General
- Ependymomas should be classified by anatomic site and by molecular group or an associated genetic alteration,
Definition
- A circumscribed glioma composed of uniform small cells with round nuclei in a fibrillary matrix characterized by perivascular anucleate zones (pseudorosettes) with ependymal rosettes also found in about one quarter of cases.
Numbers
- 10% of paediatric gliomas
- Up to 50% of CNS tumours under the age of 5 years
- 8% of all neuroepithelial neoplasms
- Male-to female ratio is 1.77:1
- Posterior fossa ependymomas mean patient age at presentation of 6.4 years
- Incidence rate decreases with increasing patient age at diagnosis, from 5.6% (at 0-14 years) to 4.5% (at 15-19 years) to 4.0% (at 20-34 years)
- Aged < 3 years, as many as 30% of all CNS tumours are ependymomas
Localisation
- Can theoretically grow anywhere in CSF spaces within the craniospinal axis (third ventricle, aqueduct)
60% infratentorial (posterior fossa ependymoma)
- Mainly in the lateral recess of 4th ventricle
- Commonly extend through foramina of Luschka and Magendie
- T1+C: extension of the ependymoma through the Left Luschka
40% supratentorial
- 50% intraparenchymal
- Large lesion
- Variable appearance: completely solid to cyst with mural nodule
- Due to trapping of embryonic rest of ependymal tissue in the developing parenchyma
- Can occur in lateral ventricle (ventricular wall)
Images
Spinal cord
- Rare, but is the also one of the most commonest intramedullary spinal cord tumours
- Myxopapillary variant here
- Ependymomas here are the most common neuroepithelial neoplasms,
- 50-60% of all spinal gliomas in adults,
- Rare in children
Molecular classification
Localization | Molecular Group | Major Molecular Markers | Prevalence within the Group | Pathogenic Impact |
Supratentorial | ST-EPN-ZFTA | ZFTA-RELA fusion, chromothripsis 11q13.1 | 90–95% | NF-kB pathway activation |
ㅤ | ㅤ | ZFTA–MAML2 | 5–10% | EP300/CREBBP gene expression pathway |
ㅤ | ㅤ | ZFTA–NCOA1 | 5–10% | EP300/CREBBP gene expression pathway |
ㅤ | ㅤ | ZFTA–NCOA2 | 5–10% | EP300/CREBBP gene expression pathway |
ㅤ | ST-EPN-YAP1 | YAP1–MAMLD1 | 95% | Hippo pathway activation |
ㅤ | ㅤ | YAP1–FAM118B | 5% | Hippo pathway activation |
Infratentorial | PF-EPN-A | EZHIP overexpression | 95% | CpG-island methylator phenotype |
ㅤ | ㅤ | HIST1H3C, HIST1H3B or H3F3A K27M substitution | <5% | CpG-island methylator phenotype |
ㅤ | PF-EPN-B | Major cytogenetic aberrations | Up to 100% | Ciliogenesis deregulation |
Spinal | Sp-MPE | HOXB cluster genes amplification | Up to 100% | Mitochondrial metabolism pathways activation |
ㅤ | SP-EPN-MYCN | MYCN amplification | 100% | Proliferative signaling |
CNS WHO grading
- Given the limitations of ependymoma histological grading, assigning a CNS WHO grade is no longer essential as part of the diagnosis of ependymomas in the paediatric population;
- However, tumours are usually CNS WHO grade 2 or 3
Tumor type | WHO grade |
Supratentorial ependymoma | Grade 2 / 3 |
Supratentorial ependymoma, C11orf95 fusion-positive | ㅤ |
Supratentorial ependymoma, YAP1 fusion-positive | ㅤ |
Posterior fossa ependymoma | Grade 2 / 3 |
Posterior fossa ependymoma, Group PFA | ㅤ |
Posterior fossa ependymoma, Group PFB | ㅤ |
Spinal ependymoma | Grade 2 / 3 |
Spinal ependymoma, MYCN-amplified | ㅤ |
Myxopapillary ependymoma | Grade 2 |
Origin
- Radial glial cell
- Progenitor cells present during neurodevelopment, and their transformation is believed to result in different molecular and anatomical subgroups of ependymoma.
Imaging
General
- Classic radiographic features of spinal cord ependymomas include:
- Distinct tumor-spinal cord border.
- An associated syrinx.
- Cysts within or adjacent to the mass.
- Hemosiderin deposits or “caps” near the poles of the tumor on T1 and T2.
- Well circumscribed
- The three main subsets of ependymomas are cellular, myxopapillary, and anaplastic.
- Cellular ependymomas are most often located in the cervical spine.
- On T1-weighted MRI, cellular ependymomas are isointense to hypointense.
- On T2-weighted MRI, they are hyperintense and may have a syrinx in 50% of cases.
- Although it is uncommon when compared to tumours like medulloblastomas, careful examination of the entire neuraxis is required to assess for the presence of CSF seeding.
CT
- Coarse calcification is common (50%)
- Cystic areas (50%)
- Solid component iso- to hypodense
- Heterogeneous enhancement
- Variable haemorrhage
MRI
- T1
- Solid portions of ependymoma
- Isointense to hypointense relative to white matter
- T2
- Hyperintense to white matter
- More reliable in differentiating tumour margins than non-contrast T1-weighted images (but less reliable than contrast enhanced T1)
- T2* (e.g. SWI)
- Foci of blooming from haemorrhage or calcification
- T1 C+ (Gd)
- Enhancement present but heterogeneous
- Enhancement with gadolinium is useful in differentiating tumour from adjacent vasogenic oedema and normal brain parenchyma
- DWI/ADC
- Restricted diffusion may be seen in solid components, especially in anaplastic tumour
- Diffusion should be interpreted with caution in masses with significant haemorrhage or calcification
Images
MRS
- Choline peak elevation according to the cellularity of tumour
- NAA peak reduction
- Elevated Cho/Cr ratio
- Lipid and lactate rise when degeneration occurs
Macroscopic
- Tumours usually arising in or near the ventricular system
- Tan-coloured and are soft and spongy
Microscopic
- Classic ependymoma generally has a low cell density and a low mitotic count.
- It very rarely invades adjacent CNS parenchyma to any significant extent.
- A well-delineated glioma with monomorphic cells characterized by a variable density and round to oval nuclei with speckled nuclear chromatin (salt-and-pepper).
- Perivascular anucleate zones (pseudorosettes)
- The pseudorosettes are composed of tumour cells radially arranged around blood vessels, creating perivascular anucleate zones of fine fibrillary processes.
- (True) ependymal rosettes.
- The ependymal rosettes and tubular canals are composed of bland cuboidal or columnar tumour cells arranged around a central lumen.
- Pseudorosettes can be found in practically all ependymomas, whereas ependymal rosettes are present in only a minority.
- No/rare mitoses
- No necrosis no / rare endothelial proliferation
- Blepharoplasts
- Are the intracytoplasmic basal bodies of cilia present in apical portions of the cells in ependymomas that stain with phosphotungstic acid hematoxylin (PTAH).
Histological subtypes
- No good correlation with outcome
- No longer listed as subtypes of ependymoma, being included instead as patterns in the histopathological description of ependymoma.
Papillary
- A rare histological variant of ependymoma characterized by well-formed papillae.
- GFAP +
- Papillae form because of high rate of growth toward the ventricles.
- Unlike the papillae in choroid plexus tumours, the papillae in ependymomas lack a basement membrane beneath the (neuro-)epithelial cells, which in ependymomas send fibrillary processes down to a vascular core in the same architectural arrangement as a pseudorosette.
Clear cell
- A histological variant of ependymoma characterized by an oligodendrocyte-like appearance, with perinuclear haloes due to cytoplasmic clearing.
- Most in supratentorial in young patients
- Clear cell ependymoma must be distinguished from oligodendroglioma, central neurocytoma, clear cell (renal cell) carcinoma, and haemangioblastoma. Done by: Ependymal and perivascular rosettes, immunoreactivity for GFAP and EMA in clear cell ependymoma.
- Clear cell ependymoma may follow a more aggressive course than other variants.
- The clear cell tumour of the lateral ventricles once classified as ependymoma of the foramen of Monro {2876} is now recognized as central neurocytoma in most instances.
Tanycytic
- A histological variant of ependymoma characterized by arrangement of tumour cells in fascicles of variable width and cell density and by elongated cells with spindle-shaped nuclei.
- Most commonly found in spinal cord ependymomas and manifests as irregular fascicles of elongated cells.
- Rosettes are rarely seen in these ependymomas, and pseudorosettes can be subtle.
- Like in other ependymomas, the nuclei display speckled (salt-and-pepper) chromatin, and anaplastic features are uncommon
- “Tanycytic ependymoma” is used for this variant because its spindly, bipolar elements resemble tanycytes - the paraventricular cells with elongated cytoplasmic processes that extend to ependymal surfaces
Immunophenotype
- +
- S100
- GFAP
- Vimentin
- EMA
- L1CAM expression( + in supratentorial ependymomas)
- Sparse:
- OLIG2 vs ( more common in other glioma)
Genetic profile
- Ependymomas display a broad range of cytogenetic aberrations,
- Gains of chromosomes 1q, 5, 7, 9, 11, 18, and 20
- 1g gain: poor outcome in posterior fossa tumours
- Losses of chromosomes 1 p, 3, 6q, 6, 9p, 13q, 17, and 22
- Monosomy 22 and deletions or translocations of chromosome 22q are particularly common in spinal cord tumours and tumours associated with neurofibromatosis type 2
- The NF2 gene is involved in ependymoma tumorigenesis, and NF2 mutations occur frequently in spinal ependymomas
- Supratentorial ependymomas
- Preferentially show loss of chromosome 9 → homozygous deletion of CDKN2A
Prognosis
- Children with ependymoma fare worse than adults.
- This difference may reflect the more frequent occurrence of paediatric tumours in the posterior fossa versus the predominantly spinal location for adult tumours.
- <1 yrs: 5-year overall survival rate of 42.4%
- 10-14 yrs: 5- yr overall survival rate 76.2%
- Gross total resection is associated with significantly improved survival
- Better outcomes Spinal > supra tentorial > post-fossa
- Factors prognostic for a favorable outcome include:
- Patient age younger than 40 years.
- Tumors with a lumbosacral location.
- Myxopapillary histologic findings.
- A grade of WHO grade I.
- Tumors amenable to GTR or STR.
- Good preoperative function of the patient.
Differential diagnosis
- Medulloblastoma
- Similar demographic, especially if around the 4th ventricle
- Arises from vermis
- Does not tend to extend through foramina
- Enhancement more homogenous
- Calcification less common
- Subependymoma
- Tends to occur in older individuals
- Usually not enhancing
- Choroid plexus papilloma
- In children usually in the trigone of the lateral ventricles
- In adults usually in the fourth ventricle (i.e. opposite to ependymoma)
- More vividly and homogeneously enhancing
- Lacks adjacent parenchymal oedema
- NB choroid plexus carcinoma can be heterogeneous and invade the brain
- Choroid plexus metastasis
- Can appear similar
- Older individuals, usually with a history of malignancy
- Glioblastoma
- Difficult to distinguish from intraparenchymal supratentorial ependymoma
- Usually older patients
- Epicentre usually in the white matter
- Central neurocytoma
- Usually arises from/in contact with septum pellucidum
- Less vivid enhancement
- Atypical teratoid/rhabdoid tumour
Treatment
General
- Surgical mainly
- But when these tumours originate from the floor of the fourth ventricle radical excision needs to be balanced carefully with the significant risk of lower cranial nerve palsies.
- In such cases, if a good dissection plane is maintained between the tumour and the floor of the fourth ventricle it is likely that postoperative cranial nerve palsies (likely to occur) are likely to improve gradually over time (although full recovery cannot be guaranteed).
- All this should be discussed carefully with the patient before the operation.
- Postoperative EBRT appears to improve local control in patients with STR ependymomas.
- EBRT is also beneficial for patients with high-grade lesions and those with neuraxis dissemination.
- In most series, the outcome for STR followed by EBRT is similar to that of complete resection.
EANO (European Association of Neuro-Oncology) guidelines
Adult
Treatment Recommendation | Class of Evidence |
Resection is recommended to obtain a histological diagnosis and should be a gross total resection whenever feasible. As the morbidity can be significant, detailed informed preoperative counseling by a surgeon experienced in performing such surgery is important. | II |
Postoperative MRI should be performed to evaluate the extent of resection. | n.a. |
A second-look surgery should be considered when the result of the first resection has not been satisfactory. | III |
Because a risk of CSF dissemination exists for all patients with newly diagnosed ependymoma, disease staging, including both craniospinal MRI and CSF cytology, is mandatory following surgery (not earlier than 2–3 wk). | n.a. |
Postoperative conformal radiotherapy with doses up to 60 Gy is recommended for patients with WHO grade III (anaplastic) ependymomas regardless of the extent of resection. | II |
Postoperative conformal radiotherapy with doses of 54–59.4 Gy is recommended for patients with WHO grade II ependymomas following incomplete resection. | III |
Craniospinal irradiation (CSI) of 36 Gy is recommended in case of CSF or spinal dissemination with a boost up to 45–54 Gy on focal lesions. | IV |
Because of the risk of asymptomatic and/or late relapses, patients should be followed long term with contrast-enhanced MRI. | n.a. |
Children
- Key recommendations for the treatment of newly diagnosed intracranial WHO grades II and III ependymomas in children
ㅤ | Class of Evidence |
Resection is recommended to obtain a histological diagnosis and should be a gross total resection whenever feasible. As the morbidity can be significant, detailed informed preoperative counseling by a surgeon experienced in performing such surgery is important. | II |
Postoperative MRI should be performed to evaluate the extent of resection. | n.a. |
A second-look surgery should be considered when residual tumor is demonstrated on postoperative MRI and gross total resection is a realistic goal. | II |
Because a risk of CSF dissemination exists for all patients with newly diagnosed ependymoma, a disease staging, including both craniospinal MRI and CSF cytology, is mandatory following surgery (not earlier than 2–3 wk). | n.a. |
Postoperative conformal radiotherapy with doses up to 59.4 Gy is recommended in children older than 18 months. | II |
Postoperative conformal radiotherapy with doses of 54 Gy is recommended in children between 12 months and 18 months or in older children with poor neurological status. | II |
Chemotherapy alone is an option in children less than 18 months old, while it is recommended in children aged less than 12 months. | III |
Craniospinal irradiation (CSI) is recommended in case of CSF or spinal dissemination with a boost on focal lesions with doses adapted to patient age. | IV |
Because of the risk of asymptomatic and/or late relapses, patients should be followed long term with an enhanced MRI. | n.a. |
Serial monitoring of cognitive and endocrine functions with specific batteries following radiotherapy is recommended whenever feasible. | n.a. |
- Key recommendations regarding nonsurgical treatment of WHO grades II and III ependymomas in children
- CT, chemotherapy; RT, radiotherapy; VEC, vincristine/etoposide/cyclophosphamide regimen; GTV, growth tumor volume; CTV, clinical target volume; 3DCRT, 3D conformal radiotherapy; IMRT, intensity modulated radiotherapy.
ㅤ | CT Indication | CT Regimen | CT Timing | RT Indication | RT Timing | GTV (defined with MRI) | CTV | Total Dose, Gy | Dose/Fraction, Gy | Technique |
Localized tumor, age >18 mo | Debatable | VEC ± cisplatin | Maintenance | Systematically | Postoperatively | Tumor bed and 3D identifiable residual disease | 5-10 mm around GTV | 59.4 | 1.8 | 3DCRT or IMRT or proton |
Localized tumor, age >18 mo with visible residual tumor after surgery | Recommended | VEC ± cisplatin ± high-dose methotrexate | Postoperatively | Stereotactic additional boost recommended within a prospective clinical trial with residue after chemotherapy | Postoperatively and post-chemotherapy | Tumor bed and 3D identifiable residual disease | ㅤ | 59.4+8 | 4 | 3DCRT or IMRT or proton |
Localized tumor, age 12-18 mo | Recommended | Baby UK | Maintenance | To be discussed | Postoperatively | Tumor bed and 3D identifiable residual disease | ㅤ | 54 | 1.6-1.8 | ㅤ |
Localized tumor, age <12 mo | Recommended | Baby UK | Postoperatively | NORT | NORT | - | - | - | - | ㅤ |
Metastatic tumor | Debatable | VEC ± cisplatin | Before RT | Salvage treatment | Postoperatively or postchemotherapy | Tumors and 3D identifiable residual disease | CSI + boost 5-10 mm around GTV | 24 or 36 depending on age + boost up to 59 | 1.8 | ㅤ |
Local relapse | None outside clinical trial | - | - | Recommended | Postoperatively | 3D identifiable disease | GTV+2 mm | 59 or in a prospective trial 25 Gy/5 fractions or 24 Gy/3 fractions | 1.8 or hypofractionation (5-8) | 3DCRT or IMRT or proton or hypofractionated stereotactic irradiation |
Recurrent
- Key recommendations for the treatment of recurrent intracranial ependymomas in adults and children
Recommendation | Class of Evidence |
Re-operation and/or re-irradiation should be proposed whenever possible. However, if only incomplete resection was achievable due to functional restrictions at first surgery, the same limitations will be faced at re-operation; hence, in these cases the indication for another incomplete resection should be made cautiously. | III |
In patients with recurrent ependymomas who are no longer eligible for local treatments, chemotherapy might be warranted, particularly in patients with a good performance status. | III |
In adults, either platinum compounds or temozolomide (based on a more favorable toxicity profile) should be considered. Options for participation in a clinical trial should be explored. | IV |
In children, the choice of chemotherapeutic drugs depends on previous exposures. Options for participation in a clinical trial should be explored. | n.a. |
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