Neuro-Oncology

Neuro-Oncology 18(7), 902– 913, 2016

doi:10.1093/neuonc/now016
Advance Access date 28 March 2016

Biology and management of ependymomas

Jing Wu, Terri S. Armstrong, and Mark R. Gilbert

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
(J.W., M.R.G.); Department of Family Health, University of Texas Health Science Center at Houston, Houston, Texas (T.S.A.)

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Corresponding Author: Mark R. Gilbert, MD, Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of
Health, Bethesda, MD ([email protected]).

Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar
but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being
age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and
III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas
with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and
subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy
are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor
biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are
essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the
translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment
and management of patients’ symptoms to ensure that treatment advances translate into improvement in quality of life.

Keywords: Collaborative Ependymoma Research Network, ependymoma, management, molecular classification, rare disease.

Ependymomas are primary tumors in the central nervous sys- genetic heterogeneity within the same histological grade
tem (CNS). They are known as neoplasms of children and young dictates the biological behavior of ependymomas and is more
adults and were thought to originate from the lining of cerebral predictive of outcomes.
ventricles or the spinal cord central canal. However, recent The management of patients with different grades of epen-
studies suggest that radial glial stem cells are the cell of origin.1 dymomas has not been standardized. Surgical resection and
These tumors may occur at any site along the ventricular sys- radiation therapies have been the mainstay therapies for this
tem and in the spinal cord but vary in different age groups and group of disease. Chemotherapy is of limited efficacy for epen-
histological subgroups. dymomas. For those with ependymomas, the overall 10-year
Ependymomas develop in all age groups but occur more fre- survival rate is 79.2% according to the 2014 CBTRUS report.2
quently in children than in adults. According to the 2014 report In general, the survival rate is the highest for those aged 20–
published by the Central Brain Tumor Registry of the United 44 years and decreases with increasing age at diagnosis. In
States (CBTRUS), ependymomas account for 5.2% of all brain fact, the 10-year survival rate is only 28.1% in those aged
and CNS tumors in children and adolescents ages 0 –19 years .75 years. In children and adolescents aged 0 – 19 years, the
compared with 1.9% of adult patients. There also appears to be 10-year survival rate is 66%. European population-based stud-
a racial disparity, with an incidence rate per 100,000 of 0.40 in ies on survival of childhood cancers and primary malignant
whites versus 0.27 in African Americans.2 brain tumors in adults have demonstrated the disparities
Ependymomas have traditionally been classified by the between countries, which might be caused by limited drug sup-
World Health Organization (WHO) Classification of Tumors of ply, lack of specialized care, and poor management of the
the Nervous System as grades I, II, and III based on their disease.6,7
grade of anaplasia. The goal of WHO classification of the CNS
tumors is to predict the different clinical prognoses for the dif- Pathology and Current Histological
ferent histological grades.3 However, there is an increasing
body of research challenging the concept that histological
Classifications
grades predict prognosis, especially in different age groups The WHO classification of the CNS tumors is currently accepted
and at different locations in the CNS.4,5 This suggests that as the standard classification system, where ependymomas

Received 20 September 2015; accepted 4 January 2016

Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2016. This work is written by (a) US Government
employee(s) and is in the public domain in the US.

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 Wu et al.: Biology and Management of Ependymomas

are classified from grades I to III. The classical histological find- contrast (Fig. 2). Chronic back pain is typically the most com-
ings for all grades of ependymoma are demonstrated and sum- mon presenting symptom for this group of patients.
marized in Fig. 1. As is true with most primary CNS tumors, the Grade II tumors are designated as ependymoma , whereas
commonly used “TNM” (tumor, lymph nodes, and metastasis) grade III tumors are called anaplastic ependymomas. The pa-
cancer staging system does not apply to ependymomas thognomonic histological features are perivascular pseudoro-
because these tumors rarely spread outside the CNS or involve settes, which originate from tumor cells arranged radially
adjacent lymph nodes. around the blood vessels with a perivascular anuclear zone
Grade I ependymomas include subependymomas and myx- (Fig. 1C) and true ependymal rosettes or tubules, which are
opapillary ependymomas, both of which are slow-growing and ependymal cells arranged around a central lumen (Fig. 1C).
are often considered to be benign neoplasms. They have dis- Multiple histological variants of ependymoma have been

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tinct localizations, imaging findings, and clinical features. Al- reported including cellular, papillary, clear cell, and tanycytic
though their inclusion within the category of ependymoma is ependymomas (Fig. 1E). Tumor geographic necrosis is not a
somewhat controversial, many reports continue to include sub- diagnostic feature of the malignancy by itself without associat-
ependymomas within the rubric of ependymoma. Clinically, ed vascular proliferation and frequent mitotic activity or high
subependymomas typically attach to a ventricle wall, most proliferative index.13 – 15 In the grade II tumors, nonpalisading
commonly the fourth ventricle, followed in frequency by the geographic foci of necrosis can be observed, while pseudopali-
lateral ventricles. Subependymomas often appear to be sharply sading necrosis and microvascular proliferation are common
demarcated nodular masses that are nonenhancing on MRI in anaplastic ependymomas. Increased cellularity and brisk
scans. Patients with subependymomas usually present with mitotic activity are also frequently observed in anaplastic epen-
symptoms of increased intracranial pressure as a consequence dymomas. Clinical manifestations of both grades are largely
of ventricular obstruction. Subependymomas can be asymp- location-dependent.
tomatic and discovered incidentally on MRI or even at autopsy.8
In contrast, myxopapillary ependymomas are almost exclu-
sively located in the region of the conus medullaris, cauda
Prognostic Factors Are Age- and Site-Specific
equina, and filum terminale of the spinal cord, although un- Identification of prognostic factors in ependymomas remains
common locations such as the cervical thoracic spinal cord, lat- an important but controversial topic that relies on correct diag-
eral ventricle, or brain parenchyma have been reported.9 – 12 On nosis (ideally from a central review), formal study with an ade-
MRI, myxopapillary ependymomas appear to be sharply cir- quate number of subjects who are well stratified by their age,
cumscribed, sausage-shaped, and enhanced by the gadolinium and tumor location. Rodriguez et al identified and studied

Fig. 1. Histological features of (A) myxopapillary ependymoma, (B) subependymoma, (C) ependymoma, and (D) anaplastic ependymoma. (E)
Description of histological characteristics of ependymomas of all grades. Red * indicates perivascular pseudorosettes, and red solid triangle
indicates ependymal rosettes. Scale bar ¼ 50 microns.

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Wu et al.: Biology and Management of Ependymomas

resection conferred a survival benefit for both pediatric and

adult patients. The unfavorable prognostic impact of a supra-
tentorial location was again demonstrated by univariate anal-
ysis from a study involving 70 patients older than aged 17
years. However, only older age, and not supratentorial location,
was found to be an unfavorable prognostic factor by multivar-
iate analysis from this study.19 A single institution study of 123
adult ependymoma patients was conducted at the University
of Texas MD Anderson Cancer Center. Forty patients had tumors
in the brain, 80 in the spinal cord, and 3 at both locations.

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Although the majority of tumors were grade I or II, the study
was able to demonstrate that a brain location (versus spinal
cord) and tumor anaplasia were associated with a worse out-
come in adults measured by both overall survival (OS) and
progression-free survival (PFS).
In order to address the limitations— such as quality of the
study data, extensiveness of information regarding clinical fea-
tures, and small numbers of samples from single institutions—
the Collaborative Ependymoma Research Network (CERN)
developed a multi-institutional, clinically annotated tissue
repository in 2009. Tissue samples that were collected represent
all locations and histological grades and were confirmed by
experienced neuropathologists. Extensive clinical information,
including tumor characteristics, diagnostic details, treatment
history, and all demographical information were collected.
Using this sophisticated data repository, the CERN investigators
analyzed data from 282 cases with the goal of further defining
the clinical and demographic factors associated with PFS in adult
patients with ependymomas involving the brain and spinal
cord.20 Participants were equally male and female with a medi-
um age at diagnosis of 43 years. All 3 grades of WHO classifica-
tion were represented, with grade II tumors being the most
common histological type (78%). The spinal cord (46%) was
the most common tumor location. Most participants underwent
gross total resection (GTR) followed by observation. Radiation
Fig. 2. MRI with gadolinium showing a myxopapillary ependymoma of was given after both subtotal resection (STR) and GTR. Fewer
the filum terminale presenting as a contrast-enhanced spinal mass. than 5% of the patients received chemotherapy agents. Approx-
imately one-third of patients had a recurrence at the time of the
analysis. Although the median time to recurrence was 14 years
2408 ependymoma cases, including 2132 grade II and 276 for all patients, there were significant differences in PFS by the
grade III tumors, from the Surveillance, Epidemiology and tumor location. The median time to progression was 3.9 years
End Results (SEER) database 1997 – 2005.16 Factors including for the supratentorial brain region, 12.3 years for the infratento-
younger age, male sex, higher tumor grade, intracranial loca- rial brain region, and was not reached by patients with a spinal
tion, and failure to undergo extensive surgical resection were cord location (Fig. 3A). When reported by tumor grade, grade III
found to be associated with poor clinical outcome. Although had the shortest PFS with the median PFS being 2.3 years,
these are important findings, the use of the central registry whereas PFS was not significantly different between grade I
does raise concerns regarding accuracy of the diagnosis. In and grade II tumors (Fig. 3B). The lack of correlation of grade I
fact, analysis of ependymoma cases in a single institution and II tumors with clinical outcomes suggests that molecular
found that nearly 20% of them had been misdiagnosed as an- features, rather than histological grades, may have greater im-
other histological type of neoplasm prior to the expert review,17 pact in tumor biology. Differences in PFS following initial treat-
suggesting that accurate diagnosis for clinical studies remains ment were also found to be significant (Fig. 4B). Those who
an important consideration. underwent STR had a shorter PFS compared with those who un-
Recognizing that prognostic factors for pediatric patients derwent GTR, regardless of the subsequent radiation treatment.
may be different from those of adults, Amirian et al identified Patients younger than aged 44 years had a shorter PFS than
the ependymoma cases from the SEER database; the prognos- those older than aged 44 years at the time of diagnosis
tic factors were analyzed separately for pediatric and adult (Fig. 4A). The multivariate analysis of PFS demonstrated that
groups.18 Anaplastic histology and infratentorial location of tu- tumor location, tumor grade, age, and initial treatment all con-
mors were associated with an increased mortality rate in pedi- tributed significantly to PFS (Table 1). When a separate multivar-
atric cases, while a supratentorial location was associated with iate analysis was done for each location, only the factor of initial
higher mortality rate in adult patients. Completed surgical treatment significantly contributed to PFS in the supratentorial

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Fig. 3. Progression-free survival distributions according to tumor location (A) and tumor grade (B). (Adapted from Vera-Bolanos et al, 2015, and
used with permission of Oxford University Press).20

Fig. 4. Progression-free survival distributions by age at diagnosis (A) and initial treatment (B). (Adapted from Vera-Bolanos et al, 2015, and used
with permission of Oxford University Press).20

Table 1. Multivariate analysis of progression-free survival

Predictor Variable HR 95% CI P Value Median PFS (y)

Age at diagnosis (y)a 44 and older 1 Not reached

43 and younger 1.22 0.74– 2.02 .428 13.4
Location* Supratentorial 1 3.9
Infratentorial 0.33 0.18– 0.63 .1 12.3
Spine 0.15 0.07– 0.31 ,.001 Not reached
Tumor grade* Grade II 1 15.8
Grade I 1.90 0.73– 4.96 .189 Not reached
Grade III 3.00 1.45– 6.07 .003 2.3
Initial treatment*,b GTR 1
STR 2.61 1.27– 5.36 .009 14
STR + radiation 2.44 1.36– 4.36 .003 11.3
GTR + radiation 0.62 0.27– 1.45 .271 10.8

Abbreviations: CI, confidence Interval; GTR + radiation, gross total resection followed by radiation; HR, hazard ratio; STR, subtotal resection
followed by observation; STR + radiation, subtotal resection followed by radiation; y, years.
(Adapted from Vera-Bolanos et al, 2015, and used with permission of Oxford University Press).20
a
Based on median age.
b
Initial treatment variable is categorized as gross total followed by observation.
*Significant at P , .05.

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Wu et al.: Biology and Management of Ependymomas

and spinal tumors, whereas both tumor grade and initial contrast, the transformation by this oncogene does not occur
treatment significantly contributed to PFS in infratentorial in radial glial stem cells isolated from hindbrain and spinal
tumors. Extent of initial surgery impacted PFS, with less than cords, suggesting a unique site-specific genetic event.
GTR increasing risk for early progression in ependymomas at all Previous studies have not only demonstrated that there are
3 locations. location-specific molecular profiles but also a high degree of
Histological features have been traditionally used to grade intertumoral heterogeneity within each CNS location.25 – 27 In
ependymomas.21 However, the prognostic importance of order to understand intertumoral heterogeneity within each
some of the histological findings has been challenged for pedi- anatomical compartment (supratentorial, infratentorial, and
atric ependymoma when the correlation of WHO grade (II ver- spinal cord), researchers performed whole genome and whole
sus III) with prognosis has been questioned.22 Attempts have exome sequencing of ependymomas in both supratentorial28

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been made to find particular histological parameters that and posterior fossa27,29 ependymomas.
may be more indicative of specific ependymoma tumor biology. In a study of supratentorial ependymomas, Parker et al dis-
For example, the CERN tissue repository was used to evaluate covered that there are genomic structures clustered within a
238 ependymoma cases to correlate individual histological highly focal region on chromosome 11q12.1-q13.3.28 This re-
features with clinical outcomes.23 Among posterior fossa gion contains gross interchromosomal and intrachromosomal
ependymomas, the presence of hypercellular areas, necrosis, rearrangement, consistent with chromothripsis. The chromo-
microvascular proliferation, and elevated mitotic rate, but not some fragments from this area fused a poorly characterized
extensive ependymal canal formation, was significantly associ- gene, C11orf95, to RELA, a known principal effector of canonical
ated with worse clinical outcomes. Similar to posterior fossa tu- NF-kB signaling pathways. This fusion occurs in about 70% of
mors, microvascular proliferation and elevated mitotic rates supratentorial tumors and is strictly specific for this location.
were associated with a worse PFS in supratentorial tumors. This study also identified YAP1-MAMLD1 fusions in the supraten-
However, in contrast to posterior fossa tumors, extensive epen- torial ependymomas without RELA fusion. Both RELA-C11orf95
dymal canal formation, but not hypercellularity and necrosis, and YAP1-MAMLD1 fusions were further confirmed by the DNA
was found to be associated with a worse PFS significantly. In methylation study,30 which demonstrated that YAP1 fusion-
contrast to both supratentorial and infratentorial ependymo- positive cases characterize a subgroup of supratentorial epen-
mas, none of these histological features were found to be dymomas that are negative for RELA fusions. In contrast to
associated with PFS in ependymomas located within the spinal C11orf95-RELA fusion, no chromothripsis was identified to un-
cord. These findings highly suggest that the clinical relevance of derlie YAP1 fusions. Both fusion proteins are oncogenic.
specific histological features in ependymomas appears to be A transcriptional profiling study of 2 independent sets of
related to the anatomical sites of their origins. ependymomas, including both grade II and III, revealed that
there are 2 demographically, genetically, and clinically distinct
Advanced Genomic Studies Decode subgroups of ependymomas in the posterior fossa (PF) that
have been designated as group A (PFA) and group B (PFB).27
Ependymoma Biology
PFA occurs predominantly in infants, is located laterally in the
Despite extensive efforts to create histological criteria for seg- PF with a balanced genome, and is associated with a poor
regating ependymoma into risk categories, tremendous vari- clinical prognosis. Conversely, PFB usually occurs in older chil-
ability has been seen in outcomes despite similarities in dren and adults and is associated with a better prognosis. In
microscopic characteristics. These observations highly suggest analyzing the signal pathways differentiating PFA and PFB,
that ependymomas are a group of diseases with discrete tumor upregulation of many cancer-related molecular pathways (eg,
biology that cannot be fully elucidated by a traditional histolog- angiogenesis, PDGFR, EGFR, and TGFb signaling) were observed.
ical classification. Therefore, molecular analyses have been un- Laminin alpha-2 (LAMA-2) and neural epidermal growth factor
dertaken to try to elucidate the pathogenesis of these tumors like-2 (NELL-2) were found and confirmed as biomarkers for PFA
and provide better prognostic groupings and potentially novel and PFB, respectively.
therapeutic targets. To better understand the biological basis of PF ependymo-
In order to understand the biological basis for the regional mas, Mack et al proposed that PFA ependymomas might be
heterogeneity in ependymomas, many investigators have per- driven by epigenetic mechanisms after they detected absence
formed genomic sequencing and demonstrated that molecular of a recurrent and significant single nucleotide variation and
changes are site-specific.23,24 Gilbertson et al performed a DNA copy number alterations in PF ependymomas.29 In a
cross-species study, which demonstrated that ependymomas study of DNA methylation pattern in a cohort of 79 ependymo-
from different CNS locations share the same gene expression mas, the finding of unsupervised consensuses clustering of CpG
profiles with radial glial stem cells in the corresponding region methylation profiles demonstrated 3 distinct subgroups includ-
of the developing brain or spinal cord.25 They observed that ing supratentorial, PF, and mixed spinal/PF tumors in a pattern
human ependymomas could be segregated into similar sub- similar to that yielded by unsupervised clustering of gene ex-
groups by using messenger RNA, microRNA, and DNA copy pression profile. Very distinct methylomes were identified in
number alteration profiles, suggesting that the subgroups are PFA and PFB ependymomas, with a higher extent of CpG island
truly distinct biological entities when defined by anatomic loca- methylation found in PFA compared with PFB ependymomas.
tion. To further support this hypothesis, the investigators dem- Therefore, the authors suggested that PFA ependymomas
onstrated that EPHB2, an oncogene identified from human can be referred to as PFA CpG island methylator phenotype
supratentorial ependymomas, can transform the radial glial (CIMP)-positive ependymomas and PFB ependymomas as PFB
stem cells from forebrain to give rise to ependymomas. In CIMP-negative ependymomas. Interestingly, the genes CpG

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 Wu et al.: Biology and Management of Ependymomas

methylated in PFA ependymomas are similar to the genes that by DNA-methylation profiling study, while myxopapillary epen-
are silenced by polycomb repressive complex 2(PRC2) in embry- dymoma is only found at a spinal cord location.
onic stem cells. PRC2 controls all forms of methylation of lysine These genomic studies make it clear that ependymomas have
27on histone H3 (H3K27) and is responsible for silencing the different biology when they arise from different CNS locations
genes involved in cell differentiation and cancers.31,32 Both and that tumors from the same location possess distinct molec-
H3K27 trimethylation (H3K27Me3) and H3K27Me3 target ular features that may be utilized to classify their biologically
genes were found in a separate cohort of PFA-CIMP+, but not unique subgroups. More recently, DNA methylation profiling of
in the PFB-CIMP- ependymomas, suggesting that tumor sup- a series of 500 ependymal tumors of all histological grades
pressor gene silencing by CpG hypermethylation secondary to and anatomical locations allowed more detailed molecular
an enhanced activity of PRC2 contributes to the pathogenesis classification.30 As summarized in Fig. 5, there are genetically dis-

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of PFA and potentially explains the poor prognosis of patients tinct subgroups identified in the classical ependymomas, grade II
with this subgroup of ependymomas. and III, at each supratentorial, infratentorial, and spinal cord
Spinal ependymomas can be a major disease component of location.: C11orf95-RELA+ and C11orf95-RELA-, but YAP1+
neurofibromatosis type 2 (NF2), indicating the potential role of supratentorial ependymomas; CIMP + and CIMP- infratentorial
the NF2 gene in ependymomas with spinal cord location. There ependymomas and spinal cord ependymomas.27 – 30
have been studies showing increased frequency of NF2 gene
mutation.33,34 Spinal ependymomas in the setting of NF2
have more indolent clinical courses. Deletion of chromosome
Management of Ependymomas Is
22 and increased expression of the homeobox (HOX) family Challenging
genes encoding transcription factors involved in embryonic
Surgical Resection and Radiation Remain the Mainstays
anteroposterior tissue pattern development were found in
spinal ependymomas.34 – 36 of Treatment for Ependymomas
Myxopapillary ependymoma and subependymoma have Surgical resection remains a critical component of ependymoma
been classified under the great category of ependymoma for management for all histological grades. The surgical procedure
their unique histological appearance. However, their clinical is essential to establish a pathological diagnosis and collect tis-
features and tumor biology are quite distinct from grade II sues for a genomic analysis to determine each ependymoma’s
and III ependymomas. An analysis of a series of 35 spinal unique molecular profile. If the tumor cannot be resected safely
ependymomas revealed that, in addition to distinct morpho- due to its location, a biopsy of the lesion is still warranted prior to
logic differences between grade II and myxopapillary ependy- the initiation of treatment. When tumor resection is feasible, the
momas, there are profound genomic and biologic differences. most extensive resection is always desirable as many clinical
This study revealed that myxopapillary ependymomas demon- studies have reported that extensive resection is associated
strated alterations in metabolic pathways such as upregulation with both PFS and OS.38 – 40 In the largest case series investigat-
of HIF1a and other proteins consistent with the aerobic glycol- ing the clinical course and PFS, data from 282 patients with
ysis seen in cancer and commonly referred to as the Warburg ependymomas suggested that GTR is the only prognostic factor
effect.37 Subependymoma was found to be in all CNS locations significantly associated with increased PFS in supratentorial

Fig. 5. Genetically distinct subgroups in supratentorial, infratentorial and spinal cord ependymomas of WHO grades II and III. Abbreviations: PFA:
CIMP+, posterior fossa group A: CpG island methylator phenotype positive; PFB: CIMP-, posterior fossa group B: CpG island methylator phenotype
negative.

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Wu et al.: Biology and Management of Ependymomas

ependymomas.20 Patients who underwent subtotal resection in the field that tumor resection should be followed by
(STR), even with the addition of radiation, have a higher chance radiotherapy.
for ultimately developing progressive disease. The same effects Proton therapy is increasingly being considered in the man-
of GTR were also confirmed in ependymomas in the spinal cord agement of ependymomas due to its unique property of sparing
region. Myxopapillary ependymomas are quite different from the normal tissue, suggesting that it may be superior to photon ther-
rest of intramedullary ependymomas in the spinal cord. They are apy for the management of pediatric ependymomas. Proton
WHO grade I and almost always arise in conus medullaris but therapy may be most beneficial for younger patients with tu-
can extend to cauda equina. Several studies have demonstrated mors that require radiotherapy near critical structures in the
that a GTR without violating the tumor capsule may lead to cure. CNS.52 In a retrospective analysis of children with ependymomas
For this reason, it is important to maintain the integrity of the receiving different modalities of radiotherapy, similar tumor

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capsule to avoid tumor dissemination and to prevent a worse volume coverage was achieved with intensity-modulated proton
clinical outcome.41 – 43 therapy (IMPT), proton therapy, and intensity-modulated radia-
An immediate postoperative brain MRI scan, ideally within tion therapy (IMRT). However, substantial sparing of normal
24– 48 hours after surgery, is recommended to determine the tissue was observed in ependymomas treated with proton ther-
extent of surgery. If there is extensive tumor burden appearing apy when compared with IMRT. Use of IMPT will allow for addi-
on the postoperative MRI and the residual disease can be read- tional sparing of some critical structures.53 Some studies showed
ily resected, several groups have proposed a second-look less acute toxicity after proton therapy in children compared
surgery to maximize the extent of surgical resection.44,45 In ad- with those who received photon therapy.54 Interestingly, a
dition to providing tissue diagnosis and improving prognosis, retrospective study that compared imaging findings after post-
the tumor resection also relieves hydrocephalus, which is com- operative IMRT and IMPT in 72 patients with nonmetastatic
mon with some supratentorial ependymomas and more fre- intracranial ependymomas has demonstrated that postradiation
quently with posterior fossa ependymomas. In most patients, MRI changes are more common after IMPT in patients younger
resection of the primary tumor is sufficient to manage the than aged 3 years.55 Prospective studies with extended
obstructive hydrocephalus without having external ventricular follow-up are warranted to evaluate the role of the 2 radiation
drainage or ventriculoperitoneal shunt. modalities in both pediatric and adult ependymomas.
Staging of ependymomas is highly recommended with
imaging of the entire neuraxis and cerebrospinal fluid (CSF)
analysis. The CSF analysis should be delayed for a minimum The Role of Chemotherapy Is Less Well Established
of 2 weeks after surgery to avoid confusing findings in the The role of chemotherapy in the management of ependymomas
CSF. Dissemination through the CSF is not common and is has not been well defined. Chemotherapy has been used in
estimated to occur in 15% of patients,42 but it will impact treat- younger patients in an attempt to defer radiation to the devel-
ment planning markedly. oping nervous system.56 – 58 In a prospective clinical trial con-
Postoperative radiation has been established as an effective ducted by the French Society of Pediatric Oncology, 73 children
adjuvant therapy for patients with grade III ependymomas or younger than age 5 years with ependymomas were treated with
those with low-grade ependymomas who cannot undergo a 16 months of multiagent chemotherapy, including alternating
complete resection. There is less clarity for grade II ependymo- procarbazine and carboplatin, etoposide and cisplatin, and
mas with GTR. The optimal radiation field and dosage are still vincristine and cyclophosphamide after surgery. The 2- and
matters of debate. However, most experts in the field of neuro- 4-year survival rates were 40% and 23%, respectively. Although
oncology recommend focal radiation therapy, rather than treatment was well tolerated during the 5 year follow-up time,
whole brain or craniospinal radiation, unless there is a sign of no tumors had shown more than 50% reduction as measured by
tumor dissemination.46,47 Dosages of 5400 cGy in 30 fractions imaging.59 The benefit of chemotherapy for adults with newly
for low-grade ependymomas and 5940 cGy in 33 fractions for diagnosed ependymomas has not been studied prospectively.
high-grade tumors have been tested in the treatment proto- In patients with recurrent disease, retrospective analyses sug-
cols.48,49 In nondisseminated diseases, a total dosage up to gested that platinum-based chemotherapy regimens appear
6000 cGy brings the same benefit.50 Results from multivariate to result in higher response rates with lower rates of progression
analysis of PFS by tumor location, conducted by CERN investiga- than nitrosourea-based regimens;60 however, cisplatin-based
tors, demonstrated that radiation following GTR may signifi- chemotherapy did not prolong PFS or OS, despite achieving a
cantly increase PFS for infratentorial ependymomas but not higher objective response rate. These findings are based on the
supratentorial and spinal ependymomas.20 results from a multicenter retrospective analysis in adults with
As described above, complete resection of a grade I myxo- recurrent intracranial ependymomas.61
papillary ependymoma can be curative if the integrity of Temozolomide (TMZ), an oral alkylating agent with a good
the capsule is maintained. However, some studies have sug- overall toxicity profile, has become the standard treatment
gested that routine radiotherapy should be included for for several primary CNS cancers. Although there is a case report
young patients with spinal myxopapillary ependymomas, espe- of one patient with recurrent intracranial ependymomas who
cially in their first 2 decades of life.51 There have been no pro- stayed in remission 10 years after being treated with TMZ,62
spective clinical studies to test the survival benefit of radiation other small series of case studies have demonstrated little
therapy after a complete resection in grade II tumors. There- efficacy in a cohort of adults with recurrent intracranial ependy-
fore, it would be a reasonable approach to follow these patients momas that are platinum-refractory.63 In contrast, a recent
closely in the setting of GTR. Due to a poor prognosis in (WHO retrospective study of response to TMZ in18 patients with recur-
grade III) anaplastic ependymomas, there is a consensus rent ependymomas suggested that TMZ has a role in recurrent

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 Wu et al.: Biology and Management of Ependymomas

chemo-naı̈ve adult patients with intracranial ependymoma The molecular subtyping described above provides insights
and should be considered as the possible first-line treatment into tumor biology for potential therapeutic targets. However,
in the recurrent setting.64 The better response rate to TMZ this may dictate that specific treatment regimens are devel-
noted in this study compared with the prior report,63 may be oped for the subgroups of ependymomas. For example, drugs
the result of treating chemotherapy-naı̈ve patients. Findings that target DNA CpG methylation, EZH2 or histone demethylase
from Buccoliero et al demonstrated that O6-methylguanine- inhibitors may be considered as potential therapeutic agents
DNA-methyltransferase is increased in recurrent anaplastic epen- for treating PFA-CIMP+ ependymomas in young children since
dymomas, suggesting a possibility that a dose-dense dosing it may decrease H3K27 trimethylation and lessen silencing on
schedule of TMZ may have better efficacy to deplete MGMT and its downstream gene targets. Conversely, the RELA fusion
subsequently lead to better clinical outcomes.65 The CERN inves- found in most supratentorial ependymomas results in constitu-

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tigators have incorporated this preclinical finding (described in tive activation of the NFkB, a potential therapeutic target.
detail below) into their clinical trial rationale to test dose-dense This subgrouping of patients, which leads to very small num-
TMZ in combination with lapatinib in adults with recurrent epen- bers of patients eligible for clinical trials, underscores the need
dymomas in all CNS locations. There was evidence of treatment for preclinical models. Atkinson et al combined multicell high
efficacy manifested as disease control and some objective throughput screening, kinome-wide binding assays, and in
responses; however, the contribution of each of the treatment vivo efficacy studies to identify potential treatments for epen-
components cannot be determined as a combination regimen.66 dymomas by using a mouse model of a specific subtype of
human ependymomas.71 This approach established a model
for expediting the process of prioritizing therapies tested in
Development of Targeted Therapy Requires In- depth
human clinical trials for specific subtypes of ependymomas.
Understanding of Tumor Biology Using this drug screening system, an ongoing effort was under-
Identifying unique molecular features and genomic alterations taken with the aim of repurposing FDA-approved drugs and
has provided an insight for developing clinical trial concepts in compounds that have not been used in brain cancers. This ef-
targeted treatments for ependymomas. Gilbertson et al discov- fort will dramatically shorten the time it takes to bring those
ered that elevated co-expression of ERBB2 and ERBB4 in . 75% drugs through different phases of clinical trials. A collection of
of ependymomas and a high level of expression of ERBB recep- several drugs have already been completed through this entire
tors is associated with aggressive behavior such as increased screening process and are now being considered for clinical
cell proliferation. Pharmacological inhibition of ERBB2 receptor trials.
tyrosine kinase activity can downregulate the downstream
pathway signals, such as AKT phosphorylation, suggesting a po-
Symptom Management Is Essential for Improving
tential therapeutic role for targeting the ERBB2 receptor.67
CERN investigators developed a novel clinical trial for adults Quality of Life
with recurrent ependymoma, testing a combination treatment Recognizing that oncology care is not just about using different
of lapatinib, a dual tyrosine kinase receptor inhibitor of EGFR/ treatment modalities to let patients live longer, we need to
ERBB1 and ERBB2, and dose-dense TMZ with the intention of ensure that patients have the best quality of life (QOL) possible
depleting MGMT (CERN 08-02, NCT00826241). Treatment was at every step of their survivorship. Therefore, in addition to
well-tolerated with only modest myelotoxicity, and the results ependymoma treatments, management of symptoms from
using PFS as a metric demonstrated activity in the spectrum of the disease and treatment-induced toxicities are equally im-
ependymoma defined by location and tumor grade, which was portant in caring for patients with ependymomas. Understand-
most efficacious in spinal cord tumors. Preliminary gene expres- ing the impact of the disease and its treatments is essential for
sion analysis of a tumor subset showed a statistically signifi- strategizing the treatments to improve patients’ QOL and pro-
cant correlation of better treatment response with a higher vide insights into the design of future clinical trials. In a recent
ERBB2 expression at the mRNA level. Ongoing molecular profil- survey of ependymoma patients, there are varied treatment
ing will determine whether ERBB2 is a predictive marker for approaches as well as a variety of physicians caring for adults
response to this treatment regimen.66 with ependymomas.72 Consequently, it may be difficult for the
Elevated VEGF expression has been observed in most of the individual provider to understand the impact of the disease
ependymomas and found to be associated with short survival upon the individual patient.
and poor prognosis, thereby providing the rationale for using Investigators from CERN have developed ependymoma out-
antiangiogenic therapy to treat ependymomas, especially comes projects in both adults and children, from which they are
recurrent ependymomas with their more aggressive behav- collecting precise information on ependymoma epidemiology,
ior.68,69 Lapatinib, combined with bevacizumab has been tested the social and psychological impact of this disease, and treat-
on children in a clinical trial by pediatric neuro-oncologists at ment effects on patients’ QOL. Through the project, patient pre-
the CERN Foundation (CERN 08-01, NCT00883688). However, sentation, clinical course, and current health status are
the study accrual was stopped because of low response measured and reported. At diagnosis, patients often present
rate.70 Given that platinum-based chemotherapy has been as- with multiple symptoms (an average of 3 symptoms) together
sociated with a higher response rate in intracranial ependymo- with reports of symptoms occurring for 6 months on average
mas,61 the CERN investigators are accruing adult patients with prior to a diagnostic surgical procedure.72 Overall, patients
recurrent ependymomas to test a combination of carboplatin with ependymoma involving the spine reported more severe
with bevacizumab, a humanized VEGF monoclonal antibody symptoms than those with ependymoma involving the brain,
(CERN 09-01, NCT01295944). despite these tumors being primarily low-grade.73 During the

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Wu et al.: Biology and Management of Ependymomas

follow-up period, the majority of patients described significant similar, tumor biology may vary based on molecular subtype,
symptom burden, and nearly 50% of patients participating in thereby mandating either separate studies or stratification
the survey reported being unable to return to work because into subgroups based on their distinct genomic and epigenomic
of ongoing symptoms related to ependymomas. The neurocog- features. The recent molecular discoveries have clearly demon-
nitive outcomes following various treatment modalities in chil- strated that the ependymoma subgroups are biologically distinct
dren have been studied extensively due to the special concern and likely require different treatment approaches; these addi-
about treatment toxicities to the developing CNS.74 – 76 The tional challenges are shared by many other rare cancers. Clinical
knowledge obtained from the project will be used as an trials testing agents against subgroup-specific targets have only
evidence-based resource for patients and their caregivers to a subset of an already uncommon disease. This makes accrual
better manage the symptoms and thus improve QOL. More im- more challenging, and the decision to proceed with a particular

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portantly, the patient outcome measurement will become a therapeutic regimen is more critical since the time required to
critical part of future clinical trials of treatment for ependymo- complete the study will likely be years. Therefore, robust preclin-
mas, incorporating these measures into the assessment of ical models that recapitulate the disease subtypes are critical so
efficacy of therapeutic regimens. that putative therapies can undergo laboratory testing prior to
implementation of a clinical trial. As with many other rare dis-
eases, lack of institutional support for rare diseases can make
Clinical Research Challenges in Management clinical research for ependymoma more complicated. In ependy-
moma, initiatives such as CERN foster collaborations between
of Ependymomas
laboratory and clinical investigators and focus on the develop-
Despite better understanding of ependymoma biology and mo- ment of clinical trials, tumor profiling and pathology, develop-
lecular classification, management of patients with ependymo- mental therapeutics, laboratory tumor models, and patient
mas remains challenging. The rarity of the disease, especially in outcome (Fig. 6). This collaboration between scientists and clini-
adults and children, makes it difficult to perform large scale or cians specializing in adults and pediatric neuro-oncology should
randomized clinical trials. This is compounded by the added foster rapid translation of laboratory findings into clinical trials
complexity by the recent findings that although histologically to maximize productivity of the research. The combination

Fig. 6. The core research projects are built around and support the development of new treatments through clinical trials.

910
 Wu et al.: Biology and Management of Ependymomas

of philanthropic support with collaborative efforts between 14. Kurt E, Zheng PP, Hop WC, et al. Identification of relevant
scientists and clinicians holds great promise for creating prognostic histopathologic features in 69 intracranial
significant advances in management of patients with ependy- ependymomas, excluding myxopapillary ependymomas and
momas—and may also serve as a model for studying other subependymomas. Cancer. 2006;106(2):388–395.
rare cancers. 15. Rawlings CE III, Giangaspero F, Burger PC, Bullard DE.
Ependymomas: a clinicopathologic study. Surg Neurol. 1988;
29(4):271–281.
16. Rodriguez D, Cheung MC, Housri N, Quinones-Hinojosa A,
Acknowledgments Camphausen K, Koniaris LG. Outcomes of malignant CNS
The authors would like to thank Ms. Kristin Odom for her artwork in ependymomas: an examination of 2408 cases through the

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figure production for this article. Surveillance, Epidemiology, and End Results (SEER) database
(1973– 2005). J Surg Res. 2009;156(2):340– 351.
17. Armstrong TS, Vera-Bolanos E, Bekele BN, Aldape K, Gilbert MR.
Adult ependymal tumors: prognosis and the M. D. Anderson
Conflict of interest statement. M.G. was on advisory boards for AbbVie,
Cancer Center experience. Neuro Oncol. 2010;12(8):862– 870.
Genentech/Roche, Foundation Medicine and Wellcome Trust and
received honoraria from AbbVie, Genentech/Roche, Foundation 18. Amirian ES, Armstrong TS, Aldape KD, Gilbert MR, Scheurer ME.
Medicine and Wellcome Trust. Predictors of survival among pediatric and adult ependymoma
cases: a study using Surveillance, Epidemiology, and End Results
data from 1973 to 2007. Neuroepidemiology. 2012;39(2):
116–124.
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