Glioneuronal and Neuronal Tumors

Main Text

Preamble

The 5th edition WHO classification of CNS neoplasms groups gliomas, glioneuronal tumors, and neuronal tumors together. Gliomas are—by far—the largest group of neoplasms in this group. In the previous chapters, we discussed adult-type diffuse gliomas, pediatric-type diffuse low-grade gliomas, pediatric-type diffuse high-grade gliomas, and circumscribed astrocytic gliomas.

Glioneuronal and neuronal tumors—much less common than the large, very broad group of gliomas discussed in previous chapters—accounts for only 1-2% of all primary brain tumors. This diverse collection of tumors includes both familiar entities, e.g., ganglioglioma as well as a number of newly recognized entities, such as multinodular and vacuolating neuronal tumor (MVNT) and myxoid glioneuronal tumor (MGNT).

Glioneuronal neoplasms are clinically important as they are usually relatively benign, slow-growing tumors that are frequently associated with epilepsy.

Glioneuronal Tumors

Preamble

We begin this section with a brief overview of ganglion cell tumors followed by a discussion of the most common histologically mixed glioneuronal neoplasm, ganglioglioma. We then turn our attention to desmoplastic infantile ganglioglioma followed by a discussion of dysembryoplastic neuroepithelial tumor (DNET), now recognized as one of the more common causes of temporal lobe epilepsy. We close the discussion of glioneuronal tumors with the pathology and imaging of several uncommon neoplasms, such as MVNTs, MGNTs, and rosette-forming glioneuronal tumors.

Overview of Ganglion Cell Tumors

Ganglion cell tumors are benign, well-differentiated neoplasms characterized by the presence of dysplastic ganglion cells. Two types of ganglion cell tumors are recognized: Gangliogliomas and gangliocytomas.

The vast majority of ganglion cell tumors are histologically mixed lesions that contain both neoplastic ganglion cell and glial elements. These neoplasms are called gangliogliomas and designated as CNS WHO grade 1.

Gangliocytomas—tumors that demonstrate exclusive neoplastic ganglion cell composition—are relatively rare and are discussed briefly following the detailed discussion of glioneuronal neoplasms.

Ganglioglioma

Terminology

Gangliogliomas (GGs) are well-differentiated, slow-growing tumors. They are so-called biphasic tumors that are composed of neuronal and glial elements, most commonly an admixture of dysmorphic ganglion cells and neoplastic glial cells.

Etiology

The neuronal and glial components in GGs both likely derive from a common precursor cell. The most frequent genetic alterations are MAPK pathway activations, most often BRAF V600E mutations (40-60%) or other MAPK pathway alterations, such as RAF1 fusion, KRAS mutation, or NF1 mutation or deletion.

Pathology

Location

GGs occur throughout the CNS. Most are solitary lesions arising in the cerebral hemispheres. Between 50-75% originate in the temporal lobe. The next most common site is the frontal lobe (10% of GGs). Approximately 15% of GGs are found in the basal ganglia or posterior fossa, usually either in the brainstem or cerebellum. GGs vary in size from 1-6 cm and virtually never metastasize.

Gross Pathology

GGs are superficially located, well-delineated neoplasms that often expand the cortex (21-1). The most common appearance is that of a cyst with mural nodule or a solid tumor (21-2). Calcification is common, but gross hemorrhage and frank necrosis are rare.

Microscopic Features

The histologic hallmark of GG is its combination of neuronal and glial elements, which can be intermixed or geographically separated. Varying numbers of dysplastic neurons are interspersed with the glial component, which constitutes the proliferative and neoplastic element of the tumor. Astrocytic cells with pilocytic or fibrillary-like features are the most common glial element. GGs are designated as CNS WHO grade 1 neoplasms.

Grading

GGs with anaplastic features in the glial component (e.g., conspicuous mitotic activity, necrosis, &/or microvascular proliferation) have been termed anaplastic gangliogliomas (AGs) by some authors and provisionally designated as grade 3 lesions. Many reported AGs lack diagnostic molecular pathology to exclude other high-grade glioma subtypes, such as H3 G34-mutant hemispheric glioma. The 2021 WHO concludes further studies are needed to confirm the existence of AG.

GGs are CNS WHO grade 1 neoplasms. Malignant degeneration of a preexisting grade 1 GG is rare, occurring in 1-5% of cases.

Aggressive ganglion cell tumors with anaplasia in the glial component (i.e., those with conspicuous mitotic activity, high Ki-67 index, microvascular proliferation, and occasional necrosis) have been reported both at initial presentation and at the time of recurrence. These tumors have been called anaplastic gangliomas by some authors and provisionally designated as grade 3 lesions. However, DNA methylation testing of some tumors reported as AG on initial histopathology and immunohistochemistry shows these tumors often represent other well-defined CNS WHO diagnoses, most often pleomorphic xanthoastrocytoma (PXA), glioblastoma, and other diffuse pediatric-type high-grade gliomas.

Clinical Issues

GG is predominantly a tumor of children and young adults; 80% of patients are younger than 30 years old. Peak presentation is 15-20 years old. Chronic, pharmacologically resistant temporal lobe epilepsy is present in the majority of cases. Seizures are generally the complex partial type.

GGs are typically very slow-growing neoplasms. Complete surgical resection is generally curative with 80% of patients becoming seizure free after tumor removal.

Imaging

General Features

GGs are cortically based superficial parenchymal lesions that have two general imaging patterns: (1) A well-defined solid or partially cystic mass with mural nodule (21-2)and (2) a diffusely infiltrating, less well-delineated mass with ill-defined borders and patchy enhancement (less common).

CT Findings

A cystic component is seen in nearly 60% of cases. Approximately 30% have a well-circumscribed hypodense cyst with isodense mural nodule (21-3A), whereas 40% are primarily hypodense. Between 30-50% of GGs calcify. Hemorrhage is rare. Only 50% of GGs enhance following contrast administration. Patterns vary from solid, rim, or nodular to cystic with an enhancing nodule.

MR Findings

GGs are hypo- to isointense relative to cortex on T1 and hyperintense on T2/FLAIR (21-3B). Surrounding edema is generally absent. Enhancement varies from none or minimal to moderate. The classic pattern is a cystic mass with an enhancing mural nodule (21-3). Homogeneous solid enhancement also occurs. Ill-defined, patchy enhancement is atypical and associated with a worse clinical outcome (21-4).

Differential Diagnosis

A supratentorial hemispheric pilocytic astrocytoma can present as a cyst with an enhancing nodule. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY)often calcifies and can be indistinguishable from GG. PXA often has a “cyst + mural nodule” and can resemble GG but frequently has a dural “tail.”

DNET is a superficial cortical neoplasm that typically has a multicystic bubbly appearance. A hyperintense rim surrounding the mass on FLAIR scan is common. In contrast to GG, enhancement is rare.

Solid, nonenhancing GGs can resemble an astrocytoma, IDH-mutant. Oligodendroglioma is rare in children; it commonly involves the cortex but is typically more diffuse and less well delineated.

Desmoplastic Infantile Ganglioglioma/Astrocytoma

Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are rare, benign cerebral hemispheric glioneuronal or glial tumors (21-5). The vast majority of DIGs/DIAs occur before the age of two years and typically present with macrocrania, bulging fontanelles, and hemiparesis.

Pathologically, DIGs/DIAs exhibit a biphasic morphology with mixed astrocytic and neuronal (ganglionic) components (DIG) or an astrocytic component only (DIA). Tumor cells are embedded in an extensive peripheral desmoplastic stroma that often adheres to the dura. Mitotic activity is rare. DIG/DIA is a CNS WHO grade 1 tumor.

On imaging studies, DIGs/DIAs are typically large, bulky, superficially located hemispheric tumors with mixed cystic/solid components. The cystic components can be uni- or multilocular, are frequently quite large, and are hypointense on T1WI and hyperintense on T2WI. Peripheral edema is minimal or absent. Intense but heterogeneous enhancement of the solid component is present. The cyst walls and septations also often enhance (21-6).

Despite their ominous-appearing imaging, gross total resection generally results in long-term survival. A few cases of CSF dissemination have been reported.

The imaging differential diagnosis of DIG/DIA is limited. Infant-type hemispheric gliomas have an infiltrative growth pattern, are more heterogeneous, often hemorrhage, and have a low ADC. Embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid/rhabdoid tumor (AT/RT) can occur in the same age group as DIG/DIA but are less often grossly cystic and often appear hyperdense on CT. Supratentorial ependymoma, ZFTAfusion positive occurs in children and young adults (generally not infants). Its cysts are often less complex than DIG/DIA, and the solid portion of the tumor is less peripherally located than DIG/DIA.

Dysembryoplastic Neuroepithelial Tumor

Ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET or DNT) are the two most common long-term epilepsy-associated tumors (so-called LEATs).

Terminology

DNET is a benign, typically cortically based lesion characterized by a lobulated, multinodular architecture with a pathognomonic glioneuronal element (21-7).

Etiology

FGFR1 alterations are key events in the pathogenesis of DNET and are present in 40-80% of cases. BRAF p.V600E mutations occur in up to 50% cases. DNETs may also occur in RASopathies, such as neurofibromatosis type 1 and Noonan syndrome.

Pathology

Location

DNETs are superficial, cortically based neoplasms. 2/3 are located in the temporal lobes, whereas 1/3 occur in the frontal lobes. Other locations, such as the lateral ventricle, are rare.

Gross Pathology

Grossly, DNETs thicken and expand the cortex. Most are solitary, varying in size from millimeters to several centimeters. Mucoid substances, solid areas, and small cysts are present in varying proportions (21-10).

Microscopic Features

Microscopic hallmarks of DNETs are its multinodular intracortical growth pattern, “floating neurons” in a mucoid matrix, and a pathognomonic “specific glioneuronal element” (bundles and columns of axons lined by small oligodendroglia-like cells). The adjacent cortex is dysplastic in nearly 80% of DNETs.

Diagnostic Molecular Pathology

DNETs have a distinct methylation and transcriptional profile. FGFR1 gene alterations are characteristic of DNETs and found in 40-80% of cases, although not specific to this diagnosis. BRAF mutations occur in 50% but should prompt diagnostic consideration of other entities, such as ganglioglioma and MAPK pathway-altered diffuse low-grade glioma.

Grading

DNETs are CNS WHO grade 1 neoplasms.

Clinical Issues

DNET is a tumor of children and young adults. The vast majority present before the age of 20 years, typically with pharmacologically resistant partial complex seizures. Although DNETs account for only 1% of all primary CNS neoplasms, they are second only to ganglioglioma as a cause of temporal lobe epilepsy.

DNETs exhibit little or no growth, but because cortical dysplasia is frequently associated with DNET, a more aggressive resection is often performed. Long-term clinical follow-up usually demonstrates no tumor recurrence, even in patients with subtotal resection. Malignant transformation and CSF dissemination are exceptionally rare.

Imaging

DNET has a distinct appearance on neuroimaging studies. A well-demarcated, triangular or wedge-shaped, “pseudocystic” or “bubbly” cortical/subcortical mass in a young patient with longstanding complex partial epilepsy is highly suggestive of the diagnosis (21-8).

NECT scans disclose a hypodense cortical/subcortical mass (21-9A). Calcification is seen in 20% of cases. Gross intratumoral hemorrhage is rare. Focal bony scalloping or calvarial remodeling is common with tumors adjacent to the inner table of the skull.

A multicystic or septated appearance is typical on MR (21-11A). DNETs are strikingly hyperintense on T2WI (21-11B) (21-9B). A FLAIR-hyperintense rim (T2/FLAIR “mismatch” sign) along the tumor periphery is present in 75% of cases (21-11C) (21-9C) (21-12). Peritumoral edema is absent. “Blooming” on T2* (GRE, SWI) occurs in a few cases, more likely related to calcification than to hemorrhage.

DNETs generally show little or no enhancement on T1WI C+(21-9D). When present, enhancement is generally limited to a mild nodular or punctate pattern.

Differential Diagnosis

The main differential diagnoses are focal cortical dysplasia (FCD) (often associated), ganglioglioma, and multinodular and vacuolating neuronal tumor of the cerebrum (MVNT). The bubbly appearance of DNET and FLAIR-hyperintense rim are helpful distinguishing features. MVNTs are typically multifocal and occur in the deep layers of the cortex and white matter, not superficially located like DNET.

A newly recognized tumor, myxoid glioneuronal tumor (MGNT) is also T2 hyperintense but occurs primarily in the septum pellucidum, subcallosal area, or juxtaventricular white matter. Similar to DNETs, MGNTs often have a FLAIR-hyperintense rim.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) more often calcifies and exhibits a somewhat more infiltrative growth pattern. Angiocentric glioma closely resembles DNET on imaging, but a hyperintense rim is seen on T1WI, not FLAIR. A stalk-like extension toward the lateral ventricle is common.

Diffuse Glioneuronal Tumor With Oligodendroglioma-Like Features and Nuclear Clusters

Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) is included in the 2021 5th edition WHO as a provisional, molecularly defined type of neuroepithelial tumor that most often occurs in children with a median age of 9-10 years. The most common presenting symptoms are seizures.

DGONCs are characterized by nuclear clusters of oligodendroglioma-like cells, strong OLIG2 and synaptophysin expression, and absence of widespread GFAP expression. Histology varies from well-differentiated tumors with low mitotic index to undifferentiated cases with brisk mitotic activity. No WHO definitive grade has been established.

A distinct methylation profile of DGONC is currently the only method to clearly identify this neoplasm and is considered essential to establish the provisional diagnosis.

To date, reported cases have been located in the cortex and subcortical white matter of the frontal or temporal lobe. DGONCs adjacent to bone often demonstrate remodeling consistent with a low-grade glioneuronal tumor. DGONCs appear sharply demarcated and are most often hyperintense on T2WI and FLAIR with a ground-glass-like appearance. The presence of internal cysts within the mass is common. Perifocal edema is typically minimal or absent. Enhancement is absent in the majority of cases and, when present, is mild to moderate. Restricted diffusion is uncommon.

Papillary Glioneuronal Tumor

Papillary glioneuronal tumor (PGNT) is a rare CNS WHO grade 1 neoplasm that primarily affects young adults. PGNTs are characterized by PRKCA gene fusion and exhibit a characteristic methylation profile. Histopathologically, PGNTs are biphasic tumors with both pseudopapillary glial structures and interpapillary neuronal components.

PGNTs occur in the cerebral hemispheres, often peripherally located or in the deep periventricular white matter adjacent to the lateral ventricles. The most common imaging presentation is a well-circumscribed T2-/FLAIR-hyperintense cyst with a mural nodule (21-13) (21-14). Typically, the nodule enhances intensely; cyst wall enhancement varies.

Rosette-Forming Glioneuronal Tumor

Terminology

Rosette-forming glioneuronal tumor (RGNT) is a rare midline/juxtamidline glioneuronal tumor with two distinct components: Neurocytes (“rosette forming”) and glial cells (piloid, oligodendroglia-like cells that resemble pilocytic astrocytoma). RGNT was originally described as occurring only in the fourth ventricle but is now recognized as occurring in other anatomic locations as well.

Etiology

RGNTs are characterized by FGFR1 mutations with frequent co-occurrence of a PIK3CA or PIK3R1&/or loss-of-function NF1 mutation.

Pathology

Location

RGNTs arise in or near midline structures. Initially reported in the fourth ventricle (and therefore designated RGNT “of the fourth ventricle”), the pineal region &/or aqueduct are also common sites. RGNTs can also involve the midbrain, thalami, quadrigeminal plate, brainstem, and cerebellum.

Size and Number

Size varies from tiny, nodular lesions to large mixed cystic/solid masses. RGNTs can spread both within the parenchyma and CSF. In nearly 1/2 of all cases, multiple small satellite lesions in the thalami, vermis, and cerebellum are present at initial diagnosis. Leptomeningeal (25%) and subependymal (15%) spread are common.

Gross Pathology

RGNTs are soft, gelatinous-appearing, well-demarcated tumors.

Microscopic Features

RGNTs exhibit biphasic histomorphology with distinct neurocytic and glial elements. The neurocytic elements form a rosette (ring-like array) around neuropil cores. The glial tumor component typically exhibits piloid or oligodendroglia-like histomorphology.

Diagnostic Molecular Pathology

Methylation class (MC) RGNT (MC-RGNT) delineates RGNT from other neurocytic CNS tumors with similar histologic features (e.g., pilocytic astrocytoma) or leptomeningeal dissemination [e.g., diffuse leptomeningeal glioneuronal tumor (DLGNT)].

Staging, Grading, and Classification

RGNTs are CNS WHO grade 1 neoplasms even if dispersed tumor nodules or leptomeningeal dissemination is present. Malignant transformation has been reported but is exceptionally rare.

Clinical Issues

RGNTs are tumors of adolescents and young/middle-aged adults. Headache and ataxia are common presenting symptoms.

Imaging

General Features

A mixed solid/cystic mass in the fourth ventricle, aqueduct, tectum, or thalamus is typical (21-15). Dispersed satellite lesions are present in nearly 50% of cases (21-16).

CT Findings

A mixed solid/cystic mass with blood-fluid levels is common. Calcification occurs in 25% of cases.

MR Findings

RGNTs are T2/FLAIR heterogeneously hyperintense with variable intratumoral cysts and hemorrhage. Multiple discrete satellite lesions in the thalami and cerebellum are common (21-16A). Enhancement varies from none to ring-like (21-16C) (21-17C)with a bell pepper configuration reported in some cases (21-15D). If satellite lesions are present, many or most do not enhance, even if the primary tumor mass does (21-17).

Differential Diagnosis

Solitary neoplasms that can resemble RGNT include pilocytic astrocytoma. Ependymoma or subependymoma in the fourth ventricle can mimic RGNT, although the bell pepper appearance on T1 C+ is highly suggestive of RGNT. RGNT with multifocal satellite lesions can resemble DLGNT.

Myxoid Glioneuronal Tumor

Terminology

Myxoid glioneuronal tumor (MGNT) is a CNS WHO grade 1 glioneuronal tumor characterized by PDGFRA p.K385 mutation and oligodendrocyte-like tumor cells embedded in a prominent mucoid matrix.

Pathology

Location

MGNTs are classically located in the septum pellucidum (nucleus accumbens or cavum septum pellucidum) or subcallosal area. Less common reported sites include the corpus callosum genu and deep white matter adjacent to the lateral ventricles. CSF spread in/around the ventricles at the time of initial diagnosis is not uncommon. Multifocal dissemination to the spinal cord and nerve roots has also been reported.

Gross Pathology

Because of their myxoid stroma, MGNTs are typically well-delineated, soft grayish-white gelatinous masses.

Microscopic Features

MGNTs consist of oligodendrocyte-like tumor cells embedded in a prominent myxoid stroma. Floating neurons, neurocytic rosettes, &/or perivascular neuropil resembling DNETs and RGNTs are not uncommon. Mitotic activity is low or absent.

Staging, Grading, and Classification

MGNTs are CNS WHO grade 1 tumors.

Diagnostic Molecular Pathology

DNA methylation profiling should be performed because of the histologic overlap with other low-grade tumors, such as MGNT, DNET, and pilocytic astrocytoma. Unlike RGNT or DNET, PIK3CA/PIK3R1 alterations or BRAF/FGFR1 mutations are absent. Most MGNTs have a PDGFRA p.K385L/I dinucleotide mutation. Less common mutations in the extracellular PDGFRA domain have been reported.

Clinical Issues

MGNTs occur across a wide age range (6-65 years), but most typically occur in children and young adults. Some cases are discovered incidentally on imaging. Others present with headache, ataxia, &/or vertigo.

MGNTs are indolent, slow-growing tumors. Prognosis is excellent, and patients do well even with CSF dissemination.

Imaging

The most common appearance of MGNT is a well-delineated septum pellucidum/corpus callosum mass. MGNTs are hypointense on T1WI and, because of their myxoid stroma, are very hyperintense on T2WIs (21-18B). A T2/FLAIR “mismatch” sign is common with a bright peripheral rim of hyperintensity surrounding an iso-/hypointense center (21-18A). Some cases exhibit intraventricular dissemination at initial presentation (21-19). MGNTs typically do not enhance on T1 C+(21-18C).

Differential Diagnosis

MGNTs in the corpus callosum genu/septum pellucidum may resemble subependymoma. Rosette-forming glioneuronal tumor is rare in the septum pellucidum. Central neurocytoma is typically located in the body of the lateral ventricle, not in the septal area. DNET shares some imaging features with MGNT but is most common in the superficial cortex, not the white matter. Colloid cyst is typically located in the foramen of Monro and splays the fornices. Ependymal cyst (of the lateral ventricle) is thin-walled, hyperintense on CISS, and suppresses on FLAIR.

Diffuse Leptomeningeal Glioneuronal Tumor

Terminology

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a mixed glioneuronal neoplasm composed of oligodendrocyte-like cells and is characterized by chromosome 1p loss. More than 80% of cases exhibit KIAA1549:: BRAF fusion while 1q gain is found in 56%.

Pathology

Location

DLGNTs are most commonly located in the leptomeninges and basal cisterns. Between 70-75% of cases exhibit diffuse nodular leptomeningeal thickening in the suprasellar cistern, sylvian fissures, and posterior fossa. Tumor deposits are frequent in the cerebral ventricles, along cranial nerves and the spinal cord surface (21-20).

Discrete parenchymal lesions are common, typically spreading along the Virchow-Robin (perivascular) spaces (VRSs). Up to 1/3 of cases have an isolated spinal cord mass.

Size and Number

Innumerable small, cyst-like tumor nodules are present throughout the basal cisterns. Nodular thickening of the cranial and spinal leptomeninges is typical.

Gross Pathology

Diffuse, nodular, glistening, mucoid-appearing leptomeningeal infiltrates along brain/cord surfaces are typical.

Microscopic Features

DLGNTs exhibit oligodendroglioma-like morphology. Features of both glial and neuronal differentiation with synaptophysin-positive neurocytes and GFAP-positive glial cells are present. Parenchymal extension along the VRSs is common, and focal mass-like lesions may be present.

Staging, Grading, and Classification

DLGNT comprises two distinct methylation classes (MCs): MC-1 and MC-2. Recent studies show that chromosome 1q gain is the only significant prognosticator affecting progression-free survival in DLGNTs, regardless of MC. While no formal CNS WHO grades have been established, DLGNTs without 1q gain have outcomes compatible with CNS WHO grade 1. Most all MC-2 tumors have 1q gain with median time to death of 51 months, an outcome compatible with WHO grade 3 lesions.

Clinical Issues

Epidemiology

DLGNTs are rare and generally occur in childhood (3-14 years with median age of five years). There is a slight male predominance.

Presentation

Headaches, seizures, and gait imbalance are common.

Natural History

Clinical behavior is variable. Prognosis is strongly associated with 1q status. Tumors with 1q gain are ~ 20x more likely to progress. MC-2 tumors with 1q gain have inferior survival compared to MC-1 tumors (± 1q gain).

Imaging

General Features

Multiple T2-hyperintense cyst-like nodules along the surfaces of the brain &/or spine accompanied by thick/nodular leptomeningeal enhancement are the classic imaging findings

MR Findings

Multiple small, T1 hypo- and T2-hyperintense leptomeningeal cysts cover the brain surfaces, especially along the basilar cisterns, sylvian fissures, and cerebellum (21-21A) (21-21B) (21-22A). The cysts remain hyperintense on FLAIR. Thick, nodular leptomeningeal enhancement along the pial surfaces is typical (21-21C). The entire spine should be imaged, as intraparenchymal lesions are common as is diffuse enhancement along the cauda equina (21-22).

Differential Diagnosis

Leptomeningeal carcinomatosis from diffuse pediatric-type high-grade gliomas, high-grade astrocytoma with piloid features, and occasionally even pilocytic astrocytomas can exhibit leptomeningeal dissemination. The associated T2-hyperintense nodules along the brain and spinal cord that are so characteristic of DLGNTs are absent.

Sulcal-cisternal enhancement from pyogenic meningitis is typically smooth rather than nodular. Occasionally, TB meningitis can exhibit a nodular configuration. “Racemose” neurocysticercosis with T2-hyperintense scolices in the CSF spaces can mimic DLGNT. Neurosarcoidosis typically affects older patients, and dural-based focal masses are more common than diffuse nodular meningeal lesions.

Multinodular and Vacuolating Neuronal Tumor

Terminology

Multinodular and vacuolating neuronal tumor (MVNT) was codified in the 2021 5th edition WHO as a true clonal neoplasm with MAPK pathway-activating abnormalities.

Pathology

Location

MVNTs are discrete or coalescent clusters of variably sized (usually small) nodules along the inner (deep) surface of the cortical ribbon in a U-shaped configuration (21-23). Scattered discrete nodules extending into the deep white matter toward the lateral ventricles are common. A few cases have been reported in the cerebellar hemispheres and vermis. These have been termed multinodular and vacuolating posterior fossa lesions of unknown significance (MV-PLUS).

Gross Pathology

MVNTs are characterized by multiple discrete or coalescent nodules, often with vacuolar changes.

Microscopic Features

Discrete tumor nodules with mature-appearing neurons and prominent intracellular, stromal vacuolation are typical (21-24). MVNTs are OLIG2 and synaptophysin positive, GFAO and NeuN negative. Mitotic activity, necrosis, and microvascular proliferation are absent.

Staging, Grading, and Classification

MVNTs are CNS WHO grade 1 lesions.

Clinical Issues

Presentation

Most MVNTs are discovered incidentally on imaging studies. Occasionally, patients present with nonfocal headache &/or, rarely, seizures.

Natural History

MVNTs are benign, clinically indolent, nonprogressive lesions. The size and imaging appearance are stable over multiple years. Unless proven as epileptogenic (very rare), MVNTs are “leave me alone” lesions that do not need to be biopsied or followed up.

Demographics

MVNTs occur at all ages. The mean age of reported cases is 39 years.

Imaging

General Features

The most characteristic MR finding is a cluster of variably sized, usually small (1- to 5-mm), sharply marginated clusters of T2-/FLAIR-hyperintense nodules (“bubbles”) hugging the inner surface of the cortical ribbon in a distinct U-shaped configuration (21-25). Discrete nodules may extend into the deep white matter (21-28).

CT Findings

CT is usually normal. Larger lesions may appear as a faint, ill-defined wedge or U-shaped subcortical hypodensity (21-26A). Calcification, mass effect, and hemorrhage are absent.

MR Findings

MVNTs are isointense with cortex on T1WI, hyperintense on T2WI, and do not suppress on FLAIR (21-27). MVNTs are occasionally bright on DWI/ADC (21-26B), which can be helpful in detecting small/subtle lesions. MVNTs do not enhance on T1 C+(21-29).

pMR shows slightly decreased cerebral blood volume. MRS can be normal but may show slightly increased Cho and decreased NAA (21-28C).

Most MVNTs are small. Occasionally, larger groups of discrete and coalescent nodules can be seen (21-28). Mass effect is absent, even with larger lesions.

Differential Diagnosis

The appearance of MVNTs is virtually pathognomonic. Subtle, scattered discrete nodules may extend into the deep white matter toward the lateral ventricle, aiding the diagnosis. Most MVNTs are discovered incidentally on imaging and are almost always asymptomatic.

MVNTs are not “atypical”or “enlarged perivascular spaces”as perivascular spaces spare the cortical ribbon and suppress on FLAIR.

Focal cortical dysplasia affects the superficial, not the deep, cerebral cortex and is generally isointense with gray matter on all sequences. The affected cortex is typically distorted and dysplastic appearing.

MVNTs are sometimes mistaken for low-grade epilepsy-associated tumors, such as ganglioglioma, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, and DNET.

MULTINODULAR AND VACUOLATING NEURONAL TUMOR

Etiology

• True clonal neoplasm

MAPK pathway-activating abnormalities

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