AUTHOR INFORMATION

Section 1 of 12

Authored by Tobey MacDonald, MD, Clinical Director of Neuro-Oncology, Children's Hospital National Medical Center; Associate Professor, Department of Pediatric Hematology-Oncology, George Washington University

Tobey MacDonald, MD, is a member of the following medical societies: American Association for Cancer Research, Children's Oncology Group, Pediatric Brain Tumor Consortium, and Society for Neuro-Oncology

Edited by Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Tobey MacDonald, MD
Editor's Email:	Samuel Gross, MD

eMedicine Journal, June 12 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 12

Background: Ependymoma is the third most common brain tumor in children, accounting for approximately 10% of primary central nervous system (CNS) neoplasms. It is a neuroepithelial tumor that arises within, or adjacent to, the ependymal lining of the ventricular system or the central canal of the spinal cord. It tends to invade locally, even if histological appearance is benign. Approximately 90% of tumors are intracranial, with up to 70% occurring in the posterior fossa. With surgery and radiotherapy, the overall 5-year survival rate is approximately 55%; however, survival rates of up to 80% can be achieved. Individual prognosis is most dependent on age and the extent of resection. The role of chemotherapy for infants and patients with postoperative residual disease is currently under investigation.

Pathophysiology: Ependymomas typically arise from the ependymal lining of the ventricular system, most often the floor, roof, or lateral recesses of the fourth ventricle. The most recent evidence suggests that radial glia cells are the stem cells of origin for this disease. Approximately one third of ependymomas are supratentorial, arising from the surface of the lateral or third ventricles; however, they may be entirely extraventricular. They may also occur in the central canal of the spinal cord and in the filum terminale, although the latter site is uncommon in children.

Histologically, ependymoma can be broadly separated into two major subsets, low-grade (cellular) and high-grade (anaplastic). Low-grade ependymoma is well differentiated and lacks mitosis and vascularity. High-grade ependymoma is poorly differentiated and has a high mitotic index, necrosis, calcifications, and endothelial proliferation. Both histological subtypes are locally invasive into adjacent brain. Those in the posterior fossa frequently infiltrate the brain stem, and as many as one third may project through the foramina to involve the medulla and upper spinal cord. Spread via cerebrospinal fluid (CSF) throughout the subarachnoid space is reported, primarily with the higher-grade tumors. Extraneural metastases to liver, lung, or bone are rare.

Frequency:

• In the US: Approximately 140 new cases are reported annually in children younger than 15 years. Ependymoma represents the third most common brain tumor in children, following astrocytoma and medulloblastoma.

• Internationally: In the United Kingdom, an estimated 30-35 new pediatric cases are diagnosed annually. More than 300 new pediatric cases per year are reported in Europe.

Mortality/Morbidity:

• Five-year survival rates: Overall survival rate is approximately 55%. Age and the extent of tumor resection are significant independent predictors of outcome. Five-year survival rate is 25% for infants younger than 1 year, 46% for children aged 1-4 years, and greater than 70% for those older than 5 years. Most patients (as high as 85%) achieve a gross total resection prior to additional therapy because of improved neurosurgical techniques. For those patients in whom complete tumor resection can be achieved, survival rates of 60-80% have been reported following local radiation. In those with partial resection or biopsy only, fewer than 30% respond to currently available best nonsurgical therapy, regardless of age or tumor histology.

• Neurologic damage: Direct distortion and destruction of normal brain tissue by tumor, as well as increased intracranial pressure and surgical trauma, may cause some degree of irreversible neurologic impairment. Also, the volume and location of radiotherapy necessary to treat the tumor may result in cognitive impairment. The expanded use of conformal radiotherapy for localized disease has helped to ameliorate some of these effects.

• Neuroendocrine deficits: Radiotherapy to the hypothalamic-pituitary axis may result in deficits of growth hormone, thyroid hormone, gonadotropin, and adrenocorticotropic hormone.

Race:

• No specific race is predisposed to ependymoma.

Sex:

• The male-to-female ratio is approximately 1:1.

Age:

• The mean age at diagnosis is 5-6 years, while 25-40% of cases occur in children younger than 3 years.

• Spinal cord ependymoma rarely occurs in children younger than 12 years.

CLINICAL

Section 3 of 12

History:

• Initial symptoms are usually nonspecific, nonlocalizing, and related to increased intracranial pressure (ICP).


• • The classic triad of raised ICP consists of morning headaches, vomiting, and lethargy. The classic headache of increased ICP is pain present upon rising, relieved by vomiting, and gradually decreasing during the day.
  
  
  
  • School-aged children more commonly complain of vague, intermittent headaches and fatigue. They may demonstrate declining academic performance and exhibit personality changes.
  
  
  
  • Infants may present with irritability, anorexia, and developmental delay or regression.
  
  
  
• Supratentorial lesions may be associated with seizures and focal cerebral deficits.



• Posterior fossa tumors may lead to cerebellar dysfunction, resulting in balance and gait disturbances that frequently are associated with vomiting and lower cranial nerve findings such as diplopia, facial weakness, tinnitus, vertigo, and hearing loss.



• Spinal cord tumors may cause symptoms of spinal cord compression, such as back pain and loss of bladder and/or bowel control.

Physical:

• Increased ICP findings


• • A funduscopic examination reveals papilledema. Infants may have only optic pallor.
  
  
  
  • Palsy of cranial nerve VI, resulting in the inability to abduct one or both eyes, is common.
  
  
  
  • Infants may demonstrate the setting sun sign, observed as an impaired upgaze and a forced downward deviation of both eyes. Measurement of head circumference in infants with open cranial sutures may reveal macrocephaly.
  
  
  
• Localized deficits in truncal steadiness, upper extremity coordination, and gait may be observed with posterior fossa tumors.



• The inability to deviate both eyes conjugatively (gaze palsy), or the inability to adduct one eye on attempted lateral gaze may be seen with tumor invasion into the brainstem.



• Extension of posterior fossa tumors through the foramina of Luschka may impair function of the lower cranial nerves (primarily VI, VII, VIII, IX, and X).

Causes:

• Epidemiological studies investigating parental occupational exposures, environmental exposures, and maternal nutritional intake have failed to identify linkages with any of the childhood brain tumors.



• DNA sequences similar to SV40 virus and the virus-encoded large T-antigen have been found in several ependymomas, but no conclusions regarding causation have been determined. SV40 and related polyoma viruses can induce ependymoma in monkeys and other mammalian species.

DIFFERENTIALS

Section 4 of 12

Astrocytoma
Medulloblastoma
Meningitis, Aseptic
Meningitis, Bacterial

Other Problems to be Considered:

Arteriovenous malformation
Brainstem glioma
Benign intracranial hypertension (pseudotumor cerebri)
Cerebral abscess or parasitic cyst
Choroid plexus papilloma or carcinoma
CNS lymphoma, leukemic meningitis
Effusion (subdural or epidural)
Ependymoblastoma
Hemangioblastoma
Hemorrhage (intracranial or subarachnoid)
Hydrocephaly, any cause
Midline tumors (germ cell, teratoma)

WORKUP

Section 5 of 12

Imaging Studies:

• Head CT scan with and without contrast


• • This study has greater than 95% sensitivity for detection of brain tumors.

  • On CT scan, hydrocephalus is present in almost all patients.

  • The tumor typically appears as hyperdense and homogeneously contrast-enhancing lesion arising from, or adjacent to, the ventricular system.

  • Cystic areas and calcifications are frequent.
  
  
  
• Head and spine MRI with and without gadolinium


• • These studies must be performed in all patients with CT scan or clinical findings consistent with ependymoma. Other tumors such as medulloblastoma and cerebellar astrocytoma may have similar appearance on CT scans. MRI can be useful in such instances by better demonstrating the anatomic origin and extent of tumor. With MRI, ependymoma is typically noted to be isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images, relative to white matter. Ependymomas commonly show enhancement with gadolinium contrast.
  
  
  
  • MRI is the most sensitive means of detecting spinal cord lesions and should always be performed because of the potential for subarachnoid seeding, which is especially likely from tumors that arise in the posterior fossa.
  
  
  
  • A postoperative MRI is required both for the measurement of the extent of surgical resection and the detection of residual disease.
  
  
  

Procedures:

• Lumbar puncture


• • A CSF cytologic examination is useful for detection of microscopic leptomeningeal dissemination.
  
  
  
  • A CT scan or MRI must be performed prior to the lumbar puncture (LP) to exclude the presence of hydrocephaly. The presence of hydrocephaly would place the patient at risk for herniation as a consequence of the procedure. In general, the LP is deferred up to 2 weeks postoperatively in order to avoid identifying tumor cells that may have been disseminated as a result of surgery.
  
  
  

They vary morphologically from well differentiated with no anaplasia and little polymorphism (cellular or low-grade) to highly cellular lesions with significant mitotic activity, anaplasia, and necrosis, which may resemble glioblastoma multiforme (anaplastic or high-grade).

Historically, they have been classified as cellular, epithelial, papillary, or mixed. This terminology, however, is currently not used anymore. Tumors arising in the conus medullaris and filum terminale are termed myxopapillary because of their unique histopathologic features.

Ependymal rosettes are radially aligned, ependymal elements about a central lumen; although uncommon, they are a diagnostic feature of ependymoma. More common are pseudorosettes, an eosinophilic halo composed of cells with tapering processes surrounding a blood vessel.

Electron microscopy may be useful in the diagnosis by demonstrating true rosettes, microvilli, and cilia on the apical surface. Immunohistochemistry and cytogenetic analysis have not been shown to demonstrate meaningful associations.

TREATMENT

Section 6 of 12

Medical Care:

• Surgery is the initial treatment. Patients with total or near total resections have significantly better survival rates than those in whom the resection is grossly incomplete.

• Radiotherapy remains the standard postoperative therapy. Whether this improves long-term survival remains controversial, especially in infants and those with completely resected tumors, in whom the risk of long-term effects of radiotherapy may outweigh the potential benefits.

• The role of chemotherapy is unknown. Clinical trials evaluating the effectiveness of different chemotherapeutic agents for infants and for sub-totally resected tumors are ongoing. Promising results have been demonstrated with cyclical oral etoposide in recurrent ependymoma, with response rates as high as 83%. However, induction of secondary leukemia in association with chronic use of this regimen has been reported.

• Involved-field radiotherapy


• • Complete resection - 59.4 Gy (infratentorial tumor) and 55.8 Gy (supratentorial tumor) to the original tumor site plus a 1-2 cm margin

  • Subtotal resection - 59.4 Gy to the original tumor site plus a 1-2 cm margin for supratentorial and infratentorial tumors
  
  
  
  • Craniospinal radiation is recommended for those with leptomeningeal dissemination.
  
  
  
• Infants younger than 3 years: Studies attempting to delay or omit radiotherapy by using postoperative chemotherapy are ongoing.



• Chemotherapy


• • Although with current regimens the role of chemotherapy appears limited, measurable responses have been documented.

  • As a single agent, cisplatin has been the most effective in phase II studies (30% response rate).

  • Other platinum compounds such as carboplatin appear less effective.

  • One study has reported significant responses to vincristine and cyclophosphamide combined.

  • Trials investigating the effectiveness of preirradiation chemotherapy using platinum or alkylator-based regimens are ongoing in infants and patients with subtotally resected tumors.
  
  
  

Surgical Care:

• The goal is for gross total or near total resection.



• Posterior fossa tumors are approached through a suboccipital craniotomy and may be incompletely resectable because of infiltration of the floor, the fourth ventricle, or brainstem.



• Supratentorial tumors tend to be large and may be intraventricular, extraventricular, or both. These tumors have a predilection for the frontal, temporal, and parietal lobes and third ventricle. Approach and degree of resection depend on the tumor's size and location.



• A regional, leptomeningeal examination must be examined for metastatic foci.



• Surgical estimates of the extent of resection may not be reliable; therefore, postoperative MRI evaluation for residual disease is required and generally should be performed within 72 hours of surgery to avoid confusion with postsurgical inflammation.



• Posterior fossa tumors often present with obstructive hydrocephaly and may require the placement of a ventriculoperitoneal shunt if primary resection to reestablish CSF flow is unsuccessful.

Consultations:

• Regular team members for the care of all patients include the following:


• • Neurosurgeon

  • Radiation oncologist

  • Pediatric oncologist or neuro-oncologist
  
  
  
  • Neurologist
  
  
  
  • Neuropsychologist
  
  
  
  • Neuroendocrinologist
  
  
  
• As a result of the tumor, therapeutic intervention, or both, some patients may require the assistance of occupational and physical therapists for rehabilitation.

Diet:

• No specific dietary restrictions or requirements exist.



• Patients who develop severe anorexia or weight loss as a result of therapy (particularly infants) may need supplemental nutrition to maintain daily requirements.

Activity:

• No activity restrictions are required unless dictated by underlying neurological deficits.



• Patients with ventriculoperitoneal shunts may be restricted from high-impact sports such as diving.

MEDICATION

Section 7 of 12

The role of chemotherapy in the treatment of ependymoma has not been established.

A number of drugs have been identified with activity against ependymoma in single-agent chemotherapy regimens in phase II trials. Of these, platinum compounds have been the most active (eg, cisplatin is the most effective single agent, with a 30% response rate).

Despite these findings, combination chemotherapeutic regimens for ependymoma have yielded disappointing results. The most encouraging data have been reported in infants using postoperative therapy consisting of cisplatin, cyclophosphamide, etoposide, and vincristine, with deferred radiation (2-y survival rate of 74%).

Current trials are evaluating the benefits of this regimen in older children with postoperative residual disease. At present, no definitive conclusions can be drawn.

An example of the dosing and administration of pre-irradiation chemotherapeutic agents used in a recent investigational protocol for children older than 3 years with postoperative residual disease is provided below.

Drug Category: Antineoplastic agents -- These agents disrupt DNA replication, which inhibits tumor growth and promotes tumor cell death. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), then finally a mitotic cell division (phase M).
The cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy and is the rationale behind current cyclic dosage schedules.
Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Name	Vincristine (Oncovin) -- Plant-derived vinca alkaloid. Acts as a mitotic inhibitor by binding tubulin. Inhibits microtubule formation in the mitotic spindle, causing metaphase arrest.
Pediatric Dose	1.5 mg/m2 (not to exceed 2 mg/dose) rapid infusion IV weekly for a total of 9 doses
Contraindications	Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth syndrome; universally fatal if administered intrathecally; severe constipation and/or peripheral neuropathy are relative contraindications
Interactions	Asparaginase may decrease vincristine clearance; acute pulmonary reactions may occur with concomitant use of mitomycin C; CYP450 3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), or nifedipine increase toxicity secondary to decreased clearance; CYP450 3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Dosage modification required in patients with impaired hepatic function, patients receiving other neurotoxic drugs, or patients with preexisting neuromuscular disease; avoid extravasation

Drug Name	Cisplatin (Platinol) -- Heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation. This leads to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication.
Pediatric Dose	100 mg/m2 IV infusion over 6 h given once every 21 d (cycle) for a total of 4 doses (4 cycles)
Contraindications	Documented hypersensitivity; preexisting renal impairment, hearing impairment, and myelosuppression
Interactions	Aminoglycosides (potentiate ototoxicity), amphotericin B (increased risk of nephrotoxicity), loop diuretics
Pregnancy	D - Unsafe in pregnancy
Precautions	Adequately hydrate patient prior to and for 24 h after cisplatin administration with a sodium chloride–containing solution to promote chloruresis, with mannitol and/or furosemide, to ensure good urine output and decrease the chance of nephrotoxicity; reduce dosage in renal impairment and in infants

Drug Name	Cyclophosphamide (Cytoxan) -- Exerts its cytotoxic effect by alkylation of DNA, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.
Pediatric Dose	1000 mg/m2 IV infusion over 1 h for 2 consecutive d given every 21 d, first dose 24 h after each cisplatin, for a total of 8 doses
Contraindications	Documented hypersensitivity; severe hemorrhagic cystitis
Interactions	Barbiturates, allopurinol, chloramphenicol, imipramine, phenothiazines; succinylcholine (prolonged neuromuscular blockade)
Pregnancy	D - Unsafe in pregnancy
Precautions	Use with caution in patients with bone marrow suppression and impaired renal or hepatic function; modification of dosage may be necessary; myelosuppression, (leukopenia, hemolytic anemia and thrombocytopenia) alopecia, hemorrhagic cystitis, cardiotoxicity (at high doses), impaired fertility, headache, darkening of skin and fingernails; moderate to high emetogenic potential (based on the dose); causes anorexia, diarrhea, stomatitis and mucositis

Drug Name	Etoposide (VePesid, VP-16) -- Glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect through stabilization of the normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks.
Pediatric Dose	100 mg/m2 IV infusion over 1 h, given every 21 d for first 3 d of each cycle, starting 1 h before cisplatin or cyclophosphamide, for a total of 12 doses
Contraindications	Documented hypersensitivity
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Dosage reduction should be considered in patients with low serum albumin, bone marrow suppression, and renal impairment

Drug Category: Antidote, cyclophosphamide-induced hemorrhagic cystitis -- This agent is a detoxifying agent used as a protectant against hemorrhagic cystitis induced by cyclophosphamide.

Drug Name	Mesna (Mesnex) -- In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity. Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Pediatric Dose	360 mg/m2 IV infusion over 1 h with cyclophosphamide, then 360 mg/m2 IV infusion over 3 h, then 360 mg/m2 IV infusion over 1 h every 3 h for 3-5 doses Dose dependent on dose of cyclophosphamide; may be administered as an initial bolus followed by IV continuous infusion, or intermittent IV infusions prior to and following chemotherapy regimen
Contraindications	Documented hypersensitivity
Interactions	May increase warfarin effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Examine morning urine specimen for hematuria prior to cyclophosphamide treatment, if hematuria develops, increase fluid hydration or reduce the dose or discontinue the drug; for children <2 y, use preservative-free mesna to decrease the amount of benzyl alcohol delivered to the infant Does not prevent or alleviate other toxicities associated with ifosfamide or cyclophosphamide; common adverse effects include hypotension, headache, GI toxicity, and limb pain

Drug Category: Colony-stimulating factors -- These agents reduce the duration of neutropenia and the associated risk of infection in patients receiving myelosuppressive chemotherapy. They act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. These agents are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

Drug Name	Filgrastim (Neupogen, G-CSF) -- Granulocyte colony-stimulating factor that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.
Pediatric Dose	5 mcg/kg/d SC beginning 24 h after last dose of cyclophosphamide of each cycle, for 10 d minimum
Contraindications	Documented hypersensitivity to Escherichia coli-derived proteins of G-CSF
Interactions	Do not use 12-24 h before or 24 h after administering cytotoxic chemotherapy since will increase sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer 24 h prior to or 24 h following the administration of chemotherapy; use with caution in patients with gout, psoriasis; monitor patients with preexisting cardiac conditions as cardiac events have been reported in clinical studies; be alert to the possibility of ARDS in septic patients

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Admit only patients who are eligible for investigational chemotherapy.



• Investigational chemotherapy may cause complications such as fever, neutropenia, or suspected infection; therefore, hospitalization may be necessary.

Further Outpatient Care:

• Radiotherapy: After the patient recovers from surgery, daily outpatient radiotherapy should begin. This is generally given for approximately 6 weeks (usual dose is 160-180 cGy per day).



• Physical and neurologic examination


• • Monitoring of clinical response and potential treatment-related side effects should be on a weekly basis during radiotherapy. Protocols using investigational chemotherapy regimens dictate how frequently these examinations are conducted during treatment.
  
  
  
  • Following completion of therapy, assessments are generally performed every 3 months for the first year to 18 months, then every 6 months for the next 2 years, and annually thereafter, provided no interim complications occur.

  • Baseline neuropsychology and developmental testing should be performed at the completion of therapy and annually thereafter.
  
  
  
• Imaging studies


• • An MRI with contrast of the head should be obtained at the completion of radiotherapy and then generally in conjuncture with the physical and neurologic examination schedule or sooner if clinically indicated.
    • Although the optimal timing of posttreatment imaging for the evaluation of both response to therapy and recurrence has yet to be determined, most clinicians agree that routine surveillance should be performed at least every 3-6 months during the first 2 years and every 6-12 months for the following 2-3 years after treatment.

    • Further MRI evaluations at 3- to 5-year intervals may be useful for the detection of late events such as radiation-induced secondary tumors. Investigational chemotherapeutic regimens also may dictate the imaging study schedules.
  
  
  
  • An MRI of the spine should be obtained at the completion of treatment and then once yearly for the first 2 years after therapy, unless there is evidence of leptomeningeal dissemination at diagnosis or during therapy, in which case the frequency of such tests is increased in accordance with the response to treatment. Routine spinal evaluations beyond 2 years from the completion of treatment may not be practical since local recurrences are far more likely than isolated neuraxial disease.
  
  
  
• Laboratory studies: A weekly CBC during radiotherapy (to monitor for hematopoietic toxicity and to determine whether intervention should be carried out to maintain hemoglobin levels at or higher than 9 g/dL to maximize radiation effect) is all that is required unless dictated by investigational chemotherapeutic regimens or clinically indicated.

In/Out Patient Meds:

• No medications are needed unless the patient is enrolled in an investigational chemotherapeutic regimen.



• Dexamethasone may be necessary to reduce the inflammatory response associated with the tumor and/or therapy.

Transfer:

• Transfer the patient to a pediatric center that can provide appropriate MRI imaging studies, neurosurgical intervention, and radiotherapy. Follow-up with a neuro-oncologist may be necessary.

Complications:

• Obstructive hydrocephaly



• Neurologic impairment



• Radiation-induced effects


• • Neurocognitive decline
  
  
  
  • Endocrinologic dysfunction
  
  
  
  • Mineralizing microangiopathy with ischemia or infarct
  
  
  
  • Secondary CNS malignancies
  
  
  
  • Transient headaches, fatigue, nausea, vomiting, and anorexia
  
  
  

Prognosis:

• Extent of tumor resection: Resection is the most important prognostic factor. Patients with gross total and near-total resections have reported survival rates of 51-80%, versus 0-26% in those with subtotal resections (<90% removal of total tumor mass, visible tumor present on MRI).



• Age: Very young patients ( <1 y), unrelated to radiation treatment, have a significantly worse prognosis (5-y survival rate of 25%). The 5-year survival rate for children aged 1-4 years is also significantly less than for children older than 5 years (46% versus >70%). Some promising results utilizing high-dose chemotherapy and delayed or omitted radiotherapy have been recently shown in this age group.



• Other factors: Historically, anaplastic features and supratentorial location have conferred a worse prognosis. More recent reports have largely dismissed histology and tumor location as significant prognostic indicators (with the exception of better outcome observed in spinal cord tumors and myxopapillary tumors of the cauda equina). Metastatic disease is probably a poor prognostic factor; however, patient numbers are too scarce to draw a conclusion.

Patient Education:

• The patient and his/her family members should be referred for psychosocial counseling.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to recognize signs and symptoms consistent with increased intracranial pressure (ICP) associated with ependymoma


• • Ependymoma is often overlooked because signs and symptoms of increased ICP are typically subacute, nonspecific, and nonlocalizing.
  
  
  
  • History of illness for more than 3 months prior to diagnosis is not uncommon.
  
  
  
  • Symptoms associated with raised ICP may be mistaken for more common etiologies such as migraine or tension headache, infectious gastroenteritis, postinfectious syndrome, chronic fatigue, or psychological dysfunction.
  
  
  
• Failure to inform the patient and/or family of the potential risks and benefits associated with therapy (surgery, radiation, chemotherapy)



• Failure to obtain signed, informed consent form, or patient's assent (if age appropriate), if investigating experimental treatment

Special Concerns:

• Childhood immunizations


• • If the patient is undergoing myelosuppressive chemotherapy as part of the treatment plan, then immunizations should be withheld for 1 year from completion of therapy.
  
  
  
  • Attenuated live virus immunizations (measles, mumps, rubella [MMR]; oral polio; varicella) may lead to active disease.
  
  
  
  • Inactivated injectable polio (IPV) should be used for all household contacts requiring polio immunization.
  
  
  
  • IPV; Haemophilus influenzae type B (HIB); and diphtheria, pertussis, and tetanus (DPT) may be given to the patient at any time; however, the recommendation is to defer for 1 year from the completion of myelosuppressive therapy to ensure adequate immune response and protection against acquired disease.
  
  
  
• Varicella exposure: Varicella zoster immune globulin (VZIG) should be administered within 72 hours of varicella exposure to all patients with no prior varicella immunization, documented immuno-protectant titers or past history of infection.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 2-year-old child presents to the emergency department with a 6-week history of fussiness and poor feeding. The infant is now refusing to walk, and on examination, is noted to have optic pallor and the setting sun sign (impaired upgaze and seemingly forced downward deviation of the eyes). Which of the following is the most appropriate initial diagnostic study?

A: Lumbar puncture (LP) for Gram stain, culture, protein, glucose, and myelin basic protein
B: Urine collection for catecholamines
C: Bone scan and skull x-ray series
D: CBC and blood culture
E: Head CT scan with contrast

The correct answer is E: The infant is displaying signs and symptoms suggestive of increased intracranial pressure (ICP). Head CT scan with and without contrast must be performed to evaluate for hydrocephaly, mass, or hemorrhage that may need immediate surgical intervention. In patients suspected of having increased ICP, an LP should not be attempted until the head CT is performed in order to exclude the presence of hydrocephaly. The remaining tests may be necessary to determine the etiology of the raised ICP.

CME Question 2: A 5-year-old child is diagnosed with a posterior fossa ependymoma. Which of the following is an expected complication of the tumor?

A: Metastasis to bone and lung
B: Seizure
C: Obstructive hydrocephaly
D: Anemia and thrombocytopenia
E: Cognitive impairment

The correct answer is C: Ependymomas of the posterior fossa typically arise from the ependymal lining of the fourth ventricle and lead to hydrocephaly due to obstruction of cerebrospinal fluid flow. This tumor is locally invasive. Metastasis to the cerebral hemispheres causing seizure is uncommon, and extraneural metastasis to the bone and lung is rare. Cognitive impairment can be seen following radiation therapy and anemia and thrombocytopenia may occur as a result of chemotherapy administered for this tumor, but these complications are not a direct result of the tumor.

Pearl Question 1 (T/F): The classic triad of symptoms associated with increased intracranial pressure consists of headaches, muscle weakness, and weight loss.

The correct answer is False: The triad consists of morning headaches, vomiting, and lethargy. The classic headache is one that occurs upon rising, is relieved by vomiting, and gradually decreases during the day.

Pearl Question 2 (T/F): The 3 most common brain tumors in children are astrocytoma, medulloblastoma, and ependymoma.

The correct answer is True: The 3 most common brain tumors in children are astrocytoma, medulloblastoma and ependymoma, in order of decreasing frequency.

Pearl Question 3 (T/F): A 7-year-old girl is diagnosed with anaplastic ependymoma of the fourth ventricle. The patient's sex and the tumor's anaplastic characteristics are the two most important prognostic factors.

The correct answer is False: The extent of surgical resection and age are the most important prognostic factors for ependymoma. Patients with gross total or near total resections have a 5-year survival rate of approximately 60-80%, while those with subtotal resections have less than 30%. For patients older than 5 years, the 5-year survival rate is higher than 70%, while those younger than 5 years have a survival rate less than 50%, and infants younger than 1 year currently have a 25% survival rate. Although somewhat controversial, recent reports have dismissed histology and tumor location as having a significant impact on prognosis. Sex has not been confirmed to have any relation to prognosis.

Pearl Question 4 (T/F): An 8-year-old child has an ependymoma that has been completely resected (gross total). Following surgery, the most appropriate management is observation alone with serial MRI evaluations every 3 months.

The correct answer is False: Following gross total resection, recommended treatment is local radiation to the original tumor site and a 1.5-cm margin. Metastatic tumors require more extensive radiotherapy to the neuraxis. To date, chemotherapy has not been demonstrated to be effective. Given the poor prognosis of partial or subtotal resected tumors treated with radiation alone, investigations using chemotherapy are ongoing.

PICTURES

Section 11 of 12

Caption: Picture 1. MRI showing an ependymoma of the fourth ventricle, compressing the cerebellum and brain stem.
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Caption: Picture 2. Sagittal section of an ependymoma of the fourth ventricle.
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Caption: Picture 3. Section displaying typical perivascular pseudorosettes of a benign ependymoma.
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Caption: Picture 4. Section displaying high cellularity, nuclear atypia, and numerous mitoses characteristic of an anaplastic ependymoma.
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BIBLIOGRAPHY

Section 12 of 12

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