Literature Review Paper

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Brain Tumors in Children

Adam J. Fleming, MD, and Susan N. Chi, MD

o a s s

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ntroduction Tumors of the central nervous system (CNS) (in-

cluding the brain and spinal cord) are rare in the pediatric population. However, as a group they make up 25% of all childhood neoplasms and represent the most common solid tumor of childhood. Significant advances in surgery, radiation, and chemotherapy have led to better treatment outcomes over the past decades. Although cure rates have been steadily improving for some types of brain tumors, many challenges remain. In this issue of Current Problems in Pediatric and Adolescent Health Care, we review the epidemiology, clinical presentation, subtypes, treatment options, and recommended follow-up for children with brain tu- mors. We hope that this serves as a useful reference for pediatricians, general practitioners, nursing, and oncology trainees for this small but important group of pediatric patients. In this article, the term “brain tumor” is often used interchangeably with “central nervous system tumor,” which includes tumors of the spinal cord as well. We limit our discussion to that of primary tumors that arise within the CNS; the number of brain lesions in children representing metastatic disease from extracranial sites is extremely low.1 This is in contrast to adult patients, where metastatic disease rep- resents a very common type of tumor in the CNS.2

Statistics and Epidemiology

In the USA, the largest information data sets on childhood brain tumors are available through the National Cancer Institute’s Surveillance Epidemiology End Results Report and through the Central Brain Tumor Registry of the USA (CBTRUS). These 2

From the Department of Pediatric Neuro-Oncology, Dana Farber Can- cer Institute, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Curr Probl Pediatr Adolesc Health Care 2012;42:80-103 1538-5442/$ - see front matter © 2012 Mosby, Inc. All rights reserved.

doi:10.1016/j.cppeds.2011.12.002

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rganizations publish detailed reports that are avail- ble to the public online and provide excellent re- ources for tracking trends on the incidence and urvival by age, geography, race, and tumor type. According to the latest CBTRUS report (February 011), the average annual incidence of brain tumors iagnosed in the 0- to 19-year-old age group is 4.84 er 100,000 population. This includes all primary CNS umors, including those classified as malignant and onmalignant. Based on these data, approximately 150 people under the age of 20 are expected to evelop a primary brain tumor in the USA in 2010.3

The prevalence of primary CNS tumors in children 0-19 years old is estimated at 35.4 per 100,000 population, meaning that over 28,000 children are living with this diagnosis in the USA. The Surveil- lance Epidemiology End Results data report a differ- ence in incidence by race, with primary CNS tumors being more common in whites than blacks (5.02 vs 3.69 per 100,000). A smaller difference was found between males and females, with a slightly higher incidence in males (4.9 vs 4.8 per 100,000).3

References occasionally are made in the news media on the “rising incidence” of brain tumors in children, speculating a link with certain environmental hazards or toxic exposures. Epidemiologic evidence to support these theories does not exist,4 and the actual incidence has not been rising according to the recent CBTRUS analysis.3 There was a measurable rise in the detection of childhood brain tumors associated with the advent of magnetic resonance imaging (MRI) scanning, pre- sumably because of the dramatic increase in the ability to find CNS tumors. Similarly, the incidence of brain tumors is also reported to be slightly higher in the developed world, most likely accountable to the wide- spread availability of MRI technology.

When faced with the devastating news that their child has a brain tumor, most parents want to under- stand why this happened to their child. Most impor-

tantly, parents need reassurance that pediatric brain

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tumors occur sporadically, and this diagnosis was not related in any way to their lifestyle or parenting choices. There are only 2 factors linked to an increased risk of developing a primary CNS tumor in childhood: having a history of receiving significant doses of radiation to the CNS, or having been born with certain genetic syndromes. Because early signs and symptoms of a brain tumor will often mimic common complaints, the primary care clinician must have a higher index of suspicion when caring for these 2 groups of patients.

Brain Tumors Associated with Prior Radiation Exposure. Children who have had prior CNS radia- tion therapy are known to have an increased risk over their lifetime of developing a secondary brain tumor.5

Although meningiomas and malignant gliomas can occur spontaneously in the general population, they also are known to arise as secondary tumors within a radiation treatment field. It is important to recognize that secondary tumors can occur many years or even decades after initial exposure, which should lower the threshold to obtain imaging in patients with such a history. There has been increasing recognition of the radiation exposure from diagnostic imaging studies, such as computerized tomography (CT) scans and X-rays.6 Whether the exposure from medical imaging s significant is a difficult question to answer, but is eing explored in prospective studies. Brain Tumors Associated with Genetic Syn- romes. There are several genetics syndromes that are ssociated with an increased risk for the development f CNS tumors. These children deserve closer moni- oring and attention to warning signs; it is critical that linicians who care for these children are aware of the isk, both in terms of the role for surveillance and for he appropriate investigation of new symptoms. On- ologists also need to be aware that many genetic yndromes can be associated with a higher risk for eveloping secondary malignancies after treatment of he primary tumor, which may influence the choice of hemotherapy or radiation. Neurofibromatosis Type 1. Neurofibromatosis type (NF-1, previously known as von Recklinghausen’s

isease) represents 1 of the most common genetic yndromes in the world.7 It has an autosomal-domi-

nant inheritance pattern and involves a mutation of the gene neurofibromin on chromosome 17. Clinical fea- tures of NF-1 include café au lait spots, Lisch’ nodules (iris hamartomas), neurofibromas, axillary freckling, and bony abnormalities.7 During their lifetime, ap-

roximately 15% of patients with NF-1 will develop a m

Curr Probl Pediatr Adolesc Health Care, April 2012

lial tumor of their optic tract (optic pathway gli- ma).8,9 These are typically low-grade brain tumors hat warrant close observation; the most important ethod of following these patients is by measuring

heir visual fields and acuity. Up to 10% of these umors will become symptomatic, but an optic glioma n a NF-1 patient will usually have a more benign ourse and may even regress spontaneously.9-11 Treat-

ment options should aim to spare neurocognitive function, because baseline deficits are not uncommon in NF-1 patients. These patients also have an increased risk of developing secondary malignancies, as well as radiation-induced vasculopathies, such as moya-moya syndrome.12,13 Aside from optic pathway gliomas,

F-1 patients have an increased chance of developing ther tumors throughout the CNS. Brain MRIs for atients with NF-1 will often show multiple small T2 right, nonenhancing areas called “unidentified bright bjects”; these are not tumors and do not require iopsy or treatment.14

Familial Cancer Predisposition Syndromes. Famil- ial cancer predisposition syndromes are defined by germ line mutations in specific genes that normally function to protect us against the development of cancer. There are now dozens of known inheritable mutations that may increase the risk of cancer in offspring who carry that specific gene. The “Li–Fraumeni syndrome” (LFS) is the prototype of the familial cancer predisposi- tion syndrome. The genetics of LFS were described over 2 decades ago,15 and it involves mutations in the “TP53” tumor suppressor gene on chromosome 17. Normally, this gene acts to encode a DNA repair protein called p53, which functions as a tumor suppressor. Having this p53 mutation will lead to a higher incidence in family members of developing solid tumors (sarcoma, adrenocorticocarcinoma), cancer in younger people (leukemia, breast cancer), and brain tumors (espe- cially choroid plexus carcinomas). Because cancer is already quite common in the general adult popu- lation, criteria to define LFS have been developed, which serve to guide genetic testing strategies and a rational screening program.16,17

The retinoblastoma gene Rb-1 was the first tumor suppressor gene identified, and the development of bilateral retinoblastoma in an individual is often asso- ciated with a germ line mutation in Rb-1. These patients are also at risk of having a tumor in the pineal region with similar histology (called “trilateral” reti- noblastoma)18,19 and for developing other solid tu-

ors (sarcomas) later in life.

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Despite our better understanding of these and other genetic cancer predisposition syndromes, very few children diagnosed with a brain tumor will have a familial cause linked to their cancer. In most patients, taking a detailed family history will guide the need for a genetics referral and possible further testing. Genetic testing should always be arranged in consultation with a Cancer Genetics Program, because the screening implications and the psychological impact of the results can be tremendous for family members.20

Neurofibromatosis Type 2. Neurofibromatosis type 2 NF-2) is due to a mutation in the gene on chromosome 2 that encodes for the protein “Merlin.” Patients with F-2 often will present in the second or third decade of

ife, typically later than in NF-1 patients.21 Like NF-1, he diagnosis is usually made clinically based on first- egree relatives and the finding of bilateral acoustic euromas. Acoustic neuromas are often detected during n evaluation for hearing loss and sometimes can be urgically resected. Patients with F-2 are at increased risk for devel- ping other rare tumors, such as ardiac sarcomas, and they are at articular risk for developing chwannomas, which can transform nto malignant peripheral nerve heath tumors.22

Tuberous Sclerosis. Tuberous sclerosis (TS) is an autosomal- dominant disorder linked to 2 genes, TSC1 (chromosome 9) and TSC2 (chromosome 16). Patients can develop wide- spread hamartomatous lesions, which lead to multiple organ problems. Cognitive delay and seizures are common, and over 90% of patients are believed to demonstrate some form of CNS involvement. Neuro- imaging can reveal “tubers” in the brain; generally these do not require a biopsy or need treatment.23

Children with TS will be at significant risk for devel- oping a low-grade type of brain tumor called a subependymal giant cell astrocytoma, which seems to respond to therapy with mammalian target of rapamy- cin inhibition.24 Having TS also increases the risk for developing other brain tumors, such as malignant gliomas.23,25

Von Hippel Lindau. Von Hippel Lindau (VHL) disease is a systemic disorder caused by a mutation in the VHL gene on chromosome 3.26 Patients develop

ultiple hamartomatous lesions called hemangioblas-

The vast pediatric ce

system t completely have no k

omas, which can arise anywhere throughout the CNS.

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lthough these are typically benign lesions with a ow-grade histology, they can cause a multitude of roblems based on their location. They are extremely ifficult to treat surgically because of the high risk of leeding; radiation is sometimes used to treat severe ases in older children.26 Children with VHL also

have a higher incidence of retinal, pancreatic, adrenal (pheochromocytomas), and renal tumors.25,27

Other Syndromes. Gorlin syndrome, also known as basal cell nevus syndrome, results from a known mutation in the “patched” gene. Patients with Gorlin syndrome are at high risk of developing a medullo- blastoma, and it is this association that has actually led to identifying a potential cell of origin for medullo- blastoma.28 These patients are very sensitive to the ffects of radiation; there have been dramatic reports f extensive basal cell tumors developing in the adiation field of patients with undiagnosed Gorlin yndrome.27,29

Patients with Turcot syndrome have an increased risk of developing both a brain tumor and colon cancer. These patients are at increased risk for developing malignant gliomas and medulloblastomas.28,29 This is due to a mutation in 1 of the mis- match repair genes or the APC gene on chromosome 5.

Cowden syndrome, 1 of the “PTEN hamartoma syndromes,” is an autosomal-dominant disorder

ith mutations in the PTEN encoding region on hromosome 10. These patients can develop numerous amartomas, including a characteristic CNS tumor alled a hamartomatous cerebellar gangliocytoma.25,30

There are many other rare genetic syndromes that have been associated with a higher incidence of CNS tumors. Physicians caring for these patients should be aware of this increased risk and be vigilant for any signs or symptoms that might suggest the presence of a CNS tumor.

General Concepts Clinical Presentation of Children with Brain Tumors

As rare as pediatric brain tumors are, it is a diagnosis feared by both parents and general practitioners alike.

jority of al nervous ors are radic and n cause.

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Pediatricians are well aware that some parents worry

Curr Probl Pediatr Adolesc Health Care, April 2012

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about a brain tumor when their child presents with common problems, such as headaches or seizures.31

The confirmation of suspected brain tumors relies on neuroimaging. The decision of whether to obtain an MRI or CT scan with an acute presentation in the emergency room is usually straightforward. By con- trast, primary care practitioners may be following the earlier, more subtle signs in their office and face a more challenging decision about when neuroimaging is justified.

Several different types and grades of pediatric brain tumors are described. It should be recognized that whatever the final diagnosis, the symptoms of initial presentation will generally relate to the tumor location and the rate of growth. With so many critical struc- tures confined within the cranial vault, even the most “benign” type of CNS tumor can sometimes be re- sponsible for life-threatening symptoms. Tumors in the frontal lobe may lead to personality changes, seizures, or headaches. A tumor located in the tempo- ral lobe can cause seizures or speech alterations. Tumors of the suprasellar region will present with endocrinopathies or visual changes. Those in the thalamus likely will result in motor and sensory deficits. Tectal plate tumors (top of the brainstem) and pineal region tumors may lead to obstructive hydro- cephalus, as will tumors invading the third or fourth ventricles. Cerebellar lesions often will cause nystag- mus, ataxia, and vomiting because of hydrocephalus, whereas lesions of the brainstem can disrupt individual cranial nerves or basic life-supporting functions. Spi- nal tumors can cause weakness and sensory distur- bances and affect bowel/bladder function.32,33

The presenting symptoms of CNS tumors can gen- erally be categorized into 2 groups.

Obstruction/Raised ICP. Children with brain tu- mors will often present with an acute or chronic history of raised intracranial pressure (ICP). Infraten- torial tumors are more common in children than supratentorial tumors3,34 and the anatomy in this area s susceptible to blockage in the flow of the cerebro- pinal fluid (CSF). An elevated ICP may be building p for days to months, depending on the growth rate of he tumor and its location. The classic presentation ncludes daily headaches that worsen with Valsalva ressure or lying flat. Vomiting is more common uring the night or early morning; any report of orning vomiting should be a trigger for immediate

nvestigation. Hydrocephalus can also cause papilloe-

ema, optic disk pallor, and vision loss; some children

Curr Probl Pediatr Adolesc Health Care, April 2012

resent with significant visual impairment. “Sunset- ing eyes” or sixth nerve palsies can be “false-localiz- ng” signs; rather than indicate a specific cranial nerve roblem, they can be a sign of raised ICP. In the more xtreme presentation, a rapidly rising ICP can lead to

decreased level of consciousness and “Cushing’s riad” of raised blood pressure, bradycardia, and al- ered pattern of respiration. Despite the “classic” signs and symptoms, clinical

ecognition of rising ICP can be challenging. Infants an have less dramatic symptoms because of the ccommodation of their skull bones, before closure of he fontanels and suture lines. Therefore, closely ollowing the head circumference and fontanel size ay be more useful than looking for the classic signs

f raised ICP. In older children, a pattern of headaches nd vomiting may be diagnosed initially as a migraine ariant, especially when there is a strong positive amily history of headaches. One must appreciate that igraines are exceedingly more common than brain

umors, but close follow-up and measuring the re- ponse to therapy should help in deciding which atients to investigate further.35-37

Patients with acute hydrocephalus will often require urgent treatment before receiving tumor-directed ther- apy. For the most acute cases, Cushing’s triad repre- sents a medical emergency that requires resuscitation and lowering of the ICP with dexamethasone, manni- tol, or hyperventilation. Neurosurgical CSF diversion techniques (third ventriculostomy, ventriculoperito- neal shunt, or extraventricular drain) are often needed to stabilize the patient and allow for further diagnostic investigations. Patients with hydrocephalus who are medically stable may be symptomatically managed on steroids (usually dexamethasone) until more definitive treatment can begin.

Compression or Infiltration of Specific Parts of the CNS.

Headaches. Headaches frequently are of great con- ern to parents and pediatricians alike. Statistically, nly a minute fraction of children who experience eadaches will have a brain tumor.36 Most headaches elated to a brain tumor will be accompanied by some ign or symptom of obstructive hydrocephalus, as escribed in the previous section. Some slow growing umors will cause head pain by direct compression of he surrounding tissues (skull, meninges).37 However,

many tumors in the brain will present without head-

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aches, because much of the brain parenchyma does not have pain receptors.

Vomiting. Most children who vomit because of a brain tumor will have some degree of obstructive hydrocephalus, as described above. In other cases, isolated vomiting can be a presenting sign when a brain tumor presses on 1 of the “vomiting centers” of the brain. A slow-growing tumor near the “area postrema” in the floor of the fourth ventricle can create a prolonged history of vomiting,38 which may be

isdiagnosed as “cyclic vomiting” or a migraine ariant. Neuropathies. Isolated neuropathies can be an om-

nous sign on presentation; initially, these may be ubtle and not noticed by the physician or parents. hildren have a remarkable ability to compensate for eurological deficits, and they may not know to draw ttention to a particular symptom. A “head tilt” can be way to correct double vision from a cranial nerve

alsy and many children with diplopia will be able to atch television or read without any complaints. ubtle signs, such as an “uneven smile” or ptosis, may appen so gradually that they are hard to notice by eople who see them every day. Other diagnoses, such s torticollis, Bell’s palsy, postviral cerebellitis, stra- ismus, and many others, can be at the forefront of the ifferential that is developing in the clinician’s ind.36

Occasionally, children will present with a classic syndrome that should raise suspicion of a tumor involving a specific location.37 The “diencephalic syndrome” is 1 example used to describe the presen- tation of emaciation, euphoria, and emesis. Children will have a thin, wasted appearance with normal linear growth, a ravenous appetite, and often seem overexu- berant on examination. This syndrome can represent the presence of a tumor in the diencephalon, placing the child at high risk of hypothalamic disturbance.39,40

Parinaud’s syndrome (also known as dorsal midbrain syndrome) can be found in patients with tumors in the pineal region or upper brainstem.41 These patients ave supranuclear upgaze palsy, and pupils that are eactive to accommodation but not direct light. When hey attempt to look up quickly, they demonstrate onvergence-retraction nystagmus, with the globes ulling inward. Before the initiation of tumor-directed therapy, pa-

ients with compressive symptoms may benefit from a hort course of steroids (usually dexamethasone). Ste-

oids often will alleviate symptoms within several

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ours and stabilize the patient until the initiation of the efinitive therapy. For symptoms that are severe or ife-threatening, early neurosurgical intervention must e prioritized. Seizures. Despite the assumption of many worried arents, a very small proportion of new onset child- ood seizures is related to a brain tumor.33,42 How- ver, low-grade tumors located in the cerebral cortex an cause seizures with very few other presenting ymptoms. The tumor creates a seizure focus and may nitiate partial or generalized seizures because of direct umor compression or invasion. The seizures can be ifficult to control, and multiple anticonvulsants may e required. Ultimately, if the area of seizure focus can e identified, surgical resection may provide a curative olution. Electroencephalography can assist in the urgical planning by mapping the area of focality, and ntraoperative electrocorticography can help guide the urgeons in determining when a sufficient resection as occurred.43

Endocrinopathies. Tumors involving or compress- ing the hypothalamic–pituitary axis can lead to endo- crinopathies, which may serve as the only presenting symptom of a childhood brain tumor. New onset diabetes insipidus should lead to neuroimaging and a full evaluation, but this disorder can be subtle in its early presentation. Fluctuations in serum sodium lev- els with diabetes insipidus can lead to excessive thirst, extreme water intake, and seizures. Correction should be gradual and cautiously monitored. Patients with compression or invasion of their pituitary stalk from a tumor can have adrenal insufficiency and may require stress dose steroids at diagnosis or presurgery.

Precocious or delayed puberty and disturbances in growth can be other ways in which brain tumors present, even though the differential diagnosis for these findings is extensive.

Spinal Cord. Although generally less common than intracranial tumors, isolated spinal cord tumors can present with back pain, scoliosis, neuropathic pain, areas of numbness, or limb weakness. Bowel or bladder signs usually represent a late and very con- cerning finding.37 Acute spinal cord compression war- rants an immediate neurosurgical consultation, and steroids should be started while further treatment planning occurs. In situations where surgical resection or debulking cannot be performed, emergency radia- tion therapy or chemotherapy may be used in an

attempt to save spinal cord function.44

Curr Probl Pediatr Adolesc Health Care, April 2012

t e d T s s

Diagnosis Centralized Care. When a brain tumor is suspected,

the acuity of the presentation dictates whether a child can be referred to an outpatient neurosurgery clinic or urgently transported for emergency care. In the more acute setting, stabilizing a patient locally is critical but every effort should be made to transport a new patient to a regional center that specializes in pediatric brain tumors. If transport is not possible, most large medical centers are able to provide recommendations for the best initial direction of care based on the patient’s history, examination, and neuroimaging studies.

Imaging. Children experiencing a slow progression of their symptoms may wait appropriately for the scheduling of an elective outpatient MRI; however, patients presenting with acute symptoms will typically undergo a noncontrast head CT as their first imaging technique. One exception might be for infants with an open fontanel, where an ultrasound may be a safer and more useful initial test for investigating a rapid in- crease in head circumference. Generally, the role of CT for imaging a suspected brain tumor should be reserved for potentially unstable patients, given the degree of radiation exposure. Once a lesion is sus- pected by clinical examination or initial imaging, the definitive imaging test is a high-quality MRI with and without contrast. Neuroradiologists use a wide variety of imaging techniques, but the following image types describe some of the neuro-oncology basics:

T1 image: used to define anatomy, will reveal area with concentrated blood products, fat in the brain, and visualize cystic areas of fluid

T1 � contrast: areas that are “contrast-enhancing” represent breakdown in the blood– brain barrier, often due to swelling and distorted tumor vasculature, or necrotic areas within a tumor

T2: “bright” or hyperintense areas represent an in- creased amount of fluid (water signal), with the ventri- cles and eye globes appearing bright

FLAIR (fluid attenuated inversion recovery): 1 imaging type that is used to show areas of swelling or edema surrounding tumor tissue

Diffusion-weighted imaging, fast steady-state acquisi- tion imaging, spectroscopy, and many other MRI tools are used at the discretion of the neuroradiologist to help further investigate some tumor types.45,46

The role of functional neuroimaging is evolving in the diagnosis of pediatric brain tumors. Positron im- aging tomography scanning is now widely used in studying extracranial solid tumors and is able to

provide additional useful information about some CNS

Curr Probl Pediatr Adolesc Health Care, April 2012

umors. New imaging technologies and contrast mol- cules are being investigated that may facilitate the ifferentiation of high-grade from low-grade tumors. his would help to determine the appropriate timing of urgery and even help guide the extent of initial urgical resection required.47,48

Histology. One of the first questions that many parents have is whether their child’s tumor is “benign” or “malignant”; these words have tremendous impli- cations to the layperson and are often interpreted to mean the difference between “life or death.” However, the distinction between “benign” and “malignant” is complicated when dealing with most pediatric brain tumors. Location is often an important factor in determining the prognosis; a “benign” tumor in an unresectable location could signify as poor a prognosis as a “malignant” tumor in a surgically accessible region of the brain. The age of the child often dictates the amount and type of treatment that can be used, which therefore also significantly affects prognosis. Although the “grading” of a pediatric brain tumor refers to its microscopic appearance, it does not always reflect prognosis. Tumors are graded 1 through 4, with 1 being the lowest grade and 4 the highest; grade 1 and 2 usually are called “low grade,” whereas grades 3 and 4 are considered “high grade.”

The accuracy of classification and grading pediatric brain tumors does depend on the expertise and expe- rience of the neuropathologist. A main reference source for subtypes and nomenclature is provided by the World Health Organization (WHO), in the publi- cation “Tumors of the Central Nervous System.” The latest version, issued in 2007 (4th edition), describes hundreds of different tumors. The clinical team relies on the neuropathologist to use the appropriate diag- nostic tools to determine the final pathologic diagno- sis. Depending on the tumor type and complexity of the case, identification after surgery may take several days or even weeks.

The primary tool for the pathologist remains the microscopic examination of the histologic specimen focusing on cell size, spacing, shape, nuclear division, and other factors. Immunohistochemistry is an evolv- ing field that uses special stains to distinguish tumor subtypes. The field of tumor genetics is rapidly grow- ing and sophisticated tools are being used to detect genetic mutations that act as a “molecular signature” to identify tumors. As the diagnosis of rare pediatric

brain tumors is challenging, difficult cases often are

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sent for second opinions from other experienced pathologists.

Treatment Multidisciplinary Team Approach. The treatment

and care of children with brain tumors are increasingly complex and require an array of disciplines and resources from within the health care system. Conse- quently, many small pediatric oncology centers at- tempt to centralize their resources when treating brain tumors.

For any pediatric solid tumor, the principles of treatment rely on a combination of surgery, radiation, and medical therapy. The primary treating physician team will usually include a neuro-oncologist, neuro- surgeon, and radiation oncologist. Pediatric neuro- oncology is a growing subspecialty and refers to the physician who guides and coordinates medical treat- ment (ie, chemotherapy) and the follow-up care. At most centers this will be either a pediatric-trained hematologist/oncologist or a pediatric neurologist. The pediatric neurosurgeon who has a special interest and experience in tumor surgery is critical to any program. A radiation oncologist with pediatric expertise also is crucial during the consultation and care of most children with brain tumors.

Beyond this primary team of clinicians, it is neces- sary to have expertise available from other pediatric specialists and general pediatricians. The availability of consultants is very important in cancer care, be- cause the impact of the tumor and/or treatment can involve almost every organ system in the body. The diagnostic medical team also plays a vital role in the quality of any neuro-oncology program. Specially trained pediatric neuroradiologists and neuropatholo- gists are needed to provide the most accurate diagnosis possible, which is critical in choosing proper treat- ment. Pediatric ophthalmologists are critical in evalu- ating optic pathway tumors and conducting surveil- lance for tumor growth or recurrence.

Comprehensive pediatric neuro-oncology programs also need to have a specialized multidisciplinary team for the successful management of children with brain tumors. The tremendous impact of this diagnosis on a family demands that psychologists or a counseling team be involved from the time of diagnosis. A neuropsychologist and school liaison professionals can measure cognitive status accurately and address school reintegration issues. Physical, occupational, and

speech-language therapists play a vital role in the

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ehabilitation of children after surgery and treatment. ocial workers assist with the tremendous burden of ancer treatments on the family, financially and oth- rwise. Throughout their treatment, children and fam- lies benefit from having nursing staff with pediatric euro-oncology expertise, both on the hospital wards nd in the clinic setting. For symptom management nd end-of-life care issues, an experienced hospital- or ospice-based palliative care team is an invaluable sset. Surgery. Children with brain tumors should be

ssessed by surgeons who have specific expertise in ediatric neurosurgery. The level of surgical expertise as been shown to have a positive impact on out- omes,49 and because surgery is needed to treat most

pediatric brain tumors, it is a central component of any brain tumor program. Patients with acute deterioration on presentation often will need urgent intervention to deal with compression or hydrocephalus. Sometimes a biopsy will be most appropriate, with the surgeon obtaining just enough tissue to determine a diagnosis or guide therapy. Some tumors will need to be “deb- ulked,” where the goal is to remove as much of the tumor as possible to provide a diagnosis and relieve symptoms, while avoiding more aggressive ap- proaches. Finally, for some tumor subtypes, the pa- tient’s survival truly depends on achieving a “gross total resection,” where the surgeon balances the po- tential morbidity against a life-saving aggressive resection.

Advances in surgical skill sets and technology are continuously improving the rate of successful com- plete resection while decreasing surgical morbidity. Endoscopic surgery has allowed for minimally inva- sive approaches for tumor biopsy, or the relief of hydrocephalus by an “endoscopic third ventriculos- tomy.” This technique involves creating a hole in the third ventricle to divert CSF flow around an obstruc- tion. An endoscopic third ventriculostomy can spare children from potentially requiring a ventriculoperito- neal shunt and therefore decrease rates of shunt complications and the potential for extracranial spread of tumor cells. Increasingly sophisticated neuromoni- toring during brain and spine surgical procedures has allowed surgeons to recognize exactly how close they are to critical nerve structures during the resection. Intraoperative MRI suites are becoming available, allowing surgeons to take a “live-time” image of the surgical resection cavity and continue to remove

residual tumor that is identified. These and many other

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techniques have allowed for great advances in the surgical aspects of neuro-oncology.50

Radiation. Radiation therapy refers to the delivery of high-energy beams to areas of suspected or known tumor. Most commonly, centers use photon energy (X-rays) delivered to a focal area (ie, the tumor bed) or to the entire craniospinal axis (whole brain and spinal cord). Radiation is given in daily fractions in an outpatient setting, usually for a total course lasting 6 or 7 weeks. This schedule allows a patient to tolerate large doses without suffering significant damage to the surrounding normal tissues, thus maximizing the chance of killing tumor cells. A different technology known as “proton” radiation is being offered in a growing number of centers in the USA.51 Although the total dose delivered to the tumor remains the same with protons, there is an ability to provide a more focused beam with sharper margins, and to determine the endpoint at which the maximal radi- ation will be delivered. In some cases, this can be advantageous for treating young children to reduce long-term side effects.52,53

Whatever source of radioactive energy is used, technology is continually improving our ability to spare normal tissue by delivering radiation to the tumor in a more precise fashion. Concurrently, many pediatric clinical trials are addressing the question of whether reducing the radiation dose will provide a comparable cure rate for a given tumor.54 Increasing the knowledge of the long-term physical and neuro- cognitive impact of radiotherapy on young children is critically important in making treatment decisions about the optimal dose of radiation.55-59

Chemotherapy. The role for chemotherapy in the treatment of brain tumors was realized more recently than for surgery or radiation. Multiple challenges exist in delivering chemotherapy to the CNS, including overriding the blood– brain barrier that is designed to prevent toxins from infiltrating of the CNS. Systemic toxicity can be significant even when drug delivery into the CNS is minimal. Although delivery of che- motherapy directly into the CSF space can treat disease close to the CSF– brain interface, drug pene- tration deep into the brain parenchyma remains poor.60

Given the rarity with which brain tumors are seen in children and adolescents, efforts should focus on enrolling patients into clinical trials whenever possi- ble. Because even large referral centers may treat a small number of each specific tumor types per year,

cooperation among centers is crucial to understanding

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he efficacy and impact of treatments. The largest etwork in North America is the National Cancer nstitute funded “Children’s Oncology Group,” which ncludes over 200 centers worldwide. The Children’s ncology Group is responsible for the design and peration of some of the largest clinical trials in hildren. Other groups operate in fewer centers and are esigned to provide access to more experimental herapies; examples include the Pediatric Brain Tumor onsortium and the Pediatric Oncology Experimental herapeutics Investigators Consortium. Information bout pediatric clinical trials for brain tumors can be ound at the US National Institutes of Health web site, ttp://www.clinicaltrials.gov. Chemotherapy for childhood brain tumors can be sed in different situations. First, lower doses of hemotherapy are used over extended periods in an ttempt to slow or halt the growth of low-grade umors. Because the duration of treatment could po- entially be years, this therapy must be well tolerated nd designed to minimize long-term toxicity. One xample of this is the weekly use of intravenous incristine and carboplatinum in the management of nresectable low-grade gliomas.61 Second, higher oses of chemotherapy are used as adjuvant (after) or eoadjuvant (before) treatment to enhance treatment ith surgery and/or radiation. The classic example is

n medulloblastoma, where patients will have a better hance of survival if they receive chemotherapy after heir surgery and radiation.62 Third, high doses of ultiagent chemotherapy are being used to treat in-

ants and young children to prevent or delay the need or radiation therapy. Over the past 2 decades this reatment approach has been used with some success, nd many protocols will use autologous stem cell escue to help children recover from the bone marrow oxicity of their chemotherapy. It must be recognized hat these treatments are acutely more toxic and urvival rates may be lower than using standard adiation techniques, but for the youngest patients this as to be balanced against the devastating long-term ffect of radiation.63 A fourth way of using chemo-

therapy is in its role as a radiation “sensitizer”; patients will receive daily or weekly chemotherapy during radiation therapy to increase its effectiveness in some tumors.

Having used traditional cytotoxic chemotherapy for decades, the field of neuro-oncology is now looking toward the use of more targeted therapies and biolog-

ical agents. Many newer drugs have been designed to

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target known pathways in tumor cell signaling, rather than relying on nonspecific toxicity to the cell. Inhi- bition of tyrosine kinases, histone deacetylases, the sonic hedgehog pathway, and mammalian target of rapamycin represent just a few examples being ex- plored in clinical trials. There may be a role for tumor “maturation” agents, with oral drugs, such as retinoic acid, being used in current trials. Other approaches, such as the “antiangiogenic” vascular endothelial growth factor antibody bevacizumab, have shown promise in adult studies and therefore are being investigated in pediatric patients. Phase I and II clinical trials aim to learn more about the safety and efficacy of novel agents, many of which will have been used in adult trials and other solid tumors first. Clinical trials are also underway to investigate viral and gene therapy in the treatment of brain tumors, infecting tumor cells directly or stimulating the body’s own immune system as a way of targeting tumor cells.64-66

Types of Pediatric Brain Tumor Gliomas

The word “glioma” can refer to any tumor originat- ing from glial tissue, whether benign or malignant (Fig 1). Glial tissue is found throughout the CNS. It acts as a scaffolding network and connective tissue array that plays different roles in different parts of the brain. Thus, glial origin tumors can be found in every different part of the brain and spinal cord; some form of glioma is almost always on the differential diagno- sis when looking at a new CNS lesion on an MRI. The primary glioma subtypes are defined by the 3 most common types of glial tissue:

● Astrocytes— cells found throughout the CNS that play many supportive and regulatory functions

● Ependymal cells— cells that line the ventricles ● Oligodendrocytes—myelin-forming cells found at

the gray--white junction (which will not be dis- cussed separately in this article).

Astrocytomas Low-Grade Astrocytomas

“Low-grade astrocytomas” (LGA) include the WHO grade I and II astrocytomas and are the most common

type of brain tumor found in childhood. Because glial o

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issue is found everywhere in the CNS, these tumors an occur in any area of the brain or spine, but in hildren LGAs most often occur in the posterior ossa.67 By histology, the most common subtype is alled “juvenile pilocytic astrocytoma” (JPA), which s classified as WHO grade I. JPAs account for pproximately 20% of brain tumors in children.3

WHO grade II tumors are referred to as “fibrillary astrocytomas” and are considerably less common than JPA.

Background and Presentation. Like most child- ood brain tumors, astrocytomas will often present in he infratentorial region; therefore, the typical clinical resentation is that of ataxia, vomiting, or headache ecause of raised ICP (Fig 2). However, it should be oted that by implication low-grade tumors grow very lowly and therefore many children will present with onths or even years of symptoms. With subtle,

lowly worsening symptoms, it can be difficult for the linician to recognize these signs as being suggestive

o Glial origin tumors

o Astrocytoma & other gliomas

� Low grade

� High grade

o Ependymoma

o Embryonal tumors

o Medulloblastoma

o CNS Primitive neuro-ectodermal tumor

o Atypical Teratoid Rhabdoid Tumor

o Choroid Plexus Tumors

o Papilloma

o Carcinoma

o Germ Cell Tumors

o Germinoma

o Non-germinomatous germ cell tumor

o Craniopharyngiomas

FIG 1. Main categories of childhood CNS tumors.

f or compatible with a brain tumor.

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Another common area of presentation in childhood is in the optic pathway, where these tumors clinically can present with proptosis or with gradual visual deterioration. As mentioned in the previous section, children with NF-1 are particularly susceptible to developing optic pathway gliomas and should have regular ophthalmology follow-up.

On MRI imaging, JPAs usually appear as well- circumscribed and strongly enhancing lesions that are bright on T2 imaging. Cystic areas are commonly seen. Very little surrounding edema is seen on FLAIR imaging. Occasionally low-grade tumors in the poste- rior fossa can result in actual thinning of the occipital skull bone as they slowly grow over long periods.

Treatment Surgery. LGA generally occur in 1 location and do

not tend to spread throughout the CSF. JPAs typically are well-circumscribed, and if they are in a surgically accessible location, then excision can be curative. By contrast, optic pathway gliomas make up a significant portion of LGAs in children. These are generally not surgically resectable without compromising the child’s vision, and even a biopsy in this area can be risky. Thus, some optic pathway gliomas are diagnosed based on a characteristic MRI appearance, rather than

FIG 2. Juvenile pilocytic astrocytoma of the posterior fossa. Note the large cystic and smaller components (MRI sagittal image, T1 � contrast).

subjecting the patient to a surgical procedure.

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Radiation. For most children with LGA, every ttempt should be made to delay radiation as long as ossible. Although most of these tumors will respond o radiation therapy, the significant long-term side ffects make radiation hard to justify as an initial herapy in a patient population with excellent long- erm survival. In older patients, radiation is generally olerated better and can be quite effective in treating a rowing unresectable lesion. Chemotherapy. Because surgical resection is the oal of treating LGA, chemotherapy is not always ecessary. However, with the desire to avoid radiation herapy, several clinical trials have been able to emonstrate a role for chemotherapy in stabilizing or hrinking LGA.61,68 Today, most children with pro-

gressive, unresectable LGA are given chemotherapy for at least 1 year, recognizing that re-treatment is often needed later in life.69

Prognosis and Follow-Up. The general prognosis or pediatric LGAs is very good, and overall survival t 5 years is greater than 90%.67 Complete surgical

resection usually is curative, but even after a gross total resection, children generally should be followed on a routine basis and have a repeat MRI scan every few months for a few years after surgery. The intervals between MRI scans will increase if no recurrence is seen, and eventually children will require follow-up appointments every 1 to 2 years. Children with resid- ual disease benefit from closer follow-up, including MRI scans and ophthalmologic assessments to look for change in the tumor size, enhancement, ventricle size, and visual fields. This information will assist in the decision of when to start (or restart) treatment.

Because LGA tend to recur locally, routine surveil- lance imaging is focused on the primary site of disease. For patients with tumors of the optic pathway, visual screening is a key component of follow-up and often can be more useful than MRI imaging in determining significant changes.

High-Grade Astrocytomas Background and Presentation.

Case 1: Diffuse Pontine Glioma. A 4-year-old girl presents with an acute 2- to 3-day history of ataxia. Her parents report that she is “walking like she is drunk.” Of note, she is drooling, her speech is a little slurred, and she is having difficulty swallowing. On physical examination, she has bilateral sixth cranial nerve palsies, facial asymmetry, and significant gait

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“High-grade gliomas” primarily include the WHO grade III or IV high-grade astrocytomas (HGA) (Fig 3). These make up most primary brain tumors in adults, but account for only 10% to 20% of pediatric tumors.3 Like LGAs, these can occur in any location

ithin the brain or spine. By nature, these are more nfiltrative, more aggressive in the speed at which they row, and more likely to recur after treatment. By istology, WHO grade III astrocytomas are called anaplastic astrocytomas,” and WHO grade IV is esignated as “glioblastoma multiforme.” Although “high grade” is a histologic description, it

mplies faster tumor growth. Children with HGA sually will have a shorter duration of symptoms efore presentation when compared to those with an GA. The presenting clinical features will depend on

he location of the tumor and usually involves direct nvasion or compression of the brain resulting in eurologic deficits. Thus, seizures, cranial neuropa- hies, and hemiparesis are common findings at the atient’s presentation. HGA will typically have a heterogenous appearance n MRI with absent enhancement or areas of ring nhancement, and significant edema on FLAIR imag-

FIG 3. High-grade astrocytoma, posterior fossa. A heteroge- neous or “ring-enhancing” appearance is a common finding (MRI axial image, T1 � contrast).

ng. Lesions typically have poorly defined margins and

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an demonstrate “mass effect” by compressing or isplacing the surrounding structures. HGAs tend to occur in 1 primary location and do not

ypically spread throughout the CNS. However, they ccasionally present with a diffuse pattern of spread hroughout different parts of the brain parenchyma, a adiologic pattern referred to as “gliomatosis cerebri.” n this case a biopsy most often will reveal histology onsistent with glioblastoma multiforme, which will ot be amenable to surgical resection because of its iffuse pattern. When arising in the pons of the brainstem, a unique

ntity called “diffuse intrinsic pontine glioma” (DIPG) ill generally behave in a high-grade fashion. DIPGs ake up almost 10% of all pediatric brain tumors. hey cause significant neurologic deterioration, typi- ally with a brief history of progressive cranial nerve eficits. The diagnosis of a DIPG most often is based n neuroimaging alone. The risk of surgical biopsy of tumor in this location is not insignificant and usually

an be avoided if the MRI features are compatible with he diagnosis. The classic findings of these tumors on

RI are nonenhancing and hypointense on T1- eighted imaging, and hyperintense on T2-weighted

maging.45

Treatment Surgery. Surgery has a role in the treatment of most

HGA.70 However, the higher the grade, the more ocally infiltrative the tumor, thus making complete urgical resection of most HGA practically impossible ithout resecting a significant amount of surrounding ormal brain tissue. Radical surgical resection has een shown to improve outcomes71 but often a biopsy

or debulking surgery is all that can be achieved. The thalamus and the pons are 2 such locations where extensive surgery is generally not feasible. For diffuse pontine gliomas, there is no curative role for surgery and the vast majority of cases will not need to be biopsied to establish the diagnosis. However, some oncology centers are starting to biopsy diffuse pontine glioma tumors to understand their biological charac- teristics better, with the hope of being able to identify therapeutic targets.72,73

Radiation. As most HGA will respond to radiation, this therapy is a critical component for prolonging survival in most patients.74,75 High-dose focal radia- tion after maximal surgery is the best known strategy

for treating high-grade gliomas. Craniospinal radiation

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typically is unnecessary as these tumors do not tend to spread via the CSF.

Chemotherapy. Historically, chemotherapy has not played a major role in the treatment of HGA.76

Although not yet part of “standard” treatment in children, there have been studies with chemotherapy agents that have shown some promise.66,77,78 One of he current chemotherapeutic drugs of interest in dults is temozolomide, an alkylating agent with elatively good CNS penetration.79,80 In 2005, a large dult series was published that demonstrated an in- reased duration of survival in patients who received adiation plus temozolomide vs radiation alone.81 Sub- equent analyses revealed that the methylation status of he promoter of a DNA repair gene differentiated those atients who would have a better response to temozolo- ide.82 When methylated, the DNA repair gene pro- oter is “turned off,” which downregulates the transcrip-

ion of a protein called methylguanine methyltransferase. s an example of epigenetic modification, being “meth- lated” seems to make the tumor cell less resistant to reatment with drugs like temozolomide. These same romising clinical data for adults have not yet been eproduced in pediatrics.75

Prognosis and Follow-Up. High-grade gliomas generally have a very poor prognosis; despite aggres- sive treatment with surgery and radiation, fewer than one-half of patients are alive 2 years following diag- nosis and long-term survival rates are very low.83

Patients with anaplastic astrocytoma do tend to survive longer than patients with glioblastoma multiforme tumors. Long-term survivors of a true DIPG tumor are almost unheard of. After their initial therapy, children should be carefully monitored with follow-up MRI scans, and when their disease recurs, they may be offered participation in phase I or II clinical trials and have palliative care services available.

Ependymoma

Background and Presentation

Ependymomas account for approximately 6% of all childhood CNS tumors3 (Fig 4). These tumors typi- ally arise from the ependymal lining of the ventricles, nd most commonly the fourth ventricle in children. Microscopically, the “classic” ependymoma pattern

s classified as WHO grade II, whereas an anaplastic

ariety exists as WHO grade III. There also is a unique

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orm of spinal ependymoma called myxopapillary pendymoma, which is classified as WHO grade I.84

On MRI imaging, an ependymoma appears as an enhancing lesion that often extends through various foramina. Obstructive hydrocephalus is a common presentation because of the typical location of the tumors in the fourth ventricle, with cranial neuropa- thies and cerebellar signs often found as well.

Ependymomas typically present as unifocal disease, but in up to 10% of cases,85 they can spread through- out the brain or spine, and very rarely outside of the CNS. Diagnostic workup should include a baseline spine MRI and CSF sampling.86

Treatment Surgery. The benefit of complete surgical resection

has been demonstrated for pediatric ependymomas, and therefore, gross total resection by an experienced neurosurgeon should be the first line of therapy when- ever possible. The extent of resection is believed to be very important for survival, and re-resection is justi- fied when the postoperative imaging suggests residual disease.87-89

Radiation. Postsurgical radiation therapy to the resection cavity improves survival for children with

FIG 4. Ependymoma arising from the fourth ventricle, causing severe obstructive hydrocephalus (MRI sagittal image, T1 � contrast).

ependymomas, even after complete resection.90 High

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doses of radiation are given locally, unless there is evidence of distant metastases (ie, disease on spine MRI or tumor cells identified in the CSF). The 1 exception is for a complete resection of the tumor in the supratentorial region, with studies revealing a classic histologic pattern. For these patients, some studies have limited follow-up to close observation only, without up-front radiation.89,91

Chemotherapy. An ependymoma is not a very “chemoresponsive” tumor.88 Because the prognosis of these children is so dependent on the ability to achieve a total resection, chemotherapy has been used in an attempt to shrink residual tumor and allow surgeons to achieve total resection in a “second-look” surgery. This has been done with some success in the past,92

and current clinical trials are investigating the role for postradiation chemotherapy in preventing recurrence.

Prognosis and Follow-Up. Children with ependymo- mas having undergone gross total resection followed by focal radiation have a good prognosis, with an approximately 80% 5-year survival. If gross total resection is not achieved, their 5-year survival dramat- ically worsens with most studies reporting a drop to 20% to 30%. Thus, the accessibility of the tumor to resection (and the availability of experienced sur- geons) determines the chance of survival. Patients with ependymomas require follow-up for many years, because late recurrences can occur. If the tumor regrows in an accessible location, there is often a role for surgical re-resection, which often can provide months or years of extended survival.93

Embryonal Tumors Background and Presentation

Case 2: Posterior Fossa Mass. A 6-year-old boy presents with a 3- to 4-week history of intermittent headaches and vomiting. He has had no diarrhea, fever, or rash. He describes diplopia and his parents report that he now is walking unsteadily. His physical examination is notable for gait ataxia, dysmetria, and diminished rapid alternating movements. The remain- der of his physical examination is unremarkable.

Embryonal tumors (sometimes referred to as neuro- nal tumors) represent the largest group of malignant tumors in childhood and can occur anywhere through- out the brain and spinal cord (Fig 5). They often are referred to in a broad category as “primitive neuroec-

todermal tumors” (PNET), which is a distinct term

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rom the “peripheral neuroectodermal tumor” label iven to certain extracranial sarcomas (ie, Ewing’s fam- ly of tumors). Embryonal tumors generally are classified y their location: in the posterior fossa they are called edulloblastoma; in the pineal region they are called

ineoblastomas; and in other locations they fall under the ategory of “central nervous system PNET.” There is lso a relatively new entity called the “atypical teratoid habdoid tumor” of the CNS, which carries a distinctive enetic mutation on chromosome 22.94 These can de- elop anywhere throughout the CNS, generally occur in oung children, and carry a worse prognosis than all ther embryonal tumors.95

Medulloblastoma is the most common type of em- bryonal tumor found in childhood. It is further classi- fied by its microscopic appearance into various sub- types: classic, nodular/desmoplastic, or large cell/ anaplastic.84 These subtypes are related to prognosis and therefore have traditionally been used to guide treatment. More recent studies have shown that there are different molecular subtypes and genetic patterns that are able to predict better outcomes, and these will likely be incorporated into the next generation of clinical trials.96-99

The current treatment for embryonal tumors is based

FIG 5. Medulloblastoma, arising from the cerebellum and growing into the fourth ventricle (MRI sagittal image, T1 � contrast).

on accepted criteria for risk stratification: “standard

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risk” patients are designated by having a medulloblas- toma with classic histology, a successful gross total resection (allowing up to 1.5 cm2 of residual disease on MRI), and no metastatic disease on spine MRI or CSF sampling.100 All other patients are considered igh risk. The age of the patient also plays a major ole, because craniospinal radiation can be so detri- ental to very young children. Tumor location is

ritical in deciding the intensity of treatment, because nly the cerebellar location (ie, medulloblastoma) has een studied sufficiently to justify a decrease in herapy intensity. Pineal region PNET tumors have een shown to have a worse prognosis than those in ther areas.101,102

A significant proportion of embryonal tumors al- ready will have metastatic disease at presenta- tion.103,104 All patients require an MRI of their spine, nd lumbar puncture for CSF sampling (usually 2 eeks after surgery). Although metastatic disease utside of the brain and spine is very rare, it can ccur.105 Any signs or symptoms of extracranial

metastasis should lead to prompt baseline investiga- tion, and many clinicians will include a bone marrow aspirate as part of their staging workup.

Treatment Surgery. Surgery plays a vital role in the treatment of

ll embryonal tumors. Gross total resection should be the oal, yet because these tumors generally respond to hemotherapy and radiation, surgery may be slightly less ggressive to preserve neurologic function. Radiation. Radiation therapy has been used for de-

ades as a key component of therapy for embryonal umors.106 The frequency of metastatic spread through-

out the CNS suggests that the entire craniospinal axis needs to be treated to maximize cure and prevent distant recurrence. For medulloblastoma, specifically, large clin- ical trials have stratified patients to determine whether the total radiation dose can be safely reduced.54,62 Using adjuvant chemotherapy, this seems to be possible while achieving similar survival rates.

Chemotherapy. The embryonal tumors respond to chemotherapy to varying degrees and the use of postradiation chemotherapy have been demonstrated clearly to improve survival.54,62 Traditional cytotoxic hemotherapy, such as vincristine, etoposide, alkylators, nd platinum agents, are used in most protocols for ewly diagnosed patients. Determining organ function is mportant before therapy, with particular attention to

aseline hearing and kidney assessments because of

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hemotherapy toxicity. Intensified postsurgical chemo- herapy has been studied for younger patients to avoid or elay the need for radiation.107-109 Although survival

rates are probably not quite as good without radiation, this strategy aims to provide an acceptable cure rate for patients while limiting the devastating neurocognitive consequences of radiation.55,104

Prognosis and Follow-Up. The embryonal tumors in childhood are treatable, and moreover, they are often curable. For example, standard risk medulloblas- toma treated with radiation and chemotherapy after gross total resection has a 5-year survival of over 80%.103,104

Outside of the posterior fossa, pineoblastomas and CNS PNETs usually carry a worse prognosis than medulloblastoma. Currently these are treated with more intensive protocols with less emphasis on reduc- ing radiation and chemotherapy doses. Further studies are needed to understand better these tumors as they appear to have distinct molecular and genetic features from medulloblastomas.110 Atypical teratoid rhabdoid umor has demonstrated an even worse prognosis on tandard therapy, although recent studies have been sing an intensive sarcoma-based treatment approach ith some improvement in survival rates.111

Surveillance imaging has been shown to improve survival for patients with medulloblastoma.112 Pa- tients should be followed with regular interval MRI scans, including the brain and spine, as any of the embryonal tumors can recur outside of the initial tumor bed.

Choroid Plexus Tumors Background/Presentation

Tumors of the choroid plexus (CPT) represent a rare group of tumors that generally present in young children less than 2 years of age (Fig 6). They account for fewer than 2% of all pediatric CNS tumors.3

Normal choroid plexus tissue plays a role in the production and reabsorption of CSF, and it is primarily located in the lateral and fourth ventricles. Choroid plexus tumors are divided into “choroid plexus papil- loma” (WHO grade I) and “choroid plexus carcinoma” (CPC, WHO grade III). This distinction is extremely important because the prognosis and treatment impli- cations are very different. An intermediate grade of CPT also exists, called “atypical choroid plexus pap-

illomas,” and this is considered WHO grade II. Atyp-

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ical choroid plexus papillomas tend to occur in chil- dren even younger than the grade I papillomas113 and ave a slightly more aggressive course. The presenting signs of a CPT in children can include bulging fontanel with accelerated head circumference

rowth, irritability, seizures, vomiting, and lethargy. etastatic disease is not uncommon at presentation,

specially with CPC. Because of the nonfused skull utures and open fontanels in infants, these tumors can row to be exceptionally large at presentation. There is an association with CPC tumors and the i–Fraumeni familial cancer predisposition syn- rome.114 Although this is a rare occurrence, every

newly diagnosed patient with a CPC should have a detailed family history taken, and referral for cancer genetics screening should be strongly considered.

The low incidence of childhood choroid plexus tumors creates a challenge in determining the optimal treatment protocols. International clinical trials are being carried out to gather sufficient patient data to assess and improve the treatment outcomes.

Treatment Surgery. Surgery plays an important role in the

reatment of choroid plexus tumors. For the lower grade

FIG 6. Choroid plexus carcinoma arising from the lateral ventricle, causing midline shift (MRI axial image, T1 � con- trast).

horoid plexus papillomas, surgical resection or debulk- e

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ng may be the only treatment required. In the treatment f the more aggressive choroid plexus carcinomas, gross otal resection with adjuvant chemotherapy or radiation ill offer the best opportunity for cure. Radiation. Postsurgical radiation therapy improves

urvival for children with CPC.115 The challenge of eciding to deliver radiation therapy to a population ith a median age around 2 years of age is daunting ecause of the long-term side effects. CPC tumors ave a tendency to metastasize, which means that the adiation oncologist needs to consider craniospinal adiation in the treatment planning. Although this reatment may offer a better chance for cure, it is also ssociated with the most severe side effects. Chemotherapy. The treatment of choroid plexus apillomas is primarily surgical and does not usually nvolve adjuvant chemotherapy. This is in contrast to horoid plexus carcinomas, which are more aggressive, et sensitive to chemotherapy. Postsurgical chemother- py for CPC does improve survival rates116 and intensive hemotherapy is often used with the aim of delaying or voiding radiation. Although several studies have dem- nstrated a benefit from combining the 2 modalities, the hemotherapy-only approach is appealing for a tumor ith such a young age at presentation.117

Prognosis and Follow-Up. The rarity of choroid plexus tumors makes it difficult to establish exact rates of recurrence and cure. However, follow-up recommenda- tions for CPC survivors are similar to those for other pediatric brain tumors, with routine MRI scanning at 3- or 4-month intervals in the first year. The prognosis for choroid plexus papilloma tumors is excellent after sur- gery, but there have been rare reported cases of malig- nant transformation,118 so these patients also require outine MRI surveillance. Neuropsychologic assess- ents are critical to follow the neurocognitive develop- ent in this young group of vulnerable patients. Those

hat have received intensive chemotherapy require spe- ific follow-up according to the medications used in their rotocol.

Germ Cell Tumors Background/Presentation

Case 3: Germ Cell Tumor. An 11-year-old boy resents with new onset diabetes insipidus. His mother eports that he has been bumping into objects in the ast few months. Primary CNS germ cell tumors (GCT) usually pres-

nt in children between 6 and 14 years old (Fig 7). For

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reasons not well understood, they have a geographic and racial predisposition, with a higher incidence in parts of Asia (especially Japan). These tumors are thought to derive from cells that have migrated from the primary gonadal ridge during embryogenesis and subsequently undergo malignant transformation. It should be emphasized that this discussion does not include metastatic tumors from a gonadal germ cell tumor, but rather true primary CNS tumors. They are classified by 2 subtypes: germinomas and nongermi- nomatous germ cell tumors. Pure germinomas are more common, comprising two-thirds of all GCT. The “nongerminomatous germ cell tumors” consist of a more heterogeneous group, which can be further subclassified as embryonal yolk sac tumors, choriocar- cinomas, endodermal sinus tumors, and malignant teratomas.119

Germ cell tumors grow in the midline of the brain, and the vast majority will present in either the suprasellar region or the pineal region. The growth rate can vary, but often symptoms will precede the diagnosis by several months. Midline lesions can present with visual disturbances, hydrocephalus, endocrinopathies, personality and sleep pattern al- terations, dramatic weight changes, school perfor-

FIG 7. Germinoma (arrow indicates tumor) with a presentation in the midline suprasellar region. Note the pituitary stalk thickening (MRI coronal image, T1 � contrast).

mance decline, headaches, or seizures. On clinical d

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xamination, patients with pineal lesions may ex- ibit Parinaud’s syndrome. Germ cell tumors are unique in that they can otentially be diagnosed by a laboratory test. In the iagnostic evaluation of a midline CNS lesion, sam- les of serum and/or CSF can be analyzed for tumor arkers (primarily alpha-fetoprotein and beta-human

horionic gonadotropin). These proteins are normally ot present in normal children, with the exception of nfants or pregnant adolescents. Tumor markers are istinctly elevated for most nongerminomatous GCTs, ut will be normal or very low in pure germinomas. On MRI germ cell tumors have a heterogeneous

ppearance. Most are T2 bright and contrast-enhanc- ng with distinct margins, and cystic components are ot unusual.120

Germ cell tumors can spread locally or via the CSF. Spine metastases at diagnosis are not uncommon and a spine MRI with a lumbar puncture for CSF analysis should be part of the diagnostic workup. This evalua- tion may also include imaging of the chest, abdomen, and pelvis if symptoms of extracranial disease are suspected.

Treatment Surgery. With the ability to use laboratory tests in

the diagnostic workup, this is 1 of the few CNS tumors that will not always require surgery. GCT will often warrant a diagnostic biopsy, but generally there is less emphasis on achieving a gross total resection. Urgent surgical intervention may be required for patients presenting with obstructive hydrocephalus, with the goal of debulking and performing a CSF bypass procedure.

Radiation. Germ cell tumors are very sensitive to adiation, which has been a critical treatment modality or many years. When the diagnosis can be made ased on positive tumor markers, radiation may even e curative in some patients. However, the goal for reating children is generally to reduce or eliminate heir radiation exposure, and chemotherapeutic regi- ens are usually used as part of the treatment

rotocol.119

Chemotherapy. Chemotherapy is very successful in treating most germ cell tumors.121 Protocols primarily nclude a platinum-based regimen along with drugs, uch as cyclophosphamide and etoposide. Recent clin- cal trials have explored the role for preradiation hemotherapy, allowing for response-based radiation

osing (for germinomas). Achieving an appropriate

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balance between radiation and chemotherapy side effects is challenging but a key aspect in the treatment for GCT.122

Prognosis and Follow-Up. As would be expected with a tumor that responds well to chemotherapy and radiation, cure rates are quite good for germ cell tumors. Germinomas have the best outcome, with long-term survival rates greater than 90%. Despite more intensive treatment being used, the prognosis for nongerminoma- tous germ cell tumors is not as good, showing a 60% to 70% overall survival.119,123 The posttreatment follow-up lan for patients with GCT is similar to that of other CNS umors in children. In patients with detectable tumor arkers at diagnosis, routine serum and/or CSF samples ill be useful in the early detection of recurrent disease. egular interval MRI scans of the brain and spine should e done every 3 or 4 months at first and then occur with ecreasing frequency in the progression-free years after reatment.

Craniopharyngioma

Background/Presentation Case 4: Supratentorial Mass. A 16-year-old boy resents with a 2-month history of progressive head- ches followed by a several day history of intermittent omiting. He was seen and treated in a local emer- ency room for dehydration and sinusitis. However, ow he is experiencing intractable vomiting and his eadaches have increased in severity. His physical xamination shows loss of visual fields. Despite its classification as a WHO grade I tumor,

raniopharyngiomas can cause a tremendous amount f morbidity and long-term complications (Fig 8). his is primarily due to their location in the suprasellar

egion. These tumors will inevitably disrupt the hypo- halamic–pituitary axis, which can lead to the full pectrum of endocrinopathies. Patients may present ith growth deficiencies, visual changes or loss, ad-

enal crisis, headaches, or seizures. On imaging, craniopharyngiomas appear as a multi-

ystic enhancing mass with some solid components. alcification is frequently found, and CT scanning can ften be helpful to distinguish a craniopharyngioma rom other tumor types. Histologically, these are low-grade WHO grade I

esions with a characteristic appearance under the micro- cope. As craniopharyngiomas cause problems locally in

he suprasellar region and do not tend to spread through-

96

ut the CNS axis, routine spinal imaging or CSF collec- ion is not essential for staging purposes.

Treatment Surgery. Craniopharyngioma is primarily viewed as

a surgical disease, and all patients should be managed by neurosurgeons who have specific expertise with this tumor. Although complete surgical resection would theoretically be curative, it is rarely accom- plished due its proximity and adherence to surround- ing vital structures in the brain. These tumors can also be very calcified, revealing rock-like characteristics intraoperatively. Multiple surgical approaches some- times are needed to provide a durable remission.

Radiation. For an unresectable craniopharyngioma, radiation can play an important role in preventing recurrence. However, because there are many critical structures in the target field, radiation should be delayed or spared in very young children. Modern techniques, such as 3-dimensional (conformal) radia- tion or proton beams, may help minimize scatter and side effects of the radiation.124

Chemotherapy. Chemotherapy plays a minor role in the treatment or stabilization of craniopharyngio- mas. As a relatively benign tumor, high-dose chemo-

FIG 8. Craniopharyngioma. Note the distortion artifact coming from the face, most commonly due to dental appliances (MRI sagittal image, T1 � contrast).

therapy has not been shown to be of benefit. Systemic

Curr Probl Pediatr Adolesc Health Care, April 2012

s g p m

i i

( s

pat

chemotherapy also has limitations in treating the cystic aspects of craniopharyngiomas. Some studies have suggested a benefit of injecting chemotherapy directly into the cysts.125 However, this approach to therapy is complicated by the presence of multiloculated cysts and the risk associated with chemotherapeutic agents leaking into the surrounding brain tissue.126

Prognosis and Follow-Up. A craniopharyngioma often progresses into a chronic condition with signif- icant morbidity. Even if tumor cysts are surgically drained and cyst walls are removed, regrowth is common and multiple surgeries are often required. The adverse effects of the tumor, surgery, and radiation can have a profound impact on patients, who are often left with hypothalamic dysfunction and panhypopituita- rism.127 Severe problems with leep, learning, vision, and weight ain are not uncommon and these atients definitely benefit from a ultidisciplinary team approach.128

Patients should receive routine sur- veillance MRI scans but nonetheless symptoms will often recur rapidly because of cyst reaccumulation.129

Late Effects in Pediatric Neuro-Oncology

The late effects of brain tumors in childhood can manifest in a wide array of problems. Neuro- cognitive decline, memory diffi- culties, social skill deficits, sec- ondary malignancies, neurologic deficits, seizures, growth deficien- cies, and endocrinopathies are just a few of the many aspects requiring long-term care in these patients.

Late Effects—Tumor

A growing brain tumor compressing the surrounding structures inevitably will lead to devastating conse- quences for children. The duration of time from the development of symptoms to diagnosis impacts the reversibility of the damage incurred. Those tumors that develop in an unresectable location (eg, brain stem, thalamus) can lead to significant motor and neurologic

The late ef tumors in c manifest in

of proble cognitive de

difficulties deficits,

malignancie deficits, sei

deficien endocrinopa

few of the requiring lon

these

dysfunction despite being slow growing. Hydrocephalus

Curr Probl Pediatr Adolesc Health Care, April 2012

tself can be a risk factor for long-term morbidity, ncluding cognitive impairment and visual loss.130

Late Effects—Surgery

The late effects of surgery can be quite significant for children, even in the absence of complications.131

Because the survival rates for some tumors are dra- matically improved by more aggressive surgery (ie, ependymoma), these patients may be at higher risk of neurological consequences because of the procedures.

An entity known as posterior fossa mutism syndrome also known as cerebellar mutism) can occur after urgical resection of a posterior fossa mass. Risk factors

are not well understood, but it is estimated that up to 10% to 20% of patients undergoing resection for medulloblastoma will develop this syndrome. Soon after the immediate postoperative period, patients be- come unable to speak or express themselves and generally have pro- nounced mood dysregulation and hypotonia. With regards to long- term effects, almost all patients with cerebellar mutism will demonstrate a slow steady recovery, but most will suffer some measurable degree of neurocognitive impairment132,133

and the emotional dysregulation can be longstanding.

Late Effects—Radiation Therapy

Therapeutic doses of ionizing ra- diation are well recognized to cause significant neurocognitive injury to

the developing brain.56,134 As might be expected, the severity of this impact is inversely proportional to age. Full-dose radiation to the brain of a young infant will probably lead to mental retardation and the need for lifelong assisted living. For a young child, there may be a measurable drop in intelligence quotient of approxi- mately 20-30 points, resulting in significant learning difficulties.135

Radiation to specific parts of the brain can lead to an increased risk of particular side effects. The blood vessels in the brain are particularly susceptible, which predispose to an increased risk of vascular events.

s of brain hood can ide array

. Neuro- e, memory

ocial skill ondary neurologic es, growth s, and s are just a ny aspects erm care in ients.

fect hild a w ms clin , s sec s,

zur cie thie ma g t

Moya-moya syndrome refers to a particular vasculopa-

97

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n i p o t a i h t w

s w l t p a t m t g i

thy that can be due to radiation, associated with an increased risk of ischemia and stroke.12 The hypotha- amic pituitary axis is quite sensitive to the impact of adiation, with varying degrees of effect depending on he affected hormone.136 Although the maximum dose f radiation is generally focused on the tumor or tumor esection cavity, there is a certain amount of “scatter” hat can affect surrounding nontargeted organs as well. he most obvious examples are the hair and skin, hich are always involved in the radiation field. lthough generally a cosmetic issue, partial or com- lete alopecia is not uncommon during radiation, and his can sometimes be a permanent effect. As the inner ar also is quite sensitive to radiation, treatment of the osterior fossa with radiation can cause secondary earing loss. Although the eyes generally are spared, catter doses can cause cataracts to develop later in ife. As the thyroid gland is very sensitive to the ffects of radiation, patients exposed to craniospinal adiation have a significant increased risk of develop- ng secondary hypothyroidism later in life. Moreover, s craniospinal radiation results in a certain amount of xposure to the chest and abdominal organs, its toxic ffects can result in pulmonary fibrosis or cardiotox- city.134

Radiation also leads to an increased risk of second- ary malignancies, or “radiation-induced tumors.” In the brain these are most commonly meningiomas, which can present anytime during a person’s lifetime. Although surgery most often is curative in these cases, anaplastic variants have been reported. Secondary high-grade gliomas arising within the radiation field have also been reported, and these have a dismal prognosis.5

Late Effects—Chemotherapy

With the increasing use of chemotherapy in the treatment of brain tumors, physicians need to be aware of the long-term impact. Chemotherapy can lead to secondary malignancies; the most common form is treatment-related leukemia associated using drugs, such as etoposide and cyclophosphamide. Alkylating agents, such as cyclophosphamide, can also have a dose-dependent impact on fertility and result in early menopause. Pretreatment fertility counseling should be offered to all patients as an important component of treatment planning. Platinum-containing drugs are im- portant in the treatment of brain tumors, but come with an increased risk of sensorineural hearing loss and

kidney damage. Although peripheral neuropathies

98

sually improve after the discontinuation of drugs, uch as vincristine or cisplatinum, the effects can ccasionally be permanent. Anthracyclines (such as oxorubicin) are less commonly used in the treatment f brain tumors compared to other pediatric cancers, ut exposure to these medications is associated with ong-term cardiotoxicity.137,138

Less is known in children about the long-term toxicity of newer experimental agents. Many of the new therapeutic approaches use drugs that target the molecular pathway implicated in tumor growth. Oth- ers target the ability of a tumor to create its own blood supply, in an “antiangiogenic” approach.78 Even if a ew drug is not “cytotoxic” like classic chemotherapy, t could have the potential for unique and even more otent toxicities to the growing child. Although most f these agents first will have been studied in adults, here is obviously a lack of emphasis placed on growth nd development in adult trials. Therefore, it will be ncreasingly important to track young patients that ave been exposed to new agents over the long term, o understand the multifactorial impact that new drugs ill have on growth and development. Follow-up screening of patients who are long-term

urvivors of brain tumors should occur in conjunction ith a multidisciplinary oncology program. Many

arge pediatric centers operate clinics that provide care o patients until early adulthood, but the issue of atients being “lost to follow-up” is common. Patients nd their families should be aware of the treatment hey received, including the cumulative doses of che- otherapy and radiation that were given. Providing

his information in a format they can share with their eneral practitioners will help facilitate them in receiv- ng the best care in the future.

Conclusions and Future Perspective on Pediatric Tumors of the CNS

Conventional treatment approaches to pediatric brain tumors have historically been based on the histology of the tumor and the patient’s age. However, the advances in recent years among all disciplines have led to knowledge that will impact management. Ad- vances in neuroimaging techniques have improved histologic prediction capability, as well as offering insights into potential markers of response. From the surgical perspective, cooperative group studies have

demonstrated that extensive tumor resection is impor-

Curr Probl Pediatr Adolesc Health Care, April 2012

c p t l

m p g t t a v n l t b t v

tant in successful outcomes for several tumor types, and improved operative techniques have enhanced the percentage of patients able to achieve extensive tumor removal. New operative techniques have also allowed for the investigation of new drug delivery technolo- gies. New radiation techniques, such as conformal intensity-modulated radiation and proton beam ther- apy, have allowed for reduction in both fields and doses, sparing children from some of the untoward long-term effects of radiation. Adjuvant chemotherapy has permitted reduction in the total dose of craniospi- nal radiotherapy for treating standard-risk medullo- blastoma, whereas intensifying chemotherapy regi- mens has improved survival for children with high- risk disease. The successful use of chemotherapy has also permitted a reduction in the size of radiation fields and dosage amounts for children with germ cell and choroid plexus tumors.

It is the burgeoning information emanating from laboratory research that offers the greatest promise for the advancement and ultimately improved survival in pediatric neuro-oncology. Biological studies have identified molecular factors that correlate with thera- peutic outcomes for several tumor types in children, including medulloblastoma, PNET, and high-grade gliomas. There is a greater understanding of age- related differences within tumor types, specifically medulloblastoma and high-grade glioma. In addition, the identification of molecular pathways implicated in tumor growth has provided the biological rationale that has led to specific targeting with investigational agents. Moving forward with these new and exciting discoveries will enhance the stratification in upfront therapeutic approaches, resulting in the next great leap toward improved outcomes.

Another major effort today lies in improving the long-term quality of life, particularly in those children who survive their disease but commonly suffer mor- bidity from treatment or the tumor itself. With the ability of identifying subgroups of brain tumors with similar favorable characteristics, risk-adapted thera- peutic strategies are being investigated to balance overall survival with quality-of-life issues. Detailed assessments and analyses are now emphasized in follow-up, particularly in the neuroendocrinologic and neuropsychological domains; these will guide future refinements in therapeutic approaches. For affected patients, timely institution of hormone replacement or educational interventions may be beneficial in opti-

mizing long-term functional outcome. In addition,

Curr Probl Pediatr Adolesc Health Care, April 2012

urrent studies examining strategies, such as neural rotection and pharmacologic remediation, offer addi- ional hope for improving the quality of life for ong-term survivors. The field of pediatric neuro-oncology requires a ultidisciplinary approach, including the experienced

ediatric neurosurgeon’s hands, the detailed neurolo- ist’s assessments, the careful planning of the radia- ion oncologist, the coordinating treatment efforts of he neuro-oncologist, and ongoing case management nd family support by the child’s primary care pro- ider. Access to specialists in neuroendocrinology, euro-ophthalmology, neuropsychology, and school iaison personnel is also of significant importance. It is his collaborative and coordinated care approach that enefits these children, so that despite their brain umors and various treatments, each may achieve their ery best outcome and highest potential.

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