Intracranial ependymomas: The role of advanced neuroimaging in diagnosis and management

Abstract

Intracranial ependymomas represent a rare subgroup of glial tumours, showing a wide variety of imaging characteristics, often representing a challenging diagnosis for neuroradiologists. Here, we review the most recent scientific Literature on intracranial ependymomas, highlighting the most characteristic computed tomography and magnetic resonance imaging features of these neoplasms, along with epidemiologic data, recent classification aspects, clinical presentation and conventional therapeutic strategies. In addition, we report an illustrative case of an 18-year-old girl presenting with an intracranial supratentorial, anaplastic ependymoma, with the aim of contributing to the existing knowledge and comprehension of this rare tumour.

Keywords

Ependymoma anaplastic ependymoma intracranial ependymoma supratentorial ependymoma ependymoma MRI ependymoma CT

Introduction

Tumours of the ependymal series represent a heterogeneous group of neoplasms that can assume different morphological features and arise anywhere along the neuroaxis. They are a rare subgroup of glial tumours originating from the ependymal cells, although their genetic and molecular alterations have not yet been fully delineated. Furthermore, more than 52% of ependymal neoplasms affect the spinal cord and the cauda equina, with only 48% involving the intracranial compartment.¹ Besides, considering that supratentorial (ST) and posterior fossa (PF) ependymal tumours, despite their histopathological similarities, are distinct diseases, with different age prevalence, peculiar genetic and transcriptional epigenetic alterations, it is clear that the diagnosis of their intracranial localisation could be challenging.^1,2

The following review is intended to highlight the main radiological features of intracranial ependymal tumours, along with pathological and clinical data, as well as providing prognostic elements and current therapeutic approaches.

For this literature review, we searched for original articles, prior reviews and clinical cases using the main English online databases (PubMed, Scopus and Cochrane) as data sources. ‘Ependymoma’, ‘ependymal tumours’, ‘ependymoma MRI’, ‘ependymoma CT’ and ‘subependymoma’ were used as keywords.

Inclusion criteria were articles dealing with primary intracranial ependymal tumours published since 2000. Exclusion criteria were papers dealing only with primary spinal ependymal tumours, ependymal intracranial metastases and radiological case-based series without certain histological/molecular diagnosis.

Epidemiology

Several review articles have aimed to provide an accurate estimation of the prevalence of ependymal tumours in the USA and Europe. Ependymal tumours are rare glial tumours that exhibit an average annual age-adjusted rate of 0.41/100,000 in the USA¹ and 0.20/100,000 in Europe.²

For Europe in particular, a geographical distribution has been recorded, with slightly higher incidence rates per 100,000 per year reported in Northern Europe (Iceland, Norway, Sweden; 0.3) compared to the remaining European countries (0.2), according to data provided from 64 different European cancer registries.² Incidence is significantly higher in males than in females (>10–15%), in whites than in other ethnicities and in non-Hispanics compared to Hispanics.³ Interestingly, an increased risk of mortality, despite lower incidence, has been reported among African American population compared to white populations.³

Ependymal tumours show a bimodal distribution, with a peak incidence at 3 and 57 years, although the highest rate is observed in the 45–64 years age group.¹ Overall, the most frequent histological type is ‘classic’ ependymoma, followed by myxopapillary ependymoma, subependymoma and anaplastic ependymoma. Nonetheless, the main histological pattern is age dependent. Notwithstanding that ependymoma remains the most frequent in all age groups, anaplastic ependymoma is six times more frequent in children and adolescents, whereas subependymoma is more common in adults.¹ Furthermore, tumour location varies among different age groups. As a general rule, ependymomas are far more common in the spine in adults and in the brain – mainly in the PF – in children. In fact, >50% of adult ependymal tumours are located in the spinal cord/cauda equine, whereas only 20% of their paediatric counterparts are affected in this anatomical structure. On the other hand, diagnoses of ependymal tumours in the brain for the 0–19 years age group substantially exceeded those observed in adult age groups. In adults, intracranial ependymomas account for about 3–9% of brain tumours² (Figure 1).

There are no specific risk factors for developing ependymomas, except for neurofibromatosis type 2, which is currently considered as the only predisposing pathology for the development of these neoplasms. In these patients, these lesions tend, however, to present a slower growth and a more benign biological behaviour.⁴

Clinical presentation

Clinical presentation is age dependent and is strongly influenced by the localisation of primary intracranial ependymoma. Particularly, neoplasms located in the fourth ventricle tend to present with symptoms related to intracranial hypertension, such as progressive lethargy, headache, vomiting and nausea. Furthermore, multiple cranial nerve palsy is common due to the vicinity of their nucleus to the fourth ventricle, as well as cerebellar dysfunction. Similarly, children with PF ependymoma tend to present with the same symptoms caused by obstructive hydrocephalus.⁵ Nevertheless, some cases of torticollis due to the growth through the foramen of Magendie have been described in this particular category.⁶

In newborns and infants before the closure of the cranial sutures, increased cranial volume is common because of hydrocephalus. ST parenchymal localisation is characterised instead by focal neurological deficits, cognitive impairment, seizures and psychiatric disturbances.⁵

Classification

According to the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumours, ependymomas were classified as follows⁷:

Subependymoma

Myxopapillary ependymoma

Ependymoma (papillary, clear cell, tanycytic)

Ependymoma, v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA) fusion-positive

Anaplastic ependymoma

Subependymoma and myxopapillary ependymoma are considered grade I tumours. Ependymoma, in its different histologic variants, is considered grade II. Ependymoma RELA fusion-positive is classified as a II–III grade neoplasia. Anaplastic ependymoma is classified as grade III.⁷

The WHO classification, however, based on histological findings, has failed to provide an accurate risk stratification for patients, since a robust association between tumour grading and patient outcome was not found, particularly for ependymoma grade II or III. In fact, ST and PF ependymomas would be better considered as biologically different diseases. Hence, a new molecular classification based on deoxyribonucleic acid (DNA) methylation pattern was recently introduced.⁸ This molecular classification distinguishes three different molecular subgroups for the ST and PF compartment. One of the three subgroups in each compartment is represented by subependymoma.

In the ST group, the majority of tumours (>70%) contain a RELA fusion transcript and are therefore classified as ST-RELA or RELA fusion positive. These tumours present a fusion between the nuclear factor kappa B effector RELA and the gene C11orf95. This rearrangement, called chromothripsis, involves the chromosome arm 11q. It has been shown that these neoplasms may occur both in children and in adults, with a male prevalence, and have a poor prognosis.⁹

The rest of the ST subgroup presents with a YAP1 fusion gene, with this subgroup designated as ST-YAP1. In the ST-EPN-YAP1 subgroup, focal aberrations on chromosome arm 11q lead to fusions between the YAP1 gene and the MAMLD1 gene. The YAP1 gene encodes for an oncoprotein, Yes Associated Protein (YAP), which represents a downstream effector of the HIPPO signalling pathway. This pathway consists of a kinase cascade, transcription coactivators and DNA binding partners, and its major functions are to restrict tissue growth in adults and to modulate cell proliferation and differentiation. When the pathway is disabled, the oncoprotein can translocate to the nucleus and interact with several transcription factors, causing increased cellular replication and reduced apoptosis.¹⁰

YAP1 tumours are more common in young children and have a good prognosis. The distinction between the two subgroups can be readily obtained by evaluating the expression of L1CAM, a fundamental neuronal cell adhesion membrane mapped on the X chromosome.⁹

Interestingly, the correlation of clinical characteristics within the two different subgroups revealed that patients with ST-RELA tumours showed significantly worse progression-free survival (PFS) and overall survival (OS) compared to the other subgroup. However, differences in this subgroup have not yet been translated into significant differences in the therapeutic management of these lesions. Notably, some ST ependymomas have been reported lacking the aforementioned genetic fusions, thus indicating that this classification still does not encompass every kind of ST ependymal tumour. Regarding PF ependymomas, they have recently been classified as PF-A and PF-B.¹¹ PF-A tumours occur predominantly in infants and young children (median age two-and-a-half years) and show a male preponderance. About two thirds of these neoplasms arise laterally and present different degrees of cerebellar involvement.⁶ PF-B tumours instead occur predominantly in adolescents and adults (median age of 20 years) and are more commonly found in the midline without a tendency to involve the cerebellar parenchyma. From a genetic point of view, these tumours are very different. In fact, PF-A exhibits a largely balanced genomic profile, with a chromosome 1q gain being the most observed, albeit rare, alteration. Group B tumours, on the other hand, show several cytogenetic abnormalities.⁶ Methylation analysis has recently showed that PF-A neoplasms present an increase in the methylation of CpG islands that may lead to tumourigenesis. CpG (cytosine to guanine separated by a phosphodiester bond) islands are short stretches of DNA with a higher frequency of dinucleotides CpG compared to the rest of the genome. Aberrant methylation of CpG islands is associated with transcriptional inactivation of several oncosuppressors.¹²

Microscopic pathology and neuroimaging

Subependymomas are benign, slow-growing neoplasms, typically attached to the ventricular wall. They are characterised by a cluster of isomorphic nuclei embedded by a dense, glial fibrillary matrix (‘bundles of flowers’). Mitosis and necrosis are rare. Interestingly, cells tend to have a microcystic appearance with bluish material, looking spongy at low magnification.¹³

Subependymomas are classified as low-grade tumours, commonly discovered during autopsies or as an incidental finding during magnetic resonance imaging (MRI) examinations. They occur most often in middle-aged patients, with a slight prevalence in men. These lesions typically arise in the fourth ventricle (50–60% of cases) or in the lateral ventricles (30–40% cases). Far less frequently, they may arise in the septum pellucidum, in the third ventricle or even in intraparenchymal locations.¹⁴

On computed tomography (CT) unenhanced scans, these tumours usually look like nodular, well-demarcated, iso-hypodense lesions, with possible internal cystic components, which may lead to a misdiagnosis of a poroencephalic cyst. In general, calcifications are not a common finding, but they can be more frequent in subependymomas of the fourth ventricle than in lesions arising from lateral ventricles. On enhanced scans, enhancement is usually absent or slight.¹⁴

On MRI, subependymomas are hypo- to isointense in T1-weighted sequences and hyperintense in T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences; mass effect or peritumoural oedema are uncommon findings. Again, enhancement is slight or absent¹⁵ (Figure 2).

Magnetic resonance spectroscopy (MRS) usually shows a normal choline (Cho) peak with a slight reduction of N-acetylaspartate (NAA) peak. These findings, however, are non-specific and common in low-grade tumours. Interestingly, in 2003, a case series of seven patients by Im et al.¹⁵ showed a higher Cho/Creatine (Cr) ratio in subependymomas showing recurrence after surgery. Hence, MRS could represent an important prognostic tool in evaluating these lesions.

Myxopapillary ependymoma is characterised by pseudopapillary formations due to perivascular mucoid degeneration and dyscohesion. Symmetrical zones of mucoid matrix surrounding branching tumescent vessels, as well as accumulation of mucin within and between tumour cells, are recognised as pathological hallmarks of this histologic subtype. Histologically, they are classified as benign (WHO grade I) tumours, generally confined to the lumbosacral spinal cord (representing approximately 27% of spinal ependymomas). They are extremely rare as primary intracranial tumours.¹⁶ Myxopapillary ependymoma is far more common in the conus medullaris and filum terminale region than in the brain. However, intracerebral involvement has been described in very rare cases. When involving the brain, this tumour has been reported to arise from the floor of the fourth ventricle, lateral ventricles or in cortical-subcortical intraparenchymal locations.^17–19 On CT, these lesions usually appear as well-delineated, pseudo-cystic, inhomogeneously hypodense formations with a solid nodular enhancing component. On MRI, the cystic component appears hypointense in T1-weighted and hyperintense in T2-weighted sequences, with homogenous enhancement of cystic walls and solid intralesional component. When involving the fourth ventricle, the lesion tends to appear as a pluri-lobulated, pseudo-cystic formation with enhancement of solid components.^18,19

Classic ependymoma is typically characterised by a discrete interface with the surrounding parenchyma and areas of regressive changes such as myxoid degeneration, haemorrhage, calcification and hyalinised vessels. These tumours are moderately cellular, with round/oval nuclei and salt-and-pepper chromatin. Mitotic activity is low. Characteristically, they show perivascular pseudorosettes of glial tumour cells that are radially arranged around the blood vessels and true ependymal rosettes of tumour cells that form a central lumen on their own. Their vasculature is relatively mature, and they show little angiogenic activity. Classic ependymoma present three histological subtypes, but they tend not to have any clinico-pathological/radiological substantial differences¹³: papillary ependymoma, formed by uniform benign-appearing epithelial cells resembling those of choroid plexus papilloma (CPP)¹⁶; clear-cell ependymoma, rare but sharing histological features with oligodendroglioma, neurocytoma and metastases from renal-cell carcinoma¹⁶; and tanycytic ependymoma, fibrillar variant with discrete margins, elongated spindle cells with dark regions of chromatin (similar to ependymoma) and marked fibrillarity (similar to astrocytoma). Ependymal rosettes are not visualised.¹⁶

Classic ependymoma is more common intracranially in children, mainly in the PF, and in the spine in adults. On CT scans, PF ependymomas usually appear as hypo-isodense masses typically developing in the fourth ventricle or sometimes in the cerebellopontine angle or even in the upper cervical canal through foramina of Luschka and Magendie. Hydrocephalus is a common finding in ependymomas of the PF. Calcifications and cystic components are not rare. On MRI, these tumours commonly appear as heterogeneous formation, hypo-isointense in T1-weighted images and hyperintense in T2-weighted sequences. Post-contrast enhancement is usually strong and almost homogeneous. In case of ST localisation, ependymomas may be observed both inside and, more commonly, outside lateral ventricles. In this latter case, they usually arise in the deep white matter, mainly in the frontal lobes. ST lesions are usually relatively large, inhomogeneous lesions showing both solid and cystic components, often presenting extensive peritumoural oedema. On CT, the lesion appears as a lobulated, well-defined formation, iso-, hypo- or hyperdense to the grey matter. Cystic, intralesional haemorrhage or calcifications are not rare.¹⁹

On MRI, cystic or necrotic intralesional components appear hypo- and hyperintense in T1- and T2-weighted sequences, respectively. FLAIR sequences may be very useful to delineate the extent of the lesion from the surrounding perilesional oedema. Post-contrast enhancement is usually moderate to strong, with areas of a lack of enhancement due to cystic components (Figures 3 and 4). Diffusion-weighted imaging (DWI) may, in rare cases, show areas of hyperintensities as for hypercellularity. Susceptibility-weighted imaging (SWI) is very sensitive to detecting possible intralesional blood products. MRS may highlight a slight increase of Cho peak and a slight reduction of NAA. These findings, however, are not specific. Perfusion-weighted imaging (PWI) generally demonstrates elevated cerebral blood volume (CBV) with a typical poor return to baseline, likely due to the presence of fenestrated blood vessels and incomplete blood–brain barrier.²⁰

Notably, in a series of 41 patients reported by Mangalore et al., the presence of calcifications on unenhanced CT is mentioned as the sole radiological finding significantly differentiating grade II and grade III (anaplastic) ependymomas.²¹ Anaplastic ependymoma demonstrates a more rapid growth, increased cellularity, brisk mitotic activity and vascular proliferation.²² Anaplastic ependymomas usually involve the PF in very young children and ST and extraventricular regions in adults.⁹ On CT unenhanced scans, anaplastic ependymomas often resemble grade II classic ependymomas. They usually appear as a hypodense lesion with a hyperintense rim and often poorly demarcated margins. CT also provides an adequate detection in case of calcifications, which can be found in up to 20% of cases or in cases of intralesional haemorrhage. In particular, in a series of 11 intracranial anaplastic ependymomas, MRI showed signs of intratumoural haemorrhage in 7/11 cases.²³ MRI, however, plays a central role in the evaluation of these lesions, as it provides fundamental information, including location, shape, boundaries and structure of the neoplasm. The majority of these tumours are irregularly lobulated, probably due to a non-uniform proliferation of cells. MRI of these lesions reflects the heterogeneity of their architecture, consisting of various different components such as cyst, necrosis, haemorrhage, calcification and fibrosis or vascular proliferation. On T1-weighted sequences, the neoplasm is hypointense to isointense relative to the grey matter; on T2-weighted sequences, the neoplasm is hyperintense or slightly hypointense. DWI may help in identifying areas of hypercellularity, characterised by signs of restricted diffusion.²³

Gradient-echo (GRE), or SWI particularly, can easily depict possible haemorrhagic intralesional components.²⁴ Post-contrast sequences usually show heterogeneous enhancement, with evidence of avid enhancement of the solid component and ring-like enhancement of the cystic components.²³

MRS may also be extremely helpful in defining the grade of aggressivity of the lesion. In fact, MRS shows elevated Cho levels and a reduction of NAA peak, suggesting a high grade of cell proliferation and neuronal loss degeneration, respectively. Perfusion MRI shows increase of relative cerebral blood volume (rCBV) in the anaplastic component. A possible role of MRS has also been mentioned in the diagnostic evaluation of RELA fusion ependymomas. In fact, some authors have reported an increase of Cho and an absent lactate peak.²⁵ These findings, however, are not specific.

Differential diagnoses

Ependymomas are a relatively heterogeneous class of tumours, and not surprisingly, there are several differential diagnoses that should be considered when analysing these lesions (Table 1). The main differential diagnosis with infratentorial ependymomas is represented by medulloblastoma (MB). Both these tumours mainly affect children and show potential leptomeningeal spread.²⁶ The majority of MB, however, arise in the cerebellar vermis with subsequent involvement of the roof of the fourth ventricle. Differently from ependymomas, they do not tend to extend into the basal cisterns.²⁵ These lesions are usually hyperdense on CT with relatively common evidence of intralesional cysts and, in about 10–20% of cases, calcifications.²⁶ They are usually hypointense and iso-hyperintense to grey matter on T1- and T2-weighted sequences, respectively, and in the wide majority of cases, they show restricted diffusion on DWI. Heterogeneous and avid gadolinium enhancement is nearly always present. MRS shows elevated Cho peak and reduction of NAA peak with possible evidence of lactate peak due to abundant mitosis, neuronal degeneration and necrosis. A study of the whole neuraxis on MRI is strictly recommended when evaluating this lesion in order to establish a correct staging. Pylocitic astrocytoma (PA) is a relatively common infratentorial, low-grade neoplasm affecting children and young adults. On CT imaging, the typical appearance is a hypodense cyst with a solid nodule showing homogeneous enhancement or a solid, slightly hyperdense, enhancing formation. On MRI, cystic PA presents a fluid-filled cystic formation with an enhancing nodule that is hypointense in T1- and hyperintense in T2-weighted sequences. Solid PA, on the other hand, are usually slightly hyperintense to cerebrospinal fluid (CSF) on T1- and T2-weighted and FLAIR sequences. DWI is not restricted. The pattern of enhancement reflects the CT appearance.²⁶

Table 1.

Neuroimaging of main differential diagnoses.

	MRI	CT	Key points
Medulloblastoma	T1: hypointense	Hyperdense	• Children• Infratentorial• Common spine involvement
	T2: iso-hyperintense	Ca++ (20%)
	T1 C+: >90% heterogeneous enhancement
	MRS: high Cho, low NAA, possible lactate peak
Pylocitic astrocytoma	T1: hypointense	Hypodense cystic formation with hyperdense solid nodule	• Young adults• Infratentorial• Cyst with mural node
	T2: hyperintense
	FLAIR: hyperintense
	T1 C+: enhancing nodule
	MRS: high NAA
Atypical teratoid/rhabdoid tumour	T1: iso-hyperintense	Inhomogeneously hyperdense formation with peripheral hypodense cystic component	• Children• Off-midline location• Peripheral cystic component
	T2: hyperintense
	DWI: restriction
	T1 C+: heterogeneous enhancement of solid component
	MRS: high Cho, low NAA, lipid peak
Central neurocytoma	T1: hypointense	Hypodense cystic and hyperdense solid components	• Young adults• Intraventricular• Hydrocephalus
	T2: hyperintense
	FLAIR: hyperintense
	T1 C+: inhomogeneous enhancement
Choroid plexus tumours	T1: iso-hypointense well-delineated mass	75% iso- or hyperattenuating	• Children (carcinoma) • Children and young adults (papilloma) • Atrium of lateral ventricles or fourth ventricle• Hydrocephalus
	T2: iso-/hyperintense
	T1 C+: homogeneous enhancement
	MRS: low NAA, high Cho
Glioblastoma multiforme	T1: isointense	Irregular isodense or hypodense mass+central hypodensity	• Adults• Perilesional oedema• Possible contralateral extension• rCBV increased
	T2: heterogeneous
	T2*GRE: susceptibility artefact common due to blood products
	T1 C+: thick, irregular ring surrounding central necrosis
	MRS: high Cho, low NAA, Lactate pick
Oligodendroglioma	T1: hypo-/isointense	Mixed density Majority calcify, nodular or clumped Ca++	• Young adults• Supratentorial, cortical• Common Ca++
	T2: heterogeneous
	T2*GRE: Ca++ (blooming)
	T1 C+: heterogeneous enhancement
Pleomorphic xanthoastrocytoma	T1:iso-/hypointense	Cystic/solid mass: hypodense with mixed density nodule	• Children, young adults• Supratentorial• Epilepsy
	T2: hyperintense; cystic portion isointense to CSF
	T1 C+: strong enhancement

MRI: magnetic resonance imaging; CT: computed tomography; C+: post-gadolinium administration; MRS: magnetic resonance spectroscopy; NAA: N-acetylaspartate; Cho: choline; Ca++: calcifications; rCBV: relative cerebral blood volume; CSF: cerebrospinal fluid.

Atypical teratoid/rhabdoid tumour (AT/RT) is a rare, highly malignant tumour, mainly affecting children and, in rare cases, adults, with a slight male predominance. This tumour may occur both in infratentorial and ST sites and it may also be multifocal. In a series of 11 cases reported by Jin et al.²⁷ AT/RT is described as a large, inhomogeneous formation, iso- to hyperintense to the grey matter on T1-weighted sequences and moderately hyperintense in T2-weighted sequences. The tumour often presents a peripheral cystic component; haemorrhagic and necrotic areas are common in the solid portion. DWI, along with apparent diffusion coefficient maps, often shows signs of restricted diffusion due to hypercellularity. Enhancement after administration of gadolinium is moderate to intense in the solid components. MRS often shows a marked increase of Cho peak with reduction of Naa and presence of a Lipid (Lip) peak, respectively, due to increased cellular turnover, neuronal degeneration and necrosis. Most of the aforementioned findings, however, are not specific and common in highly malignant neoplasms. AT/RT should always be considered in the presence of an inhomogeneous, enhancing formation in a child, particularly if in an off-midline location, presenting a peripheral cystic component and showing restricted diffusivity.²⁷

Differential diagnosis of ST ependymoma includes a wide spectrum of intra- and extraventricular neoplasms.⁹ Central neurocytoma is a WHO grade II intraventricular tumour, often located in the lateral ventricles with a typical attachment to the septum pellucidum and a tendency to involve the contralateral ventricle. They are most often diagnosed in young adults. On CT, they present a mixed solid-cystic density, showing irregular contrast enhancement; obstructive hydrocephalus is a common finding. On MRI, the tumour shows a characteristic ‘bubbly’ multi-lobulated appearance, hypointense in T1- and hyperintense in T2-weighted and FLAIR sequences, with evident and inhomogeneous enhancement.²⁸

Choroid plexus tumours can arise anywhere choroid epithelium is present and occur in about 90% of cases in the atrium of lateral ventricles or in the fourth ventricle. Choroid plexus neoplasms may be roughly divided into CPP, atypical choroid plexus papilloma and choroid plexus carcinoma (CPC). These tumours may all demonstrate CSF dissemination. Thus, imaging the whole neuroaxis is recommended. CPP present as WHO grade I tumours more commonly in the paediatric population who often present with hydrocephalus caused by overproduction of CSF, obstruction of the CSF pathway or haemorrhage. CPP in fact are highly vascular lesions showing avid enhancement after contrast administration. They frequently have a papillary appearance with possible cystic components. CPP are iso- to hyperattenuating lesions on CT. On MRI, they are iso- to hypointense in T1-weighted images and iso- to hyperintense in T2-weighted sequences. Among the possible differential diagnosis of intraventricular ependymoma, CPC should be considered. CPC is a high-grade tumour that typically arises from lateral ventricles, with a tendency to invade the contiguous parenchyma. Intralesional cysts, haemorrhages and flow voids are common findings. Enhancement is strong and mildly inhomogeneous. Different from high-grade ependymoma, however, CPCs tend to affect very young children, causing obstructive hydrocephalus, headache, nausea and vomiting. Moreover, the formation is usually mostly located inside the ventricle rather than in the parenchyma.²⁹

ST extraventricular anaplastic ependymoma in middle-aged adults can easily mimic anaplastic astrocytoma or glioblastoma, both showing imaging features of a high-grade inhomogeneous neoplasm. However, the presence of intralesional cysts or fluid-fluid levels is more typical for ependymoma.^23,30 Differential diagnosis is often very challenging solely with imaging findings, and thus histopathological examinations are often required.

Illustrative case

Informed consent was obtained from the patient. An 18-year-old girl was admitted to our emergency department with a history of severe headache, nausea, diplopia and hypofunction of the left external rectus muscle in the last four days. There was no history of trauma or significant co-morbidities.

An unenhanced CT scan (TOSHIBA Aquilion ONE) showed a mildly hypodense lesion with a prevalent cystic component of possible pineal origin associated with remarkable ex-empty dilatation of the posterior horn of the left lateral ventricle. Moreover, a 9 mm shift of the midline structures was present, without relevant hydrocephalus. MRI examination performed the following day (Discovery MR 750, 3T; GE) confirmed a voluminous intra-axial neoplasm measuring about 55 mm × 38 mm × 44 mm (LL × AP × CC) that appeared to originate from the left atrium, occupying most of the interposed veil cistern, mainly developing inside the left lateral ventricle with involvement of the ipsilateral thalamus. A slight cranial displacement of the corpus callosum with compression of internal cerebral veins and posterior aspect of the third ventricle was also evident. The formation showed a prevalent, lobulated cystic component with evidence of solid tissue. There was no evidence of haemorrhagic or calcific intralesional components. Post-contrast imaging showed intense and inhomogeneous enhancement of the solid component and of the cystic wall and septa. Moreover, a widespread and homogeneous enhancement of the left ventricular ependyma and supra- and infratentorial leptomeningeal spaces was evident. The proton magnetic resonance spectroscopic (1H-MRS) study, performed with single and multivoxel technique, documented an evident increase in Cho peak and marked reduction of NAA peak, with a Cho/NAA ratio of >1 as signs of high cell replication and neuronal loss degeneration (Figure 5). Magnetic resonance perfusion evaluation showed a marked increase in rCBV in the solid component compared to the contralateral normal-appearing white matter.

An intraventricular high-grade ependymoma was suspected, and the decision was taken to perform an MRI study of the whole spine, which highlighted a widespread, linear enhancement of leptomeningeal perimedullary spaces from the cranio-cervical junction up to S2. The patient was referred to the neurosurgical department where she underwent a frameless stereotactic cerebral biopsy. Subsequent histological examinations revealed a WHO grade III ependymoma with anaplastic component showing Ki67+ in 20–25% of tumoural cells and p53 mutation. The patient was subsequently transferred to another hospital to attempt surgical treatment.

Prognosis and therapeutic management

It is becoming progressively clear that risk stratification is strictly associated to age, tumour grade, location (ST, infratentorial and spinal) and genetic markers.^31,32 These elements play a central role in planning treatment and predicting survival. Ostrom et al. reported a five-year OS rate of 83.4% and a 10-year OS rate of 79.1%, observing epidemiological data of patients affected by ependymal tumours.³³

As mentioned above, there are nine molecular subgroups of ependymal tumours based on genome-wide DNA methylation patterns across all age groups, three in each anatomical compartment of the CNS (ST, infratentorial and spinal). A refined risk stratification of patients is a fundamental step in order to guarantee the best treatment strategy.³⁴

Therapeutic management of these lesions remains challenging, requiring an experienced multidisciplinary approach. Surgical resection is considered the mainstay of treatment for ependymomas. In the majority of studies, the extent of resection has emerged as one of the most significant predictors of outcome.^2,35 In cases of incomplete resection, a surgical second look may often be considered shortly after the first intervention.³⁶

Adjuvant radiotherapy (RT) is recommended for adults diagnosed with anaplastic (WHO grade III) ependymomas,^7,37 whereas the role of RT in patients with WHO grade II ependymoma is still controversially discussed. There is agreement that postoperative RT should be included after an incomplete resection of ependymomas (WHO grade II). On the other hand, it is still not clear if RT is needed after a gross total resection (GTR).³⁸ Adjuvant RT has a relative role in intracranial subependymoma. In fact, usually these patients benefit from a surgical resection alone, and RT is reserved to few situations after subtotal or partial resection.⁵

In paediatric patients, most of intracranial ependymomas are located in the PF and affect children younger than three years of age.^39,40 The mainstay of therapy for children is, as it is for adults, maximal safe surgical resection.⁹ Thus, an incomplete resection is the strongest predictor of poor prognosis.^41–43

Postoperative RT revealed good results in terms of local control and survival rates in young patients⁴¹ using different doses according to age. Doses up to 59.4 Gy are recommended in children older than 18 months of age, whereas in those aged between 12 and 18 months or in children with poor neurological status, doses can be lowered to 54 Gy.⁴⁴ In case of local relapse, hypofractionated stereotactic boost added to standard RT has been proposed.⁴⁵ This strategy revealed to have a good impact on PFS, as shown in an Italian trial.⁴⁶

Proton therapy is increasingly considered as an alternative to conventional photon therapy in order to minimise the toxicity of RT in younger children due to its unique advantage of sparing normal tissue.⁴⁷ Nevertheless, the pros and cons of proton treatment need to be investigated further in prospective studies.⁴⁸ Chemotherapy still has a controversial role in the management of intracranial ependymomas.⁴⁹ It has been advocated as a strategy for younger patients in a radiation-sparing approach or in addiction to RT in older children. Several studies have depicted good response rate using different combinations of vincristine, etoposide, cyclophosphamide, platinum derivatives and high-dose methotrexate as regimens of postoperative treatment.^46,50,51 Chemotherapy alone is commonly reserved for patients <12 months and for adults in cases of recurrence if further surgery and irradiation are no longer applicable. Temozolamide (TMZ), an alkylating agent, is considered the standard treatment for several primary CNS tumours. It has been used against recurrent WHO grade II or III ependymomas in adults in different studies,.^52–54 In a retrospective study on effect of TMZ in recurrent ependymomas, a response was observed only in chemotherapy-naive patients.⁵⁵ TMZ has been also used in combination with lapatinib, a dual tyrosine kinase receptor inhibitor, showing a better response in case of higher ErbB2 mRNA expression in tumour tissue.⁵⁶ Bevacizumab, an anti-angiogenic monoclonal antibody that targets VEGF, has been used in a small cohort of recurrent ependymomas of adults, obtaining a median OS of 9.4 months.⁵⁷

In this complex scenario, the aforementioned molecular classification of ependymal tumours is a concrete starting point for future clinical trials in targeted treatments for ependymomas.³⁴ In the PF, two different molecular subgroups have been described: PF-A and PF-B. Group A is common in younger patients, located laterally, with possible cerebellar invasion and high rate of recurrence.⁵⁸ On the other hand, group B more often affects young adults, and it usually has a higher rate of survival. From these findings, an international consensus conference⁸ agreed that for group A, in patients older than 12 months of age, maximal safe surgery followed by focal RT is recommended. Interestingly, a randomised clinical trial comparing observation and standard RT in group B after GTR could be launched. Regarding ST ependymomas, a subgroup characterised by fusion between C11orf95 and the RELA gene has been described,^34,59 affecting both children and adults. In this specific molecular group with a poor prognosis, the extent of resection does not seem to have an impact on the outcome. For this reason, in these patients, adjuvant RT is always considered the standard of care. Gain of chromosome arm 1q has been described has an independent negative prognostic factor,⁶⁰ whereas harbours recurrent fusion with the oncogene YAP1 is associated with a good prognosis.^34,59 In conclusion, all of these molecular data allow patients to be stratified better, hopefully developing distinct personalised therapies.

Discussion

Ependymomas represent a heterogeneous class of glial neoplasms arising from ependymal cells throughout the entire neuraxis, often including the spine. These tumours are slightly more common in men and present a bimodal age distribution, with different typical locations according to the patient’s age.¹⁶ Their biological behaviour ranges from WHO grade I neoplasms (subependymoma) to WHO grade III tumours (anaplastic ependymoma).⁷

In recent years, a new molecular classification, based on different DNA methylation patterns, was introduced in order to provide a more accurate and reliable differentiation among intracranial ependymal tumours belonging to the same WHO grade, albeit presenting a different biological behaviour and hence a different prognosis.⁸

Neuroimaging represents a fundamental diagnostic tool in the evaluation of these neoplasms, enabling the size and location of the tumour to be detected accurately, along with the relationship with adjacent structures. Moreover, beyond the conventional FLAIR T1, T2 and FLAIR MR sequences, the pattern of contrast enhancement, and the possible clinical application of MRS and PWI which were discussed above, it is noteworthy to highlight that in recent years, SWI has gained a wide interest thanks to its ability to detect possible foci of neoangiogenesis accurately inside the tumoural mass as areas of intralesional hypointensity due to flow voids.⁶¹ Since neoangiogenesis is a phenomenon which typically occurs in high-grade tumours, SWI may provide a useful adjunctive diagnostic tool in the attempt to grade intracranial ependymomas in adults.⁶² Less encouraging results have been recently reported in paediatric tumours, likely due to their structural heterogeneity and abundant vascularity.⁶¹

In some cases, however, neuroimaging may still not be sufficient to provide a definite diagnosis, since the spectrum of possible differential diagnoses, especially when analysing a high-grade ST neoplasm in an adult, is wide. Hence, histological examination remains a fundamental step in order to determine the most suitable therapy.²⁵ Therapy for intracranial ependymal tumours is still an issue, and a multidisciplinary approach is advisable.⁴⁷ Nowadays, surgery is still considered the mainstay in the treatment of low-grade ependymal tumours, and the extent of the resection is still considered a fundamental prognostic factor.³⁸ Adjuvant RT is mainly recommended in high-grade neoplasms affecting adults, particularly after incomplete resections, while its role in children should always be carefully evaluated.⁴⁴ A possible role of chemotherapy or monoclonal agents is still to be adequately verified.^54–56

Footnotes

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Marco Varrassi

Emanuele Tommasino

Alessandra Splendiani

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