not permitted.

It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA

© 2017 EDIZIONI MINERVA MEDICA Journal of Neurosurgical Sciences 2018 February;62(1):46-50

Online version at http://www.minervamedica.it DOI: 10.23736/S0390-5616.17.04152-2

REVIEW
C U R R E N T T R E AT M E N T S F O R E P E N D Y M O M A

Epidemiology, molecular classification

and WHO grading of ependymoma
Jens-Martin HÜBNER 1, Marcel KOOL 1, Stefan M. PFISTER 1, 2, Kristian W. PAJTLER 1, 2 *

1Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center

(DKFZ), Heidelberg, Germany; 2Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg,
Germany
*Corresponding author: Kristian W. Pajtler, Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German
Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. E-mail: k.pajtler@dkfz-heidelberg.de

ABSTRACT
Ependymoma can arise throughout all compartments of the central nervous system with prevalence for intracranial and spinal location in
children and adults, respectively. The current histopathology based WHO grading system distinguishes grade I, II ‘classic’, and III ‘anaplastic’
ependymoma. However, analysis of multiple cohorts of intracranial ependymoma demonstrate a wide variance in the utility of the grade II
versus grade III distinction as a prognostic marker that may additionally be confounded by the anatomic compartment. Recent (epi)genomic
profiling efforts have identified molecularly distinct groups of ependymoma arising from all three anatomic compartments of the central nervous
system that outperform the current histopathological classification regarding clinical associations. These advances have led to the cognition that
molecular classification should be part of all future clinical trials in ependymoma patients. Clinical management of intracranial ependymomas
(WHO Grade II/III) is challenging and molecular classification based risk stratification may help to intensify treatment and surveillance in
high-risk patients but to de-escalate therapy in certain patient groups at low risk for recurrence. Finally, experience of neurosurgeons, and other
disciplines, as well as intensified co-operation between all stakeholders involved hold promise to finally improve outcome of patients affected
with ependymoma.
(Cite this article as: Hübner JM, Kool M, Pfister SM, Pajtler KW. Epidemiology, molecular classification and WHO grading of ependymoma. J Neu-
rosurg Sci 2018;62:46-50. DOI: 10.23736/S0390-5616.17.04152-2)
Key words: Ependymoma - Neoplasm grading - Neoplasms, neuroepithelial.

E pendymomas are neuroepithelial tumors arising

throughout all compartments of the central nervous
system. The WHO classification of tumors of the cen-
tral nervous system histopathologically classifies epen-
dymomas into grade I, II and III. Although these tumors
can occur at any time in life there are two major peaks
around 0-4 and 55-59 years of age, respectively.1 There
are clear differences regarding predominant location,
treatment options and clinical outcome between tumors
in adult and pediatric patients. In adults, the major-
or other proprietary information of the Publisher.
for 4% of brain tumors in adults,3 resulting in an age-
adjusted incidence rate of 0.3/100,000 in the US (US
Cancer Statistics Working Group, 2017).4 In contrast,
pediatric ependymomas are almost exclusively (90%)
located intracranially with two-thirds of these tumors
occurring in the PF.5 With an age-adjusted incidence
rate of 0.2/100,000 in the US (US Cancer Statistics
Working Group, 2017), ependymomas make up 10% of
all brain tumors in children and have a male to female
ratio of 1.77:1.6 Few familial cancer syndromes have

ity (46%) of ependymal neoplasms is diagnosed in the been associated with ependymoma, e.g. neurofibroma-
spine (SP) while the posterior fossa (PF, 35%), and su- tosis type 2 (NF2) that is responsible for an increased
pratentorial (ST, 19%) brain regions are less frequently incidence of spinal ependymomas.7
affected.2 Overall, intracranial ependymomas account Subependymomas (WHO grade I) are often locat-

46 Journal of Neurosurgical Sciences February 2018

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
Epidemiology, molecular classification and WHO grading of ependymoma HÜBNER
ed intracranially and preferably arise in the fourth or
lateral ventricles. However, occasionally subependy-
momas are also diagnosed in the spine.8 Subependy-
momas are almost exclusively found in adults with a
strong gender bias towards males.9 Macroscopically,
subependymomas can easily be distinguished from the
surrounding brain parenchyma since they are clearly
demarcated and not infiltratively growing. On the
microscopic level, subependymomas display a nodu-
lar pattern often disrupted by zones of high nuclear
density or dense fibrillary stroma. Occasionally, for-
mation of pseudorosettes or cysts can be observed.
Mitotic cells indicative of proliferative activity are
only found in a very low number of cases.10 Myxopap-
illary ependymomas (WHO grade I) are also mainly
occurring in adult patients and may arise in the spi-
nal cord, predominantly in the region of the conus
medullaris, the cauda equina or filum terminale.11 In
pediatric patients, myxopapillary ependymoma is also
found in extramedullar soft tissues of the sacrococcy-
geal region where its behavior might be more indo-
lent compared to tumors arising in the spinal cord.12
Histopathologically, myxopapillary ependymomas
are characterized by papillary structures encompass-
ing areas that show myxoid degeneration and hyalin-
ized blood vessels.13 Despite their more benign nature,
myxopapillary ependymomas might show a relatively
high rate of dissemination in pediatric patients render-
ing long-term follow-up of patients necessary.14 Grade
II ependymomas are referred to as “classic” ependy-
momas and may show perivascular pseudorosettes as
well as the pathognomonic true ependymal rosettes.
Apart from these general characteristics, different his-
tological variants termed papillary, clear cell or tany-
cytic ependymoma can be distinguished. Anaplastic
ependymomas, which are assigned to WHO grade III,
exhibit pseudopalisading necrosis and microvascular
proliferation, while increased cellularity and abundant
mitotic activity are also frequently observed in these
tumors.15 The molecular variant “ependymoma, RELA
fusion-positive” has recently been added to the revised
version of the WHO classification of tumors of the
central nervous system and defines a distinct subset
or other proprietary information of the Publisher.
of grade II and grade III ST ependymomas in children
and young adults. These tumors harbor a fusion be-
tween the genes RELA and C11orf 95 originating from
a local chromothripsis event on chromosome arm 11q
Vol. 62 - No. 1 Journal of Neurosurgical Sciences 47
and may be readily distinguished from other ependy-
momas by expression of L1CAM.16, 17
Intracranial ependymomas in both adults and chil-
dren are frequently treated with surgery followed by
radiotherapy.3, 18, 19 Chemotherapy has so far failed to
show a significant effect on overall patient survival
in both adults and children but is still controversially
discussed for its potential role in radiotherapy deferral
strategies in infants.20 Primary intracranial ependymo-
ma (WHO grade II/III) commonly present with locally
invasive growth patterns and clinical management is
often challenging. Surgery is of high importance for lo-
cal tumor control and the extent of resection has been
demonstrated as being the most consistent independent
prognostic factor.21-23 Treatment strategies that are cur-
rently systematically evaluated in clinical trials often in-
clude aggressive de-bulking and second-look surgeries,
since event-free as well as overall survival of patients
with complete versus incomplete resection varies dra-
matically. Careful assessment of pre- and postsurgical
imaging by experienced neuroradiologists is, therefore,
indispensable in the treatment of ependymoma patients.
In addition to neurosurgical interventions, postoperative
involved field radiotherapy is considered the standard
of care in the absence of metastases to lower the risk
of local recurrence.18 The 5-year overall survival rate
across all child age groups diagnosed with ependymo-
ma is 72.7%.24 Notably, children with only partially re-
sected tumors show poor survival rates of only 32.5%.22
Therapeutic strategies at relapse include re-operation
and even reirradiation. Overall survival increases with
patient age ranging from 42.4% in infants to more than
80% in adults.1, 25 Apart from the extent of resection and
age, overall survival is influenced by factors such as
gain of chromosomal arm 1q, telomerase reactivation,
tumor location, gender and molecular subgrouping.26-30
Within the recent years, ongoing advances in the field
of next-generation sequencing and array platforms have
significantly reduced the costs of these techniques en-
abling more and more centers to integrate molecular
analyses into their diagnostic workflows. Consequently,
clinicians now have access to a broader panel of mo-
lecular patient data allowing for a more differentiated
diagnosis and, ideally, optimizing treatment strategies.
DNA methylation profiling has emerged as a robust
source for the reliable distinction of different brain tu-
mor entities or the identification of clinically relevant
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
HÜBNER Epidemiology, molecular classification and WHO grading of ependymoma
subgroups within a specific tumor entity.31, 32 Consider-
ing the wide variance in the grade II versus grade III dis-
tinction, even between experienced neuropathologists,
thereby limiting clinical utility of grading in ependy-
moma,33, 34 an unbiased methylation-based classification
system enables a more precise and uniform diagnostic
process. Recently, an international collaborative study
has established a now widely accepted 35 classification
model of pediatric and adult ependymomas based on
DNA methylation data of 500 patient-derived primary,
treatment naïve tumor samples.28 The molecular classifi-
cation approach divides ependymal tumors into nine dis-
tinct groups, with three in each anatomical compartment
(SP, PF and ST) of the central nervous system. In each of
these compartments, tumors that were histologically rec-
ognized as grade I subependymomas formed their own
molecular groups labeled SP-SE, PF-SE or ST-SE. The
two remaining groups in the spinal region showed very
good concordance with grade I myxopapillary ependy-
momas and grade II/III ependymomas and were termed
SP-MPE and SP-EPN, respectively. In line with previ-
ous findings, in the posterior fossa region two distinct
molecular groups consisting of both grade II and grade
III ependymomas were identified, which were termed
PF-EPN-A and PF-EPN-B, respectively.29, 30 Within the
supratentorial compartment, ependymomas driven by
distinct gene fusions involving either the NF-κB effector
RELA or the HIPPO signaling regulator YAP1 16 split up
into two molecular groups referred to as ST-EPN-RELA
and ST-EPN-YAP1, respectively. Notably, each of the
nine molecular groups showed different characteristics
regarding copy number aberrations, tumor location, pa-
tient age, and most importantly clinical outcome while
outperforming grading as prognostic marker.28 More de-
tailed analysis of SP-SE, PF-SE and ST-SE revealed an
overall balanced genome apart from a frequent loss of 6q
in the SP-SE and PF-SE groups. All three “molecular”
subependymoma groups were restricted to adults and
were associated with favorable clinical outcome. SP-
MPE and SP-EPN tumors harbored multiple chromo-
somal aberrations with almost all tumors of the SP-EPN
subgroup showing loss of 22q, thus further supporting
previous works that identified loss of the chromosomal
or other proprietary information of the Publisher.
arm 22q or mutations of the NF2 gene located on 22q
as a hallmark and potential driving event of spinal ep-
endymoma.36 Both SP-MPEs and SP-EPNs had a very
good prognosis and were predominantly occurring in
48 Journal of Neurosurgical Sciences February 2018
adults.28 Striking differences regarding molecular char-
acteristics, age and clinical outcome could be observed
between PF-EPN-A and PF-EPN-B tumors. Except for
gain of chromosome arm 1q, which has been repeat-
edly demonstrated to correlate with poor prognosis in
intracranial ependymoma,37-41 copy number aberrations
were almost entirely absent in the PF-EPN-A group. In
stark contrast, PF-EPN-B tumors exhibited drastic copy
number changes, i.e. chromosomal instability, includ-
ing loss of chromosome 6 in almost all cases analyzed.
Furthermore, PF-EPN-A tumors had a dismal prognosis
with a 10-year overall survival of 56% whereas 10-year
overall survival in PF-EPN-B tumors was 88%. While
PF-EPN-A tumors are mainly diagnosed in infants and
children, PF-EPN-B tumors are predominantly found
in adolescents and adults.28-30 Molecular subgroups of
the supratentorial compartment, ST-EPN-YAP1 and ST-
EPN-RELA, demonstrated focal aberrations and local
chromothripsis events on chromosome arm 11q, respec-
tively, resulting in formation of different fusion genes
with C11orf95 fused to RELA (in ST-EPN-RELA) and
YAP1 fused to MAMLD1 (in ST-EPN-YPA1) being the
most frequent ones. ST-EPN-RELA, accounting for
more than 70% of supratentorial ependymomas, primar-
ily occurred in children and young adults and were asso-
ciated with a poor 10-year overall survival of only 50%.
On the contrary, ST-EPN-YAP1 tumors occurred in very
young children only and seem to have a markedly favor-
able prognosis.
A retrospective analysis of a large series of posterior
fossa ependymomas (N.=820 cases) found that patients
with either PF-EPN-A or PF-EPN-B tumors benefit
from gross total resection. PF-EPN-A tumors, for which
no complete resection could be achieved, are associated
with a particularly poor prognosis, even if followed by
radiation therapy.42 Since PF-EPN-A tumors mostly
affect infants and are predominantly laterally located,
experience of the neurosurgeon is regarded as a cru-
cial factor.35 Notably, the above mentioned retrospec-
tive study also demonstrated that many patients with
completely resected PF-EPN-B tumors did not have a
relapse of their disease, even in the absence of radio-
therapy, potentially suggesting therapy de-escalation
strategies for this group in the framework of clinical
trials.35 There is not enough evidence for distinct treat-
ment recommendations in ST-EPN-RELA and ST-EPN-
YAP1 tumors yet but molecularly informed prospective
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
Epidemiology, molecular classification and WHO grading of ependymoma HÜBNER
as well as retrospective analyses of international trial
cohorts are expected to pinpoint promising therapeutic
strategies soon.
Taken together, there is sufficient evidence that ep-
endymal tumors from different compartments of the
central nervous system are biologically distinct with
additional phenotypically divergent groups within each
anatomic compartment. The differentiation between
histologically defined grade II versus grade III/anaplas-
tic ependymomas is inter-observer dependent and as
such of only limited utility for clinical decision-making.
Future clinical trials should assess molecular profiles
of ependymal tumors to allow for clinicobiologic risk
stratification. Current consensus review supports maxi-
mal safe microneurosurgical removal followed by local
radiotherapy for PF-EPN-A ependymoma in patients
over the age of 12 months. In contrast, a subset of PF-
EPN-B ependymoma patients who undergo gross total
resection might even be cured in the absence of radio-
therapy, which has to be further evaluated in a clinical
trial in these patients. Clinical characteristics of mo-
lecular groups of supratentorial ependymoma require
additional investigation before specific treatment rec-
ommendations can be evaluated in clinical trials. Sig-
nificant improvement of outcome in patients suffering
from the rare entity ependymoma necessitates exten-
sive co-operation between all stakeholders, i.e. neuro-
oncologists, neurosurgeons, neuro-radiologists, neuro-
pathologists, radiation oncologists, and basic scientists,
as well as advanced levels of experience of individuals
treating these patients.
References
1. Villano JL, Parker CK, Dolecek TA. Descriptive epidemiol-
ogy of ependymal tumours in the united states. Br J Cancer
2013;108:2367-71.
2. Vera-Bolanos E, Aldape K, Yuan Y, Wu J, Wani K, Necesito-Reyes
MJ, et al. Clinical course and progression-free survival of adult intrac-
ranial and spinal ependymoma patients. Neuro Oncol 2015;17:440-7.
3. Ruda R, Gilbert M, Soffietti R. Ependymomas of the adult: Molecular
biology and treatment. Curr Opin Neurol 2008;21:754-61.
4. US Cancer Statistics Working Group. United States Cancer Statistics:
1999-2014 Incidence and Mortality-web-based Report. Atlanta: US
Department of Health and Human Services, Centers for Disease Con-
trol and Prevention and National Cancer Institute; 2017 [Internet].
or other proprietary information of the Publisher.
Available from www.cdc.gov/uscs [cited 2017, Sep 6].
5. Kilday JP, Rahman R, Dyer S, Ridley L, Lowe J, Coyle B, et al.
Pediatric ependymoma: Biological perspectives. Mol Cancer Res
2009;7:765-86.
6. Purdy E, Johnston DL, Bartels U, Fryer C, Carret AS, Crooks B,
et al. Ependymoma in children under the age of 3 years: A report
Vol. 62 - No. 1 Journal of Neurosurgical Sciences 49
from the canadian pediatric brain tumour consortium. J Neurooncol
2014;117:359-64.
7. Yao Y, Mack SC, Taylor MD. Molecular genetics of ependymoma.
Chin J Cancer 2011;30:669-81.
8. Jain A, Amin AG, Jain P, Burger P, Jallo GI, Lim M, et al. Sube-
pendymoma: Clinical features and surgical outcomes. Neurol Res
2012;34:677-84.
9. Scheithauer BW. Symptomatic subependymoma. Report of 21 cases
with review of the literature. J Neurosurg 1978;49:689-96.
10. Rushing EJ, Cooper PB, Quezado M, Begnami M, Crespo A, Smir-
niotopoulos JG, et al. Subependymoma revisited: Clinicopathologi-
cal evaluation of 83 cases. J Neurooncol 2007;85:297-305.
11. Mack SC, Agnihotri S, Bertrand KC, Wang X, Shih DJ, Witt H, et al.
Spinal myxopapillary ependymomas demonstrate a warburg pheno-
type. Clin Cancer Res 2015;21:3750-8.
12. Cimino PJ, Agarwal A, Dehner LP. Myxopapillary ependymoma in
children: A study of 11 cases and a comparison with the adult experi-
ence. Pediatr Blood Cancer 2014;61:1969-71.
13. Wang H, Zhang S, Rehman SK, Zhang Z, Li W, Makki MS, et al.
Clinicopathological features of myxopapillary ependymoma. J Clin
Neurosci 2014;21:569-73.
14. Fassett DR, Pingree J, Kestle JR. The high incidence of tumor dis-
semination in myxopapillary ependymoma in pediatric patients.
Report of five cases and review of the literature. J Neurosurg
2005;102:59-64.
15. Pfister S, Hartmann C, Korshunov A. Histology and molecular pa-
thology of pediatric brain tumors. J Child Neurol 2009;24:1375-86.
16. Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD,
Li Y, et al. C11orf95-rela fusions drive oncogenic nf-kappab signal-
ling in ependymoma. Nature 2014;506:451-5.
17. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. Who classifica-
tion of tumours of the central nervous system. Fourth Edition. Lyon:
International Agency For Research On Cancer; 2016.
18. Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Con-
formal radiotherapy after surgery for paediatric ependymoma: A pro-
spective study. Lancet Oncol 2009;10:258-66.
19. Merchant TE. Current clinical challenges in childhood ependymoma:
A focused review. J Clin Oncol 2017:JCO2017731265.
20. Khatua S, Ramaswamy V, Bouffet E. Current therapy and the evolv-
ing molecular landscape of paediatric ependymoma. Eur J Cancer
2017;70:34-41.
21. Bouffet E, Perilongo G, Canete A, Massimino M. Intracranial
ependymomas in children: A critical review of prognostic factors
and a plea for cooperation. Med Pediatr Oncol 1998;30:319-29;
discussion 29-31.
22. Cage TA, Clark AJ, Aranda D, Gupta N, Sun PP, Parsa AT, et al. A
systematic review of treatment outcomes in pediatric patients with
intracranial ependymomas. J Neurosurg Pediatr 2013;11:673-81.
23. Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ. The
prognostic value of histological grading of posterior fossa ependymo-
mas in children: A children’s oncology group study and a review of
prognostic factors. Mod Pathol 2008;21:165-77.
24. Ostrom QT, De Blank PM, Kruchko C, Petersen CM, Liao P, Finlay
JL, et al. Alex’s lemonade stand foundation infant and childhood pri-
mary brain and central nervous system tumors diagnosed in the united
states in 2007-2011. Neuro Oncol 2015;16(Suppl 10):x1-x36.
25. Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et
al. Childhood cancer survival in europe 1999-2007: Results of euro-
care-5--a population-based study. Lancet Oncol 2014;15:35-47.
26. Araki A, Chocholous M, Gojo J, Dorfer C, Czech T, Heinzl H, et al.
Chromosome 1q gain and tenascin-c expression are candidate mark-
ers to define different risk groups in pediatric posterior fossa epend-
ymoma. Acta Neuropathol Commun 2016;4:88.
27. Gojo J, Lotsch D, Spiegl-Kreinecker S, Pajtler KW, Neumayer K,
Korbel P, et al. Telomerase activation in posterior fossa group a
ependymomas is associated with dismal prognosis and chromosome
1q gain. Neuro Oncol 2017 Mar 24 [Epub ahead of print].
28. Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F,
et al. Molecular classification of ependymal tumors across all cns
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
HÜBNER Epidemiology, molecular classification and WHO grading of ependymoma

compartments, histopathological grades, and age groups. Cancer Cell
2015;27:728-43.
29. Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al.
Delineation of two clinically and molecularly distinct subgroups of
posterior fossa ependymoma. Cancer Cell 2011;20:143-57.
30. Wani K, Armstrong TS, Vera-Bolanos E, Raghunathan A, Ellison
D, Gilbertson R, et al. A prognostic gene expression signature in in-
fratentorial ependymoma. Acta Neuropathol 2012;123:727-38.
31. Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA,
et al. Decoding the regulatory landscape of medulloblastoma using
DNA methylation sequencing. Nature 2014;510:537-41.
32. Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D,
Ng S, et al. Multiplatform analysis of 12 cancer types reveals
molecular classification within and across tissues of origin. Cell
2014;158:929-44.
33. Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G,
Pietsch T, et al. Histopathological grading of pediatric ependymoma:
Reproducibility and clinical relevance in european trial cohorts. J
Negat Results Biomed 2011;10:7.
34. Godfraind C. Classification and controversies in pathology of epend-
ymomas. Childs Nerv Syst 2009;25:1185-93.
35. Pajtler KW, Mack SC, Ramaswamy V, Smith CA, Witt H, Smith A, et
al. The current consensus on the clinical management of intracranial
ependymoma and its distinct molecular variants. Acta Neuropathol
2017;133:5-12.
36. Ebert C, Von Haken M, Meyer-Puttlitz B, Wiestler OD, Reifenberger
G, Pietsch T, et al. Molecular genetic analysis of ependymal tumors.
Nf2 mutations and chromosome 22q loss occur preferentially in in-
tramedullary spinal ependymomas. Am J Pathol 1999;155:627-32.
37. Mendrzyk F, Korshunov A, Benner A, Toedt G, Pfister S, Radlwim-
mer B, et al. Identification of gains on 1q and epidermal growth factor
receptor overexpression as independent prognostic markers in intrac-
ranial ependymoma. Clin Cancer Res 2006;12:2070-9.
38. Kilday JP, Mitra B, Domerg C, Ward J, Andreiuolo F, Osteso-Ibanez
T, et al. Copy number gain of 1q25 predicts poor progression-free
survival for pediatric intracranial ependymomas and enables patient
risk stratification: A prospective european clinical trial cohort analy-
sis on behalf of the children’s cancer leukaemia group (cclg), societe
francaise d’oncologie pediatrique (sfop), and international society for
pediatric oncology (siop). Clin Cancer Res 2012;18:2001-11.
39. Godfraind C, Kaczmarska JM, Kocak M, Dalton J, Wright KD,
Sanford RA, et al. Distinct disease-risk groups in pediatric su-
pratentorial and posterior fossa ependymomas. Acta Neuropathol
2012;124:247-57.
40. Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M,
et al. Molecular staging of intracranial ependymoma in children and
adults. J Clin Oncol 2010;28:3182-90.
41. Massimino M, Buttarelli FR, Antonelli M, Gandola L, Modena P, Gi-
angaspero F. Intracranial ependymoma: Factors affecting outcome.
Future Oncol 2009;5:207-16.
42. Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler
KW, et al. Therapeutic impact of cytoreductive surgery and irradia-
tion of posterior fossa ependymoma in the molecular era: A retrospec-
tive multicohort analysis. J Clin Oncol 2016;34:2468-77.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Article first published online: September 8, 2017. - Manuscript accepted: July 17, 2017. - Manuscript received: July 10, 2017.
or other proprietary information of the Publisher.

50 Journal of Neurosurgical Sciences February 2018