Clinical manifestations

Presentation and course

Ganglioglioma is the top differential diagnosis in any patient presenting with chronic, medically refractory epilepsy during the first 3 decades of life, in which a temporal mass isointense to gray matter on T1-weighted images is found on brain MRI. Eighty percent of all gangliogliomas present by 30 years of age, with the majority (63%) after age 10 years and less than 5% before the first year of life (08). Median age at diagnosis is 19 years old for low-grade gangliogliomas, with a slight male predominance for either grade.

Gangliogliomas can occur anywhere in the brain or spinal cord but are most commonly found in superficial hemispheres (greater than 90%), especially temporal lobes (greater than 45%). They have been reported in the pineal and sellar regions, basal ganglia, ventricles, and, less frequently, infratentorially and within the cranial nerves. Multifocal intracranial gangliogliomas at diagnosis have also been described (27). Rarely, leptomeningeal dissemination of ganglioglioma with anaplastic features can occur (32).

Focal seizure is the most frequent presenting symptom of cerebral ganglioglioma (occurring in greater than 75% of patients), and long-standing epilepsy is not uncommon; in fact, ganglioglioma represents one of the most common epilepsy-associated tumors and even may be an incidental finding on temporal lobectomies performed for epilepsy management (33). Otherwise, the locus of the ganglioglioma in the brain often determines the presenting symptoms or signs. In posterior fossa and intraventricular gangliogliomas, obstructive hydrocephalus, with symptoms of increased intracranial pressure such as headache or depressed consciousness, is the most frequent presentation. For spinal gangliogliomas, the most common presenting symptom is extremity weakness, followed by sensory impairment, gait problems, urinary disturbances, and back pain (10; 47; 54).

Prognosis and complications

Prognostic factors associated with aggressive behavior include older age, higher grade histology, and loss of p16 or CDKN2A mutation (53).

Clinical vignette

LT, a 30-year-old, right-handed mechanical engineer, had a history of focal seizures since 12 years of age; these seizures were characterized by odd smell, spreading discomfort, and “déjà-vu” lasting less than a minute, with postictal anxiety and no altered consciousness. Seizure frequency increased over the years from a few annually to a few daily and went unmanaged.

Over the next several years, he experienced intermittent short-term memory loss and increasing word-finding difficulties. At 30 years of age, he had a generalized tonic-clonic seizure with postictal speech production difficulty. On ensuing brain MRI, he was found to have a non-enhancing left mesial temporal mass. The lesion was hyperintense on T2/FLAIR weighted imaging and contained a small cyst.

Imaging differential diagnosis included dysembryoplastic neuroepithelial tumor and ganglioglioma. He was started on antiepileptic drug and referred to neurosurgery. A preoperative comprehensive neuropsychological testing reported baseline impaired naming and reduction in auditory attention, suggesting some compromise of the left temporal lobe. An interictal EEG showed continuous left temporal slowing.

Given his course, the patient proceeded with surgical resection. He was considered at risk of postoperative language deficits because of the location of the lesion; thus, awake craniotomy with speech mapping and intraoperative electrocorticography was done to localize extra lesional epileptiform activity, and the lesion was completely resected. The pathology was consistent with a WHO grade 1 ganglioglioma. The patient experienced postoperative transient word-finding difficulties that resolved with time. Postsurgery, he remained seizure-free for 3 years, though remained on antiseizure medication; he continued semiannual MRI follow-up without recurrence to date.

Biological basis

Etiology and pathogenesis

The etiology and the molecular pathogenesis of ganglioglioma remain unclear. The cell of origin is suggested to be a common glioneural precursor with clonal neoplastic proliferation of the glial cell population.

Although no specific mutation has been identified as a solely causative genetic aberration, gangliogliomas have been characterized by alterations that activate the MAPK signaling pathway, similar to pilocytic astrocytomas, pleomorphic xanthoastrocytomas, dysembryoplastic neuroepithelial tumors, rosette-forming glioneural tumors, polymorphous low-grade neuroepithelial tumors, and multinodular and vacuolating neuronal tumors (37). In a cohort of 40 gangliogliomas on which targeted next-generation sequencing was performed, 36 had mutations activating MAPK signaling pathway (18 BRAF V600E mutation, five had other BRAF mutation, four BRAF fusion, two KRAS mutation, one RAF1 fusion, one NF1 biallelic mutation, and five FGFR1/2 alterations). In the majority, genetic alterations with the MAPK pathway was the solitary genetic alteration identified. None had IDH, TP52, ATRX, TERTp, CIC, or FUBP1 mutation; MYB-MYBL1 rearrangement; or TSC1-TSC2 mutation (37).

Somatic BRAF V600E mutation in developing neurons has been implicated in the intrinsic epileptogenicity in ganglioglioma (15; 05). The BRAF V600E-induced epileptogenesis seems to be mediated by RE1-silencing transcription factor, which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy (15). In that study, seizure control in mice was significantly improved with a BRAF inhibitor, vemurafenib.

Genetic susceptibility. Rare cases of gangliogliomas have been described in patients with cancer predisposition syndromes such as neurofibromatosis types 1 and 2 and Peutz-Jeghers syndrome (STK11 mutation) (44; 06; 45; 09; 04).

Pathology. Macroscopically, gangliogliomas are well-circumscribed solid or cystic lesions with minimal mass effect and occasional calcifications. Microscopically, gangliogliomas, as suggested by their name, consist of a combination of two cell populations in varying proportions:

(1) Ganglion cells (ganglio-) are large mature dysplastic neurons. Dysplastic neurons are characterized by lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, and binucleated or clustering appearance.

(2) Neoplastic glial cells (-glioma) can resemble pilocytic astrocytoma, fibrillary astrocytoma, or oligodendroglioma.

Other prominent features include perivascular lymphocytic infiltrates, important capillary network, dystrophic calcifications, and mild to moderate cellularity (occasional mitoses and small foci of necrosis are compatible with the diagnosis). In less than 5% of cases, these tumors show aggressive histopathological features such as increased cellularity, nuclear pleomorphism, increased mitosis, vascular proliferation, and necrosis. In such cases, exclusion of diffuse glioma with entrapped neurons is mandatory. Also, note that the 2021 WHO classification does not define criteria for WHO 2 gangliogliomas and has abolished WHO 3 gangliogliomas (25). Indeed, as most cases of grade 3 gangliogliomas from previous series lacked molecular analyses to exclude other high-grade gliomas subtypes, the 2021 WHO Classification states that “further studies are needed to confirm the existence of anaplastic ganglioglioma.”

The neuronal elements are demonstrated by positive immunostaining for neuronal markers such as microtubule-associated protein 2, neurofilament, chromogranin-A, synaptophysin, and CD34. CD34 is positive in about 80% of gangliogliomas and is not present in adult brain neurons (24). Glial elements are demonstrated by cytoplasmic positivity for GFAP. The mean MiB1 labeling index, calculated from the glial component, is less than 3%.

Genetic profile. About 30% of gangliogliomas have chromosomal abnormalities, with gain of chromosome 7 being the most frequently described. Firm associations between cytogenetic data and clinical outcome are lacking (24). BRAF V600E mutation is the most common genetic alteration found in 20% to 60% of gangliogliomas (36). BRAF V600E is not specific for ganglioglioma because this mutation is also found in pleomorphic xanthoastrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumors, and epithelioid glioblastoma. Identification of IDH1/2, TP53, or PTEN mutations or of CDK4 or EGFR amplification strongly argues against the diagnosis of ganglioglioma.

Epidemiology

Gangliogliomas account for 0.4% to 1.3% of all central nervous system tumors (24) and for up to 10% of all pediatric central nervous system tumors (14; 34). In population-based epidemiological data on newly diagnosed and histologically confirmed gangliogliomas from 2006 to 2011 in France, the worldwide adjusted incidence rate was estimated to be less than 0.2 out of 100,000 person-years for WHO grade 1 ganglioglioma (07). About 80% of WHO grade 1 gangliogliomas are diagnosed in patients less than 30 years of age (49). Median age at diagnosis is 19 years for low-grade ganglioglioma, but they can occur at any age. Spinal gangliogliomas appear to affect children and young adults and most frequently involve the cervicothoracic spine (54). There is a slight male predominance (1.14:1) (07).

Prevention

No preventive measure is known.

Differential diagnosis

Confusing conditions

Clinical presentation and imaging. The clinical differential diagnosis of ganglioglioma is broad and varies with patients and imaging characteristics. Most importantly, ganglioglioma should be considered high on the list of causes in any child/young adult presenting with temporal lobe epilepsy with an intra-axial temporal lesion seen on MRI, especially if it is a cortically-based, partially cystic enhancing mass. However, ganglioglioma should also be included in the differential of all lesions with unusual imaging characteristics seen in the optic pathway, sellar, pineal, intraventricular, and cerebellar-pontine angle regions. Ganglioglioma may also present with atypical intracerebral hemorrhage without vascular abnormality on cerebral angiogram in a young adult (20).

Supratentorial tumors. In supratentorial tumors, the main differential diagnosis includes dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, desmoplastic infantile astrocytoma and ganglioglioma, diffuse astrocytoma, and oligodendroglioma. If the lesion is hemispheric and cortically based, the differential diagnosis is further restricted to dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, and oligodendroglioma. Dysembryoplastic neuroepithelial tumor can be differentiated from ganglioglioma due to the dysembryoplastic neuroepithelial tumor’s multi-cystic “bubbly” appearance and milder, infrequent contrast enhancement; oligodendroglioma may be more heterogeneous due to frequent calcifications and hemorrhagic components; pleomorphic xanthoastrocytoma usually shows prominent contrast-enhancement of both the cystic wall and its mural nodule abutting the pia. In the case of a superficial mass associated with skull remodeling, meningioma also needs to be considered. Desmoplastic infantile astrocytoma and ganglioglioma, as its name implies, most commonly occurs in children younger than 2 years of age and manifests as an exceptionally large cerebral hemispheric cystic and solid mass, most commonly in frontal and parietal lobes.

Infratentorial tumors. In infratentorial tumors, the differential diagnosis includes pilocytic astrocytoma, diffuse astrocytoma, medulloblastoma, and hemangioblastoma.

Histology. Histologically, the neoplastic glial component of the tumor can resemble pilocytic astrocytoma, fibrillary astrocytoma, or oligodendroglioma and may, therefore, be mistaken for such tumors, among others. The presence of anaplastic features such as mitoses, increased proliferative activity, necrosis, or vascular proliferations expands the differential diagnosis to include high-grade astrocytic tumors. In a pathological review of 22 previously-termed “anaplastic gangliogliomas,” nine (41%) cases were reclassified (52). In the case of midline tumors, the H3K27M mutation must be searched as cases of H3K27M-mutant diffuse gliomas have been reported to phenotypically mimic “anaplastic” ganglioglioma (17).

Diagnostic workup

As with all neoplasms, the workup for ganglioglioma includes cerebral imaging (CT or MRI) followed by surgical resection. Imaging characteristics are highly variable due to the various patterns of growth and possible locations of these tumors. Supratentorial gangliogliomas present as a sharply demarcated lesion, either as a solid-only (in approximately 50% of cases) or as a cystic or solid-cystic mass. Over 60% demonstrate contrast enhancement, with either a nodular, rim, or solid enhancement pattern. Intraventricular gangliogliomas often have cystic degeneration and calcifications (47). Compared to supratentorial gangliogliomas, infratentorial gangliogliomas have less cystic changes (about 20% compared to 50%) and more contrast-enhancement (over 70% compared to less than 50%), especially when located in the cervicomedullary junction (100% are enhancing) (23; 12).

On CT, approximately 30% of gangliogliomas show calcifications, and bony remodeling can be seen (24). Gadolinium-enhanced MRI is the imaging modality of choice, and both the brain and spine should be performed if leptomeningeal dissemination or ventricular seeding of ganglioglioma is suspected. On MRI, the solid component is iso- to hypointense to grey matter on T1-weighted imaging (T1WI), hyperintense on T2WI, and the solid component shows variable enhancement intensity and pattern on T1WI post-contrast imaging. The cystic component has variable T2WI signal depending on the presence of blood products and the amount of proteinaceous material. Peritumoral T2/FLAIR edema is distinctly uncommon in ganglioglioma, arguing against the diagnosis. On susceptibility-weighted imaging, about 30% of gangliogliomas will show blooming signal loss corresponding to calcified areas and rarely to blood products. Higher-grade (formerly anaplastic) gangliogliomas seem to lose the typical radiological characteristics of grade 1 gangliogliomas, especially their cystic and well-circumscribed features, and they gain characteristics of grade 3 gliomas and glioblastomas, such as necrosis, surrounding cerebral edema and mass effect (52).

It must be emphasized that the diagnosis of a ganglioglioma cannot be excluded by a negative CT or MRI examination only. There are reports of histologically confirmed ganglioglioma without a recognizable tumor on either CT or MRI images.

Management

Gross total surgical resection followed by close observation with serial MRI is the treatment of choice for ganglioglioma, as the extent of resection is considered the single most important prognosis factor (12). Fluorescence-guided tumor resection has been used to improve intraoperative visualization and resection extent during the resection of gangliogliomas (11). In cases of subtotal resection, the 2022 EANO-EURACAN-SNO guidelines on rare glial and neuroglial tumors recommend considering the use of adjuvant radiotherapy to improve local tumor control, as well as of BRAF or MEK inhibitors in ganglioglioma with BRAF alteration (46). On recurrence or tumor regrowth, surgical resection should be repeated whenever feasible.

After gross total resection, adjuvant radiation therapy has no clear benefit (41). For those with subtotal resection or biopsy, the role of radiation is controversial, as it may improve progression-free survival but not overall survival in both low- and high-grade gangliogliomas; this point was illustrated in a large study comparing four therapies for local control and overall survival in 402 patients with ganglioglioma (42). The 10-year local control and overall survival rates were 89% and 95% after gross total resection, 90% and 95% after gross total resection plus radiotherapy, 52% and 62% after subtotal resection, and 65% and 74% after subtotal resection plus radiotherapy, respectively. After subtotal resection, irradiation significantly improved local control but not overall survival. After gross total resection, irradiation did not significantly improve local control or overall survival. Given that most gangliogliomas are found in young adults and are in the temporal lobe, the benefit of radiation must be carefully considered against long-term toxicity, especially its neurocognitive impact. In addition, some in the field have expressed concern that radiation therapy may contribute to a transformation to a more anaplastic tumor (51). As such, adjuvant radiation after a subtotal resection should be reserved for those with a high risk of recurrence, such as gangliogliomas with anaplastic features, in whom a retrospective review showed a three times increased rate of recurrence among gangliogliomas with highly anaplastic features, compared to those with moderate anaplastic features (18). However, there are insufficient data to make a firm recommendation about the role of radiation therapy after subtotal resection of low-grade gangliogliomas.

Stereotactic radiosurgery appears to be a safe and effective treatment option for patients unfit for surgery and for surgically inaccessible, recurrent, and residual gangliogliomas (28).

Chemotherapy may also be considered to prevent ganglioglioma recurrence, although the agent of choice and the optimal duration are unknown. Various chemotherapeutics agents have been used as adjuvant therapy, including temozolomide, vincristine, procarbazine, and nitrosoureas.

Bevacizumab, an anti-VEGF antibody, has been described to rapidly shrink the cystic component of a low-grade ganglioglioma (21).

Targeted therapy with oral selective BRAF V600E inhibitors represents a promising therapeutic option in the 20% to 60% gangliogliomas harboring BRAF V600E mutation. BRAF is a member of the RAS/RAF/MEK/ERK pathway, and the BRAF V600E mutation activates MERF-ERK signaling, promoting cell proliferation, differentiation, and survival. BRAF V600E mutation in some tumors can be sensitive to BRAF V600E mutant-specific inhibitors such as vemurafenib and dabrafenib. In a review summarizing the available data on BRAF V600 point mutations and the antineoplastic activity and toxicity profiles of BRAF inhibitors in neuroepithelial brain tumors such as gangliogliomas, BRAF inhibitors were active and well tolerated in recurrent tumors after failure of other therapies in both pediatric and adult patients (40). A report on the use of dabrafenib in three children with unresectable brainstem ganglioglioma observed rapid and durable clinical and radiological improvement but with a rapid relapse within days to weeks following treatment discontinuation. Notably, all three patients showed similar rapid and sustained therapeutic response when dabrafenib was reintroduced, with good tolerability despite up to 5.5 years of use (39). A partial response has been noted in a patient with ganglioglioma with anaplastic features treated with vemurafenib in the prospective VE-BASKET trial (13).

Intolerance and, more frequently, acquired resistance to BRAF inhibitor have been reported, and a combination of BRAF and MEK inhibitors seems to improve both tolerance and efficacy (16). Combination therapy with dabrafenib (BRAFi) and trametinib (MEKi) is FDA-approved in a histology-agnostic fashion for patients whose tumors harbor BRAF V600E mutation. Cases of progressive gangliogliomas have responded to a combination of dabrafenib and trametinib and of vemurafenib and cobimetinib (29; 53; 48; 56; 01). The interim analysis of the basket trial ROAR reported a promising 69% objective response rate in the low-grade gliomas cohort (including four gangliogliomas) with the combination of BRAF inhibitor dabrafenib with the MEK inhibitor trametinib (55).

As 90% of ganglioglioma harbor mutations activating the MAPK pathway (37), acquired resistance to vemurafenib may result from persistent MAPK activation downstream to BRAF V600E, and the combination of BRAF/MEK inhibition could overcome resistance.

Nonetheless, the status for BRAF V600E mutation should be tested for all gangliogliomas to at least allow for the possibility of dual-targeted therapy in case of tumor regrowth or of incomplete resection, as recommended by the National Comprehensive Cancer Network Guidelines for central nervous system cancers (16).

More recently, a report demonstrated the efficacy of dual-targeted therapy with dabrafenib/trametinib in a non-V600E BRAF-mutated progressive ganglioglioma (BRAF p.T599dup mutation). Prior in vitro studies of p.T599dup demonstrated kinase activity and cellular MER/ERK activation potential comparable to that of p.V600E. Yet, the value of combination targeted therapy aimed at BRAF alterations other than p.V600E/K needs further clinical evidence (31).

Lastly, adequate symptom management of increased intracranial pressure and epilepsy is important. When hydrocephalus is present, ventricular shunting may be necessary. Although seizures due to ganglioglioma can usually be controlled with appropriate antiepileptic medications, surgical resection of the tumor is curative in most patients (02).

Outcomes

The typical patient with ganglioglioma generally follows a “manageable” clinical course, but tumor recurrence, malignant progression, and secondary glioblastoma have been observed in some cases. Good prognosis has been associated with lower grade, temporal location, epilepsy, and gross total resection. Greater extent of resection is the most important variable associated with long-term disease-free survival (26; 42; 03; 12).

The overall prognosis of patients with low-grade ganglioglioma is favorable, with a 95% 7.5-year recurrence-free survival rate (08). Survival rates of 93% at 5 year, 98% at 7.5 year, and 94% at 15 year have been reported from large series (26; 03; 08).

Brainstem and spinal cord gangliogliomas tend to have a worse prognosis than supratentorial tumors because of increased subtotal resection and operative morbidity (19). In one retrospective review including only patients with brainstem gangliogliomas, the 3-year survival rate was 91%, with a 3-year event-free survival rate of 68% and a mean recurrence-free survival rate of 5.5 months (35). The 5-year survival rate for brainstem gangliogliomas compared to non-brainstem gangliogliomas was reported in two large studies showing 79% to 81% versus 93% to 97%, respectively (19; 08). Brainstem gangliogliomas also exhibited a 3-year event-free survival rate and a 5-fold increase risk of recurrence (19).

In a large population-based study of 703 adults with low-grade ganglioglioma, younger age, female gender, temporal lobe location, and gross total resection were positive prognosis factors (22).

Anaplastic ganglioglioma. The previous 2016 WHO Classification included an anaplastic variant for those gangliogliomas with features such as high mitotic activity, microvascular proliferations, or necrosis in the glial component, often associated with aggressive clinical behavior. However, as most cases of anaplastic gangliogliomas lacked molecular analyses to exclude other high-grade glioma subtypes, the 2021 WHO Classification has abolished WHO grade 3 gangliogliomas. Indeed, in the largest multicenter retrospective analysis of 43 adults with pathologically confirmed anaplastic ganglioglioma, survival was only slightly improved compared to glioblastomas despite gross total resection and adjuvant therapy (52). It is possible that some prior reports of anaplastic gangliogliomas included higher-grade glial tumors.

Epilepsy. The prognosis for epilepsy in the setting of ganglioglioma is excellent. The meta-review of patients after ganglioglioma resection on epilepsy outcomes, including 20 retrospective articles since 1995, with a total of 553 patients, concluded that resection leaves most patients seizure-free and many with freedom from antiepileptic therapy, regardless of patients’ demographic, tumor characteristic, and operative variables (02). Although reporting standards vary widely, the most consistent finding across studies was the correlation of increased seizure freedom with increased extent of resection. Other prognostic factors associated with seizure freedom included shorter duration of epilepsy and younger age at surgery. Reported rates of seizure freedom following surgery ranged from 63% to 100%, with mean follow-up intervals ranging from 3 to 10 years. Many of the included studies had follow-up times of longer than 5 years, suggesting durable response. Between 17% to 77% of seizure-free patients were weaned from antiepileptic drugs in the studies reporting this measure (02; 30).

Special considerations

Pregnancy

No data are available to suggest any correlation of this tumor with pregnancy. Non-enhanced MRI is the imaging modality of choice and has been demonstrated safe for both the mother and the fetus as gadolinium crosses the placenta, although it has not been associated with birth defects at conventional doses (50). Symptomatic relief of headaches and seizures can be accomplished with well-known medications accepted as being of low fetal risk. Hydrocephalus, if serious enough to produce papilledema or other significant effects, can be surgically corrected during pregnancy, as demonstrated in one review (43).

Anesthesia

No special anesthetic precautions are mandated by the presence of this tumor. General symptoms of increased intracranial pressure may require an alteration in patient preparation for anesthesia.