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Neuronal and Mixed Glioneuronal Tumors

  • Francesco CarlettiEmail author
Living reference work entry

Abstract

Neuronal and mixed neuronal-glial tumors are a group of rare tumors of the central nervous system (CNS) characterized by either neoplastic neuronal cells or a combination of neuronal and glial neoplastic cells. Most of these tumors are benign with a favorable prognosis, although there are a minority of anaplastic and aggressive tumors. Clinical neuroradiology plays an essential role in distinguishing these benign tumors from others with a less favorable outcome. The most sensitive radiological technique for imaging these tumors is Magnetic Resonance Imaging (MRI) but Computed Tomography (CT) may be used in an emergency setting, when MRI is contraindicated, and to detect calcifications. This chapter aims to offer an overview of neuronal and mixed neuronal-glial tumors with a focus on their imaging and pathological features as well as their clinical characteristics.

Keywords

Mixed neuronal-glial Glioneuronal DNT Ganglioglioma Gangliocytoma Lehrmitte-Duclos Neurocytoma Paraganglioma Multinodular and vacuolating neuronal tumor 

List of Abbreviations

ADC

Apparent diffusion coefficient

AGG

Anaplastic ganglioglioma

CECT

Contrast-enhanced computed tomography

Cho

Choline

CN

Central neurocytoma

CNS

Central nervous system

CSF

Cerebrospinal fluid

CT

Computed tomography

DCG

Dysplastic gangliocytoma of the cerebellum (Dysplastic cerebellar gangliocytoma)

DIA

Desmoplastic infantile astrocytoma

DIG (or DIGG)

Desmoplastic infantile ganglioglioma

DLGNT

Diffuse leptomeningeal glioneuronal tumor

DNT (or DNET)

Dysembryoplastic neuroepithelial tumor

DWI

Diffusion-weighted imaging

EVN

Extraventricular neurocytoma

FCD

Focal cortical dysplasia

FLAIR

Fluid attenuated inversion recovery

GC

Gangliocytoma

GFAP

Glial fibrillary acidic protein

GG

Ganglioglioma

GM

Gray matter

GRE

Gradient-recalled echo

IDH

Isocitrate dehydrogenase

iMRI

Intraoperative MRI

LDD

Lehrmitte-Duclos disease

MAP 2 K1

Mitogen-activated protein kinase 1

MB

Medulloblastoma

MIBG

Metaiodobenzylguanidine

MRI

Magnetic resonance imaging

MVNT

Multinodular and vacuolating neuronal tumor of the cerebrum

NAA

N-AcetylAspartate

NECT

Non-enhanced computed tomography

NeuN

Neuronal nuclear protein

NF-1

Neurofibromatosis type 1

PGL

Paraganglioma

PGNT

Papillary glioneuronal tumor

PNET

Primitive neuroectodermal tumor

PTEN

Phosphatase and tensin homologue

PXA

Pleomorphic xanthoastrocytoma

RGNT

Rosette-forming glioneuronal tumor

SDH

Succinate dehydrogenase

SHH

Sonic hedgehog

SWI

Susceptibility-weighted imaging

TLE

Temporal lobe epilepsy

WHO

World Health Organisation

WM

White matter

Introduction

Definition of Entity

Neuronal and mixed neuronal-glial tumors are rare neoplasms characterized by either neoplastic neuronal cells or a combination of neuronal and glial neoplastic cells. This group of tumors includes 14 entities, according to the most recent update (2016) of the World Health Organization (WHO) classification of Central Nervous System (CNS) tumors (see Table 1).
Table 1

List of neuronal and mixed neuronal-glial tumors

 

Entity

WHO grade

1.

Dysembryoplastic neuroepithelial tumor

I

2.

Gangliocytoma

I

3.

Ganglioglioma

I–II

4.

Anaplastic ganglioglioma

III

5.

Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

I (if neoplastic)

6.

Desmoplastic infantile astrocytoma and ganglioglioma

I

7.

Multinodular and vacuolating neuronal tumor of the cerebrum

I

8.

Papillary glioneuronal tumor

I

9.

Rosette-forming glioneuronal tumor

I

10.

Diffuse leptomeningeal glioneuronal tumor

Not assigned

11.

Central neurocytoma

II

12.

Extraventricular neurocytoma

II

13.

Cerebellar liponeurocytoma

II

14.

Paraganglioma

I

Basic Epidemiology/Demographics/Pathophysiology

Age at diagnosis of neuronal and mixed neuronal-glial tumor is variable ranging from 6 months for a desmoplastic infantile astrocytoma and ganglioglioma (DIA and DIG) to 50 years for a cerebellar liponeurocytoma. However, diffuse leptomeningeal glioneuronal tumor (DLGNT) and DIA and DIG occur preferentially in children. Tumors such as dysembryoplastic neuroepithelial tumour (DNT), ganglioglioma (GG), gangliocytoma (GC), and papillary glioneuronal tumor (PGNT) occur more frequently in children or young adults. Paraganglioma (PGL) and cerebellar liponeurocytoma are more frequently diagnosed in adults.

Clinical Scenario and Indications for Imaging

Neuronal or a mixed neuronal-glial tumor can occur in the brain or the spinal cord. Symptomatology varies with the location and size of the tumor. Broadly speaking one can distinguish between supratentorial and infratentorial tumors which differ in their clinical presentations. Patients with supratentorial neuronal and mixed neuronal-glial tumors often present with seizures. Patients with a DNT typically have drug-resistant focal epilepsy, with or without secondary seizure generalization. Patients with GG or GC have a history of chronic temporal lobe epilepsy or focal seizures. Headache and other symptoms or signs of raised intracranial pressure (either caused by the lesion itself or by obstructive hydrocephalus) are common presentations of both supra- and infratentorial tumors. In patients with DIAs and DIGs, signs of raised intracranial pressure include lethargy, rapidly progressive macrocephaly, tense and bulging fontanelles, and both eyes are driven downwards with the inferior border of the pupil covered by the lower eyelid (“setting sun” sign). Cerebellar signs may be present when the lesion is infratentorial (for instance in cases of cerebellar liponeurocytoma, Lehrmitte Duclos disease, but sometimes in cases of papillary glioneuronal tumor or rosette-forming glioneuronal tumor). Spinal PGL can present with low back pain, sciatica, motor deficits, sensory disturbance, and sometimes sphincter dysfunction. Finally, it is worth noting that some multinodular and vacuolating neuronal tumors of the cerebrum (MVNT) can be entirely asymptomatic, and in some cases, PGNT and RGNT are discovered incidentally on imaging performed for other reasons.

Imaging Techniques and Recommended Imaging Protocols

MRI and CT are the investigations of choice for detecting and characterizing neuronal and mixed neuronal-glial tumors.

Although CT images are less detailed than images obtained from MRI scans, CT remains the first line diagnostic examination in emergency settings when there are signs of raised intracranial pressure, or when patients present with nonspecific neurological presentations, which may occasionally be caused by a neoplasm. CT is ideal for quickly defining what might be causing the patient’s seizures or raised intracranial pressure. CT is also used in patients unable to have an MRI scan, because they have a heart pacemaker or other device incompatible with MRI, or in patients who would require an anesthetic to have an MRI. CT can reveal the presence of calcification, information which is not readily available on MRI.

MRI is the investigation of choice in the evaluation of neuronal and mixed neuronal-glial tumors. Dedicated “tumor protocol” may vary slightly from centre to centre in the choice of the pulse sequence and slice thickness, but typically includes post-contrast imaging. MR imaging protocols used to characterize tumors of the CNS are described elsewhere in this book (see “Clinical Presentations, Differential Diagnosis and Imaging Work-up of Cerebral Mass Lesions”). Dedicated “epilepsy protocols” (see “Long-Term Epilepsy Associated Tumours” for example) are used for patients presenting with focal epilepsies. Where possible, dedicated epilepsy protocols should be acquired on high-field strength (3 T) MRI scanners, which offer improved signal to noise ratio when compared to 1.5 T MRI scanners. A preoperative MRI, or CT if MRI is contraindicated or not available, obtained with fiducial markers, can be used for image-guided biopsy when the diagnosis is uncertain.

As the extent of tumor resection is an important prognostic factor in patients with neuronal and mixed neuronal-glial tumors, preoperative surgical planning relies upon MRI obtained a few days or immediately before the surgery. Additional imaging, such as Functional MRI (fMRI) and Diffusion-Tensor Imaging (DTI), may aid in surgical planning when tumors are located in the proximity of eloquent brain areas and in patients with intractable epilepsy (please refer to the chapter “Imaging Techniques for Neurosurgical Planning of Tumour Resection” of this book for further details about protocols). Unfortunately, the tumor localization based on preoperative MRI images is invalidated once the cranium and dura are opened. This is due to a phenomenon called “brain shift” which consists of anatomical and physiological changes; this sometimes makes an aggressive tumor resection difficult. The brain shift can be controlled with intraoperative MRI (iMRI). iMRI can help to delineate residual tumor from normal brain parenchyma intraoperatively and aid neurosurgeons in providing an accurate tumor resection.

Follow-up imaging consists of MRI scans (unless MRI is contraindicated). Where possible, MR sequences should be acquired identically to previous studies (using the same scanning plane, slice thickness, and sequences) to facilitate the comparison of scans. Follow-up imaging should be performed at intervals as determined by the local neuro-oncology multidisciplinary team meeting. A baseline MRI scan should be considered within 72 h of surgical resection. The timing of clinical reviews and follow-up imaging generally depends on several factors, including the presence of any residual tumor, the treatment used and the type tumor.

Pathological Features

Except for anaplastic ganglioglioma (grade III), these tumors are all considered low grade (grade I–II) and grow slowly. Given the limited patient numbers and follow-up reported, DLGNT has still not been assigned a WHO grade.

Treatment Monitoring

Surgery to remove the tumor is often the primary treatment and often results in an excellent long-term outcome (see Table 2). The extent of resection is the most important prognostic factor. The treatment plan may include adjuvant radiation therapy and chemotherapy in some cases. Tumor recurrence after therapy is rare. Metastatic spread is unusual in neuronal or mixed neuronal-glial tumors. However, rare metastases to the CNS have been reported in patients with anaplastic ganglioglioma (AGG), rosette-forming glioneuronal tumor (RGNT), DIA and DIG and extraventricular neurocytoma (EVN), and up to 10–20% of patients with PGL.
Table 2

Treatment and outcome of neuronal and mixed glioneuronal tumors

 

Entity

Treatment

Outcome

1.

DNT

Surgical

No evidence of recurrence even in case of partial tumor resection

Malignant transformation is rare

2.

GC

Surgical

7.5 years recurrence-free survival rate in the near totality of patients

3.

GG

Surgical with or without chemotherapy and radiotherapy

Good outcome

4.

AGG

Surgical with or without chemotherapy and radiotherapy

Less favorable prognosis than GG but limited data available

Spread to the CNS can occur

5.

LDD

Surgical

Rare recurrence

6.

DIA and DIG

Surgical

Chemotherapy is helpful in case of disease recurrence or progression

Total resection: 15.1 years (DIA) and 8.7 years (DIG) recurrence-free survival rate

7.

PGNT

Surgery without adjuvant therapy offers a good outcome of long-term survival. Adjuvant chemotherapy or radiotherapy has been used in few cases with high MIB-1 labeling index and subtotal resection

No recurrence or spread reported after total resection

One case of systemic metastases (pleural, pericardial and to the left breast) 4.5 years after initial resection

8.

RGNT

Surgery

Adjuvant chemotherapy and radiotherapy in cases of progression or progressive symptoms

No recurrence in the majority of patients

9.

DLGNT

Chemotherapy with or without craniospinal radiotherapy

N/A (limited data available)

10.

CN

Surgical

Some authors suggest postoperative radiotherapy after subtotal resection to prevent recurrence

Recurrence-free after gross total resection in 95% (at 3 years) and 85% (at 5 years) of cases. Recurrence-free in 55% (at 3 years) and 45% (at 5 years) after subtotal resection

Craniospinal dissemination is very rare

11.

EVN

Surgical

Recurrence is rare. However, the outcome can vary considerably from patient to patient

Rare craniospinal dissemination can occur as distant metastasis or along the surgical route

12.

Cerebellar liponeurocytoma

Surgical with or without adjuvant radiotherapy

Survival longer than 5 years (the longest known survival is 18 years)

Recurrence can occur

Radioresistance and malignant progression have been reported

13.

PGL

Surgical

Some authors suggest considering radiotherapy only in case of subtotal resection (even if resistance to this treatment has been reported)

Rare recurrence, usually after suboptimal resection

Metastases to the CNS in 10–20% of cases One case of bone metastasis from cauda equina paragangliomas has been reported

Dysembryoplastic Neuroepithelial Tumor

Definition of Entity and Clinical Highlights

DNT is a benign mixed glial-neuronal neoplastic lesion occurring in children or young adults affected by longstanding drug-resistant partial complex seizures. Surgical resection of DNT has shown an excellent outcome in treating epilepsy. Disease recurrence or progression is rare.

Basic Epidemiology/Demographics/Pathophysiology

DNT represents less than 1% of all primary brain tumors. The reported incidence rates of DNTs following epilepsy vary significantly among institutions and range from 7% to 80% depending on the histopathological diagnostic criteria used for the diagnosis. DNT is slightly more frequent in male patients. In the majority of cases, the first seizure occurs before the age of 20 years. The mean age at seizure onset is 15 years (range: 3 weeks–38 years) and the mean age at surgery is 25.8 years. Several factors suggest a dysontogenetic/malformative origin, but the exact histogenesis of DNT remains unknown. DNT is sporadic. BRAF V600E mutations have been identified in 30% of DNTs. Occasionally, DNTs might affect patients with neurofibromatosis type 1 or XYY syndrome.

Pathological Features

DNTs are more frequently located in the temporal lobe, preferentially involving the mesial structures, although they can also occur in the frontal lobe and, less frequently, in other locations such as the caudate nucleus, lateral ventricles, the septum pellucidum, the trigonoseptal region, the midbrain and tectum, the cerebellum, or brain stem. DNTs are intracortical tumors. Depending on their volume (ranging from a few millimeters to several centimeters), they may expand the gyri affected and may show an exophytic portion. DNTs are solitary lesions although occasional multifocal DNTs have been reported.

DNT has viscous consistency with multiple or single nodules of firmer tissue. The histopathological hallmarks of DNT are the multinodular growth pattern and the “specific glioneuronal element”. The specific glioneuronal element consists of bundles of axons lined by small oligodendrocyte-like cells arranged in columns, oriented perpendicularly to the cortical surface. Between these columns, neurons are floating in a mucoid matrix with scattered stellate astrocytes.

Simple and complex histological forms have been defined. The specific glioneuronal element complex characterizes the simple form of DNT. The complex variant of DNT is composed of specific glioneuronal element and glial nodules, which give the tumor its distinctive multinodular architecture. The criteria for other (unspecific and diffuse) forms of DNT are still under debate. Focal cortical dysplasia (FCD) and DNTs are frequently associated. FCD should be diagnosed only in areas of cortical abnormalities without tumor cell infiltration.

DNT is a WHO grade I neoplasm with slow growth and low proliferation rates (Ki-67 index varies between 0% and 8%).

Imaging Features

DNT typically appears as a well-demarcated cortical multilobulated, bubbly mass without mass effect or surrounding edema (see Fig. 1). The mass can have circumscribed, wedge-shaped, pseudocystic, or multicystic appearance. In the majority of cases, DNT is intracortical. While small DNTs may involve only a portion of a gyrus (see Fig. 2), large lesions can affect a large portion of the lobe (see Fig. 3). In a minority of cases, the signal abnormality can extend into the subcortical white matter. DNT may remodel the overlying bone (up to 60% of cases; see Fig. 3a).
Fig. 1

20-year-old female with dysembryoplastic neuroepithelial tumor. The patient has a history of longstanding drug-resistant partial complex seizures. The left frontal mass is intracortical, well-defined, multicystic with bubbly appearance (a, b)

Fig. 2

25-five-year-old male with a dysembryoplastic neuroepithelial tumor. The patient has seizures. MRI shows a small, complex, multicystic mass in the left parahippocampal gyrus and subcortical white matter. The tumor returns mixed signal on T2-weighted (a) and FLAIR (b) images and is hypointense on T1-weighted images. There is a small focus of T1-weighted hyperintensity which likely represents calcification or haemosiderin

Fig. 3

40-year-old female with a dysembryoplastic neuroepithelial tumor. The patient has a history of longstanding drug-resistant partial complex seizures. The mass has caused bone remodeling over time (a). The multicystic neoplasm involves the right inferior parietal lobe and, to a lesser extent, the posterior portion of the right superior temporal gyrus. Note the lack of mass effect or surrounding edema despite the size of the tumor (b, e). The tumor returns mixed signal on FLAIR (b), the lesion is hyperintense on T2-weighted images and hypointense on T1-weighted images (c, d). Note the presence of calcifications or haemosiderin along the deep margin of the tumor (f)

DNTs are hyperintense on T2-weighted images and hypointense on T1-weighted images. They are mixed hypo/iso/hyperintense on FLAIR with a peripheral hyperintense ring. Calcifications are often seen on the gradient echo images and SWI (or CT). When present, they occur in deeply located tumor portions, usually in the vicinity of contrast-enhancing regions and hemorrhages. Intralesional hemorrhages are uncommon but do occur in association with microvascular abnormalities and can readily be appreciated on T2 and SWI images. DNT shows low DWI signal and high diffusivity on ADC maps. Usually DNT does not enhance. Enhancement is usually due to ischemic and hemorrhagic changes rather than malignant transformation. Focal nodular or ring enhancement can be seen in about 20–30% of DNTs. Nodular or ring-shaped contrast enhancement may occur in a previously non-enhancing tumor.

Gangliocytoma, Dysplastic Gangliocytoma of the Cerebellum, Ganglioglioma, Anaplastic Ganglioglioma, Desmoplastic Infantile Ganglioglioma and Astrocytoma

Definition of Entity and Clinical Highlights

Ganglioglioma (GG) and gangliocytoma (GC) are two rare and benign tumors composed of dysplastic ganglionic and neoplastic glial cells (GG) or exclusively ganglionic cells (GC). GG and GC are slow-growing lesions assigned WHO grade I (about 20% of GGs are WHO grade II). Anaplastic ganglioglioma (AGG) is a rare form of ganglioglioma designated as WHO grade III. GG and GC are a common cause of temporal lobe epilepsy (TLE).

A dysplastic cerebellar gangliocytoma (DCG) is a form of gangliocytoma affecting the cerebellum. DCG is a benign cerebellar mass lesion composed of dysplastic ganglion cells that adapt to the existing cortical architecture of the cerebellum and thicken the cerebellar folia. The presence of a dysplastic cerebellar gangliocytoma is known as Lehrmitte-Duclos disease. The dysplastic cerebellar gangliocytoma is a CNS manifestation of Cowden syndrome. There is uncertainty as to whether the dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) is a neoplasm or a hamartoma. If a neoplasm, it would be considered WHO grade I.

Desmoplastic infantile astrocytoma and ganglioglioma are benign glioneuronal tumors composed of a prominent desmoplastic stroma with a neuroepithelial population of cells of neoplastic astrocytes (DIA), or neoplastic astrocytes and variable neuronal component (DIG). DIA and DIG are also histologically WHO grade I tumors. DIA and DIG are grouped in the WHO classification because these lesions have similar clinical, neuroimaging, pathological features and both have a good prognosis.

Basic Epidemiology/Demographics/Pathophysiology

Gangliogliomas and gangliocytomas together account for 0.4% of all CNS tumors and 1.3% of all brain tumors. GGs are the most common mixed neuronal-glial tumor. AGG forms a minority (5–10%) of all GGs. GG and GC are more frequently encountered in children or young adults. There is no gender predilection. GGs are thought to stem from the neoplastic transformation of precursor cells. The most common mutation (20–60% of cases) in ganglioglioma is BRAF V600E mutation. GGs have been reported in patients with neurofibromatosis type 1, neurofibromatosis type 2, Turcot and Peutz-Jeghers syndrome. The etiology of GC is unknown. GC appears sporadic without a genetic susceptibility factor.

DCG is a component of the Cowden syndrome, an autosomal dominant syndrome causing a variety of hamartomas and neoplasms. Cowden syndrome results from mutations in the gene for phosphatase and tensin homologue (PTEN), mutations in the KLLN gene which provides instructions for making a protein called killin, and from variants in succinate dehydrogenase B (SDHB) and D (SDHD) subunits which alter the function of succinate dehydrogenase (SDH), a critical enzyme which regulates cell energy production, survival, and proliferation. A reduced amount of tumor suppressors (as a result of PTEN or KLNN gene mutation) or the presence of variants in SDHB or SDHD may allow abnormal cells to survive and proliferate inappropriately, leading to the formation of tumors.

DIAs and DIGs account for 16% of brain tumors of infancy but are considered rare (0.3%) among all the CNS tumors in patients across all age groups. DIA and DIG present within the first year of life in the majority of cases (median age at diagnosis: 6 months; range: 1–24 months). There are reports of non-infantile cases (age range at diagnosis: 5–25 years). DIA and DIG occur more frequently in males. The origin of DIAs and DIGs is unknown, but they probably arise from primitive small-cell populations expressing both glial and neuronal proteins and subpial astrocytes of the developing brain. DIA and DIG show inconsistent chromosomal gains or losses. BRAF V600E mutation is an uncommon finding in DIA/DIG.

Pathological Features

Gangliogliomas and gangliocytomas are solitary lesions. The majority of GG and GC occur in the temporal lobe. GG and GC occur less frequently in other lobes and can occur anywhere in the CNS, including the brain stem, cerebellum, spinal cord, optic nerves, pituitary, and pineal gland. In Lehrmitte-Duclos disease, DCG affects the cerebellum. Unlike GG, AGG does not preferentially occur in the temporal lobes but affects any lobe of the brain and the spinal cord. AGG may occur either de novo (primary tumor) or following the malignant transformation of a GG (secondary tumor). AGG can metastasize to the rest of the CNS, but GG and GC usually do not disseminate.

GG and GC appear macroscopically as solid or cystic lesions, expanding the cortex but exerting little mass effect on the surrounding structures. Calcifications are common. Hemorrhage and necrosis are rare. The histopathological hallmark of GG is a combination of neoplastic neuronal and glial cells. The spectrum of ganglioglioma varies from tumors with a predominantly neuronal population to variants with a dominant glial component. Some cases also contain cells of intermediate differentiation. Anaplastic gangliogliomas show increased cellularity, pleomorphism, increased numbers of mitotic figures of the glial component associated with vascular proliferation, and necrosis. GC is composed of mature neoplastic ganglion cells, often with dysplastic features. The stroma of GC consists of nonneoplastic glial elements. The neoplastic ganglion cells of GG and GC are positive for synaptophysin. About 70% to 80% of gangliogliomas exhibit CD34 immunoreactivity (CD34 is an oncofetal neuronal marker which is not present in an adult brain). Neoplastic glial cells of GG are GFAP positive. The proliferation index of the glial component in GG and GC is low.

DCG displays a thickening of cerebellar folia with a preserved gyral pattern. These macroscopic appearances reflect a diffuse enlargement of the molecular and internal granular layers of the cerebellum where there are ganglionic cells of various sizes. The outer molecular layer is thickened by a layer of abnormally myelinated axon bundles in parallel arrays extending from abnormal cells in the granular layer. The granular layer is thickened by hypertrophic granular cells. Purkinje cells are fewer or absent. As a result of these microstructural changes, dysmorphic cerebellar folia exhibit an “inverted cortex” pattern, consisting of reduced central white matter volume and hypermyelination of the superficial layer. Immunohistochemistry shows positivity for synaptophysin in the dysplastic ganglion cells; most of the dysplastic cells exhibit loss of PTEN protein expression and increased expression of phosphorylated AKT and S6. The nature of this lesion is still under debate. Malformative histopathological features, very low or absent proliferative activity, and the absence of progression would support a hamartomatous nature. However, animal models of PTEN loss, reports of rare recurrence, and de-novo development of DCG in adult patients with previously normal MRI scans would support a neoplastic etiology.

DIAs and DIGs appear as large cystic lesions with a solid component involving the superficial cerebral cortex and leptomeninges, frequently attached to dura through a desmoplastic reaction. DIAs and DIGs arise in the supratentorial compartment, more frequently in the frontal and parietal lobes, followed by the temporal lobe and, least frequently, the occipital lobe. The cystic component can be uniloculated or multiloculated and with clear or xanthochromic fluid content. Cysts can be huge (up to 13 cm in diameter) resulting in macrocephaly and bulging fontanelles. The ventricular system adjacent to the tumor is often compressed as a result of mass effect. The solid component of the tumor is firm or rubbery in consistency and appears grey or white at inspection and does not show features of gross hemorrhage or necrosis. Calcifications are common. On histology, DIAs and DIGs show a dominant desmoplastic leptomeningeal component with a variable poorly differentiated neuroepithelial component made up exclusively of astrocytes (DIA) or astrocytes and neoplastic neurons (DIG). The Ki-67 proliferation index is typically low (2–5%), with rare higher proliferation (as high as 45%) only in unusual forms of DIAs and DIGs. The neoplastic neuronal cells in DIG express neuronal markers on immunohistochemistry (e.g., synaptophysin, neurofilament heavy polypeptide, and class III beta-tubulin). The neuroepithelial cells are GFAP and vimentin positive.

Imaging Features

GG and GC have a variable density on CT, and they can show calcifications and cause scalloping of the calvarium adjacent to the cortical mass. DIAs and DIGs present as large, hypodense cystic masses with a solid tumor nodule isodense or slightly hyperdense to the grey matter portion that displays marked contrast enhancement. Calcifications are extremely rare in DIA and DIGs. The cystic portion is usually located deep in the cerebrum, whereas the solid portion is peripheral and extends to the overlying meninges. On CT, DCG appears as an area of heterogeneous density distorting the fourth ventricle and cisterna magna. When DCG is large and compresses the fourth ventricle, CT shows features of obstructive hydrocephalus (Fig. 6). Thinning of the skull can be occasionally appreciated on the bone window.

Contrast-enhanced MRI with or without high resolution coronal T2-weighted images of the temporal lobes is recommended to characterize these tumors further.

GG typically appears as a circumscribed intracortical cyst(s) of variable size (up to several centimeters) with mural nodule with a cortical (and subcortical) signal increase on FLAIR and T2-weighted images (Fig. 4). Less frequently GG can appear as a solid mass expanding the gyri. GG rarely presents as an infiltrative mass with poorly delineated margins. There is no surrounding edema. Focal cortical dysplasia has been associated with GG.
Fig. 4

Gangliglioma in a 37-year-old man. The patient has a history of recent generalized seizures and 2–3 years of estimated absent seizure. MRI shows a solitary left superior temporal and inferior parietal tumor. The mass has a central cyst with surrounding signal increase on the FLAIR and T2-weighted images (a, b, d, e). Note the tumor shows a peripheral rim of enhancement (c, f)

GC has been reported to have variable T2-weighted signal ranging from low to high signal. Tumor calcification is frequent in both GG and GC and can be detected on GRE and SWI images. Contrast enhancement of GG and GC is usually present, and the pattern of enhancement can be solid, rim, or nodular (Figs. 4 and 5).
Fig. 5

19-year-old male with gangliocytoma. The patient presented with three generalized tonic-clonic seizures. No focal neurology, visual, or memory deficits. MRI shows a peripherally enhancing (e) right temporal lesion measuring approximately 1 cm in size. There is no mass effect or edema. The lesion consists of a nodule with a cystic component associated. In this case, based on imaging, the differential diagnosis includes a ganglioglioma or a gangliocytoma. A pleomorphic astrocytoma would be less likely because no definite leptomeningeal enhancement is demonstrated

On T1-weighted images, DIAs and DIGs show a hypointense cystic component with an isointense peripheral nodular or plaque-like solid component that enhances with gadolinium. The cystic component of DIAs and DIGs is hyperintense on T2-weighted images but isointense to CSF on FLAIR, whereas the solid portion is hypointense on T2-weighted images and hyperintense on FLAIR. There is no hemorrhage or calcification and no restricted diffusion. Edema around DIAs and DIGs is usually very mild or absent.

On MRI, DCG typically shows enlargement of cerebellar folia with alternating T1-hypointense and T2-hyperintense striated (corduroy or tigroid) or gyriform pattern (Fig. 6). Axial and coronal T2-weighted images are beneficial in characterizing the cerebellar morphology. DCGs are usually unilateral (but can be bilateral) and frequently involve the vermis. DCG may show cysts which suppress signal on FLAIR and calcifications which appear hyperintense in T1-weighted images and hypointense on GRE and SWI. SWI shows abnormal veins around the thickened folia. Signal increase on DWI with variable ADC values is thought to reflect hypercellularity or increased axonal density. Contrast enhancement may or may be not present.
Fig. 6

48-year-old male with Lhermitte-Duclos disease (LDD). The patient presents with headache. The initial CT scan (a) showed a hypodense cerebellar mass distorting the posterior fossa structures and causing tonsillar herniation. MRI was acquired shortly after CT and showed a dysplastic growth of the left cerebellar hemisphere and vermis with the typical striated pattern (b, d) and DWI signal increase (c) of Lhermitte Duclos disease. Please note that LDD caused obstructive supratentorial hydrocephalus and tonsillar herniation which required urgent decompression

Multinodular and Vacuolating Neuronal Tumor of the Cerebrum

Definition of Entity and Clinical Highlights

MVNT is a benign lesion of the cerebral hemispheres composed of neuronal cells of variable size arranged in nodules involving the deep cortex and subcortical white matter, which shows stromal and cytoplasmic vacuolation. MVNT is classified as a pattern of gangliocytoma but with “uncertain class assignment” in the current 2016 WHO classification of CNS tumors. MVNTs can be asymptomatic or cause headache and seizures. MVNT is consistent with WHO grade I and, unless epileptogenic, is managed conservatively.

Basic Epidemiology/Demographics/Pathophysiology

According to the existing scant literature on MVNTs, these lesions can occur at all ages. MVNTs commonly occur in adults (median age at diagnosis: 43, range: 21–71) although there are reports of pediatric and adolescent cases (Pekmezci et al. 2018; Thom et al. 2018). MVNT is slightly more frequent in females.

The pathophysiology of MVNT is unclear (Louis et al. 2016). Some authors suggest that MVNT is a malformation (Cathcart et al. 2017; Thom et al. 2018) and other authors suggest that MVNT is instead a true clonal neoplasm (Choi et al. 2018; Pekmezci et al. 2018). There are reports of few cases of MVNTs with BRAF and MAP2K1 mutations (Pekmezci et al. 2018) and one case of FGFR2-ZMYND11 gene fusion on chromosome 10 (Choi et al. 2018). No IDH1/IDH2 mutations have been reported.

Pathological Features

All MVNTs reported were located in the cerebrum. They appear as a cluster of small (ranging from 1 to 5 mm in diameter), discrete, round, or ovoid nodules located in the deep half of the cortex and subcortical white matter with occasional scattered nodules extending into deep white matter towards the ventricles. Although individual nodules are a few millimeters large, confluent clusters of nodules can reach several centimeters in dimension.

Histologically, MVNT shows nodules of small to medium-sized neuronal cells with intracellular and stromal vacuolation. The cells express neuronal markers (such as synaptophysin, ELAV3/4), are frequently positive for OLIG2 but are negative for the neuronal nuclear protein NeuN, chromogranin, or the glial marker GFAP.

Imaging Features

On CT, findings are typically normal with some ill-defined subcortical hypodensity in case of large lesions. There is no mass effect or calcification.

On MRI, MVNT appears as a cluster of small subcortical or juxtacortical nodules with U-shaped configuration which are hyperintense on T2-weighted and FLAIR images (Fig. 7). Nodules do not restrict on DWI and typically do not enhance (although a faint enhancement has been reported in few cases). There is no surrounding mass effect or edema associated (Nunes et al. 2017).
Fig. 7

25-year-old male with multinodular and vacuolating neuronal tumor of the cerebrum. The patient presents with chronic headache, cognitive difficulties, anxiety, and fatigue. MRI shows a cluster of discrete nodular lesions within the inner, deep portion of the frontal cortex and in the adjacent subcortical white matter. The cluster of lesions does not exert an appreciable mass effect. Nodules return high FLAIR (a) and T2-weighted (b) signal. The lack of CSF signal suppression on FLAIR is possibly related to a high protein or solid component of vacuoles

Papillary Glioneuronal Tumor

Definition of Entity and Clinical Highlights

Papillary glioneuronal tumors (PGNTs) are relatively well-circumscribed, clinically indolent cerebral neoplasms with astrocytic and neuronal elements. PGNTs behave like WHO grade I tumors, but in a minority of cases they have shown atypical features or late biological progression (Newton et al. 2008).

Basic Epidemiology/Demographics/Pathophysiology

PGNTs are rare tumors occurring in young adults without any gender predilection. PGNTs account for less than 0.02% of intracranial tumors. The mean age at diagnosis is 23 years (range: 4–75 years).

Pathological Features

PGNTs are characterized by GFAP-positive astrocytes lining hyalinized vascular pseudo-papillae and synaptophysin-positive interpapillary sheets of neuronal cells, ganglion cells, or medium-sized ganglioid cells with accompanying neuropil. PGNTs have a low proliferation index. The absence of necrosis and vascular hyperplasia reflects a benign nature (WHO grade I). Histogenesis of PGNT is uncertain. It has been suggested that PGNT might originate from multipotent precursor cells capable of divergent glioneuronal differentiation.

Imaging Features

PGNTs usually occur in the supratentorial brain parenchyma. PNGTs are typically located in the temporal deep white matter, adjacent to the lateral ventricles, from where they may rarely extend to the ventricles (Newton et al. 2008). Less frequently, PGNTs may be located in the frontal or parietal and occipital lobes (Komori et al. 1998). Although uncommon, pure intraventricular localization of PGNTs (Matyja et al. 2015), pure pineal gland (Kaloostian et al. 2013) and pineal region PNGTs extending to the ventricles (Husain and Husain 2009) have been reported. PNGTs can present on imaging in four patterns: entirely cystic mass, cyst with mural nodule(s), purely solid mass, or a part cystic and part solid mass (Schlamann et al. 2014). PGNTs may or may not show focal calcifications, and hemorrhage is present in less than 10% of cases (Louis et al. 2016). The size of PGNT varies from 1 to 7 cm (Causil et al. 2016). Local mass effect is generally mild with minimal or no peritumoral edema (even when large) in 85% of the cases.

PGNTs have a nonspecific appearance on imaging, and histologic analysis of tissue specimens is required for the diagnosis. On CT, the tumor appears as hypodense mass, with or without calcifications (Fig. 8a). On MRI, the mural nodule or the solid portion of the tumor is isointense or hypointense on T1-weighted images, and hyperintense on T2-weighted images and FLAIR images. The cystic tumor component might suppress on FLAIR sequences (Fig. 8be). On postcontrast T1-weighted images, the tumor shows heterogeneous (nodular or ring-like) strong enhancement (Fig. 8f). Intraventricular PNTGs appear as a solid partially cystic mass in the lateral ventricles with intense gadolinium enhancement which can potentially cause acute obstructive hydrocephalus.
Fig. 8

20-year-old male with a papillary glioneuronal tumor. The patient presents with headache and blurred vision. A large solitary, intra-axial, multicystic, right parietal mass was found on imaging. The lesion has well-defined margins, moderate mass effect and perilesional edema (af). Non-enhancing T2-weighted hyperintensity extends into the corpus callosum (c), but at least some of this may represent edema. The small peripheral cysts show mixed T1- and T2-weighted signals in keeping with hemorrhage (be). The peripheral margins of the large cyst return low signal on the SWI from previous bleeding (d). A rim of enhancement is present in the postcontrast T1-weighted images (f)

Rosette-Forming Glioneuronal Tumor

Definition of Entity and Clinical Highlights

Rosette-forming glioneuronal tumor (RGNT) is a rare and slow-growing neoplastic lesion most commonly involving the wall or floor of the fourth ventricle (Fig. 9), occasionally with aqueductal and cerebellum (vermian) extension. It is less frequently found in the pineal region, optic chiasm, spinal cord (Fig. 10), and septum pellucidum.
Fig. 9

25-year-old female with rosette-forming glioneuronal tumor (RGNT). The patient presents with acute onset of headache three days before the scan, vomiting, nausea, and confusion. The CT and MRI scans show acute obstructive hydrocephalus and tonsillar herniation caused by an intraventricular tumor. The tumor occupies the third and fourth ventricle extending through the aqueduct. (a) On CT, the tumor has intermediate and heterogeneous density with heterogeneous enhancement. (bf). On MRI the neoplasm is hyperintense on T2-weighted images with peripheral cystic components but no calcification or hemorrhage. It is heterogeneously enhancing on the post-contrast T1-weighted images. The mass lesion causes compression and inferior displacement of the tectal plate. There is resultant hydrocephalus with dilatation of the third and lateral ventricles and effacement of the cerebral sulcal spaces and some transependymal CSF seepage. There is crowding at the foramen magnum with an 8 mm descent of the cerebellar tonsil. Bulging of the anterior and posterior recesses of the third ventricle is caused by loculations of CSF or tumor related cysts

Fig. 10

27-year-old male, with rosette-forming glioneuronal tumor (RGNT) of the spinal cord. The patient presents with progressively deteriorating symptoms in his lower limbs including weakness, numbness, unsteadiness and loss of balance when walking. MRI shows an intradural intramedullary cystic lesion cystic at the T11 vertebral level. There is abnormal T2-weighted hyperintensity extending cranially to the lower thoracic region

Basic Epidemiology/Demographics/Pathophysiology

RGNT commonly affects young adults, more frequently females (female-to-male ratio of 1.6:1). The mean age at the diagnosis is 31 years (range 6–79 years).

Pathological Features

RGNT has a glial component, the morphology of which resembles pilocytic astrocytoma, and a neurocytic component consisting of cells forming rosettes around a core of fibrillary material. RGNT is considered a WHO grade I tumor because it lacks aggressive histologic features and is characterized by a low proliferative index. Although one case of RGNT in a neurofibromatosis type 1 (NF-1) patient has been reported (Kumar et al. 2013), there is no genetic link with NF-1.

Imaging Features

Most RGNTs are as well-circumscribed, solid (40%), mixed solid and cystic (34%), or only cystic (26%) masses located in the midline around the fourth ventricle and superior vermis (Fig. 9). RGNT is rarely located in the pineal region, cerebellopontine angle, brain hemispheres. Lesion size ranges from 0.5 to 10 cm (Hsu et al. 2012). RGNT may expand the cortex and involve underlying white matter or be deeply situated abutting the ventricles. Generally, RGNT does not cause edema in the surrounding structures.

Plain CT head shows a midline posterior fossa cystic/solid mass with the variable presence (25%) of intralesional calcifications and hemorrhage (Kumar et al. 2013). Postcontrast CT is not required. The recommended protocol is MRI head with contrast (including SWI or T2 images to identify areas of calcification or hemorrhage). Depending on the structure of the mass, RGNT appears iso/hypointense on T1-weighted images and heterogeneously hyperintense on T2-weighted images. The majority (70%) of RGNTs show variable gadolinium enhancement (Hsu et al. 2012) with focal (50%), heterogeneous (19%), minimal (13%), or ring and nodular (9%) pattern of enhancement (Fig. 9).

Diffuse Leptomeningeal Glioneuronal Tumor

Definition of Entity and Clinical Highlights

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare neoplasm characterized by widespread infiltration of the leptomeninges by glial tumor cells with or without the brain or spinal cord parenchymal components. Prior to its introduction in the WHO classification as a distinct entity in 2016, DLGNTs were considered diffuse leptomeningeal presentations of oligodendrogliomas or extraventricular neurocytomas and were given various names (e.g., “primary diffuse leptomeningeal olidendrogliomatosis” or “disseminated oligodendroglial-like leptomeningeal tumor of childhood”). DLGNTs have been added to the list of neuronal and mixed neuronal-glial tumors (Louis et al. 2016) because tumors showed “oligodendroglia-like” cells with variable neuronal components (from neurocytes to ganglioid cells) or appeared “neurocytoma-like” but had glial components suggesting a novel mixed glioneuronal tumor type.

Patients with DLGNT often present with signs and symptoms of acute raised intracranial pressure due to obstructive hydrocephalus (Lyle et al. 2015). Some patients present with ataxia and signs of spinal cord or cauda equina compression (Causil et al. 2016). Symptoms and signs similar to those of chronic infectious meningitis have also been described (Kosker et al. 2014; Heijink et al. 2012). Most DLGNTs have a slow clinical progression, with a more aggressive course only in a minority of cases. Patients are often assessed for infection, rheumatologic disease and disseminated primary malignancy.

Basic Epidemiology/Demographics/Pathophysiology

DLGNTs are rare; they mostly occur in children (median age at diagnosis is five years) and only occasionally in adults. Age of patients with DLGNT might range from 5 months to 46 years (Louis et al. 2016). DLGNTs are more common in males than females (male-to-female ratio of 1.7:1). The etiology of DLGNTs is unknown. There is no evidence of genetic predisposition although one patient with a 5p deletion syndrome has been reported (Louis et al. 2016).

Pathological Features

DLGNT has oligodendroglial-like cytology with frequent immunopositivity for OLIG2 and S100, variable GFAP (less than 50% of cases), and synaptophysin expression.

Most DLGNT are histologically low-grade; the Ki-67 proliferation index is usually low (median value of 1.5%) (Louis et al. 2016). However, some tumors demonstrate features of anaplasia with increased mitotic and proliferative activity with one study reporting less favorable outcome associated with a proliferation index greater than 4% (Rodriguez et al. 2012).

Imaging Features

CT shows indirect signs of the disease, such as communicating hydrocephalus. The characteristic MRI features of DLGNTs are diffuse leptomeningeal enhancement along the surface of the brain and spinal cord with small, cystic or enhancing, nodular, intramedullary T2-weighted hyperintense lesions. FLAIR sequences might show hyperintense signal in sulci and cisterns. There are reports of 6 cases of spinal cord DLGNT without gross leptomeningeal enhancement on MRI which could be detected microscopically (Kang et al. 2018). Hydrosyringomyelia and tumor spread along the central canal of the spinal cord have been described (Ruppert et al. 2011).

Central Neurocytoma

Central neurocytoma (CN) has been discussed elsewhere in this book (see “Extra-axial Tumors”).

Extraventricular Neurocytoma

Definition of Entity and Clinical Highlights

Extraventricular neurocytoma (EVN) is a sporadic form of neurocytoma located outside of the ventricular system. EVNs are frequently associated with poorer outcomes compared with central neurocytomas (CNs) and, for this reason, EVNs represent a distinct entity in the new WHO guidelines (Louis et al. 2016). EVNs have been reported in most parts of the nervous system. Most of EVNs are supratentorial (71% of cases), although they can occur in the thalamus, hypothalamic region, cerebellum, pons, cranial nerves, the sellar region, cord and cauda equina, and outside the craniospinal compartment (Sweiss et al. 2015). They are classified as WHO grade II. Patients with EVNs present with symptoms and signs of increased intracranial pressure, seizures, gait disturbances, vision changes, and headaches. Spinal lesions are associated with motor, sensory deficits of the upper or lower extremities secondary to the mass effect of the tumor. Patients commonly present with myelopathy, weakness, numbness, and paraesthesia. Bowel and bladder sphincter dysfunction may occur with involvement of the conus medullaris.

Basic Epidemiology/Demographics/Pathophysiology

Extraventricular neurocytoma can present in patients of any age. The mean age of presentation is approximately 27 years, but the patient’s age at diagnosis ranges from 1 to 79 years. EVN occurs equally in males and females. Spinal EVN affects more frequently male patients (male-to-female ratio of 1.9:1).

Pathological Features

Histologic features of EVNs are more complex than the highly cellular, uniform, and morphologic pattern of CNs. EVNs have a variable histological pattern with sheet-like, clusters, ribbon-like appearance, or Homer-Wright rosettes. EVNs differ from CNs for their frequent astrocytic, typically pilocytic features and ganglionic-like appearance. A minority of EVNs show atypical features including increased proliferative index (MIB-1 index greater than 2%), increased vascularity, or necrosis, and for these reasons are called “atypical neurocytomas.”

Imaging Features

EVNs show a broad spectrum of imaging patterns dependent on cellularity and anatomic locations. Histopathologic diagnosis is often required for the final diagnosis.

On CT, cerebral EVNs appear as solitary, well-defined, part cystic, and part solid mass lesions of variable density with mild perilesional edema (51%). EVNs might show areas of calcification (34%), cystic degeneration, and hemorrhage.

On MRI, the solid component of cerebral EVNs is hypo/isointense on T1-weighted images but may be hypointense. On T2-weighted and FLAIR images, the lesion is predominantly hyperintense. EVNs show variable contrast enhancement. On MRI, spinal EVNs appearances are variable and resemble other common spinal cord tumors, such as ependymomas, astrocytomas, and oligodendrogliomas. Biopsy and pathologic examination are often required for the diagnosis. Spinal EVNs commonly appear as intramedullary masses, iso-intense on T1-weighted images, and hyperintense on T2-weighted imaging, showing variable enhancement (Kim and Lim 2015). An unusual spinal EVN with exophytic growth from the thoracic spinal cord mimicking a meningioma has been reported (Tsai et al. 2011).

Cerebellar Liponeurocytoma

Definition of Entity and Clinical Highlights

Cerebellar liponeurocytoma is a rare adult cerebellar neoplasm with neuronal/neurocytic and adipocyte differentiation of cells. Most cerebellar liponeurocytoma have low proliferative activity and a favorable prognosis. However, recurrence and malignant progression have been reported (Gembruch et al. 2018).

Basic Epidemiology/Demographics/Pathophysiology

Cerebellar liponeurocytoma occurs in adults (range: 24–77 years), with a peak incidence in the third to sixth decades of life (the mean patient age at diagnosis is 50 years). It is equally common in both genders (Louis et al. 2016).

Pathological Features

Cerebellar liponeurocytoma most commonly occurs in the cerebellar hemispheres but can also be located in the paramedian region or vermis. Some have been found in the supratentorial ventricular/periventricular regions. Surrounding edema is minimal or absent. The distinctive histological feature of a cerebellar liponeurocytoma is the focal accumulation of cells with a high-fat content that resembles adipocytes but instead represents neuroepithelial tumor cells with intracellular lipid accumulation.

Most liponeurocytomas correspond histologically to WHO grade II and have a favorable prognosis. However, some more aggressive liponeurocytomas have been reported. Recurrent liponeurocytomas may display increased mitotic activity and Ki-67 proliferation index, vascular proliferation, and necrosis (Louis et al. 2016).

Imaging Features

Liponeurocytomas demonstrate a high-fat content on imaging. On CT they appear as a nonspecific hypodense mass lesion. On MRI they are hyperintense on T2-weighted images and noncontrast T1-weighted. The adipose tumor component suppresses with fat saturation.

Paraganglioma

Definition of Entity and Clinical Highlights

PGLs are neuroendocrine tumors arising from the extra-adrenal autonomic paraganglia. Paraganglia are chemoreceptors derived from the embryonic neural crest which respond to changes in blood oxygen and carbon dioxide levels by synthesizing catecholamines. The most common symptom of spinal PGLs is low back pain, sciatica, motor deficits, sensory disturbance, and sometimes sphincter dysfunction.

Basic Epidemiology/Demographics/Pathophysiology

PGLs are rare. The combined annual clinical incidence of pheochromocytomas and paragangliomas is estimated to be approximately 3 cases per million persons per year (Louis et al. 2016). Primary spinal PGLs represent only 10% of cases; most often (about 90% of cases), paraganglioma occurs in the head and neck regions (within the carotid bodies, glomus jugulare, glomus vagale, or glomus tympanicum). Cauda equina PGLs generally occur in adults (range: 9–75 years), with the peak incidence in the fourth to sixth decades of life (the mean patient age at diagnosis is 46 years). PGLs are slightly more common in males (Louis et al. 2016).

Pathological Features

PGLs are considered benign, corresponding histologically to WHO grade I tumors. In a minority of cases, PGLs have shown malignant features. About 10–20% of PGLs have been reported to show metastases to the CNS. Bone metastasis from cauda equina paragangliomas has been reported only once. Factors associated with malignancy include SDHB mutations, high proliferation index, and large tumor size (greater than 5–6 cm of diameter) and weight (greater than 80–150 g).

The etiology of cauda equina PGLs is unclear. Some authors hypothesize that PGLs originate from paraganglion cells of the cauda equina even though such cells have yet to be identified at this site. Others hypothesize that neuroblasts usually present in the adult filum terminale may undergo a paraganglionic differentiation. Jugulotympanic PGLs presumably arise from microscopic paraganglia within the temporal bone.

Unlike nonspinal extra-adrenal paraganglioma, most spinal paragangliomas are sporadic. A study of 22 spinal paragangliomas reported a germline mutation in the gene encoding for the subunit D of the succinate dehydrogenase (SDHD) of one patient with recurrent spinal paraganglioma and a cerebellar metastasis. Cauda equina paragangliomas are not associated with other spinal paragangliomas. Concurrent spinal paraganglioma and brain tumors, spinal epidural haemangioma, syringomyelia, and intramedullary cysts have been reported, but this is coincidental rather than to be a genuine association.

Macroscopically, PGLs are encapsulated, soft, dark red-brown masses. PGLs are highly vascularized with occasional capsular calcification and cystic components. PGLs are well-differentiated tumors which look like normal paraganglia. They are composed mostly of chief cells forming nests (called Zellballen) supported by a variable number of sustentacular cells. About a quarter of all cauda equina paragangliomas contain mature ganglion cells and are termed gangliocytic paragangliomas. Some PGLs show ependymoma-like perivascular formations, angiomatous, adenomatous, and pseudorosette patterns reminiscent of carcinoid tumors or melanin-containing cells. Chromogranin and synaptophysin positivity is the most important marker for paraganglioma which may confirm the diagnosis on immunohistochemistry analysis.

Most spinal PGLs of the cauda equina and filum terminale are entirely intradural and are attached either to the filum terminale or one of the filaments of the cauda equina. In decreasing order of frequency, spinal PGLs have also been reported in the thoracic region (mostly extradural with intravertebral and paraspinal components) and cervical region. PGLs occasionally penetrate the dura and invade the bone. Jugulotympanic PGLs can extend intracranially. Rare cases of purely intracranial PGLs (in the sellar region, cerebellopontine angle, cerebellar parenchyma, and forebrain) have been reported.

Imaging Features

On CT, spinal PGLs appear as intradural tumors, which may cause bony remodeling, vertebral scalloping, and foraminal enlargement. Following contrast administration, PGLs can show large draining veins.

MR imaging findings of spinal PGLs are nonspecific, and the definitive diagnosis depends on pathological examination. Paraganglioma appears as a extramedullary, well-delineated round, ovoid, or lobulated mass located in the distal thecal sac. Its size varies from 1 cm to more than 5 cm. It is hypointense or isointense on T1-weighted images relative to the cord, and heterogeneously hyperintense relative to the cord on T2-weighted images, with possible intralesional cyst formation and hemosiderin rim (the so-called cap sign) from prior hemorrhage. Due to its hypervascular structure, PGL demonstrates prominent flow voids due to enlarged draining veins resulting in a salt-and-pepper appearance on T2-weighted images. Serpiginous intratumoural vessels (which are not present in neurinomas and ependymomas) can represent a useful diagnostic finding. On postcontrast imaging, PGL returns intense enhancement (Fig. 11). There is no peritumoral edema or associated hydrosyringomyelia.
Fig. 11

53-year-old male with spinal paraganglioma. The patient reports one-year history of lower back pain with bilateral sciatica. MRI of the lumbar spine shows a well-defined extramedullary mass lesion filling the vertebral canal at the level of L3

Digital subtraction angiography of the medulla demonstrates the vascularized pedicle of spinal PGL (which distinguishes PGL from other tumors).

Most paragangliomas are positive on scintigraphy scans using radioiodinated metaiodobenzylguanidine (MIBG), an analog of norepinephrine. Somatostatin receptor-based imaging (with Octeotride or 68Ga-labeled radioligands) is also of great utility in looking for primaries and determining the extent of metastatic disease (Maxwell and Howe 2015).

Interpretation Checklist for Neuronal and Mixed Glioneuronal Tumors

Table 3 provides a synoptic view of salient clinical and imaging features in neuronal and mixed glioneuronal tumors.
Table 3

A synopsis of neuronal and mixed neuronal-glial tumors

Tumor

Location

Clinical presentation

CT

MRI

DNT

Temporal > frontal > caudate nucleus, lateral ventricles, the septum pellucidum, trigonoseptal region, midbrain and tectum, cerebellum, brain stem

Mean age at seizure onset: 15years (range: 3weeks–38years)

Mean age at surgery: 25.8years

Drug-resistant focal epilepsy, with or without secondary seizure generalization

NECT: Cortical/subcortical hypodense mass

Calcifications may be present

Bone remodelling

CECT: Nonenhancing in most cases

Multilobulated, bubbly mass. No mass effect or edema

T1WI: Hypointense mass

T2WI: Hyperintense mass

T2 GRE/SWI: Ca++ and microhemorrhages

DWI: Low DWI signal and high ADC values

T1WI C+: Nonenhancing in most cases (nodular or ring enhancing in 20–30% of cases)

GG, AGG, and GC

Temporal > anywhere in the CNS (including brain stem, cerebellum, spinal cord, optic nerves, pituitary and pineal gland)

Children or young adults

Variable according to tumor size and location

Chronic temporal lobe epilepsy

History of focal seizures

NECT: Solid and cystic, intracortical mass of variable density

Ca++

May cause bone remodeling

CECT: Enhancing solid portion

Intracortical cyst(s) of variable size. No edema

T1WI: Hypo/isointense to GM

T2WI: Variable T2-weighted signal ranging from low to high signal. Look for associated cortical dysplasia on FLAIR/T2WI

T2 GRE/SWI: Ca++

T1WI C+: Variable enhancement. Meningeal enhancement rare

DCG (LD)

Cerebellum

Any age

Dysmetria and other cerebellar signs

Signs of increased intracranial pressure

NECT: Well-demarcated hypodense mass

Rarely cysts or Ca++

Hydrocephalus, bone remodeling

CECT: Variable enhancement

T1WI and T2WI: Iso/hypointense striations

FLAIR: Hyperintense striations

T2 GRE/SWI: Prominent veins between folia

DWI: High DWI signal and variable ADC values

T1WI C+: Variable enhancement

DIA and DIG

Supratentorial: Frontal > parietal > temporal > occipital

Involving the superficial cerebral cortex and leptomeninges

Median age at diagnosis: 6months; range: 1–24months Reports of noninfantile cases (age range at diagnosis: 5–25years)

Raised intracranial pressure Occasionally, seizures and focal neurological signs

NECT: Hypodense cyst, solid nodule(s) isodense/hyperdense to GM

Dural attachment

Ca++ rare

CECT: Enhancing solid portion

T1WI: Heterogeneous solid tumor

T2WI: Hypointense solid tumor

T2 GRE/SWI: No microbleeds or Ca++

DWI: No restriction

T1WI C+: Enhancement of the solid tumor nodule and of the adjacent leptomeninges. Cyst follows the CSF signal in all sequences. Deep location relative to the enhancing solid nodule

MVNT

Deep cortex and subcortical white matter of the cerebral hemispheres

Adults (median age at diagnosis: 43year, range: 21–71years) > pediatric and adolescent

Asymptomatic, or nonfocal headache or seizures

NECT: Subcortical hypodensity in case of large lesions

No Ca++, no mass effect

CECT: Does not enhance in most cases

Cluster of small subcortical or juxtacortical nodules sparing the cortex. No mass effect or edema

T1WI: Isointense to the cortical GM

T2WI: Hyperintense

FLAIR: Hyperintense

DWI: No restricted diffusion

T1WI C+: Does not enhance in most cases

PGNT

Deep temporal white matter > frontal or parietal lobes

Uncommon: Pure intraventricular, pure pineal gland, and pineal region

Mean age at diagnosis: 23years (range: 4–75years).

Asymptomatic, or nonspecific signs (headaches and seizures)

Rare focal neurological deficits

NECT: Hypodense mass, with or without cysts and Ca++

Intraventricular PNTGs can cause acute obstructive hydrocephalus

CECT: Heterogeneous enhancement

Four patterns: Entirely cystic mass; cyst with mural nodule(s); purely solid mass; part cystic and part solid mass

Mild local mass effect, minimal or no edema (even when large)

T1WI: Iso/hypointense

T2WI: Heterogeneously hyperintense

FLAIR: Heterogeneously hyperintense, cyst signal suppression

T2 GRE/SWI: Ca++ variable; hemorrhage in < 10% of cases

T1WI C+: heterogeneous enhancement

RGNT

Midline around the 4th ventricle, superior vermis. Rarely in the pineal region, cerebellopontine angle, brain hemispheres

Mean age at diagnosis: 31years (range: 6–79years). Signs and symptoms of obstructive hydrocephalus

Occasionally cervical pain. Rarely asymptomatic

NECT: Cystic/solid mass

Ca++ variable, hemorrhage common

CECT: Heterogeneous enhancement

T1WI: Iso/hypointense cystic/solid mass

T2WI: Heterogeneously hyperintense

T2 GRE/SWI: Ca++ variable, hemorrhage common

T1WI C+: Variable enhancement (focal > heterogeneous > minimal > ring and nodular pattern of enhancement)

DLGNT

Spinal and cerebral leptomeninges

Mostly in children (age at diagnosis 5years; range: 5months–46years)

Variable clinical presentation depending on the site of tumor bulk

NECT: Indirect signs of the disease, such as communicating hydrocephalus

T1WI C+: Diffuse leptomeningeal enhancement along the surface of the brain and spinal cord

T2WI: Small, cystic or enhancing, nodular, intramedullary hyperintense lesions

FLAIR: Hyperintensity in sulci and cisterns

EVN

Mostly supratentorial, but also in thalamus, hypothalamus, pons cerebellum, cranial nerves, sella, cord, cauda equina, outside the craniospinal compartment

Any age (age at diagnosis: 1–79years)

Symptoms and signs of increased intracranial pressure, seizures, gait disturbances, vision changes, and headaches

NECT: Solitary, well-defined, part cystic, and part solid mass lesions of variable density with mild perilesional edema (51%). Ca++ variable (34%), hemorrhage

T1WI: Hypo/isointense part cystic and part solid mass

T2WI: Predominantly hyperintense

T2 GRE/SWI: Ca++ or microbleeds

T1WI C+: Variable contrast enhancement

Cerebellar liponeurocytoma

Cerebellum

Mean age at diagnosis: 50years (range: 24–77years)

Symptoms and signs of raised intracranial pressure and cerebellar signs

NECT: Hypodense (fat density) cerebellar mass

T1WI: Hyperintense

T1WI with fat suppression: Hypointense

T2WI: Hyperintense

T1WI C+: Heterogeneous enhancement

PGL

Cauda equina and filum terminale>thoracic region and cervical region

Mean age at diagnosis: 46years (range: 9–75years)

Low back pain, sciatica, motor deficits, sensory disturbance, and sphincter dysfunction

NECT: Bony remodeling, vertebral scalloping, thinning of pedicles, and foraminal enlargement

CECT: Enhancing intradural mass

Extramedullary mass, no peritumoral edema or syrinx

T1WI: Iso/hypointense relative to the cord

T2WI: Heterogeneously hyperintense, sometimes with prominent flow voids due to enlarged draining veins

T2 GRE/SWI: Hemosiderin from hemorrhage

T1WI C+: Intense enhancement

DNT

  • “Bubbly” cortical mass in child/young adult with longstanding partial complex epilepsy.

  • Differential diagnoses include, among others, focal cortical dysplasia type II and ganglioglioma. The lack of enhancement and the typical supratentorial location of DNT help to differentiate it from ganglioglioma.

  • On CT, DNT may mimic a stroke (wedge-shaped cortical and subcortical hypodensity), but there is no atrophy over time.

GG, GC, and DCG (LDD)

The differential diagnosis of GG includes GC, low-grade astrocytoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), and oligodendroglioma.
  • Low-grade astrocytoma typically does not enhance compared to GG. A supratentorial pilocytic astrocytoma is rarely cortical and more frequently occurs in the hypothalamus/chiasm. It is cystic with a nodule but does not show calcifications.

  • A supratentorial PXA (most commonly located in the temporal lobe) appears as a cortical cyst with mural nodule very similar to GG. However, PXA has a dural “tail” which helps to differentiate it from GG.

  • DNT has a multicystic bubbly appearance and rarely enhances compared to GG.

  • Oligodendroglioma is less delineated than GG and only rarely looks like a cyst with mural nodule (in which case they are indistinguishable from GG on imaging).

DIA and DIG

The differential diagnosis of DIA and DIG includes primitive neuroectodermal tumor (PNET), supratentorial ependymoma, pleomorphic xanthoastrocytoma (PXA), hemangioblastoma, and ganglioglioma.
  • Cortical PNET differs from DIA and DIG because it frequently contains calcifications and areas of hemorrhage or necrosis.

  • PXA and ganglioglioma also commonly contain calcifications, whereas these are rare in DIA and DIG. Ganglioglioma is generally smaller in size and affects slightly older patients. In the absence of calcification, PXA in the temporal lobe may appear identical to DIA and DIG.

  • Hemangioblastoma appears as a cyst with a mural nodule, but it is rare in children and mostly located in the posterior fossa, rather than the supratentorial compartment.

DCG

The appearance of DCG is very characteristic and usually has a very limited differential diagnosis. Sonic hedgehog medulloblastoma (SHH-MB), which affects the cerebellar hemispheres and the vermis, can mimic DCG. SSH-MB may present with a striated appearance and increased DWI signal but shows a marked increase in Cho/NAA.

MVNT

The differential diagnosis of MVNT includes dysembryoplastic neuroepithelial tumor (DNT), focal cortical dysplasia (FCD), and enlarged perivascular spaces.
  • MVNT differs from DNT because the latter involves the superficial cortex, causes a local mass effect and lacks intra- or perilesional tumor nodules.

  • Small MVNTs can simulate focal cortical dysplasia although the cortex in FCD is thickened.

  • Enlarged perivascular spaces follow the CSF signal on all sequences and spare the cortex, whereas the MVNT does not suppress in FLAIR.

RGNT

  • Consider RGNT when you see a solid/cystic neoplasm of the fourth ventricle/superior vermis in an adult.

  • Differential diagnosis includes dysembryoplastic neuroepithelial tumor, pilocytic astrocytoma, medulloblastoma, ependymoma, choroid plexus papilloma, ETMRs, and metastases.

PGNT

  • PGNT is a histologic diagnosis.

  • On imaging, other tumors (ganglioglioma, oligodendroglioma, ependymoma) or parasitic infections (neurocysticercosis) might present with imaging characteristics described above.

  • Cases which present with extensive hemorrhage may mimic a bleed from cavernoma.

DLGNT

  • A biopsy is required for the final diagnosis of DLGNT.

  • DLGNT has a broad differential diagnosis on MRI which includes infective etiology meningitis (tuberculosis meningitis or fungal diseases), inflammatory disorders (neurosarcoid) or other neoplasms (lymphoma, leukemia).

EVNs

  • Differential diagnosis of EVNs includes pilocytic astrocytoma and ganglioglioma.

  • Biopsy and pathologic examination are often required to differentiate the mass from other common spinal cord tumors.

Cerebellar Liponeurocytoma

  • Consider a liponeurocytoma if you see a cerebellar mass with adipose content in adults.

  • Anaplastic Oligodendroglioma rarely occurs in the cerebellum, and the ependymoma is a fourth ventricular mass rather than a cerebellar mass.

Clinical Case and Sample Report

Patient history: 24-year-old female patient presenting with a history of epileptic fits and suspected right parietal lesion on CT performed at the referring hospital.

Clinical Diagnosis: Dysembryoplastic neuroepithelial tumor (DNT).

Purpose of MR study: To investigate the cause of epilepsy and confirm presence of lesion suspected on CT.

Imaging technique: MRI brain tumor protocol.

Full Findings (Fig. 12): Images show a multicystic lesion involving the cortex right inferior parietal lobe with some extension into the posterior aspect of the right superior temporal gyrus. The intracortical lesion has “bubbly appearance,” is hyperintense on the T2-weighted images, and shows mixed signal without suppression on FLAIR. There is no pathological enhancement associated following gadolinium administration. There is no mass effect or surrounding edema. The remaining intracranial appearances are otherwise within normal limits for age.
Fig. 12

24-year-old female with DNT. History of epileptic fits and suspected right parietal lesion on CT performed at the referring hospital. MRI shows a solitary, multicystic lesion involving the cortex of the right inferior parietal lobe with some extension into the posterior aspect of the right superior temporal gyrus (d, e). The lesion expands the cortex, is hyperintense on T2-weighted images (a, d), shows a mixed signal on FLAIR (b), and is hypointense on T1-weighted images (e). There is a peripheral rim of hyperintense signal on FLAIR (b). Following contrast administration, the lesion does enhance (c)

Interpretation: The appearances are consistent with a right temporoparietal DNET.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Lysholm Department of NeuroradiologyNational Hospital for Neurology and Neurosurgery (NHNN), and University College Hospital (UCH)LondonUK

Section editors and affiliations

  • Rolf Jäger
    • 1
  1. 1.University College LondonLondonUK

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