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Thursday 8 July 2004

ependymomas, ependymal tumors

AGCOH ORPHA301 MIM.131445 ICD-10 C71.7

Definition: Ependymomal neoplasms are glial tumors (gliomas) of children and young adults, originating from the cerebral ventricle or from the spinal canal.


- Ependymoma with true ependymal rosette

Ependymomas are well-delineated moderately cellular gliomas. Histolological features are perivascular pseudo rosettes and ependymal rosettes.

The 2007 WHO classification of tumors of the central nervous system distinguishes:
- classic ependymoma (WHO grade II)
- anaplastic ependymoma (WHO grade III)
- myxopapillary ependymoma (WHO grade I)
- subependymoma (WHO grade I).

The myxopapillary ependymomas are characterized by their quasi-exclusive location in the cauda equina/filum terminale region, whereas subependymomas are slowly growing, often asymptomatic, intraventricular neoplasms.

Accurately diagnosing and grading ependymomas may be difficult, especially intracranial examples.

Figarella-Branger et al. recently reviewed 216 cases of intracranial neoplasms diagnosed as ependymoma between 1990 and 2004; almost half of those cases were reclassified as, for example, oligodendroglioma or glioneuronal tumor.

Moreover, the presence of mitoses, vascular proliferation and necrosis is a sign of anaplasia and aggressive biological behavior in diffuse astrocytomas and oligodendrogliomas; the prognostic value of those morphological features in ependymomas is yet to be determined.

Identification of histoprognostic factors has been hampered by the retrospective nature of the studies, the small size of the series and inclusion of non-related entities, such as subependymoma and ependymoblastoma, which is an embryonal tumor (WHO grade IV).

The molecular diagnostic approach to improve the classification and histoprognosis of cerebral neoplasms appears promising, but few genomic studies have been performed on ependymomas.


Ependymoma is the third most common malignant pediatric brain tumor, with over 50% of cases arising in children younger than 5 years of age. In the central nervous system (CNS), they account for 3,9 % of all neuro-epithelial tumors.

In children, 30 % of ependymomas appear before the age of 3 years and are more aggressive than in adults. Nearly 90 % of pediatric ependymomas are intra cranial : they occur in supratentorial or posterior fossa locations, and only 10 % are intraspinal. Ependymomas account for 6 to 12 % of brain tumors in children and represent the third most common central nervous system neoplasms in this age range, following astrocytoma and medulloblastoma.

In adults, 60 % of ependymomas are tumors of spinal cord and only 40 % are intracranial. Intramedullary spinal ependymomas can be seen in patients with neurofibromatosis type 2 (NF2), a hereditary disease. Clustering of ependymomas has been noted in some families suggesting inheritance of a genetic susceptibility to this type of tumor.


Clinical manifestations of these tumors are localization dependent.


In children and adults, ependymomas can arise in three distinct locations:

- the spinal cord

  • Spinal ependymomas are associated with better outcome than cerebral tumors. Cerebrospinal localization shows a poor prognosis.
    - the supratentorial brain (supratentorial ependymoma)
  • Supratentorial ependymomas are associated with better survival rates compared to posterior fossa tumors.
    - the posterior fossa.

Over 90% of pediatric ependymomas arise intracranially with approximately 70% of cases occurring in the posterior fossa.

Ependymomas from these three anatomical compartments are histologically indistinguishable and were, therefore, assumed to be biologically similar.

Ependymomas from the spinal cord, supratentorial brain, and infratentorial region are histologically indistinguishable and were therefore presumed to share a similar biology.

However, anatomically specific differences in chromosomal abnormalities or lack of genetic alterations suggested that ependymomas of different anatomical location were in fact molecularly distinct diseases.

According to age

The majority of pediatric ependymomas occurring often in the posterior fossa exhibites a balanced genetic profile reminiscent of balanced karyotypes seen in early cytogenetic analyses.

It is important to note that the majority of ependymomas in children occur in the posterior fossa, and half of these cases demonstrated a balanced genomic profile raising the possibility that more focal genetic events or aberrant epigenetic mechanisms might be involved.


WHO classification differentiate four major types :

- 1. Ependymoma and variants (grade 2)

  • cellular ependymoma : a variant of ependymoma with conspicuous cellularity but often less prominent pseudo-rosette or rosette formation.
  • papillary ependymoma : a rare variant which looks like choroid plexus papilloma.
  • clear cell ependymoma : a rare variant which may be confused with oligodendroglioma neurocytoma or metastatic renal cell carcinoma.

- 2. anaplastic ependymoma (malignant ependymoma) (grade 3) : An ependymoma with histological evidence of anaplasia.

- 3. myxopapillary ependymoma (grade 1) : It occurs almost exclusively in the conus-cauda-filum terminale region, with a generally favourable prognosis.

- 4. subependymoma (grade 1) : Benign tumor composed of nests of ependymomal cells in a dense glial fibrillary matrix.


The great majority of ependymomas display GFAP immunoreactivity. It is usually observed in pseudo-rosettes, but GFAP is not specific of ependymomas. It is observed in all gliomas.

Ependymomas typically express S 100 protein and Vimentin.

In ependymomas WHO grade II, epithelial membrane antigen (EMA) immunoreactivity has been reported.


Grading controversy arises from elusive WHO features and individual characteristics of ependymomas including tumour location, tumour pattern/variant and variable expression of biomarkers.

There is a need for a grading scheme with a proven general ability to dissociate grades, and to predict individual clinical evolution. Only then will stratified and targeted therapeutics for ependymal tumours be possible. (19212775)


- myxopapillary ependymoma

Molecular subtypes

- RELA-associated ependymoma


No specific cytogenetic abnormality has been described. 30 % of ependymomas show aberrations involve chromosome 22 and less frequent are structural abnormalities of chromosomes 1, 6, and 17 and numerical abnormalities of 7, 9, 12 and 20.

Common genetic abnormalities in ependymoma involve loss of chromosome 1p, 3, 6q, 9p, 10q, 13q, 16p, 17, 21, and 22q and gains of 1q, 4q, 5, 7, 8, 9, 12q, and 20.


Interestingly, a common finding in several studies was that a large proportion of ependymomas, in some cases nearly 40%, exhibited a balanced genetic CGH profile associated with a younger age and intracranial origin.

aCGH analyses on a large set of ependymomas confirmed known regions of recurrent low-level gain such as chromosome 1q which correlated significantly with pediatric patients, intracranial tumor localization, and grade III tumors.

The most frequently detected chromosome (chr) abnormalities were gain of chr 7, 9, 12 and 15 and loss of chr 22.

- Co-occurrence of those five alterations characterize spinal ependymomas.

- Myxopapillary ependymomas display a specific genomic profile defined by concurrent gain of chr 5, 7, 9, 16 and 18.

- Overall, the number of chromosomal abnormalities detected was inversely correlated with the malignancy grade.

- Gain of chr 1q correlates with intracranial high-grade tumors.

- Loss of chr 6q is mainly observed in infratentorial and World Health Organization (WHO) grade 3 lesions.

- Chr 10q loss is associated with high-grade ependymomas.

- The +7/+9/+12/+15/-22 genomic profile is significantly associated with WHO grade 2 spinal ependymomas, whereas the +5/+7/+9/+16/+18 genomic pattern is specific of myxopapillary ependymomas.

- Identification of specific genomic imbalances at a given tumor location suggests that ependymomas from different central nervous system (CNS) regions represent genetically distinct diseases.

- Detecting genomic alterations associated with aggressive biological behavior may help stratify patients in high- and low-risk disease.

- One half of posterior fossa ependymomas exhibite a balance karyotype.

  • (1) This group may be heterogeneous in nature and genetic aberrations may be very sporadic,
  • (2) Highly focal genetic changes at the copy number or sequence level may have been missed,
  • (3) Epigenetic mechanisms such DNA methylation, histone modification, and non-coding RNA regulation may be playing a significant role.

CGH gains

These initial aCGH studies identified multiple regions of recurrent gain including: 1p34, 1q, 2q23, 3p14, 3q29, 6p21, 7p21, 7q11.23–22.1, 7q35, 8q11.2, 9p24.3-qter, 11q13-q23, 12p, 12q13.13–13.3, 13q21.1, 14q11.2, 14q32.2, 15q21.3, 16p11.2, 16p13.3, 16pter, 17q21, 18, 19p13.3, 20p12, Xp21.2, and Xq26.3.

CGH losses

Multiple regions of recurrent loss was identified at 5q31, 6q25.3, 6q26, 7q36, 9p21, 9p23, 15q21.1, 16q24, 17p13.3, 19p13.2, 22q12, and 22q13.3.

Regional amplifications

- MYCN (9p24 amplification)
- EGFR (7p11.2 amplification)
NOTCH4 (6p21.32 amplification)
VAV1 (19p13.3 amplification)
DNASE1L3 (3q25.2 amplification)
PRM1 (16q12.2 amplification)
TYR (11p13 amplification)
CDC6 (17p13.3 amplification)
- YAP1, BIRC2, and BIRC3 (11q22 amplification)

- CGH gains

  • 9qter (21% diagnostic, 54% relapse)
  • 1q (0% diagnostic, 12% relapse)

By chromosomes

- Chromosome 22

Chromosome 22 loss was also observed, and interstitial losses identified 22q13 loss in 55% of intracranial ependymomas analyzed.

30 % of ependymomas show aberrations involve chromosome 22 as the most frequent change. Monosomy 22 as well as deletions or translocations involving 22q can appear.

Chromosome 22 loss has been reported to be the most common copy number alteration in both sporadic intracranial and spinal ependymomas.

While LOH and gene mutation point to NF2 as a likely candidate in spinal ependymomas, a chromosome 22 tumor suppressor gene, important in the case of pediatric intracranial ependymomas, remains elusive.

Chromosome 22 loss has been found in numerous reports to be the most frequent overall genetic abnormality in sporadic ependymoma, with a frequency varying from 26% to 71%.

Supporting this finding, cytogenetic studies reported complete or partial monosomy 22 in 8–40% of ependymomas.

Loss of heterozygosity (LOH) mapping also identified chromosome 22q as an important region of loss and collectively pinpointed common regions of deletion: 22pter-22q11.2, 22q11.21–12.2 and 22q13.1–13.3, coinciding with translocation breakpoints and deletions mapping to this region.

Notably, allelic loss on chromosome 22q was observed more frequently in intramedullary spinal ependymomas than intracranially and more often in adult versus pediatric cases.

Hence, studies in ependymoma have long searched for a tumor suppressor gene on chromosome 22 irrespective of location and age of occurrence.

The most likely candidate on 22q was the neurofibromatosis 2 (NF2) tumor suppressor gene which is mutated in individuals with neurofibromatosis type II. These patients can develop a variety of central nervous system malignancies including ependymomas, schwannomas, and meningiomas.

However, in several studies, NF2 mutations were found only in spinal ependymomas and were extremely rare in childhood intracranial ependymomas. This suggests that another putative tumor suppressor gene exists on 22q in the case of pediatric infratentorial and supratentorial ependymomas.

Although NF2 deletions and mutations may account for the majority of adult and spinal ependymomas, low-copy chromosomal gain on 1q have also been found with the highest reported incidence of 22% in childhood ependymomas.

- Arm 1q gain

Arm 1q gain was also found to be preferentially associated with the posterior fossa location, anaplastic histological features, and was a significant prognostic indicator of poor outcome.

In several cases, 1q gain or isochromosome 1q was the sole genetic abnormality detected; in others, 1q gain was a progression event found only in the recurrence.

This suggests that chromosome 1q may harbor initiation and progression genes important in ependymoma tumorigenesis.

There have been reported a number of translocation breakpoints between 1q11and 1q25, many of which result in partial trisomy 1q.

High-level amplifications with a minimal overlapping region of 1q24-31 have also been found, as well as high-level amplification on 1q22-31.

Because these aberrations have been mapped by low-resolution CGH and cytogenetics, differentiation between driver versus passenger genes on 1q in ependymoma has been difficult.

- Arm 6q loss

In addition to chromosome 1q gain, infratentorial tumors are also characterized by chromosome 6q loss.

Reardon et al. found that loss of 6q was the most frequent autosomal change in ependymoma.

Like chromosome 1q gain, chromosome 6q loss was reported as the only copy number alterations in a small cohort of ependymomas.

By microsatellite analysis, allelic deletions of 6q were reported in 69% of patients, and two common regions of deletions emerged: 6q24.3 and 6q25 to approximately 6q25.3.

Analysis of LOH revealed genetic loss in 30.3% of ependymomas at chromosome 6q.

Further, pediatric anaplastic intracranial ependymomas harboring the 6q25.3 deletion showed significantly longer overall survival suggesting that the 6q25.3 locus may have prognostic relevance.

- monosomy 10

Monosomy 10 was reported in few cases of anaplastic ependymomas associated with LOH of 17p.

- monosomy 13 or 13q loss

Monosomy 13 was observed in eight cases half of which occurred in paediatrics patients. Rearrangements or deletions of chromosome 6 have been reported.

- monosomy 17

The 17p13 region was lost in 50% of cases, with a preferential occurrence in infratentorial tumors.

Another large chromosomal abnormality commonly identified in ependymoma is monosomy 17 with complete or partial loss on both chromosomal p and q arms.

Several studies suggested that loss of genetic material on chromosome 17 occurred more frequently on the 17p arm, in some cases, upwards of 50% of ependymomas exhibited 17p loss at the p-terminal end.

The frequency of LOH reported at this locus varies widely; however, the consensus is that TP53 is not the candidate tumor suppressor of this region as TP53 mutations are rare in both adult and childhood ependymoma.

Other large chromosomal aberrations identified in ependymoma include gain of chromosome 7 found almost exclusively in spinal ependymomas.

- 16q losses

16q losses have also been found in adult and pediatric ependymoma suggesting PTEN as a potential candidate tumor suppressor gene. However, numerous studies have found no mutations of PTEN in ependymoma.

- 9p loss

Chromosome 9p loss has been identified preferentially in supratentorial ependymomas and was shown to contain CDNKN2A/p16INK4a deletions in a subset of ependymomas.

- 9qter gain

  • Gain of 9qter is associated with tumor recurrence, age older than 3 years, and posterior fossa location. (19289631)
  • Overexpression of two potential oncogenes at the locus 9qter: Tenascin-C (TNC) and NOTCH1. (19289631)
  • NOTCH1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). (19289631)
  • Inhibition of Notch pathway with a gamma-secretase inhibitor (GSI) impaired the growth of ependymoma stem cell cultures. (19289631)
  • The activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. (19289631)

- 6q gain (6% diagnostic, 27% relapse)

- 7p gain

The region of chromosome 7 gain found commonly in spinal ependymomas was narrowed to a region on 7p harboring the candidate proto-oncogene TWIST1 and HDAC9, while highly recurrent gains were also found at 7q34 encompassing ARHGEF5.


- NOTCH pathway

The NOTCH pathway was also implicated in ependymoma tumorigenesis with chromosome 20 gains involving JAG1 and amplification of NOTCH4.

Further, corresponding expression studies demonstrated that JAG1 is highly expressed in all supratentorial ependymomas.

Gene expression profiling

Gene expression profiling has also distinguished ependymomas based upon localization, and narrowed in on potentially important candidate genes in regions of chromosomal alteration, and has suggested gene pathways which may be dysregulated in ependymoma.

Similar to aCGH studies, gene expression analyses in ependymoma distinguished supratentorial, posterior fossa, and spinal ependymomas largely by genes regulating neural precursor cell proliferation and differentiation.

Supratentorial ependymomas have elevated EPHB-EPHRIN (EPHB2/3/4 and EPHRINA3/4), NOTCH (JAGGED1/2), and cell-cycle-related genes (CYCLINB2/D1/G2, CDK2/4, and CDKN1C/2C), while posterior fossa tumors express many inhibitors of differentiation (ID1/2/4) and the aquaporin (AQP1/3/4) family of genes.

Spinal ependymomas, however, were characterized by expression of various homeobox genes including HOXA7/9, HOXB6/7, and HOXC6/10.

Taylor et al. also demonstrated that patterns of gene expression in ependymoma were similar to those of radial glial cells, suggesting that the cell of origin in ependymoma may lie in this primitive neural precursor population.

Indeed, the lack of knowledge regarding the normal ependymoma counterpart has hindered gene expression studies in these tumors.

However, by comparison to normal cerebral samples and neoplastic samples from other brain tumors, studies by Modena et al. were able to determine gene expression patterns perturbed in ependymoma.

Five families of genes emerged as differentially expressed in ependymoma including the NOTCH signaling pathway and overexpression of NOTCH1, NOTCH2, HES1, FZD1, HEY2, LFNG, and JAG.

The sonic hedgehog signaling pathway was also affected with over expression of GLI1, GLI2, STK36, and downregulation of PRKAR1B.

Genes involved in development and differentiation were also affected including MSX1, IGF2, EGF, EGFR, ERBB3, and SRC.

Cell motility and adhesion genes were also perturbed including ITGB1, EGFR, VIL2, CAPN2M, PRKAR1B, and MLC1.

Lastly, the cell stress-response pathway was activated with overexpression of HSPB1, MAPKAPK3, BCL2, CDC2, and FAS.

Importantly, association of these expression studies with copy number alterations narrowed potential candidate genes in regions commonly affected in ependymoma.

For example, SULT4A1 is found in the frequently deleted region on 22q13.3 and had decreased expression in intracranial ependymoma.

Gene mutations

Genes involved in ependymomas remain to be uncovered. Mutations or deletions of the tumor suppressor genes CDKN2 A et CDKN2 B and amplification of CDK4 or CCND1 have been reported. Mutations of TP53 were occasionally observed in ependymomas.

Increased incidence of ependymomas in neurofibromatosis type 2 has suggest that NF2 represents an obvious candidate gene. Some authors have presented evidence for mutations of NF2 suppressor gene at 22 q12 . Whereas others have been unable to identify such mutations of the NF2.

Investigators show that the most frequently recurrent genomic loss in ependymomas does not involve the proximal 22 q11.2 chromosome region.

They suggest that another not-yet identified tumor suppressor gene located distally to the HSNF5 / INT1 locus on the 22q and independent of NF2 locus may be involved in ependymomas.

Molecular groups

- Age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. (20516456)


- CDKN2A, CDKN2B and p14ARF are frequently and differentially methylated in ependymal tumours. (14636164)

Epigenetic events in ependymoma pathogenesis


The most commonly methylated tumor suppressor gene in ependymoma was RASSF1A in all clinical and pathological subtypes reported with an incidence of 86% of cases.

- 17p13.3 and HIC1

Previous studies have demonstrated that significant LOH occurs at chromosome 17p13.3 in ependymoma.

This region contains the transcriptional repressor hypermethylated in cancer 1 (HIC1), a putative tumor suppressor gene, which exhibits promoter hypermethylation and transcriptional downregulation in a variety of tumors including medulloblastoma and glioma. Waha et al. demonstrated that HIC1 was methylated in 83% of ependymomas and was associated with a non-spinal localization.

- 9p

Potential target genes on chromosome 9p, including CDKN2A, CDKN2B, and p14ARF were found to be frequently methylated at incidences of up to 21%, 32%, and 28%, respectively.

Other commonly methylated genes in ependymoma included BLU, GSTP1, DAPK, FHIT, MGMT, MCJ, RARB, TIMP3, THBS1, TP73, and a family of TRAIL pathway-related genes CASP8, TFRSF10C, and TFRSF10D.

Management and treatment

The treatment of ependymomas is mainly exeresis of tumor and radiotherapy after exeresis

To date, treatment for ependymoma remains as surgical resection followed by radiotherapy with cure rates of approximately 60%.

In the case of unresectable, recurrent, or metastatic disease, the prognosis is significantly worse. Furthermore, survivors are often left with serious neurological impairments as a result of the disease and its treatments.

Despite numerous multi-center clinical trials, no chemotherapy regimens have been shown to improve overall survival.


Ependymoma is a recurrent tumor. The identification of parameters with prognostic value in ependymomas is very important, but controverted.

By order of importance the following factors are considered : Age and extent of resection Prognosis in children is significantly worse than in adults.

The children¼s cancer group reported a 5 year progression-free survival of 5 % in children with intracranial ependymomas. A retrospective analysis of 83 pediatric ependymomas revealed are below 3 years incomplete tumour resection as indication of a poor outcome.

In adult patients survival at 10 years is 45 %.

Complete or near complete resection emerged as an independent prognostic factor.




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