Extraventricular neurocytomas (EVNs) are rare neoplasms with many similar morphologic features compared with central neurocytomas. EVNs have been reported in a variety of locations and mainly occur within the cerebral hemispheres. These lesions display wide variability in morphologic features, cellularity, and proliferation rates. In addition, given their aggressive biological nature and tendencies to affect eloquent areas, EVNs are associated with a poorer prognosis. The epidemiology of these rare tumors is not definitively known, and effective treatment strategies have not been developed. This article reviews these tumors, including their epidemiology, clinical presentation, locations, radiological findings, treatment options, and prognosis.
Key points
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Extraventricular neurocytomas (EVNs) are rare neoplasms with many similarities and differences compared with central neurocytomas (CNs); much remains to be learned about the clinical and biological behavior of these tumors.
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Clinical presentation depends on the area in which EVN is present, and gross total resection (GTR) can be affected with involvement of eloquent areas.
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There is significant overlap in the appearance on different imaging modalities when comparing with other primary intracranial neoplasms, possibly leading to misdiagnosis.
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Surgical resection and pathologic and immunohistochemistry studies are needed in order to obtain a definitive diagnosis.
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GTR and subtotal resection with radiotherapy do offer good clinical outcomes; however, prognosis is affected by extremes of age, extent of resection, and atypical histologic features.
Introduction
Central neurocytomas (CNs) are rare neuronal tumors that were classified by the World Health Organization (WHO) as a separate pathologic entity in 2007. CNs were first described by Hassoun and colleagues in 1982 after presenting 2 cases of intraventricular tumors with neuronal features on electron microscopy. CNs were so named due to the neuronal origin and midline location within the ventricular system. Neurocytomas may also occur as periventricular and parenchymal masses, or even in locations remote from the ventricles, and are so-called extraventricular neurocytomas (EVNs). EVNs are rare and are frequently associated with poorer outcomes compared with CNs. For this reason, EVNs were listed as a distinct entity in the new WHO guidelines.
CNs have many histopathological characteristics that mimic oligodendrogliomas and ependymomas. For this reason, CNs are commonly misdiagnosed. The same diagnostic dilemma applies for EVNs. There is increasing evidence of oligodendrogliomas with neuronal and neurocytic differentiation creating morphologic overlap, leading to further difficulties in diagnosis. Nonetheless, various immunohistochemical methods have helped in differentiation. Due to the infrequency of EVNs, the literature is based off case reports as well as small case series and has not been well characterized with limited clinical, radiological, management, and prognostic information.
Introduction
Central neurocytomas (CNs) are rare neuronal tumors that were classified by the World Health Organization (WHO) as a separate pathologic entity in 2007. CNs were first described by Hassoun and colleagues in 1982 after presenting 2 cases of intraventricular tumors with neuronal features on electron microscopy. CNs were so named due to the neuronal origin and midline location within the ventricular system. Neurocytomas may also occur as periventricular and parenchymal masses, or even in locations remote from the ventricles, and are so-called extraventricular neurocytomas (EVNs). EVNs are rare and are frequently associated with poorer outcomes compared with CNs. For this reason, EVNs were listed as a distinct entity in the new WHO guidelines.
CNs have many histopathological characteristics that mimic oligodendrogliomas and ependymomas. For this reason, CNs are commonly misdiagnosed. The same diagnostic dilemma applies for EVNs. There is increasing evidence of oligodendrogliomas with neuronal and neurocytic differentiation creating morphologic overlap, leading to further difficulties in diagnosis. Nonetheless, various immunohistochemical methods have helped in differentiation. Due to the infrequency of EVNs, the literature is based off case reports as well as small case series and has not been well characterized with limited clinical, radiological, management, and prognostic information.
Epidemiology
The true incidence of EVNs is not recorded in the literature. CNs represent 0.1% to 0.5% of all primary brain tumors, and EVNs are much less common compared with CNs. Small case studies provide some insight into the epidemiology of these tumors. The current literature does not display a relationship between gender and the formation of EVNs. In 2002, Brat and colleagues reported 32 cases that spanned over an 8-year period revealing an equal ratio of males to females diagnosed with EVNs. Additionally, these tumors can arise over a wide range of ages, with case reports of ages ranging from 1 to 79 years, with a median age occurring in the 4th decade of life. In 2013, Han and colleagues reported 47 cases of EVNs occurring in the pediatric population. Within this group, there was a slight male predominance in 29 of the 47 reported cases.
Location
In regards to EVNs, cases have been described within multiple locations. Unlike EVNs, for CNs, the predominant location is within the lateral ventricles. Reports describe EVNs developing throughout the periventricular and intraparenchymal tissues. Table 1 contains a summary of intracranial EVNs reported in the literature to date that meet inclusion criteria. Inclusion criteria were case studies and reports that included age, tumor location, histopathological description, treatment, follow-up, and recurrence information. In adults, EVNs are most likely to occur within the frontal lobe, followed subsequently by temporal, parietal, and occipital lobes. In the pediatric population, tumor location was predominant, with 34% of reported cases occurring in the frontal lobe. This was followed by temporal lobe (13%), spinal (13%), and parietal lobe (11%).
| Location | Number (%) |
|---|---|
| Frontal lobe | 29 (30) |
| Temporal lobe | 19 (20) |
| Parietal lobe | 14 (15) |
| Occipital lobe | 6 (6) |
| Cerebellum | 6 (6) |
| Frontoparietal lobe | 4 (4) |
| Parieto-occipital lobe | 3 (3) |
| Thalamus | 2 (2) |
| Sellar/Suprasellar region | 2 (2) |
| Hypothalamus | 2 (2) |
| Pineal region | 2 (2) |
| Temporal–parietal | 1 (1) |
| Corpus callosum | 1 (1) |
| Cerebral | 1 (1) |
| Tectum of midbrain | 1 (1) |
| Parasagittal | 1 (1) |
| Sphenoid wing | 1 (1) |
| Pons | 1 (1) |
| Internal auditory canal | 1 (1) |
| Total | 97 (100) |
Clinical presentation
Because of the myriad of locations, symptomatology can be based on the lesion’s mass effect on the surrounding structures involved. Presenting symptoms include seizures, vision changes, headaches, and vomiting. Although CNs present with similar symptoms, they typically result in obstructive hydrocephalus caused by the CN’s location within the ventricles. Other documented symptoms include altered mental status, memory disturbances, dementia, seizures, paresthesias, balance problems, and weakness. Intramedullary lesions within the spine initially present with paraparesis, which is followed by bladder and autonomic involvement as progression occurs. Liu and colleagues and Patil and colleagues reported duration of symptoms ranging from 2 weeks to 16 years. It is thought that the duration of symptoms does not correlate with the aggressiveness of tumors.
Radiographic findings
As with CNs, EVNs are difficult to differentiate from other intraparenchymal tumors on the basis of computed tomography (CT) and MRI. EVNs appear to have a wide spectrum of patterns on conventional imaging due to many variations in cellularity and anatomic locations.
Computed Tomography
CT scans of the lesions appear to be isodense to hyperdense; this appearance is thought to be due to areas of calcifications and cystic zones. One-half to three-fourths of these masses tend to have cystic degeneration. Up to one-half of EVNs contain calcifications, with instances of complete calcification being reported in the literature. These calcifications have been described as being spot-like. Other distinct imaging characteristics on CT scan include perilesional edema and heterogeneous contrast enhancement. Intralesional hemorrhages have also been identified on CT scan. With administration of contrast, EVNs on CT show heterogeneous enhancement.
Magnetic Resonance Imaging
MR imaging characteristics of EVNs vary widely based on the current literature. This is thought to be due to the wide morphologic spectrum of EVNs. On T1 weighted images, the solid parts of the tumor, which include the cystic wall, are isointense, with small areas that are hyperintense and/or hypointense in comparison with the gray matter. T2 weighted images and fluid-attenuated inversion recovery (FLAIR) images show heterogeneity and hyperintensities of these lesions. Cystic tumor components are hypointense on T1 weighted images, hyper-intense on T2 weighted images, and hypointense on FLAIR images.
On contrast-enhanced images, EVNs demonstrate heterogeneously enhancing lesions. There is great variability in the amount of enhancement seen, ranging from mild to strong contrast enhancement. Case reports have described different enhancement patterns including ring-like, patchy, and zebra-like. Case reports have described total lack of enhancement in a small percentage of EVNs, likely resulting from hypovascularity.
EVNs have similar radiographic appearances to low-grade gliomas. EVNs may be differentiated from low-grade gliomas by their general isointensity to slight hyperintensity on T1 weighted images, which is distinct from the hypointensity on T1 weighted images found in gliomas.
Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy can be used to further characterize EVNs with similar findings as those found in more common tumors. Unlike CNs which do have a high N-acetylaspartate peak (NAA) peak, this peak in EVNs may be absent or significantly decreased. This is thought to occur because of the presence of neurons within EVNs, which may be too immature to produce NAA. There is a strong choline peak associated with EVNs. With many morphologic variations being reported throughout the literature, further characterization via magnetic resonance spectroscopy is needed to determine whether findings are consistent.
Histopathology
Although both CNs and EVNs are of neuronal origin and share many histopathological characteristics, EVNs demonstrate a wider variety of histologic morphology. Uniform small, round cells with clear cell morphology in a neuropil background are found in both tumor types, which can sometimes make it difficult to differentiate them from oligodendrogliomas with neuronal characteristics. CNs show a more uniform morphologic pattern, but EVNs can exhibit sheet-like patterns, clusters, ribbon-like appearance, or Homer-Wright rosettes. Moreover, EVNs exhibit more ganglionic differentiation compared with CNs, 56.9% versus 5% to 10% respectively. Hyalinized vessels and myxoid background are seen in EVNs but rarely in CNs. Atypical EVNs, which have higher rates of recurrence and mortality than typical EVNs, have an MIB-1 index greater than 3%, focal necrosis, and increased vascularity and mitoses.
Immunohistochemistry (IHC) staining shows strong positivity for neuronal markers such as synaptophysin and neuron-specific enolase in both CNs and EVNs, but GFAP positivity is seen in about 30% of EVNs and rarely in CNs. However, adding to the diagnostic dilemma, some oligodendrogliomas can also stain positively with synaptophysin, although it is usually less intense than EVNs.
Although a specific genetic profile has not been found in EVNs, 1p-19q deletions have been described in some atypical cases (25%), and these may portend a more aggressive behavior and worse outcome. There are no reports of 1p-19q deletions in CNs. Moreover, recently some authors have proposed using IHC for isocitrate dehydrogenase 1 (IDH1) mutation to differentiate EVNs from oligodendrogliomas, because this mutation has not been reported in EVNs thus far. Myung and colleagues also found that EVNs lacked p53 overexpression, alpha-internexin positivity, and MGMT promoter methylation in their genetic analysis of 7 samples. In the advent of high-throughput sequencing and advancing technology, additional clinically useful genetic markers for tumor differentiation can be expected.
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