ependymoma (1)

8/17/14 Ependymoma

www.uptodate.com.proxy-ub.rug.nl/contents/ependymoma?topicKey=ONC%2F5224&elapsedTimeMs=0&source=search_result&searchTerm=ependymoma+ad 1/15

Official reprint from UpToDate www.uptodate.com 2014 UpToDate

AuthorMark W Kieran, MD, PhD

Section EditorsJay S Loeffler, MDPatrick Y Wen, MDAmar Gajjar, MD

Deputy EditorApril F Eichler, MD, MPH

Ependymoma

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jul 2014. | This topic last updated: Mar 17, 2014.

INTRODUCTION Ependymomas are an uncommon group of glial tumors that typically arise within or adjacent to the ependymal lining of the ventricular system [1].

Ependymomas occasionally occur within the brain parenchyma or outside the central nervous system (CNS).

Ependymomas account for less than 10 percent of tumors arising in the central nervous system (CNS) and 25 percent of primary tumors originating in the spinal cord.

The clinical presentation and management of ependymomas arising in the brain will be reviewed here. Ependymomas arising in the spinal cord are discussed

separately. (See "Spinal cord tumors".)

EPIDEMIOLOGY

Age and anatomic location The incidence of ependymomas is approximately equal in males and females. The median age at diagnosis in children is five years

of age, and 25 to 40 percent of patients are less than two years old.

The fourth ventricle is the most common infratentorial site and extension into the subarachnoid space occurs frequently, sometimes with encasement of the medulla

and upper cervical cord. Supratentorial lesions can be either intraventricular, typically in the lateral ventricles, or parenchymal.

The typical locations in which ependymomas arise differ depending upon patient age:

Risk factors The etiologic factors responsible for the development of ependymoma are not known. A link to exposure to simian virus 40 was postulated based upon

identification of the virus in tumor tissue. However, a causal relationship has not been confirmed, and SV40 is no longer considered either a risk factor or an etiologic

agent in the development of ependymoma. (See "Risk factors for brain tumors", section on 'Viral infection'.)

There is an increased association of intramedullary spinal cord ependymoma in patients with neurofibromatosis type II (NF2) [3,4], although abnormalities in the NF2

gene have not been identified in the majority of sporadic ependymoma patients [5].

PATHOLOGY

Classification In the World Health Organization (WHO) classification of brain tumors, ependymal tumors are divided into four major subtypes: myxopapillary

ependymoma (WHO grade I), subependymoma (WHO grade I), classic ependymoma (WHO grade II), and anaplastic ependymoma (WHO grade III) (table 1) [6]. (See

"Classification of gliomas".)

Ependymoma Ependymomas are generally slow-growing tumors of children and young adults and are usually classified as classic ependymoma or WHO

grade II and anaplastic ependymoma or WHO grade III. These tumors can occur anywhere in the ventricular system or spinal canal; they are most common in the

fourth ventricle and spinal cord. Ependymomas are usually well demarcated with frequent areas of calcification, hemorrhage, and cysts. The tumor cells often form

ependymal rosettes, which are diagnostic but not always present. Ependymomas are divided into cellular, papillary, clear cell, and tanycytic subtypes. Further

classification of ependymomas into additional subtypes is probable, based at least in part upon advances in understanding the molecular biology of these tumors [7].

There is considerable controversy regarding the prognostic significance of ependymoma grade (grade II versus grade III). While some reports have indicated a poorer

prognosis for anaplastic ependymoma (grade III), this has not been confirmed in most studies, the majority of which were performed retrospectively. Variability in the

histologic differentiation of classic from anaplastic ependymoma between neuropathologists may account for these results [8]. In a large molecular analysis of 379

patient samples, nestin expression was correlated with a poor prognosis and was more accurate than histologic grading in predicting outcome [9].

Subependymoma Subependymomas are rare tumors found in the fourth or lateral ventricles of adults [6]. Subependymomas are more common in males.

These lesions are usually slow growing and histologically appear benign.

Myxopapillary ependymoma Myxopapillary ependymomas are slow-growing tumors that typically are found in young adults and are more common in males.

These tumors arise almost exclusively in the conus medullaris and filum terminale. Molecular analysis suggests that adult and pediatric tumors differ [10]. (See

"Spinal cord tumors", section on 'Myxopapillary ependymoma'.)

Ependymoblastoma (ETANTR) Ependymoblastomas are highly malignant tumors most commonly seen in infants. Although ependymoblastomas formerly

were considered a variant of ependymoma, these tumors are now classified in the group of primitive neuroectodermal tumors (PNETs) and are referred to as

embryonal tumors with abundant neuropil and true rosettes (ETANTR). Ependymoblastomas were included in some early series describing the natural history of

ependymoma and accounted for many of the cases of leptomeningeal dissemination previously associated with this tumor (See "Uncommon brain tumors", section on

'Embryonal tumors with multilayered rosettes (ETMR)'.)

Molecular pathogenesis Genetic changes are common in ependymomas and may vary based on anatomical location [11-21].

One comprehensive genomic study divided ependymoma into three distinct subgroups based upon site of origin (supratentorial, posterior fossa, and spinal cord) and

suggested the presence of molecular subgroups within each anatomical location [22]. Another group documented two easily distinguishable molecular subgroups

within posterior fossa tumors that have prognostic implications [23]. The poor prognostic subgroup, found predominantly in infants, exhibited a CpG island methylator

phenotype and transcriptional silencing of the polycomb repressive complex 2, leading to repressed expression of differentiation genes [24].

In supratentorial ependymomas, a novel oncogenic fusion between RELA, the principal effector of NF-B signalling, and C11orf95, a poorly characterized gene also

In children, approximately 90 percent of ependymomas are intracranial, including 60 percent located in the posterior fossa, while the remainder arise in the

spinal cord. Infratentorial ependymomas are most common in children under the age of three [2].

In contrast, approximately 75 percent of ependymomas in adults arise within the spinal canal.

8/17/14 Ependymoma


located on chromosome 11, has been identified [25]. This genetic alteration was present in 29 out of 41 supratentorial tumors and zero out of 64 posterior fossa

tumors examined. Another group found the same alteration in 14 out of 18 supratentorial ependymomas [26].

Prospective confirmation of these data is needed, but an understanding of the molecular pathogenesis may eventually allow clinicians to specifically target therapies

to distinct molecular subgroups of ependymoma [27].

CLINICAL PRESENTATION The clinical presentation of patients with ependymoma depends upon the location of the tumor:

DIAGNOSIS The differential diagnosis for tumors that present in the posterior fossa includes medulloblastoma, astrocytoma, and brainstem or choroid plexus

tumors. In the supratentorial location, glial tumors, PNETs, and choroid plexus carcinoma or papilloma should be considered.

The appearance of these tumors on preoperative magnetic resonance imaging (MRI) or computed tomography (CT) may suggest the diagnosis of ependymoma. On

MRI, these tumors have a hypointense appearance on T1, and are hyperintense on T2 or proton density images; gadolinium enhancement is usually prominent (image

1A-D) [30]. Extension into the foramen of Luska is commonly observed. The CT appearance is often hyperdense with homogeneous enhancement; cysts and

calcifications are common. The presence of calcifications within a tumor located in the fourth ventricle is highly suggestive but not diagnostic of ependymoma.

A subependymoma should be suspected in adults who present with a long clinical history and evidence of a non-enhancing, well-demarcated, nodular intraventricular

tumor that is isodense on CT, and isointense in T1 and hyperintense in T2-weighted images on MRI [31,32].

The diagnosis of ependymoma requires histologic confirmation. Because gross total resection is so important, we favor open surgery and not stereotactic biopsy for

most patients. Biopsy is recommended in adult patients where the diagnosis is in question.

All patients should have MRI of the entire neuraxis to exclude metastatic disease, since up to 10 percent of patients have evidence of spinal seeding (image 2).

Cerebrospinal fluid cytology is important for staging for patients with posterior fossa lesions and those with anaplastic tumors. Ideally, CSF should be obtained from

either the lumbar site presurgery, which often is contraindicated due to obstructive hydrocephalus, or one to two weeks postoperatively. The prognostic significance of

ventricular or cisternal fluid is not well defined. Although uncommon, the presence of metastatic disease significantly affects both treatment and prognosis. One third

of patients with metastatic disease may be identified only on the basis of positive CSF cytology [33].

TREATMENT The initial treatment for patients with ependymoma arising in the brain consists of maximal safe resection, which is usually followed by adjuvant

radiotherapy. Chemotherapy does not appear to play an important role in the management of these tumors in adults and older children, but may in young children [34]

or in patients with bulk residual disease.

Until better molecular prognostic markers are available, current therapeutic approaches continue to focus on the degree of resection as the major determinant of

treatment. Incompletely resected ependymomas of either grade (II or III) require a short course of chemotherapy followed by second-look surgery if there is residual

signal, followed by conformal radiation therapy. Ependymomas of either grade that achieve a complete resection up-front should go directly to conformal radiation

therapy. An exception to these approaches should only occur in the context of approved prospective clinical trials.

Because of the complexity involved in these cases, patients with ependymomas should be referred to highly specialized centers whenever possible.

Treatment of spinal cord ependymal tumors is reviewed elsewhere. (See "Spinal cord tumors", section on 'Ependymomas'.)

Surgery There are no randomized trials evaluating the extent of surgery. Observational data indicate that patients undergoing gross total resection have a better

prognosis than those in whom only a partial resection is possible [35-41]. Resection is particularly problematic for lesions of the posterior fossa, which are in close

proximity to cranial nerves and the brainstem, where there is a significant risk of long-term neurologic dysfunction with gross total resection. (See 'Prognostic factors'

below.)

Radiation therapy The role of adjuvant radiation therapy (RT) following surgery depends upon the anatomic location of the tumor, its histology, and the extent of

resection.

Ependymoma Postoperative RT is the standard of care following complete resection for most patients with posterior fossa and supratentorial ependymomas in

order to reduce the likelihood of recurrence in the tumor bed. However, in young children, RT can cause severe neurocognitive impairment and other radiation-induced

complications. Chemotherapy is being studied as a way to postpone or completely avoid the need for RT. (See 'Chemotherapy' below.)

Retrospective data indicate that patients with supratentorial non-anaplastic tumors who have gross tumor resection with a wide margin of normal tissue may do well

without adjuvant RT, and the role of adjuvant RT in this setting remains controversial [41,44-46]. Because most recurrences are local, patients who recur can often be

salvaged with further surgery and postoperative RT.

The amount of normal tissue to be included in the RT treatment volume of posterior fossa ependymoma and anaplastic supratentorial ependymoma has been a source

Most patients with posterior fossa lesions have evidence of increased intracranial pressure [28]. As a result, headache, nausea and vomiting, ataxia, vertigo, and

papilledema are common at presentation. Cranial nerve palsies are also common, especially involving cranial nerves VI to X. Brainstem invasion may occur. (See

"Evaluation and management of elevated intracranial pressure in adults", section on 'Clinical manifestations'.)

Seizures or focal neurologic deficits are common presentations when the tumors arise in the supratentorial compartment.

Tumors involving the spinal cord present with deficits due to involvement of ascending or descending nerve tracts or the exiting peripheral nerves. Specific

abnormalities are related to the anatomic level of the tumor. (See "Spinal cord tumors".)

Dissemination of tumor through the cerebrospinal fluid (CSF) is observed in less than 10 percent of patients at diagnosis when ependymoblastomas (ETANTR)

are excluded [29]. The incidence is higher with infratentorial ependymomas compared to supratentorial tumors (9.0 versus 1.6 percent) [29]. Although historical

data suggested a correlation between high-grade histology (classic grade II versus anaplastic grade III) and spinal seeding, more recent data have not confirmed

this relationship. (See 'Ependymoma' above.)

Cerebellar mutism, also referred to as posterior fossa syndrome, is a recognized complication of posterior fossa surgery and is most common when brainstem

invasion is observed [42]. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma".)

Lesions invading the brainstem can be particularly challenging. Patients with incomplete resections do less well than those with gross total resection. As a

result, many centers consider a second-look operation following chemotherapy in order to achieve macroscopic clearance. (See 'Chemotherapy after partial

resection' below.)

Cerebellopontine angle lesions can often result in significant cranial nerve damage, although, at least in infants, recovery of function may follow successful

resection [43].

8/17/14 Ependymoma


of controversy in the past. Data from observational series have now defined local radiotherapy, using contemporary techniques, as the standard of care.

There are no randomized trials comparing adjuvant RT with observation in patients with ependymoma. However, the outcomes from adjuvant RT are illustrated by a

single-institution series of 153 children with localized ependymoma (80 percent infratentorial), including 85 with anaplastic ependymoma [49]. The median age was

three years. All patients had undergone prior resection, which was complete in 125 (82 percent), and 85 (56 percent) had received prior chemotherapy. After a median

follow-up of five years, the seven-year event-free and overall survival rates were 69 and 81 percent, respectively.

Subependymoma Patients with subependymomas often do well after complete resection alone, underscoring the different natural history of these lesions

compared to other brain ependymomas. Whether RT and/or chemotherapy significantly improve outcome for these patients compared with surgery alone is unclear.

Chemotherapy The use of chemotherapy for patients with ependymoma has been based upon the demonstration of antitumor activity in children with recurrent or

refractory disease. Cisplatin, carboplatin, and etoposide appear to be the most active agents, and higher response rates have been observed with more intense

combination regimens [50-55].

In patients who have undergone partial or gross total surgical resection, chemotherapy has been studied in a variety of settings.

Chemotherapy after partial resection One indication for the use of chemotherapy in ependymoma is in patients with partial resection following initial surgery

[56].

In a cooperative group study of pre-radiation chemotherapy in 35 children with unresectable disease, 40 percent achieved a complete response, 17 percent had partial

response, 29 percent had minor response or stable disease, and 14 percent demonstrated progressive tumor growth [57]. The 5-year overall survival (OS) and event-

free survival (EFS) of all patients was 71 and 57percent. The EFS in the pre-radiation group was comparable to that of patients with no residual tumor who received

irradiation alone (55 versus 58 percent, P=0.45), although the benefit of chemotherapy was restricted to patients with greater than 90 percent tumor resection.

This strongly suggests that limited pre-radiation chemotherapy can be used in patients with incompletely resectable disease, and may be combined with second-look

surgery to improve the EFS and OS prior to focal radiation therapy.

Chemotherapy in lieu of RT Chemotherapy may have a role in delaying or avoiding postoperative cranial irradiation in children less than three years old

[35,36,51,58,59]. There are no randomized trials comparing immediate RT following surgery with a strategy in which surgery is followed by chemotherapy, and RT is

deferred.

The potential role of this approach is illustrated by two cooperative group series:

In a pilot study, five children with anaplastic ependymoma, all under the age of three, were treated with high-dose chemotherapy and stem cell rescue [60]. Four

patients had bulk residual and three presented with metastatic disease. All patients made it to age three without radiation therapy, and only one progression has been

noted at a median follow-up of 45 months.

Additional study is needed to establish the role of chemotherapy as a component of primary treatment in young children with ependymoma, particularly with the

emergence of conformal radiation techniques that have reduced concerns for developmental delay. At present, chemotherapy in place of RT should only be used

within the context of a formal protocol.

Adjuvant chemotherapy after surgery and RT The benefit of adjuvant chemotherapy after surgery and postoperative RT is unclear.

In one report, 19 children (aged 3 to 14 years) underwent postoperative chemotherapy and radiation after subtotal resection of an intracranial ependymoma [61]. The

five-year progression-free survival rate was 74 percent, a value that appears higher than published survival results for radiation alone. In contrast, two small randomized

studies did not support the role of chemotherapy after surgical resection and RT [35,62].

Although the role of chemotherapy remains uncertain, it may be considered with RT in patients with residual tumor following resection.

Treatment of recurrence The long-term prognosis for patients with recurrent disease is poor, and while patients can be palliated for extend periods of time, most

will eventually succumb within years of relapse. Recurrent disease may be due to local failure, distant disease, or a combination of both [63]. While multiple treatment

options are available, it is important that patients and caregivers understand the poor long-term prognosis of patients with recurrent or progressive ependymoma after

radiation therapy. Careful selection of treatment options for these patients can provide excellent palliation and good quality of life; no single option is considered

standard or proven effective.

Outside of a formal clinical trial, each patient should be managed on a case-by-case basis, taking into account their age, location of the original and recurrent

disease, presence of metastases, prior treatment and functional status.

In addition to experimental therapy, multiple approaches have been tried in this population:

Conformal techniques allow irradiation of the tumor bed and an adequate margin of adjacent normal tissue while sparing much of the brain. The current standard

for a dose to the target is at least 54 Gy for lesions in the brain, and higher doses may be recommended for areas with residual macroscopic disease.

Although prophylactic craniospinal irradiation (PCI) was advocated at one time for all resected ependymomas, local recurrence is the predominant site of failure

and PCI does not appear to improve survival [47,48]. More extensive radiation fields are indicated if there is evidence of tumor dissemination based upon

neuroimaging or cerebrospinal fluid cytology.

In a series of 80 children under five years of age who presented without metastatic disease, the initial treatment following maximal surgical resection consisted

of seven cycles of chemotherapy. At a median follow-up of six years, the overall five-year survival was 63 percent, and the five-year event-free survival was 42

percent. Overall, 34 of 80 children (43 percent) required RT for recurrent disease.

In another study, 89 children aged three years or less were treated with combination chemotherapy after maximal surgical resection [59]. Of the 80 patients

without metastatic disease at presentation, 50 eventually relapsed. At a median follow-up of six years, the five-year event-free and overall survival rates were 63

and 42 percent, respectively, and the five-year incidence of avoiding RT was 42 percent.

Aggressive surgical resection may provide effective palliation in some patients. Chemotherapy with or without RT may have a role in reducing residual or

recurrent tumor prior to attempted reresection , all aimed at prolonging the time to further disease progression and death [50,53,64].

Reirradiation of recurrent tumors may be beneficial and has yielded a salvage rate in carefully selected cases [65-68]. Available techniques include stereotactic

radiosurgery (SRS), focal fractionated reirradiation, and craniospinal irradiation, depending upon the location and extent of recurrence [65]. Patients treated with

focal reirradiation remain at risk for the development of disseminated metastases, and recurrence at the primary site eventually occurs in most patients.

High-dose chemotherapy with stem cell rescue has not demonstrated benefit in children with recurrent disease. In a series of 15 cases, five died of treatment-

8/17/14 Ependymoma


Prognostic factors A number of factors affect the likelihood of disease-free survival after treatment of ependymomas arising in the brain:

LONG-TERM OUTCOMES Children who are long-term survivors after treatment for central nervous system tumors are at risk for a number of problems, including

neurocognitive deficits, focal neurologic deficits, growth abnormalities, endocrine abnormalities, and second malignancies. These problems can be due to the damage

originally done by the tumor or the treatment (surgery, RT, and/or chemotherapy) [93-99]. The nature and extent of these problems will be influenced by the location of

the tumor and the specific treatment given. (See "Overview of the management of central nervous system tumors in children", section on 'Long-term morbidity'.)

Adult patients can experience significant long-term morbidity including fatigue, numbness, pain and altered sleep [100].

Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at

www.survivorshipguidelines.org [101].

SUMMARY AND RECOMMENDATIONS Ependymomas arising in the brain are uncommon glial tumors that typically develop within or adjacent to the ependymal

lining of the ventricular system. These tumors are most commonly seen in young children.

There are no published randomized clinical trials to guide the management of patients with ependymoma.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Shuangshoti S, Rushing EJ, Mena H, et al. Supratentorial extraventricular ependymal neoplasms: a clinicopathologic study of 32 patients. Cancer 2005;103:2598.

related toxicities within two months of marrow reinfusion, eight died from progressive disease a median of six months posttransplantation, one has died from

unrelated causes, and one was alive at two years with further disease recurrence [69].

Conventional chemotherapy may provide symptom palliation. In a series of 28 adults with recurrent or progressive intracranial ependymoma, six had an objective

response to chemotherapy; the response rate was higher with platinum-based regimens [70]. Responses are usually short-lived and tumor progression after

chemotherapy alone usually occurs quickly.

In a series of eight adults, six had a partial response to bevacizumab, with a median time to progression of six months [71], although other retrospective series

have not demonstrated significant efficacy [72]. A clinical trial of bevacizumab and irinotecan in 13 children with recurrent or progressive ependymoma also failed

to show significant activity (no objective responses, median time to progression 2.2 months) [73].

There is a growing interest in potential molecular targets for ependymoma, including the epidermal growth factor receptor (EGFR) [74] and c-Kit [75]. Prospective

trials have not yet been performed, and all of these approaches are currently considered investigational.

Extent of resection Approximately 90 percent of recurrences are local, underscoring the importance of a gross total resection to outcome [37,38,76-78].

Although the reported degree of benefit has varied, all studies have indicated that patients who can be treated with gross total resection have a better prognosis

[37,38,76].

Tumor location Comparisons of survival based on tumor location have yielded conflicting results. While at least one study has suggested that supratentorial

tumors have a better survival [79], others have found that patients with infratentorial lesions do better [76]. Involvement of the cervical spinal cord has been

associated with decreased survival due to failures outside the primary site [80].

Histologic grade Higher grade ependymomas are associated with poor outcome in most [80-84] but not all studies [66,85]. In one retrospective review of 80

patients with ependymoma, patients with low and high-grade tumors had a five-year survival rate of 87 and 27 percent, respectively [83]. Better results may

reflect the inclusion of patients with subependymomas while poorer results may reflect including ependymoblastomas in the analyzed series.

Other factors In children, better performance status [86,87] and older age are also associated with better prognosis [78]. Compared to older children, infants

may do less well partly because they have a higher incidence of infratentorial tumors, and partly because they tend not to receive timely adjuvant radiotherapy

due to toxic effects on brain development.

Chromosomal changes Deletion of CDKN2A and gain of chromosome 1 are associated with shorter overall and progression-free survival. In contrast, loss of

chromosome 6 or gains of chromosomes 9, 15, or 18 were associated with significantly better overall and progression-free survival [19].

Adults Two large European multi-institution series that included a total of 222 patients and 123 patients from a single US institution have analyzed the

outcomes and prognostic factors for adults with intracranial ependymomas [88-90]. In these series, the five-year survival rate ranged from 67 to 85 percent, and

the ten-year survival varied from 50 to 77 percent. On multivariate analysis, factors associated with a poor prognosis included high histologic grade, incomplete

surgical resection [91], location [90,92], and a Karnofsky performance status 80 (table 2) [89]. The prognostic importance of incomplete resection has also

been observed in a population-based study of both adults and children with ependymoma using the Surveillance Epidemiology and End Results (SEER)

database [40].

For all patients with ependymoma arising in the brain, we recommend gross total resection, rather than biopsy or subtotal resection, when this can be

accomplished without excessive morbidity (Grade 1C). Observational studies indicate that gross total resection is associated with an improved likelihood of

prolonged survival compared to lesser resections. (See 'Surgery' above.)

For patients with an ependymoma who are older than age one to three years, we recommend adjuvant radiation therapy following complete resection, rather than

observation and salvage therapy if a relapse occurs (Grade 1C). Observation following surgery may be an alternative for patients with a supratentorial non-

anaplastic ependymoma who have undergone a gross total resection with a wide resection margin. (See 'Radiation therapy' above.)

For children less than one to three years of age who have had a complete resection of an ependymoma, we suggest adjuvant three-dimensional conformal

radiation therapy following surgery (Grade 2C). Chemotherapy may represent an alternative to RT following surgery to avoid the neurologic complications of

radiation therapy, but this should be undertaken only in the context of a formal clinical trial. (See 'Radiation therapy' above and 'Chemotherapy' above.)

For all patients with incompletely resected ependymoma arising in the brain, we suggest postoperative chemotherapy followed by second-look surgery in an

attempt to achieve a gross total resection (Grade 2C).

The management of ependymomas arising in the spinal cord is discussed separately. (See "Spinal cord tumors".)

8/17/14 Ependymoma


2. Grill J, Pascal C, Chantal K. Childhood ependymoma: a systematic review of treatment options and strategies. Paediatr Drugs 2003; 5:533.

3. Ebert C, von Haken M, Meyer-Puttlitz B, et al. Molecular genetic analysis of ependymal tumors. NF2 mutations and chromosome 22q loss occur preferentiallyin intramedullary spinal ependymomas. Am J Pathol 1999; 155:627.

4. Pollack IF, Mulvihill JJ. Neurofibromatosis 1 and 2. Brain Pathol 1997; 7:823.

5. Rubio MP, Correa KM, Ramesh V, et al. Analysis of the neurofibromatosis 2 gene in human ependymomas and astrocytomas. Cancer Res 1994; 54:45.

6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. Classification of Tumours of the Nervous System, IARC Press, Lyon, France 2007.

7. Korshunov A, Neben K, Wrobel G, et al. Gene expression patterns in ependymomas correlate with tumor location, grade, and patient age. Am J Pathol 2003;163:1721.

8. Ellison DW, Kocak M, Figarella-Branger D, et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trialcohorts. J Negat Results Biomed 2011; 10:7.

9. Milde T, Hielscher T, Witt H, et al. Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol 2012; 22:848.

10. Barton VN, Donson AM, Kleinschmidt-DeMasters BK, et al. Unique molecular characteristics of pediatric myxopapillary ependymoma. Brain Pathol 2010;20:560.

11. Rousseau A, Idbaih A, Ducray F, et al. Specific chromosomal imbalances as detected by array CGH in ependymomas in association with tumor location,histological subtype and grade. J Neurooncol 2010; 97:353.

12. Reardon DA, Entrekin RE, Sublett J, et al. Chromosome arm 6q loss is the most common recurrent autosomal alteration detected in primary pediatricependymoma. Genes Chromosomes Cancer 1999; 24:230.

13. Mazewski C, Soukup S, Ballard E, et al. Karyotype studies in 18 ependymomas with literature review of 107 cases. Cancer Genet Cytogenet 1999; 113:1.

14. Carter M, Nicholson J, Ross F, et al. Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. Br J Cancer 2002; 86:929.

15. Yokota T, Tachizawa T, Fukino K, et al. A family with spinal anaplastic ependymoma: evidence of loss of chromosome 22q in tumor. J Hum Genet 2003;48:598.

16. Hulsebos TJ, Oskam NT, Bijleveld EH, et al. Evidence for an ependymoma tumour suppressor gene in chromosome region 22pter-22q11.2. Br J Cancer 1999;81:1150.

17. Suarez-Merino B, Hubank M, Revesz T, et al. Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcriptsat 22q12.1-q13.3. Neuro Oncol 2005; 7:20.

18. Huang B, Starostik P, Schraut H, et al. Human ependymomas reveal frequent deletions on chromosomes 6 and 9. Acta Neuropathol 2003; 106:357.

19. Korshunov A, Witt H, Hielscher T, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 2010; 28:3182.

20. Wani K, Armstrong TS, Vera-Bolanos E, et al. A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 2012; 123:727.

21. Yang I, Nagasawa DT, Kim W, et al. Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas. J Clin Neurosci 2012; 19:779.

22. Johnson RA, Wright KD, Poppleton H, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 2010;466:632.

23. Witt H, Mack SC, Ryzhova M, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011; 20:143.

24. Mack SC, Witt H, Piro RM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014; 506:445.

25. Parker M, Mohankumar KM, Punchihewa C, et al. C11orf95-RELA fusions drive oncogenic NF-B signalling in ependymoma. Nature 2014; 506:451.

26. Pietsch T, Wohlers I, Goschzik T, et al. Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-Bsignaling pathway. Acta Neuropathol 2014; 127:609.

27. Atkinson JM, Shelat AA, Carcaboso AM, et al. An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell2011; 20:384.

28. Prayson RA. Clinicopathologic study of 61 patients with ependymoma including MIB-1 immunohistochemistry. Ann Diagn Pathol 1999; 3:11.

29. Vanuytsel L, Brada M. The role of prophylactic spinal irradiation in localized intracranial ependymoma. Int J Radiat Oncol Biol Phys 1991; 21:825.

30. Chen CJ, Tseng YC, Hsu HL, Jung SM. Imaging predictors of intracranial ependymomas. J Comput Assist Tomogr 2004; 28:407.

31. Maiuri F, Gangemi M, Iaconetta G, et al. Symptomatic subependymomas of the lateral ventricles. Report of eight cases. Clin Neurol Neurosurg 1997; 99:17.

32. Sun B, Wang C, Wang J, Liu A. MRI features of intramedullary spinal cord ependymomas. J Neuroimaging 2003; 13:346.

33. Moreno L, Pollack IF, Duffner PK, et al. Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma. J Pediatr Hematol Oncol 2010;32:515.

34. Reni M. Guidelines for the treatment of adult intra-cranial grade II-III ependymal tumours. Forum (Genova) 2003; 13:90.

35. Robertson PL, Zeltzer PM, Boyett JM, et al. Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: a reportof the Children's Cancer Group. J Neurosurg 1998; 88:695.

36. Duffner PK, Krischer JP, Sanford RA, et al. Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 1998;28:215.

37. Healey EA, Barnes PD, Kupsky WJ, et al. The prognostic significance of postoperative residual tumor in ependymoma. Neurosurgery 1991; 28:666.

38. Timmermann B, Kortmann RD, Khl J, et al. Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of theGerman prospective trials HIT 88/89 and HIT 91. Int J Radiat Oncol Biol Phys 2000; 46:287.

39. Rodrguez D, Cheung MC, Housri N, et al. Outcomes of malignant CNS ependymomas: an examination of 2408 cases through the Surveillance, Epidemiology,and End Results (SEER) database (1973-2005). J Surg Res 2009; 156:340.

40. Amirian ES, Armstrong TS, Aldape KD, et al. Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology,and End Results data from 1973 to 2007. Neuroepidemiology 2012; 39:116.

41. Aizer AA, Ancukiewicz M, Nguyen PL, et al. Natural history and role of radiation in patients with supratentorial and infratentorial WHO grade II ependymomas:results from a population-based study. J Neurooncol 2013; 115:411.

42. Doxey D, Bruce D, Sklar F, et al. Posterior fossa syndrome: identifiable risk factors and irreversible complications. Pediatr Neurosurg 1999; 31:131.

43. Sanford RA, Kun LE, Heideman RL, Gajjar A. Cerebellar pontine angle ependymoma in infants. Pediatr Neurosurg 1997; 27:84.

44. Hukin J, Epstein F, Lefton D, Allen J. Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 1998; 29:40.

45. Palma L, Celli P, Mariottini A, et al. The importance of surgery in supratentorial ependymomas. Long-term survival in a series of 23 cases. Childs Nerv Syst2000; 16:170.

8/17/14 Ependymoma


46. Rogers L, Pueschel J, Spetzler R, et al. Is gross-total resection sufficient treatment for posterior fossa ependymomas? J Neurosurg 2005; 102:629.

47. Merchant TE, Fouladi M. Ependymoma: new therapeutic approaches including radiation and chemotherapy. J Neurooncol 2005; 75:287.

48. Taylor RE. Review of radiotherapy dose and volume for intracranial ependymoma. Pediatr Blood Cancer 2004; 42:457.

49. Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 2009; 10:258.

50. Siffert J, Allen JC. Chemotherapy in recurrent ependymoma. Pediatr Neurosurg 1998; 28:314.

51. Grill J, Le Deley MC, Gambarelli D, et al. Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial ofthe French Society of Pediatric Oncology. J Clin Oncol 2001; 19:1288.

52. Chamberlain MC. Salvage chemotherapy for recurrent spinal cord ependymona. Cancer 2002; 95:997.

53. Gornet MK, Buckner JC, Marks RS, et al. Chemotherapy for advanced CNS ependymoma. J Neurooncol 1999; 45:61.

54. Bouffet E, Foreman N. Chemotherapy for intracranial ependymomas. Childs Nerv Syst 1999; 15:563.

55. Fouladi M, Gururangan S, Moghrabi A, et al. Carboplatin-based primary chemotherapy for infants and young children with CNS tumors. Cancer 2009; 115:3243.

56. Van Poppel M, Klimo P Jr, Dewire M, et al. Resection of infantile brain tumors after neoadjuvant chemotherapy: the St. Jude experience. J Neurosurg Pediatr2011; 8:251.

57. Garvin JH Jr, Selch MT, Holmes E, et al. Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Groupprotocol 9942: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012; 59:1183.

58. van Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, et al. Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg2002; 97:827.

59. Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: theUKCCSG/SIOP prospective study. Lancet Oncol 2007; 8:696.

60. Sung KW, Lim do H, Lee SH, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children youngerthan 3 years of age. J Neurooncol 2012; 107:335.

61. Needle MN, Goldwein JW, Grass J, et al. Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood. Cancer 1997; 80:341.

62. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, Finlay JL. Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with orwithout adjuvant CCNU, vincristine, and prednisone: a Childrens Cancer Group study. Med Pediatr Oncol 1996; 27:8.

63. Zacharoulis S, Ashley S, Moreno L, et al. Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis. ChildsNerv Syst 2010; 26:905.

64. Merchant TE. Current management of childhood ependymoma. Oncology (Williston Park) 2002; 16:629.

65. Merchant TE, Boop FA, Kun LE, Sanford RA. A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 2008;71:87.

66. Stafford SL, Pollock BE, Foote RL, et al. Stereotactic radiosurgery for recurrent ependymoma. Cancer 2000; 88:870.

67. Liu AK, Foreman NK, Gaspar LE, et al. Maximally safe resection followed by hypofractionated re-irradiation for locally recurrent ependymoma in children.Pediatr Blood Cancer 2009; 52:804.

68. Bouffet E, Hawkins CE, Ballourah W, et al. Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol BiolPhys 2012; 83:1541.

69. Mason WP, Goldman S, Yates AJ, et al. Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranialependymoma--a report of the Children's Cancer Group. J Neurooncol 1998; 37:135.

70. Brandes AA, Cavallo G, Reni M, et al. A multicenter retrospective study of chemotherapy for recurrent intracranial ependymal tumors in adults by the GruppoItaliano Cooperativo di Neuro-Oncologia. Cancer 2005; 104:143.

71. Green RM, Cloughesy TF, Stupp R, et al. Bevacizumab for recurrent ependymoma. Neurology 2009; 73:1677.

72. Couec ML, Andr N, Thebaud E, et al. Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. PediatrBlood Cancer 2012; 59:34.

73. Gururangan S, Fangusaro J, Young Poussaint T, et al. Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a PediatricBrain Tumor Consortium study. Neuro Oncol 2012; 14:1404.

74. Mendrzyk F, Korshunov A, Benner A, et al. Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markersin intracranial ependymoma. Clin Cancer Res 2006; 12:2070.

75. Zavalhia LS, Romitti M, Netto GC, et al. Evaluation of the expression of C-kit (CD117) in ependymomas and oligodendrogliomas. Dis Markers 2012; 33:61.

76. Mansur DB, Perry A, Rajaram V, et al. Postoperative radiation therapy for grade II and III intracranial ependymoma. Int J Radiat Oncol Biol Phys 2005; 61:387.

77. McLaughlin MP, Marcus RB Jr, Buatti JM, et al. Ependymoma: results, prognostic factors and treatment recommendations. Int J Radiat Oncol Biol Phys 1998;40:845.

78. Bouffet E, Perilongo G, Canete A, Massimino M. Intracranial ependymomas in children: a critical review of prognostic factors and a plea for cooperation. MedPediatr Oncol 1998; 30:319.

79. Horn B, Heideman R, Geyer R, et al. A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J PediatrHematol Oncol 1999; 21:203.

80. Shu HK, Sall WF, Maity A, et al. Childhood intracranial ependymoma: twenty-year experience from a single institution. Cancer 2007; 110:432.

81. Korshunov A, Golanov A, Sycheva R, Timirgaz V. The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in themicroneurosurgical era: an analysis of 258 patients. Cancer 2004; 100:1230.

82. Vanuytsel LJ, Bessell EM, Ashley SE, et al. Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy. Int J Radiat Oncol Biol Phys1992; 23:313.

83. Schwartz TH, Kim S, Glick RS, et al. Supratentorial ependymomas in adult patients. Neurosurgery 1999; 44:721.

84. Schild SE, Nisi K, Scheithauer BW, et al. The results of radiotherapy for ependymomas: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys 1998;42:953.

85. Ernestus RI, Schrder R, Sttzer H, Klug N. The clinical and prognostic relevance of grading in intracranial ependymomas. Br J Neurosurg 1997; 11:421.

86. Ross GW, Rubinstein LJ. Lack of histopathological correlation of malignant ependymomas with postoperative survival. J Neurosurg 1989; 70:31.

87. Stben G, Stuschke M, Kroll M, et al. Postoperative radiotherapy of spinal and intracranial ependymomas: analysis of prognostic factors. Radiother Oncol1997; 45:3.

8/17/14 Ependymoma


88. Reni M, Brandes AA, Vavassori V, et al. A multicenter study of the prognosis and treatment of adult brain ependymal tumors. Cancer 2004; 100:1221.

89. Metellus P, Barrie M, Figarella-Branger D, et al. Multicentric French study on adult intracranial ependymomas: prognostic factors analysis and therapeuticconsiderations from a cohort of 152 patients. Brain 2007; 130:1338.

90. Armstrong TS, Vera-Bolanos E, Bekele BN, et al. Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience. Neuro Oncol 2010;12:862.

91. Vitanovics D, Blint K, Hanzly Z, et al. Ependymoma in adults: surgery, reoperation and radiotherapy for survival. Pathol Oncol Res 2010; 16:93.

92. Amirian ES, Armstrong TS, Gilbert MR, Scheurer ME. Predictors of survival among older adults with ependymoma. J Neurooncol 2012; 107:183.

93. Broniscer A, Ke W, Fuller CE, et al. Second neoplasms in pediatric patients with primary central nervous system tumors: the St. Jude Children's ResearchHospital experience. Cancer 2004; 100:2246.

94. Spiegler BJ, Bouffet E, Greenberg ML, et al. Change in neurocognitive functioning after treatment with cranial radiation in childhood. J Clin Oncol 2004; 22:706.

95. Duffner PK, Krischer JP, Horowitz ME, et al. Second malignancies in young children with primary brain tumors following treatment with prolonged postoperativechemotherapy and delayed irradiation: a Pediatric Oncology Group study. Ann Neurol 1998; 44:313.

96. Garwicz S, Anderson H, Olsen JH, et al. Second malignant neoplasms after cancer in childhood and adolescence: a population-based case-control study in the5 Nordic countries. The Nordic Society for Pediatric Hematology and Oncology. The Association of the Nordic Cancer Registries. Int J Cancer 2000; 88:672.

97. Stavrou T, Bromley CM, Nicholson HS, et al. Prognostic factors and secondary malignancies in childhood medulloblastoma. J Pediatr Hematol Oncol 2001;23:431.

98. Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl CancerInst 2001; 93:618.

99. Devarahally SR, Severson RK, Chuba P, et al. Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence.Pediatr Hematol Oncol 2003; 20:617.

100. Armstrong TS, Vera-Bolanos E, Gilbert MR. Clinical course of adult patients with ependymoma: results of the Adult Ependymoma Outcomes Project. Cancer2011; 117:5133.

101. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 2004; 22:4979.

Topic 5224 Version 22.0

8/17/14 Ependymoma


GRAPHICS

WHO* classification of primary brain tumors according to histology and grade

Tumor classification Tumor grade (WHO)

Astrocytic tumors

Pilocytic astrocytoma I

Diffuse astrocytoma II

Anaplastic astrocytoma III

Glioblastoma IV

Oligodendroglial and oligoastrocytic tumors

Oligodendroglioma II

Anaplastic oligodendroglioma III

Oligoastrocytoma II

Anaplastic oligoastrocytoma III

Glioblastoma with oligodendroglioma component IV

Ependymal tumors

Subependymoma I

Myxopapillary ependymoma I

Ependymoma II

Anaplastic ependymoma III

Choroid plexus tumors

Choroid plexus papilloma I

Choroid plexus carcinoma III

Neuronal and mixed neuronal-glial tumors

Ganglioglioma I or II

Central neurocytoma II

Filum terminale paraganglioma I

Dysembryoplastic neuroepithelial tumor (DNET) I

Pineal parenchymal tumors

Pineocytoma II

Pineoblastoma IV

Embryonal tumors

Medulloblastoma IV

Supratentorial primitive neuroectodermal tumor (PNET) IV

Atypical teratoid/rhabdoid tumor IV

Menigeal tumors

Meningioma I

Atypical, clear cell, chordoid II

Rhabdoid, papillary, or anaplastic (malignant) III

* WHO: World Health Organization.

Data from: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.). World Health Organization Histological Classification of Tumours of the Central Nervous

System. Lyon: International Agency for Research on Cancer, 2007.

Graphic 55058 Version 8.0

8/17/14 Ependymoma


Posterior fossa ependymoma

A T1 weighted sagittal MR image of the brain without contrast

identifies a large hypointense mass in the posterior fossa (arrow).

Courtesy of Mark Kieran, MD.


8/17/14 Ependymoma

www.uptodate.com.proxy-ub.rug.nl/contents/ependymoma?topicKey=ONC%2F5224&elapsedTimeMs=0&source=search_result&searchTerm=ependymoma+a 10/15


A T2 image demonstrating the ependymoma in the posterior fossa.



8/17/14 Ependymoma



Proton image of the same posterior fossa ependymoma as seen in the

previous images.



8/17/14 Ependymoma



T1 weighted axial MR image demonstrating a posterior fossa lesion

that enhances with gadolinium.



8/17/14 Ependymoma


Metastatic ependymoma

MR image of a spinal cord ependymoma (upper arrow) discovered to

be metastatic to multiple sites within the neuraxis (lower arrows) at

diagnosis.



8/17/14 Ependymoma


Karnofsky performance status scale

Value Level of functional capacity Definition

100 Normal, no complaints, no evidence of disease Able to carry on normal activity and to work; no special care needed

90 Able to carry on normal activity, minor signs or

symptoms of disease

80 Normal activity with effort, some signs or symptoms

of disease

70 Cares for self, unable to carry on normal activity or

to do active work

Unable to work; able to live at home and care for most personal needs;

various degrees of assistance needed

60 Requires occasional assistance, but is able to care

for most needs

50 Requires considerable assistance and frequent

medical care

40 Disabled, requires special care and assistance Unable to care for self; requires equivalent of institutional or hospital care;

disease may be progressing rapidly30 Severely disabled, hospitalization is indicated

although death is not imminent

20 Hospitalization is necessary, very sick, active

supportive treatment necessary

10 Moribund, fatal processes progressing rapidly

0 Dead


8/17/14 Ependymoma


Disclosures: Mark W Kieran, MD, PhD Grant/Research/Clinical Trial Support: GSK [BRAF V600E in pediatric low -grade gliomas(Dabrafenib)]. Jay S Loeffler, MD Nothing to disclose. Patrick Y Wen, MD Grant/Research/Clinical Trial Support: Amgen; Angiochem;Astra Zeneca; Exelixis; Genentech/Roche; GlaxoSmith Kline; Merck; Novartis; Sanofi-Aventis; Vascular Biogenics [all pertaining toneurooncology]. Speaker's Bureau: Merck [neuroonocology]. Consultant/Advisory Boards: Celldex; Genentech/Roche; Midatech; Momenta;Novartis; SigmaTau; Vascular Biogenics [all pertaining to neurooncology]. Amar Gajjar, MD Nothing to disclose. April F Eichler, MD,MPH Equity Ow nership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Employment: Employee ofUpToDate, Inc.

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting througha multi-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures

ependymoma (1)

Documents

ependymoma ependymomas

spinal cord tumors

percent of tumors

ependymal tumors

development of ependymoma

anaplastic ependymoma

classic ependymoma

ependymomas account