Glioneuronal Tumors: A Pictorial Review and Practical Approach

Desmoplastic infantile gangliogliomas (DIGs) and astrocytomas (DIAs) occur most often in infants under age 24 months. ⁴ DIGs demonstrate a slight male predominance (~60%) while DIAs have no gender predilection. ^4,5 In contrast to other glioneuronal tumors, DIG/DIA presents with seizures in a minority of cases. ^4,6 DIGs/DIAs are large tumors most often located within the superficial cortex in the frontal or parietal lobes (Figure 1). ^4,6 Cystic components are found in most cases (>90%) and often located deep to solid components (Figure 1). ⁶ The peripheral solid components enhance vividly. ^4,5 While these tumors are considered benign, they can demonstrate metastatic behavior; one case series has documented metastasis at presentation in 11.7% of cases (Figure 1B). ⁷

The main differentials are pleomorphic xanthoastrocytoma (PXA), ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), and atypical teratoid/rhabdoid tumor (AT/RT). DIAs/DIGs typically present at younger ages and have stronger T2 hyperintensity compared with PXAs and gangliogliomas. ⁴ In addition, DIAs and DIGs enhance more strongly than DNETs. ^4,6 AT/RTs are more likely to calcify and hemorrhage than DIAs and DIGs; however, calcification and hemorrhage can be seen in DIA/DIG cases with acute clinical symptoms. ^4,5 Total resection is uncommon (27-30% of cases), and adjuvant therapy is recommended only in cases of documented tumor progression. ⁶

Imaging offers a few key predictors of patient outcomes. ⁶ The leptomeninges are the most common site of metastasis (Figure 1), but intracranial and spinal metastases have also been reported. ⁶ Midline location is associated with more aggressive histological behavior, increased chance of recurrence, and increased intraoperative risk. ^4,6 Specifically, involvement of the hypothalamus should be reported, as it is associated with increased mortality secondary to postoperative respiratory compromise. ⁴ Finally, the solid components of DIAs/DIGs usually encase vessels, which can help with diagnosis but can also limit surgical resection. ⁶

Slow-growing and cortical-based, DNETs most commonly affect patients <20 years and are found in the temporal and frontal lobes. ⁸

DNETs demonstrate a characteristic multicystic, “bubbly” lesion with high T2 and low T1 signal (Figure 2). ⁸ Multicystic morphology is associated more with DNETs than with other cortically based lesions such as oligodendrogliomas and gangliogliomas. ⁹ Most DNETs extend into the subcortical white matter, occasionally in a tapered fashion. ⁹ The FLAIR rim sign has been suggested as a specific finding for DNET (82% specificity in one case series) (Figure 2B). ¹⁰

Some DNETs will demonstrate peripheral contrast enhancement, may contain macroscopic calcification (~20%), and rarely contain intratumoral hemorrhage. ¹¹ They frequently present with multiple satellite lesions, preferentially occurring along the medial aspect of the primary lesion. ⁸ Additionally, focal cortical dysplasia can be associated with higher-grade DNETs. ¹²

Surgical resection provides effective seizure control. Persistent seizures have been seen in 46% of patients with satellite lesions but only 18% of patients without satellite lesions. ¹³

Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) were previously considered a subtype of DNET, differentiated via mutations within the MAPK pathway. ¹⁴ They are primarily seen in children and young adults, ¹⁵ occurring only rarely in older adults. ¹⁶ Typically, PLNTYs are cortically based, heterogeneous cystic or mixed solid cystic masses (Figure 3) classically with central calcification ¹⁷ and mild, heterogeneous enhancement. ¹⁸ A “transmantle”-like signal abnormality (linear increased T2 signal in the deep white matter extending peripherally) can be seen, with some mixed evidence around its postresection persistence for predicting poorer seizure control. ¹⁸ Beyond seizure-associated morbidity, the tumor follows a benign course with minimal mass effect. There is low recurrence after total resection ¹⁷ ; however, a recent meta-analysis reported that the extent of resection was not significantly associated with postoperative seizure control. ¹⁹

Gangliogliomas are the most common epilepsy-associated neoplasm, typically found in the temporal and frontal lobes. ^20,21 They can occur infratentorially, including in the spinal column. They occur in both pediatric and adult populations, with most pediatric cases diagnosed in those over the age of 10 years ²¹ and adult cases at a median age of 32 years. ²²

On imaging, gangliogliomas are typically superficial, well-circumscribed mixed cystic and solid tumors, but a diffuse infiltrative appearance is possible. Enhancement is variable and associated with the solid components (Figure 4); infratentorial gangliogliomas are more likely to demonstrate “paintbrush” enhancement (dorsal predominant) compared with supratentorial tumors. ²² Brainstem gangliogliomas are associated with older patient age (median of 30 years), peritumoral edema, higher solid proportion, and lower rates of calcification. ²³

With their variable imaging appearance, the differential is wide, including PXA, PLNTY, and oligodendrogliomas. In general, PXAs enhance more vividly than gangliogliomas and very rarely calcify, while up to 50% of gangliogliomas calcify. ²³ Finally, gangliogliomas have been reported to have higher normalized cerebral blood volume and lower normalized apparent diffusion coefficient compared with oligodendrogliomas. ²⁴

Tumor locations associated with worse outcomes include the brainstem, cerebellopontine angle, spinal cord, and midline tumors. ²² Brainstem involvement is often the defining factor for total vs subtotal resection. ²¹ There is mixed evidence for the ability of resection extent to predict long-term outcomes. ^22,25,26 Finally, there have been rare case reports of malignant degeneration; in these cases, leptomeningeal involvement was common and MRS showed anaplastic features (increased choline, lipid, and lactate). ²²

Cerebral gangliocytomas (CGs) are rare (<3% of CNS tumors), occurring most frequently in children and young adults. ² These tumors typically arise in the cerebral cortex, most often in the temporal lobe (~75%) (Figure S1), though occasional exophytic and rare extra-axial presentations have been described.

Sometimes exhibiting variable imaging features, CGs can be difficult to distinguish from other tumors, particularly gangliogliomas. Meningioma is in the differential, given that CGs can be extra-axial and demonstrate a dural tail. ^2,27 MRS may be a helpful diagnostic adjunct, as CGs demonstrate a highly elevated choline signal and reduced N-acetylaspartate, a pattern more typical of high-grade gliomas than other glioneuronal tumors such as ganglioglioma. ²⁷ Diagnosis is ultimately based on histopathology.

Previously known as “DNET of the septum pellucidum,” ^1,28 myxoid glioneuronal tumors (MGTs) are now defined by a gain-of-function mutation in the PDGFRA gene. ²⁹ Given their similar histology and patient populations, MGTs and DNETs are difficult to distinguish from each other; therefore, imaging and genetic testing play an important diagnostic role.

The pathognomonic finding of MGT is location within the septum pellucidum (Figure 5), but they have also been reported in the midbrain. ²⁹ Other imaging characteristics are similar to DNETs, with a multicystic morphology with well-defined margins and variable enhancement. ³⁰ Unlike DNETs, no macrocalcifications have been reported in histologically proven MGTs. ²⁹

Originally classified as oligodendrogliomas, central neurocytomas (CNs) are now recognized as a distinct entity. ^31,32 These tumors present at a median age of 30-31 years and typically demonstrate no gender predilection. ^31,32

Classically, CNs are found in the frontal horn of the lateral ventricles in close association with the foramen of Monro. ^31,32 Most are unilateral at presentation, with bilateral involvement more common in larger tumors. ³² These tumors consist of mixed calcific, cystic, and solid tissue components, resulting in heterogeneous imaging characteristics (Figure 6). CNs may contain coarse “popcorn” calcifications on CT, ^31,32 while cystic components produce a “Swiss-cheese” or “soap bubble” appearance on T2 sequences. ^31,33 The solid tissue component dictates the degree of diffusion restriction and postcontrast enhancement, with the adjacent choroid plexus used for baseline enhancement comparison. ^31,33,34

While the imaging appearance of CNs can vary, specific characteristics can assist with diagnosis and prognosis. These include a broad-based septum pellucidum attachment (Figure 6), peripheral cystic components, periventricular edema, and the “scalloping sign,” a wavy ventricular wall with adjacent rows of cysts. ^12,15,16 On MRS, CNs typically demonstrate elevated choline and reduced creatinine and N-acetylaspartate ^31,33 ; elevated glycine is considered a sensitive but nonspecific finding for CN. ³²

Total resection is the gold standard treatment for CNs; however, this is limited by the degree of vascularity and potential neurologic complications, the rates of which range from 30% to 70%. ³³ Adjuvant radiation is controversial in cases of subtotal resection but may be considered for tumors that demonstrate atypical and/or aggressive histologic features (~20% of CNs). ^31,32,35 Imaging findings associated with aggressive histologic features include enhancement, larger size, and the presence of irregular vessels. ³⁶ Radiation is also considered for recurrent disease, which typically occurs 3-4 years post-treatment. ^31,35

Primarily occurring in adults, multinodular and vacuolating tumors (MVNTs) present at mean and median ages ranging from 38 to 45 years. ^37,38 They are benign tumors with very slow growth and do not typically require resection. ³⁸

Their classic MRI appearance is a cluster of nonenhancing T2 and FLAIR hyperintense nodules centered at the cortical-subcortical junction, most commonly in the temporal lobe (Figure 7), without restriction. ^37,38 The differential is wide and includes other glioneuronal tumors and non-neoplastic processes such as prominent perivascular spaces or focal cortical dysplasia. The most appropriate follow-up MRI protocol for MVNTs continues to be debated. ³⁸

Extremely rare entities, papillary glioneuronal tumors (PGNTs) primarily affect adults in their second decade. ³⁹ There is no gender-based predilection.

The imaging features of these tumors are similar to those of other glioneuronal tumors, with a mixed solid cystic appearance. The 2 features suggestive of PGNT are location—80% are within or adjacent to the lateral ventricles—and septated cystic components, though these are not specific. ⁴⁰ PGNTs are generally diagnosed histologically, genetically differentiated by the fusion of SLC44A1-PRKCA proteins. ⁴¹ Treatment involves resection, which has a good prognosis. ²

Rosette-forming glioneuronal tumors (RGNTs) are defined histologically ⁴² and typically present in adults at a mean of 23 years, with a slight female predilection (1.36:1). ⁴³ The classic location is adjacent to the 4th ventricle, with local parenchymal extension (Figure 8). ² Less common sites include the cerebellum and spine. ⁴³ Given their mixed solid-cystic composition, their imaging appearance is variable; thus, tissue sampling is required for diagnosis.

The main differential considerations are pilocytic astrocytoma and DNET. Most reported RGNTs are <3.0 cm, ⁴³ with a diameter <3.5 cm being just over 3 times more likely for RGNT. ⁴⁴ Calcifications in RGNTs are exceedingly rare, with only 2 cases reported, ⁴³ while pilocytic astrocytomas and DNETs have reported calcification incidences of 17% ⁴⁵ and 20%, ¹¹ respectively. Microhemorrhage is common in RGNTs (Figure 8), and while pilocytic astrocytomas can hemorrhage, it is exceedingly rare for DNETs, reported in 3%. ⁴⁶

While RGNTs are considered benign, ² mass effect can be significant and require resection. ⁴⁷ Pineal involvement is possible and should be reported, as it changes surgical approach. ⁴⁸ Overall recurrence rates between total and subtotal resection of these tumors are similar, at about 10% ⁴⁴ ; however, the recurrence/progression timeline for subtotal resection vs total resection is reported at an average of 2.9 and 6.2 years, respectively. ⁴⁴ Additionally, there is evidence that a higher proportion of solid tissue within the tumor predicts higher recurrence risk and worse histological features. ⁴³ Rarely, RGNTs can develop satellite lesions and CSF involvement, which can lead to drop metastases; thus, postcontrast series should be evaluated for leptomeningeal involvement. ^42,43 Finally, MRS usually shows elevated choline, reduced N-acetylaspartate, and absent lactate and lipid peaks ² ; deviations from this pattern should raise suspicion for malignant transformation.

Also known as Lhermitte-Duclos disease, dysplastic cerebellar gangliocytomas are found primarily in patients with Cowden syndrome. ⁴⁹ Arising in the cerebellum, they are benign, with no reported malignant transformation. ⁴⁹ Surgical resection provides definitive treatment in acute cases; however, these tumors often do not require intervention. ⁵⁰

MRI demonstrates a unilateral cerebellar parenchymal mass with T2 hyperintensity, no enhancement, and variable diffusion restriction. Widened cerebellar folia create the pathognomonic “tiger-stripe” pattern, ^49,50 which is primarily seen in adults. ⁵¹ SWI and contrast-enhanced sequences can demonstrate prominent vascular structures within the folia (Figure S2), ⁵² while MRS may reveal reduced choline and an inverted lactate peak. ^52,53 The differential is limited, but subacute infarct or cerebritis can be considered in patients with acute deterioration.