterization somewhat difficult, with most information gleaned from case reports and small case series. Ongoing efforts are working towards a better understanding of the genetic alterations that contribute to their development.

Epidemiology

This is a rare group of brain tumors totaling approximately 0.5 to 2% of all primary CNS tumors.[4] Ganglioglioma and DNET make up the majority of the group, while descriptions of many of the newly classified lesions such as MVNT, DGONC, MGT, and others are limited to case reports and small case series, likely representing a very small portion of all primary CNS tumors. These are primarily tumors of childhood and young adulthood. An age of diagnosis greater than 30 years old represents a rare clinical scenario.

Pathophysiology

Neuronal and glioneuronal tumors are primary CNS tumors arising, at least in part, from mutations in cellular growth pathways, as noted earlier. The precise molecular characterization of many of these tumors remains difficult due to their rarity, but ongoing efforts continue to uncover genetic aberrations leading to their development.

Tumor location plays a major role in the pathophysiology of most of these lesions as they are typically WHO 1. Central neurocytoma, extraventricular neurocytoma, and cerebellar liponeurocytoma are WHO grade 2 lesions. The anaplastic form of ganglioglioma represents the only WHO grade 3 lesions in the group. Some newly described tumors, such as DLGNT and MGT, do not yet have a classification due to their rarity. As noted, these tumors can occur anywhere in the supratentorial or infratentorial space, although certain tumors have a predilection for a specific location. For example, dysplastic cerebellar gangliocytoma occurs in the cerebellum as Lhermitte-Duclos disease in the setting of Cowden syndrome.[17]

However, the most common tumor location appears to be in the temporal lobe, partly because ganglioglioma and DNET are the most common tumor types within this group and have a predilection for this location. These tumors are also found in extra-temporal locations.[18] Location in the temporal lobe and other epileptogenic regions contributes to the development of seizures, which is the most common presenting symptom of this group of tumors.[9][10] Due to this, they are often referred to as long-term epilepsy-associated tumors (LEATs), and their seizures are often refractory to maximal medical therapy.[6][18][19] 

The propensity for these tumors to cause seizures may not only be related to their location since intra-tumoral EEG recordings have demonstrated intrinsic epileptogenic activity in both DNET and ganglioglioma, likely related to their abnormal neuronal cells and structure.[19][20][21][22] Additionally, some studies suggest an upregulation of glutamate receptors (GluR) and downregulation of gamma-aminobutyric acid receptors (GABA-R), which help to create a hyper-excitable state within the tumor.[19][23][24][25][26]

Other symptoms are also related to location. Headache, nausea, vomiting, papilledema, hydrocephalus, cerebellar dysfunction, and focal neurological deficit have also been described. Headache, vomiting, and papilledema are signs of elevated intracranial pressure, which is expected with space-occupying lesions. Since many of these lesions are slow-growing, they may reach large sizes before clinical recognition, with these signs and symptoms being the initial presenting factor that leads to tumor recognition.

Hydrocephalus is mainly secondary to intraventricular or posterior fossa lesions, as tumors in these locations can disrupt the normal cerebrospinal fluid (CSF) outflow pathways. This is usually obstructive-type hydrocephalus, which may be acute if there is a sudden block of normal CSF outflow pathways, as in rare cases of central neurocytoma.[27] Cerebellar dysfunction is common with dysplastic cerebellar gangliocytoma due to its location, and other focal neurological deficits are related to individual tumor location with the cerebrum.

Histopathology

The histological features of neuronal and glioneuronal tumors are heterogeneous. All neuronal and glioneuronal tumors should demonstrate positivity for immunohistochemical staining with neuronal cell markers, such as synaptophysin or neuron-specific enolase (NSE).[28][29] However, only the glioneuronal subgroup of tumors should demonstrate positivity for markers of glial differentiation in addition to neuronal marker positivity, which classically is seen with glial fibrillary acidic protein (GFAP) positivity. The Ki-67 marker of cellular proliferation is typically low, although higher proliferation rates may be seen for higher-grade tumors such as anaplastic astrocytoma. Cells with oligodendroglia-type cells often demonstrate Olig2 positivity. The major histopathological features of each type of tumor are summarized in table 1, although details of the immunohistopathological profile of each tumor are not exhaustive in this report.

Table 1: Histological features of individual neuronal and glioneuronal tumors.[30][31]

History and Physical

The findings for an individual patient with a neuronal or glioneuronal brain tumor will be variable. A detailed history of the patient’s seizure history should be obtained, including a detailed description of the seizure, whether the patient has previously been evaluated for seizures, and whether there are any family members with a history of seizures. The presence, duration, and severity of other signs and symptoms such as headache, nausea, vomiting, balance difficulties, focal weakness or sensory changes, changes to eyesight, or others should also be obtained at this time. A detailed history of current and previous diagnoses with the inclusion of current and previous prescription and non-prescription medication should also be obtained.

Next, the practitioner should perform a detailed physical exam with a particular focus on the neurological system. When possible, the examiner must evaluate for mental status changes, visual field deficits, cranial nerve dysfunction, focal neurological deficits including motor or sensory disruptions, cerebellar dysfunction, and papilledema.

For most patients, the physical examination will be within normal limits. Rarely, patients may present with acute alteration in mental status and obtundation signifying acute hydrocephalus secondary to CSF outflow obstruction, which may occur with intraventricular tumors such as central neurocytoma or with seizure.

Patients with posterior fossa lesions will often demonstrate cerebellar symptoms on examination, such as ataxia, unsteady gait, and a positive Romberg sign, among others. Other focal neurological deficits may include sensory changes or focal weakness, but again would be rare due to the indolent nature of most of these lesions and the ability of the brain to compensate. Post-ictal patients and those presenting with acute status change secondary to acute hydrocephalus will require frequent serial neurological evaluation.

Evaluation

The initial evaluation of a patient suspected of a neuronal or glioneuronal brain tumor requires a detailed history and physical examination, as noted above. Importantly, although rare, patients that present with acute neurological status changes need an emergent evaluation of the airway status, breathing/oxygenation, and circulatory system (ABCs). This scenario may occur in patients with acute hydrocephalus and may also be true for patients presenting with generalized tonic-clonic or subclinical seizure activity. There should be a low threshold for intubation and resuscitation when there is compromise noted on the initial assessment of the ABCs. However, most patients present with focal partial seizures and signs of increased intracranial pressure, such as headaches. 

CT

Patients presenting with acute deficit should first undergo a head CT without contrast after clinical stabilization due to the rapidity of the test and its ability to demonstrate common causes of acute status change such as hemorrhage. Its most useful feature is the ability to demonstrate hydrocephalus, which may require emergent surgical action.[27] Depending on the tumor location, CT findings consistent with hydrocephalus may include enlargement of the temporal horns, triventricular or tetraventricular enlargement, and hypodensities around the frontal horns suggesting transependymal flow of CSF.[32][33]

Other CT findings include hyperdensity within the ventricular system for intraventricular lesions such as central neurocytoma and hypo- or iso-density in the brain parenchyma representing intraparenchymal lesions.[34][35] The head CT may also show calcification, but this is likely present in less than half of all neuronal and glioneuronal brain tumors. Approximately 10% of DNET and 35 to 50% of ganglioglioma demonstrate calcifications, while other primary CNS lesions like oligodendroglioma demonstrate some level of calcification in up to 90% of lesions.[36]

MRI

The imaging test of choice for evaluation of this group of brain tumors is MRI.[36][37] Sequences should include T1- and T2-weighted images with and without gadolinium contrast. Fluid-attenuated inversion recovery (FLAIR) imaging for tumor characterization and edema, susceptibility-weighted imaging (SWI) for hemorrhage and calcification, diffusion-weighted imaging (DWI) for an assessment of cellularity, and perfusion-weighted imaging (PWI) for an assessment of angiogenesis should be included as part of a standard brain tumor imaging protocol when a primary CNS tumor is suspected.

Other advanced MRI techniques such as MR spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI) can also be useful. The most common MRI characteristics for each tumor are demonstrated in table 2. Due to the rare nature of many of these lesions, complete imaging characteristics are still being defined. Additionally, many of these lesions have heterogenous imaging characteristics, and individual tumors may not demonstrate the standard features noted here.

Table 2: MRI characteristics for individual neuronal and glioneuronal brain tumors.[4][17][38][39][40]

Most of the tumors within this group are primary intracranial lesions without dissemination or occurrence in other compartments within the CNS. However, patients with DLGNT, in particular, should undergo MRI with and without contrast of the entire neuroaxis due to its proclivity for dissemination throughout the neuroaxis. Consideration to imaging the spinal axis should also be given for other patients with focal neurological deficit or signs of myelopathy that cannot be explained by their intracranial lesion alone.

EEG

An important consideration for this group of brain tumors is electroencephalography (EEG) since they commonly present with seizures. Spot EEG may be useful in some cases, but continuous video EEG monitoring allows for better characterization of seizure semiology and assists with localization of an epileptogenic focus. Invasive EEG monitoring with either subdural strip electrodes or depth electrodes can also be considered in patients with seizures that cannot be localized to the region of the tumor with noninvasive recording techniques. The specific histologic characteristics of an individual tumor may affect EEG characteristics. Tumors with mostly neuronal histology often demonstrate continuous spiking.[41] However, there are limited data regarding specific EEG characteristics for these tumors.

WADA Testing

Many LEATs are in locations where surgical resection may compromise language function. WADA testing is typically employed in these patients before resection to identify language dominance and assist with surgical planning.[42] fMRI has also been used for this purpose, but may not be as accurate as WADA testing, which remains the gold standard for determining language dominance.[43]

Interprofessional Discussion

LEAT patients should be discussed in interprofessional epilepsy conferences involving neurosurgeons, epilepsy neurologists, neuroradiologists, and neuropathologists to make appropriate diagnostic and treatment plans for these often-complicated patients. Furthermore, these patients and others with tumors that are identified for another reason should be discussed at an interprofessional tumor board conference consisting of neurosurgeons, neurologists, neuroradiologists, neuropathologists, radiation oncologists, and medical oncologists to assist with appropriate diagnostic and treatment planning.

Treatment / Management

Observation

Asymptomatic or minimally symptomatic lesions identified on imaging for another reason can be reasonably followed with serial examination and neurological imaging due to the primarily low-grade nature of this group of tumors. Changes to the radiological characteristics of the tumor or the development of new neurological symptoms should prompt discussion at interprofessional conferences to consider intervention.

Medical Treatment for Seizures

Medical treatment for this group of tumors chiefly encompasses the use of anti-epileptic medications for LEATs. The specific agents used are variable, and typically a variety of different agents are trialed. However, these tumors are often refractory to maximal medical therapy and typically require surgical intervention.[19]

Surgical Treatment

Surgical resection is the treatment of choice for symptomatic neuronal and glioneuronal tumors.[44] Patients that present with acute obstructive hydrocephalus require emergent surgery to prevent permanent neurological injury and death. However, that clinical scenario is unusual for this group, and most others can typically be scheduled on an outpatient basis after the decision for the need for surgical intervention has been reached in interprofessional conferences. The specifics of the intervention are highly dependent on the location of the tumor. This typically involves a craniotomy with the goal of gross total tumor resection. However, some data suggest that a small amount of residual tumor may still result in sufficient resection in the case of LEATs.[44]

Gross total resection for higher-grade lesions appears to be more important. A higher extent of resection (EOR) appears to improve survival in patients with anaplastic ganglioglioma, which is similar to data from other high-grade CNS lesions such as glioblastoma.[45][46] The increasing EOR in central neurocytoma has also demonstrated a survival benefit.[47] Intraventricular lesions within this group have historically been treated with standard craniotomy and tumor resection, but modern minimally invasive surgical techniques using tubular retractor systems are beginning to emerge.[48][49]

These may help reduce some of the morbidity related to intraventricular surgery for large tumors. Laser interstitial thermal therapy (LITT) is another emerging minimally invasive surgical strategy for intracranial lesions that have been applied to brain tumor and epilepsy surgery.[50] This technique utilizes light energy to cause a thermal reaction within the target tissue, resulting in lesionectomy. Its application to neuronal and glioneuronal tumors, in particular, is limited at this time but may emerge as an alternative to formal surgical resection for tumors in deep-seated and eloquent tissues.

Radiation Therapy

The role of radiation is somewhat limited for this group of tumors since most are WHO grade I. However, higher-grade lesions including anaplastic ganglioglioma, liponeurocytoma, and some central/extraventricular neurocytoma may require adjuvant radiation therapy. Radiation is most commonly employed for anaplastic ganglioglioma, although it is not employed in all cases.[51][52] 

In cases of gross total resection for anaplastic ganglioglioma, adjuvant radiation therapy alone may be considered, but in cases of subtotal resection, clinicians should consider adjuvant chemoradiation therapy.[53] The use of adjuvant radiation therapy for central and extraventricular neurocytoma is also common and appears to improve survival, especially in cases of subtotal resection or tumor recurrence.[54][55][56]

Liponeurocytoma may also be treated with postoperative radiation. Patients who underwent subtotal resection or recurrent liponeurocytoma have been successfully treated with adjuvant radiotherapy in case reports and small case series.[57][58][59] Further study, ideally with randomized controlled clinical trials, will be necessary to define the exact role of radiation therapy for this group of tumors as a whole, but this may be difficult due to the rare nature of many of these tumors.

Chemo- and Immunotherapy

Chemo- and immuno-therapies are typically reserved for grade 2 and 3 tumors in a fashion similar to radiation therapy. Immunotherapies targeting BRAF are emerging as adjuvant therapy for use in anaplastic ganglioglioma.[45][60][61] Examples of BRAF inhibitors include vemurafenib, dabrafenib, and encorafenib. The use of chemotherapy in central neurocytoma is variable and typically reserved for patients with recurrent tumors.[62]

Agents such as vincristine, cisplatin, etoposide, carboplatin, cyclophosphamide, and lomustine have all been documented in case reports and small cases series for use in central neurocytoma.[63] However, temozolomide, an alkylating agent available in oral and intravenous forms that is a common agent for central nervous system malignancies, has recently been favored. Treatment using chemo-or immuno-therapies for liponeurocytoma is not well documented.

Differential Diagnosis

The differential diagnosis for neuronal and glioneuronal brain tumors is broad due to their heterogeneous nature. Other primary central nervous system tumors, especially other low-grade tumors, may appear similar. 

• Diffuse astrocytoma
• Pilomyxoid astrocytoma
• Pleomorphic xanthoastrocytoma
• Pilocytic astrocytoma
• Oligodendroglioma
• Lymphoma
• Ependymoma
• Intraventricular tumors for central neurocytoma: Subependymal giant cell astrocytoma (SEGA); meningioma; choroid plexus papilloma or carcinoma; metastasis
• Dural based tumors for DIG/DIA: Meningioma; dural-based metastases
• Cerebritis

Prognosis

Most data regarding outcomes for this group of tumors are related to ganglioglioma and DNET since they are the most common tumors within the group. Seizure outcomes after surgical intervention are of particular interest since seizures are the most common presenting symptom of these tumors. Mehrotra et al. reviewed seizure outcomes for a series of 26 patients with seizures related to neuronal/glioneuronal brain tumors.[64] 

Favorable prognostic factors for postoperative improvement included earlier diagnosis, younger patient age, and focal partial seizure semiology. Early operative intervention was associated with the best long-term seizure outcomes. The extent of resection may also play an essential role in creating seizure freedom with surgery. A comprehensive review of the literature, including 1181 patients undergoing tumor resection with the intent of seizure control, demonstrated that 79% of patients that underwent a gross total tumor resection were seizure-free compared to only 43% of patients that underwent subtotal resection.[65]

Furthermore, patients with gross total resection plus resection of some surrounding tissue experienced 87% postoperative seizure freedom, which suggests that it may be important to resect surrounding dysplastic tissue during tumor resection. Similar findings have been demonstrated in children with epilepsy related to neuronal/glioneuronal brain tumors.[66] Significantly, shorter seizure duration is associated with improved cognitive outcomes in children, so prompt diagnosis and management in children with these brain tumors are of the utmost importance.

A specific outcome measure that is important for central neurocytoma is the need for long-term management of hydrocephalus with CSF shunting. The gross total resection of these tumors is related to lower ventricular shunting rates.[67]

Anaplastic ganglioglioma carries the worst prognosis of any tumor within this group. An analysis of available cases in the literature suggested a poor overall survival with the median at 29 months despite maximal therapy.[53]

Generating accurate prognoses for many of the other tumors in this group is somewhat difficult due to their rare nature. However, most appear relatively benign on histological and molecular characterization and are given low WHO grades, which suggests a favorable long-term survival, with the main concern being the ability to control symptoms related to the tumors, often via surgical intervention as discussed.

Complications

Complications related to neuronal and glioneuronal brain tumors are variable based upon different treatment modalities. Adverse effects from anti-epileptic medications are common and include irritability, dizziness, drowsiness, blurred vision, difficulty with coordination, generalized fatigue, and weight gain.[68]

More serious side-effects are also possible, including severe skin reactions and congenital disabilities in children if taken during pregnancy. Other complications are related to surgical intervention, including infection, intracranial and extracranial bleeding, postoperative hydrocephalus, new neurological deficit, lack of seizure control, injury to structures surrounding the tumor such as cranial nerves or blood vessels, cerebral edema and brain swelling, and death.

Consultations

Patients with a neuronal or glioneuronal brain tumor require interprofessional discussion. Patients with LEATs require consultation with neurosurgeons, epilepsy neurologists, neuroradiologists, and occasionally medical oncologists, radiation oncologists, and neuropathologists. These consultations often occur in the form of an interprofessional epilepsy conference. These and other patients with neuronal and glioneuronal brain tumors may also be discussed at an interprofessional tumor board conference, including neurosurgeons, neurologists, neuroradiologists, neuropathologists, radiation oncologists, and medical oncologists.

Deterrence and Patient Education

Patients with tumor-related epilepsy should be educated regarding seizure precautions and avoidance of secondary injury that may occur during a seizure. Family members should also be educated in recognizing seizure activity and the necessary action to take when a seizure occurs. Patients with brain tumors should notify their provider of any new neurological symptoms, potentially representing changes to the tumor.

Enhancing Healthcare Team Outcomes

Neuronal and glioneuronal brain tumors are a heterogeneous group of tumors, so their presentations and management are variable. Therefore, effective evaluation and treatment require interprofessional input, which typically occurs in the form of epilepsy or tumor board conferences. Epilepsy evaluation requires the coordinated efforts of technicians, nurses, advanced practice providers, and physicians to appropriately identify seizure foci and ensure accurate and effective treatment for patients.

The recognition of acute neurological status changes by emergency medical personnel is important to expedite emergency evaluation and medical or surgical responses, which helps minimize morbidity and mortality related to brain tumors. The inpatient care of postoperative brain tumor patients is complicated and requires the coordinated care of therapists, nurses, advanced practice providers, physicians, and other healthcare team members.

Specialty training regarding neurological evaluation is of utmost importance so that changes to a patient’s status are promptly recognized and action can be taken. Therefore, increasing the awareness of these tumors among various healthcare providers will help facilitate early recognition and the effective care of these patients. [Level 5]