VOLUME 28 • NUMBER 4
February 28, 2006
Incidence and Natural History
Ependymomas are among the most common primary
brain tumors of children younger than 5 years of age,
accounting for 10% to 12% of all brain tumors in the pediatric
population and 2.5% of all intracranial gliomas.
Ependymomas are believed to develop from oncogenetic
events, in which ependymal lineage cells arising from the
ventricular lining of the brain and the central canal of the
spinal cord are transformed. These tumors classically show
an age-based site preference, with supratentorial and spinal
compartments more often involved in adults and the
infratentorial compartment more often involved in children.
Ninety percent of ependymomas occur intracranially,
and approximately two thirds of these arise in the posterior
fossa. The mean age at the time of diagnosis is between
3 and 6 years, with more then 25% of ependymomas found
in children under the age of 3 years. Sixty percent of supratentorial
ependymomas are found within the lateral or third
ventricles; the remaining 40% may lie in an extraventricular
cerebral parenchymal location. Ependymomas occur
with equal frequency in both sexes. Most ependymomas
are sporadic tumors, but some may be associated with neurofibromatosis
type 2 (NF2). There are no known causative
agents for ependymomas, although various viruses, such
as SV-40, have been implicated in some studies.
Treatment Modalities for Ependymomas in Children
Krishan Bansal, MD, M Ch, Paul Kongkham, MD, and James T. Rutka, MD, PhD, FRCSC
Learning Objectives: After reading this article, the participant should be able to:
1. Describe the clinical presentation of a child with an intracranial ependymoma.
2. Explain the role of surgery for patients with ependymomas.
3. Recall operative complications that can arise following surgery for posterior fossa ependymomas.
A BIWEEKLY PUBLICATION FOR CLINICAL NEUROSURGICAL
CONTINUING MEDICAL EDUCATION
Category: Neuro-oncology
Key Words: Ependymoma, Supratentorial, Infratentorial, Surgery, Radiation
therapy
Dr. Bansal is a visiting Clinical Fellow, Dr. Kongkham is a Resident
in Neurosurgery, and Dr. Rutka is Professor and Chairman, Division
of Neurosurgery, Suite 1504, Hospital for Sick Children, 555
University Avenue, Toronto, Ontario, Canada, M5G 1X8, and the
Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto,
Ontario;
The authors have disclosed that they have no significant relationships
with or financial interests in any commercial organizations
pertaining to this educational activity.
Wolters Kluwer Health has identified and resolved all faculty conflicts
of interest regarding this educational activity.
Figure 1. Funduscopic image of a 6-year-old boy with supratentorial
ependymoma who presented with nausea, vomiting, and
dysphasia. Gross papilledema was present bilaterally during ocular
examination, indicating raised intracranial pressure. (The same
patient is shown in Figure 4.)
2
The prognosis for patients with ependymoma is linked
to age, with children younger than 3 years of age faring
worse than older children. Posterior fossa ependymomas
grow within the fourth ventricle, but they can extend inferiorly
through the foramen of Magendie, laterally through
the foramen of Luschka, and into the cerebellopontine angle.
These tumors may, rarely, seed along cerebrospinal fluid
(CSF) pathways along the neuraxis. The prognosis is better
for patients with supratentorial ependymomas than
those with infratentorial tumors. Five-year progression-free
survival after treatment in ependymoma ranges from 23%
to 45%, and 5-year survival ranges from 50% to 60% in various
major series. The median time to recurrence is within
2 years after diagnosis. Most recurrences are local.
Clinical Presentation
Ependymomas of the fourth ventricle often cause hydrocephalus
by blocking CSF outflow pathways, with resulting
signs and symptoms of raised intracranial pressure. Funduscopy
must be performed in children with suspected posterior
fossa or supratentorial tumors, because papilledema
is a common finding (Figure 1). Intractable paroxysmal vomiting
not related to a particular time of the day or posture,
often is the first symptom, and it is caused by the tumor’s
attachment to the area postrema of the brainstem. Pressure
on or invasion of the cerebellum or brainstem may result in
long tract signs or lower cranial nerve palsies.
Supratentorial ependymomas may cause focal neurologic
deficits, seizures, and raised intracranial pressure from
Figure 2. A, T1-weighted, gadolinium-enhanced sagittal MRI scan of a 14-year-old girl who presented with a brief history of headache,
nausea, and vomiting. An enhancing, midline posterior fossa tumor is seen. B, One year after surgery and focal radiation therapy, no
residual tumor is identified.
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EDITOR: Ali F. Krisht, M.D.*
University of Arkansas for Medical Sciences
ASSISTANT EDITOR: Cargill Alleyne, Jr., M.D.*
Medical College of Georgia
PRODUCTION ASSISTANT: Ronalda Williams
EDITORIAL BOARD:
Badih Adada, M.D.
Ossama Al-Mefty, M.D.
Rick Boop, M.D.
Evandro de Oliveira, M.D.
Allan Friedman, M.D.
Gerardo Guinto, M.D.
Douglas Kondziolka, M.D.
Jacques Morcos, M.D.
Tom Origitano, M.D.
Nelson Oyesiku, M.D.
Kalmon Post, M.D.
Richard Rowe, M.D.
Martin Weiss, M.D.
M. Gazi Yas¸argil, M.D.
* Dr.Krisht has disclosed that he has no significant
relationships with or financial interests
in any commercial organizations pertaining to
this educational activity.Dr. Alleyne has
disclosed that he is a consultant for Cordis.
A B
mass effect. Headaches usually are intermittent and may
be worse in the morning. CSF dissemination is unusual,
but it can occur in patients presenting with signs of
meningismus or nerve root involvement.
Pathologic Findings
Grossly, ependymomas are grayish-red, often well-circumscribed
tumors. Histologically, they are characterized
by the presence of perivascular pseudorosettes and true
ependymal rosettes of the Homer-Wright type. The World
Health Organization divides ependymomas into three
grades as follows:
• Grade I: subependymoma and myxopapillary ependymoma;
• Grade II: four variants—cellular, papillary, clear, and
tanycytic; and
• Grade III: anaplastic ependymomas.
Microscopic examination demonstrates a predominant
glial pattern studded with islands of cells with epithelial features.
Pseudorosettes, the most common epithelial feature,
appear as eosinophilic zones surrounding blood vessels.
Molecular Biology
Losses of chromosomes 6q, 22q, and the X chromosome and
gains of chromosome 1q or 9q are common in ependymoma.
The 22q abnormality is much more common in spinal ependymomas.
Gain of 1q seen in childhood anaplastic ependymomas
appears to be associated with posterior fossa tumor.
Although both cranial and spinal ependymomas occur
in patients with NF2, the locus involved in sporadic tumors
seems to be different from the NF2 gene locus, because sporadic
tumors harboring 22q loss occur almost exclusively
in the spine. Recently, co-overexpression of certain receptor
tyrosine kinases, ERBB2 and ERBB4, has been demonstrated
to correlate with proliferative indices and worsened
patient prognosis. Although no specific tumor suppressor
gene has been identified for ependymomas, CDKN2A,
CDKN2B, and p14ARF expression often are silenced by
aberrant methylation. Taylor et al. recently have shown that
ependymomas arising in different locations of the neuraxis
may develop from radial glia progenitor cells at these sites
caused by disturbances in separate signaling pathways.
Imaging Findings
Ependymomas typically appear as isodense to heterogeneously
enhancing midline cerebellar or hemispheric
tumors on both CT and MRI scans (Figures 2–4). MR spectroscopy
can be used as an adjunct to MRI in the evaluation
of ependymomas, but its diagnostic utility is still under
investigation. In addition to cranial imaging, an MRI scan
of the spine should be obtained preoperatively to assess the
presence of possible CSF metastases. Postsurgical MRI
should be performed within 48 to 72 hours of surgery to
detect any residual tumor before postsurgical changes occur.
Treatment
Surgical Technique
Posterior fossa ependymomas are removed using modern
microsurgical techniques. Posterior fossa surgery may
be done with the patient in the prone, concord, lateral, or
sitting position. Amidline suboccipital posterior fossa craniotomy
currently is preferred. Blunt, subperiosteal dissection
of the inferior surface of the C1 lamina, progressing to
the superior surface, where the medial portion of the sulcus
arteriosus is identified, reduces the risk of injury to the
vertebral artery.
3
Figure 3. A, T1-weighted, gadolinium-enhanced midline MRI scan
of a 12-year-old boy, who presented with poor school performance
of 6 months duration. A large intraventricular tumor is seen. B,
After surgery and local radiation therapy, the tumor is under good
control 2 years postdiagnosis.
B
A
The dura is opened with a Y-shaped incision reaching to
the limits of the bony confines. At the intersection of the
arms of the Y, brisk venous bleeding from the occipital sinus
may be observed, especially in younger children. This bleeding
usually can be controlled by aggressive bipolar cautery.
Hemostatic clips should be avoided because they cause artifacts
on postoperative images and may lead to future difficulty
with dural repair at these sites. After the dura has
been opened, the arachnoid is opened widely and CSF liberated
to facilitate cerebellar mobilization.
For midline lesions, the cerebellar tonsils are separated
gently, after which the floor of the fourth ventricle is identified
clearly. A cottonoid pad is kept at its outlet (Figure 5).
Once the tumor is exposed, attempts are made to develop
planes laterally around the tumor before central debulking
takes place. For debulking, the ultrasonic aspirator is recommended.
Once further debulking is achieved, attention
is focused on removing the tumor margins, particularly from
the aqueduct, vermis, and hemispheres. Tumor adherent to
the floor of the fourth ventricle should be shaved off in a tangential
plane with the ependymal surface. No attempts should
be made to resect tumor that infiltrates the floor, because
attempts to do so may result in significant morbidity.
After microscopic resection is complete, hemostasis is
achieved under normotensive conditions. A duraplasty is
performed as needed, and fibrin glue is applied to the dural
repair. The bone flap is secured with sutures or miniplates
followed by a multilayered closure encompassing the fascia,
subcutaneous tissue, and skin. Postoperatively, antibiotics
are continued for 24 hours and corticosteroids are
tapered gradually over a period of 5 to 7 days. A contrastenhanced
CT or MRI scan should be obtained within 24
hours for assessment of residual tumor.
Operative Complications
In the past two decades, advances in anesthesia and
microsurgical techniques, along with a better understanding
of microsurgical anatomy, have resulted in a decrease
in postoperative morbidity and mortality. However, some
inherent morbidity in performing posterior fossa surgery
in children remains.
Hydrocephalus develops as either an early or a delayed
postoperative complication, and it must be recognized and
treated. Factors that may predict the need for postoperative
shunting include the patient’s age, the location of the
tumor, the type of tumor, the use of dural substitutes, the
development of a pseudomeningocele, and the extent of
surgical excision. Approximately one third of all patients
will require CSF diversionary procedures at some time.
Meningitis may be seen within the first 1 to 2 weeks following
surgery, prolonging the postoperative course and
adding to morbidity. Bacterial meningitis is more likely to
occur if there has been a CSF leak from the operative wound
after surgery. Occasionally, sterile or “chemical” meningitis
is seen. This may respond to corticosteroid therapy, but
those agents should be used only after bacterial meningitis
has been excluded.
Cerebellar mutism is seen following resection of posterior
fossa tumors in children. The incidence of mutism after
posterior fossa surgery is difficult to establish, but it may
occur in as many as 15% to 20% of cases. The typical presentation
is that of a child who may speak immediately after
surgery only to become mute after the first 24 hours. This
complication probably results from disruption of projection
fibers of the dentatothalamic-cortical pathway. The
mutism usually is self-limiting, with a spontaneous return
of improved speech patterns. However, mutism has been
reported to last as long as 52 months after surgery.
The Role of Surgery in Ependymoma
For ependymomas, the ultimate goal of treatment should
be total microsurgical resection. The extent of surgical resection
has been found to be the most significant determinant
of survival in almost every large pediatric ependymoma
4
Figure 4. A, Gadolinium-enhanced axial MRI scan of the 6-yearold
boy whose funduscopic image of papilledema is shown in Figure
1. A large cystic tumor is seen in the left frontal lobe. B, After
surgery and local radiation therapy, there is no evidence of recurrent
tumor 5 years after diagnosis.
B
A
5
series. Unfortunately, the ability to resect these tumors totally
differs based on their location. Overall, 35% to 50% of posterior
fossa ependymomas can be resected completely, but
only 23% to 40% of those occurring adjacent to the brainstem
in the fourth ventricle can be completely resected safely.
Complete resection is achieved more easily for supratentorial
tumors. Between 60% and 85% of supratentorial
ependymomas can be removed completely. Aggressive
attempts to remove tumors in other locations, including
those involving lower cranial nerves, are associated with
increased morbidity. Sutton et al. reported a 5-year progression-
free survival rate of 80% in patients who underwent
gross total resection of their tumor. However, Vinchon
et al. determined that this survival advantage was reduced
to 48%, 22%, and 0% for near-total resections, partial resections,
and biopsies, respectively. Pollack’s series demonstrated
a sudden drop in 5-year progression-free survivals
from 80% to 8.9% with total and subtotal tumor removal,
respectively. Perilongo et al. retrospectively analyzed 92
children with ependymoma who were enrolled in the Italian
Pediatric Neuro-oncology Group study. For patients
who underwent gross total resection, the 10-year survival
rate was 70%, and the progression-free survival rate was
57%; for patients who had subtotal resection, the 10-year
survival rate was 32%, and the 10-year progression-free survival
rate was only 11%. Robertson et al. prospectively
treated 32 patients and reported a 5-year progression-free
survival rate of 66% for patients with residual tumor measuring
1.5 cm2 or less and 11% for patients with residual
tumor measuring greater than 1.5 cm2. All of their patients
received postoperative radiation therapy.
Vinchon et al. recently reported the results of reoperation
in ependymoma. They achieved total resection in recurrent
cases, describing a survival rate greater than 50% at
74.7 months of follow-up after reoperation. Because maximal
surgical extirpation is critical to long-term outcome, it
is now advocated that a postoperative enhanced MRI scan
be obtained within 48 hours of surgery, with the intention
being to perform a second operation if accessible tumor is
found on the imaging study.
Radiation Therapy for Ependymoma
Mork et al. were the first authors to document that postoperative
radiation therapy improves the outcome in ependymoma.
They reported a 17% survival rate for patients who
underwent resection alone versus 40% for those who received
cranial radiation after surgery. Since then, postoperative
radiation therapy has been considered vital in the treatment
of patients who have undergone surgery for ependymoma.
Radiation therapy can now be given as craniospinal radiation
with a posterior fossa boost, conformal radiation therapy
(CRT), or stereotactic radiotherapy (SRT) and stereotactic
radiosurgery (SRS) as provided with the gamma knife.
Craniospinal radiation with a posterior fossa boost has
been used in the past because of the known tendency for
some ependymomas to metastasize. However, craniospinal
irradiation has serious long-term side effects, the most serious
of which is neurocognitive decline. Therefore, efforts
are being made to eliminate craniospinal irradiation as standard
treatment and instead to deliver fractionated radiotherapy
to the tumor and tumor margins.
CRT initially was developed for the treatment of adults
with prostate and head and neck cancers. This technique
requires three-dimensional imaging (CT and MRI) as part
of the planning process. The successful application of CRT
to ependymoma in children may improve outcomes by
reducing radiation-related treatment effects and as a treatment
option for very young children. Nonetheless, guidelines
for the use of CRT are needed to ensure that the
appropriate volume of the brain receives the prescription
dose and that disease control is not compromised.
SRT typically requires a linear accelerator, with doses of 54
Gy in daily fractions of 1.8 Gy over 6 weeks given via precise
delivery of the radiation dose. SRT usually is administered
with the patient in a stereotactic, relocalizable head frame.
Gamma knife SRS is a noninvasive procedure that delivers
radiation with high precision while sparing normal tissue.
Therapy is given in a single sitting. Astereotactic head
frame first is placed on the patient, and the tumor then is
localized in the three-dimensional stereotactic system by use
of MRI. Dose planning is performed with the GammaPlan
Figure 5. Intraoperative photograph of the patient whose imaging
sequences are shown in Figure 2. The cerebellar tonsils are shown
splayed apart by a vascular midline ependymoma that descends
below the foramen magnum and rests on the dorsal aspect of the
high cervical spinal cord. The tumor was removed through a minimal
split of the cerebellar vermis.
(Elekta Instruments) sophisticated software system. The total
dose ranges from 26 to 42 Gy, depending on the size of the
tumor, including tumor bed and marginal tumor dose. The
drawback of the gamma knife is that it cannot be used for
tumors larger than 3 cm.
The Role of Radiation Therapy in Ependymoma
Duffner et al. found that children with completely
resected ependymoma in whom radiation therapy was
delayed for 2 years experienced a worse outcome than those
in whom therapy was given at 1 year (5-year survival rate,
38% versus 88%, respectively). Hyperfractionated radiation
therapy does not appear to be beneficial for ependymoma.
In a phase II trial of CRT, Merchant et al. documented a
3-year progression-free survival rate of 75% after a median
follow-up of 38.2 months.
Various studies have shown a dose-dependent response
for ependymoma, with a dose threshold of 45 to 50 Gy.
Recent studies have proven that dose escalation in subtotally
resected posterior fossa ependymoma provides favorable
results. Kovner et al. observed a 50% 4-year event-free
survival rate with 69.6 Gy, compared with a 24% 4-year survival
rate after lower-dose radiation. Other studies also
have demonstrated that an increase in radiation dose to the
primary site appears to improve local control. SRS is being
used increasingly in patients with residual, unresectable,
or recurrent ependymoma.
Adjuvant Chemotherapy
Although the role of chemotherapy for ependymoma is
not yet established, it commonly is used in children younger
than 3 years when radiation therapy cannot be given. Various
retrospective and prospective trials have been published
showing minimal benefit in terms of improving
long-term disease-free survival. The main chemotherapeutic
agents used are vincristine, ifosfamide, etoposide, and carboplatin,
in a variety of schedules. Myelosuppression is the
major toxicity noticed during combination chemotherapy.
The development of a multidrug chemotherapy regimen
for primary malignant brain tumors was based on the cellular
heterogeneity within individual tumors.
Most researchers consider ependymoma a chemoresistant
tumor. Overexpression of the multidrug-resistance-1
gene and the 06-methylguanine-DNA methyl transferase
gene has been blamed as possible mechanisms for this phenomenon.
Cisplatin is the only agent that has demonstrated
some value in ependymoma, with a cumulative response
rate of 34%. The Children’s Cancer Study Group protocol
942 was the only randomized trial to compare survival after
radiation alone versus the combination of radiotherapy and
chemotherapy. Outcome was not improved despite combination
therapy.
Current Postoperative Treatment Protocols
Various institutions have approved protocols using different
approaches to the child with intracranial ependymoma.
Some investigators are exploring the efficacy of
pre-irradiation chemotherapy, second-look surgery for residual
tumor, and multiagent chemotherapy followed by craniospinal
radiotherapy.
Conclusion
Local tumor control is single most important prognostic
factor for ependymoma. This is best achieved through gross
total tumor resection whenever possible. If aggressive, total
resection is not possible, long-term control may be achieved
through adherence to state-of-the-art radiation therapy practices.
Chemotherapy with current agents does not appear
to hold much promise. However, it may be useful in the
context of providing the surgeon with an opportunity to
perform further surgery on a tumor that is less vascularized.
It remains important to continue to enroll patients in
current clinical trials.
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From the Editor:
I am very pleased to announce that retroactive to Volume 25, Issue 1, the American Association of Neurological Surgeons
attests that this educational activity has been recognized for co-sponsored/endorsement for 1.5 Category 1 CME credits of
the American Association of Neurological Surgeons’ Continuing Education Award in Neurosurgery.
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8
1. Ependymomas in children are situated more commonly in the
supratentorial than the infratentorial compartment.
True or False?
2. Ependymomas are found more commonly in patients with
neurofibromatosis type 2 than in patients with neurofibromatosis
type 1.
True or False?
3. Patients with infratentorial ependymomas have a better prognosis
for survival than those with supratentorial ependymomas.
True or False?
4. Vomiting due to irritation of the area postrema of the brainstem
can be one of the first presenting symptoms of posterior
fossa ependymomas.
True or False?
5. Cerebellar mutism is caused by interruption of the spinocerebellar
tracts.
True or False?
6. The most significant factor that predicts survival in patients
with intracranial ependymoma is extent of resection.
True or False?
7. Craniospinal irradiation should be used in all patients with
intracranial ependymoma.
True or False?
8. Ependymoma is a chemosensitive tumor.
True or False?
9. Stereotactic radiosurgery may be used for locally recurrent
ependymomas.
True or False?
10. Homer-Wright rosettes are a histopathologic feature of ependymoma.
True or False?
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