Epidemiology and Etiology

Pediatric central nervous system (CNS) tumors account for nearly 20% of all childhood neoplasms, exceeded in incidence only by leukemia, and are the leading cause of cancer death in childhood. Incidence is about 1 per 30,000 children each year.¹ Although roughly two thirds of all patients are alive 5 years after diagnosis, survivors suffer from neurologic, cognitive, psychologic, and endocrinologic sequelae of both the disease and its treatment. Boys and girls are equally affected, except for medulloblastoma, germ cell tumors, and ependymoma, in which more boys are affected.^2–4 Tumors can rarely appear in association with genetic syndromes (Table 53-1), but more often appear to arise spontaneously. The tumors are sometimes found to harbor somatic genetic changes, such as mutations in single genes in atypical teratoid rhabdoid tumor (ATRT; INI1) or high-grade astrocytoma (p53), aberrant gene expression pathways in medulloblastoma (SHH, Wnt, and Notch), and chromosomal losses or gains in high-grade astrocytoma (10), medulloblastoma (17p, 8q24), ependymoma (22), and germ cell tumors (12p).⁵ Some tumors, do not have a consistent genetic or chromosomal abnormality. Environmental exposures, aside from radiation, have been difficult to associate consistently with development of any CNS tumor. High-dose ionizing radiation clearly increases the risk of developing a meningioma or malignant glioma.⁶

Table 53-1 Syndromes Associated With Pediatric Central Nervous System Tumors

CNS, Central nervous system.

Anatomy

In contrast to adults, the majority of pediatric CNS tumors are infratentorial (i.e., cerebellum, brain stem, and fourth ventricle) and primary in origin. The location of the tumor may be related to cause; for example, germ cell tumors are likely to develop in the midline periventricular region after abnormal migration of stem cells, and medulloblastoma may arise in the cerebellar external granule cell layer. Tumor location also dictates presenting symptoms (see Clinical Presentations, in the following text). For example, intrasellar or parasellar lesions may produce hormonal and visual abnormalities. Anatomy likewise plays a key role in determination of treatment and prognosis. For instance, pilocytic astrocytomas of the cerebrum or cerebellum are often completely resected and fully cured, whereas those in the diencephalon or brainstem can less easily be resected and require radiotherapy or chemotherapy. Patients with ependymoma, or embryonal and germ cell tumors involving the ventricles, may require more extensive postoperative irradiation as the circulation of the cerebrospinal fluid (CSF) is an important route for tumor dissemination.

Pathologic Conditions

Whereas most adult primary brain tumors are high-grade astrocytomas, the heterogeneity of histologic diagnoses in children is striking. Photomicrographs of the most common tumors, pilocytic astrocytoma, medulloblastoma, ependymoma, and germinoma, are shown in Fig. 53-1 through Fig. 53-4. Historically, brain tumors have been identified by correlative normal cells of putative origin: astrocytes, neurons, and oligodendroglia. However, biologic proof of such derivation is wanting.⁷ There is only minimal correlation between the incidence of particular histologic types of cancer in the brain and the absolute number of potential precursor cells in that region.⁸

FIGURE 53-1 • Astrocytoma. A, Grade I; B, grade II; C, grade III.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

FIGURE 53-2 • Ependymoma.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

FIGURE 53-3 • Medulloblastoma: Homer-Wright rosettes.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

FIGURE 53-4 • Germinoma.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

At present, the most recent classification by the World Health Organization (WHO) sorts CNS tumors as follows: tumors of neuroepithelial tissue, tumors of cranial and paraspinal nerves, tumors of the meninges, tumors of the sellar region, lymphomas and hematopoietic neoplasms, germ cell tumors, or metastatic tumors.⁵ Neuroepithelial tumors can be subtyped further into astrocytic, oligodendroglial, oligoastrocytic, ependymal, choroid plexus, neuronal, pineal, or embryonal tumors. Although the majority of pediatric brain tumors are reported to be glial in origin (e.g., pilocytic and diffuse astrocytomas), children also display a diversity of tumors seldom or never seen in adults: medulloblastoma, choroid plexus papilloma and carcinoma, ganglioglioma, astroblastoma, pleomorphic xanthoastrocytoma (PXA), and dysembryoplastic neuroepithelial tumor (DNT). Previously, medulloblastoma and other embryonal neoplasms were all lumped together as primitive neuroectodermal tumors (PNETs), but now are known to be biologically distinct as medulloblastoma, atypical teratoid rhabdoid tumor, pineoblastoma, ependymoblastoma, and other supratentorial PNETs.⁹ Certain adult tumors, such as oligodendroglioma, oligoastrocytoma, and well-differentiated astrocytoma, are relatively uncommon in children, and such diagnoses should be questioned for accuracy. For example, DNT is commonly mistaken as oligodendroglioma and PXA sometimes misinterpreted as glioblastoma.¹⁰ Calcification and cyst formation are representative of a chronic course and typically indicative of more indolent tumors, such as craniopharyngioma, epidermoid tumor, ganglioglioma, and pilocytic astrocytoma. For the pediatric patient with a CNS tumor, consultation with a neuropathologist skilled in the range of childhood brain tumor diagnoses is highly warranted, especially because diagnosis determines treatment planning.

Tumor grade less often determines treatment and outcome, compared with adults. Although the WHO employs a traditional I to IV scale of increasing anaplasia, some tumors have no variability in grade, or, for some, tumor grade may not distinguish outcome or be mistakenly reassuring of outcome. All medulloblastomas are recorded as grade IV, although there is now a movement to subclassify these neoplasms based on anaplasia, desmoplasia, and nodularity.¹⁰ Ependymomas are graded only as well-differentiated (WHO grade II) or anaplastic (WHO grade III), although numerous studies have failed to show a difference in outcome.¹¹ All pilocytic astrocytomas are graded as I. Nevertheless, suprasellar and other midline pilocytic tumors often require chemotherapy or irradiation and result sometimes in death, unlike the grade I cerebral and cerebellar gangliogliomas and pilocytic astrocytomas cured simply by surgical removal. The majority of astrocytomas in children are pilocytic astrocytomas (WHO grade I) and do not undergo anaplastic transformation, in distinction to diffuse astrocytomas (well-differentiated astrocytoma [WHO II], anaplastic astrocytoma [WHO III], and glioblastoma multiforme [WHO IV]), more commonly seen in adults. Recently the diagnosis of pilomyxoid astrocytoma has been adopted by the WHO as a grade II, more aggressive variant of pilocytic astrocytoma.⁵

Clinical Presentations

The presenting symptoms and signs of intracranial lesions in the developing child vary, depending on tumor location, grade or growth rate, and age at presentation (Table 53-2). These factors also influence the time to diagnosis. A long prodrome over months to years often indicates a more favorable histology and grade, whereas a short prodrome of just weeks or months may indicate an aggressive neoplasm. Symptoms and signs may be generalized (e.g., developmental delay, irritability, growth failure), or secondary to an increase in intracranial pressure (e.g., headache, vomiting, papilledema). If the sutures have not yet fused, toddlers often manifest increased intracranial pressure chronically by macrocephaly with an increased head circumference, and sometimes split cranial sutures or tense, open anterior fontanelle.

Table 53-2 Frequent Symptoms and Signs of Pediatric Central Nervous System Tumors

Some symptoms and signs are more specific and localizing (e.g., change in handedness, focal motor or sensory deficit, ataxia, optic nerve atrophy). Infratentorial tumors present most often with headache, vomiting, ataxia, and strabismus. Supratentorial lesions may be heralded by seizures and focal deficits. Involvement of the optic nerves, chiasm, or tracts produces visual field deficits and loss of visual acuity. In a child younger than 2 years of age, developmental delays and “failure to thrive” are seen with diencephalic lesions. Involvement of the hypothalamus or sellar region may produce endocrinologic aberrations (e.g., diabetes insipidus, abnormal weight gain, precocious puberty, amenorrhea, acromegaly, and galactorrhea). Pineal tumors may cause pressure on the tectum, resulting in Parinaud syndrome (i.e., upgaze paralysis, sluggish pupillary responses, and abnormal convergence). Brainstem lesions typically produce cranial nerve palsies and motor, sensory, and cerebellar deficits.

Routes of Spread

Childhood astrocytomas, other gliomas, and a number of other brain tumors generally do not relapse or recur far from the primary lesion. Unfortunately, as vital structures are compressed within the confines of the skull, it is destruction of the primary organ, rather than metastasis, that results in great morbidity and mortality. Malignancies such as medulloblastomas, ATRT, pineoblastoma, supratentorial PNET, germ cell tumors, and sometimes ependymoma can spread through the ventricular system and metastasize along the meninges or spine. It is particularly common for medulloblastoma to metastasize beyond the posterior fossa to involve the meninges or parenchyma of the spine or cerebrum. Although brain tumors can metastasize outside the CNS, this is currently thought to be a rare occurrence, and the documentation of such events in earlier reports may have been the result of tumor cells that spread through unfiltered shunts during an era when chemotherapy was seldom used for brain tumors.¹² Hematogenous and lymphatic tumor spread are not relevant in brain tumors.

Diagnostic and Staging Studies

With the exception of germ cell tumors, there are presently no biochemical markers for brain tumors that can be evaluated from the blood. Germinomas may produce low levels of beta-human chorionic gonadotropin in some cases, but its elevated presence or that of any alpha fetoprotein is always indicative of choriocarcinoma or endothermal sinus (yolk sac) tumor, respectively, or mixed nongerminomatous germ cell tumors (NGGCTs). CSF should be evaluated for cellular metastases in all patients with medulloblastoma and other embryonal tumors, including ATRTs, along with ependymoma and germ cell tumors. Cytology and biochemical studies of the CSF should be performed 10 to 14 days after surgical extirpation to avoid misinterpretation by postoperative cellular debris. Patients with lesions involving the optic nerve, chiasm, or pituitary gland should undergo formal ophthalmologic examination and visual-field testing after surgery and before radiation therapy. Furthermore, all lesions in the region of the hypothalamus or pituitary require careful pretreatment as well as post-treatment evaluation of hormonal function. Pediatric patients who undergo cranial irradiation should be evaluated for cognitive function before and after treatment. Documentation of growth and hearing by audiometry should be performed as well. In addition to these studies, the emotional needs of the family, parents, and siblings, as well as the patient, should not be overlooked.

Dramatic improvement in neuroimaging during the past 2 decades have resulted in major advances in diagnosis and targeting of therapy for lesions of the CNS. Young children often require sedation or general anesthesia for any study, but magnetic resonance imaging (MRI) yields the best definition of parenchymal lesions, as well as clear views of the posterior and middle cranial fossa. MRI has replaced myelography for evaluation of the spine, and is therefore the modality of choice for evaluation of the craniospinal axis. Preoperative MRI with gadolinium contrast should include images of the brain, and when there is a posterior fossa tumor or a supratentorial tumor suspected to be embryonal or germ cell, the entire neuraxis should be imaged. Postoperative MRI scan with gadolinium contrast needs to be performed within 48 hours of surgery to evaluate the extent of resection, prior to the onset of postoperative edema and potentially artifactual enhancement. All these MRI data are of critical importance for planning further treatment and for defining the gross tumor volume (GTV) and the clinical treatment volume. Following radiotherapy, the results of treatment are followed by routine interval MRI scans, and in cases of ambiguous findings, MRI techniques such as spectroscopy and diffusion-weighted imaging, or positron emission tomography (PET), may be used to distinguish between recurrent tumor and treatment effects, such as radiation necrosis. Figure 53-5 demonstrates the radiographic appearance of the common tumors by MRI.

FIGURE 53-5 • Magnetic resonance images of common lesions. A, Medulloblastoma; B, astrocytoma (B1, juvenile pilocytic astrocytoma; B2, anaplastic astrocytoma; and B3, glioblastoma multiforme); C, ependymoma; and D, germinoma.

(Courtesy Dr. A. James Barkovitch, University of California–San Francisco.)

Staging System

In contrast to staging systems for other types of cancer, CNS tumors are staged mostly by extent of metastasis using the M scoring of the Chang staging system (Table 53-3), with some consideration of extent of resection.¹³ Tumor extent at diagnosis by the Chang T score is no longer used. Indeed, T_3B brainstem invasion in medulloblastoma was once considered to place a patient at higher risk of recurrence, but has now been shown not to be predictive.¹⁴ At present, medulloblastoma in children ages 3 and older is risk-stratified as average- and high-risk. Less than total resection (>1.5 cm² residual), any metastasis (M+), or severe anaplasia on the histologic specimen place a child into high-risk status. Only complete resection, no metastasis, and absence of diffuse anaplasia are consistent with average risk. For other pediatric CNS tumors, histologic type and M-stage largely indicate risk and dictate dosage and volume of radiotherapy, whereas extent of removal merits therapy based only on the histologic type.

Table 53-3 Chang Staging System

Standard Therapeutic Approaches

Pediatric brain tumors require initial surgical evaluation in almost all cases. During the past 20 years, the availability and resolution of MRI has improved the ability to diagnose and localize CNS tumors, thereby decreasing postoperative morbidity. Surgical intervention provides a histologic diagnosis and offers therapeutic benefit by tumor debulking or removal. In selected cases, especially when the lesion is inaccessible, computed tomography (CT) or MRI-guided stereotactic biopsy can limit the morbidity of obtaining a tissue diagnosis. Endoscopy can also be successfully employed to take biopsy samples of periventricular tumors under direct visualization. Endoscopy can also be used sometimes to perform a third ventriculostomy, rather than place a ventriculoperitoneal shunt, and redirecting CSF flow while avoiding shunt dependency. Should the normal CSF pathways be severely compromised, children may nonetheless require CSF diversion via a ventriculoperitoneal or ventriculoatrial shunt to relieve obstructive hydrocephalus.

Functional mapping to distinguish the motor and sensory cortex permits the identification of critical brain structures to be avoided. In addition, stereotactic surgery and techniques using handheld, computer-guided instruments offers the opportunity to localize the surgical procedure with much greater accuracy than was previously possible. Surgical resection using ultrasonic aspirators improves the probability of achieving a gross total resection and decreases the risk of damage to normal tissues.

The benefit of performing maximal debulking of the tumor mass safely should be sought, because it improves prognosis and limits adjuvant therapy.¹⁵ Only for germ cell tumors has extent of removal been shown not to influence outcome.¹⁶ In some instances, surgical resection or biopsy is not performed, namely some optic pathway gliomas (i.e., pilocytic astrocytomas), diffuse intrinsic pontine gliomas, and some germ cell tumors diagnosed by tumor markers. Diffuse intrinsic pontine gliomas are often diagnosed simply by radiographic appearance on MRI of a ventral pontine tumor engulfing the basilar artery in a child with strabismus, ataxia, and weakness over just weeks or several months. Elevated serum or CSF alpha-fetoprotein in the setting of a sellar or pineal tumor is considered diagnostic of an NGGCT, and some individuals consider an elevated serum or CSF beta-human chorionic gonadotropin of less than 50 IU/L without elevation of alpha-fetoprotein diagnostic of germinoma. Except in very young children, incomplete surgical resection of most high-grade malignancies requires postoperative radiotherapy.

Chemotherapy provides in some children the opportunity to delay radiation therapy until older or to augment the survival benefit of radiation alone, or in some cases allows reductions in volumes or dosages of radiation. Whether based on prospective, randomized clinical trials; single-arm prospective studies; or parallels drawn from adult experiences; the modern era has seen chemotherapy incorporated into the treatment of most pediatric brain tumors.

Radiotherapy is a key component of treatment for most pediatric CNS tumors. Although planning techniques and the ability to localize tumor volumes have improved significantly in recent years, it is difficult to correlate this progress with improvements in survival. Likewise, it has been difficult to prove any benefit from altered fractionation schemes that have come from radiobiologic studies. In contrast, recent studies have suggested that sophisticated treatment planning and sparing of normal tissues have perhaps mitigated neurocognitive sequelae associated with radiation therapy to the young brain (see Toxicity of Radiation Therapy, in the following text).

Radiotherapy of childhood brain tumors should be performed at centers with dedicated pediatric oncology departments. Although radiation therapy plays a key role in the treatment of CNS tumors, delivery of adequate therapy must always be balanced against potential treatment-related toxicity. Both biologic and physical techniques can maximize the therapeutic ratio of radiation, thus enhancing tumor kill while protecting normal tissues. Precise planning and delivery of radiation have evolved rapidly in the past decade.

Improved imaging technology, specifically MRI and CT, and biologic, metabolic imaging such as PET, have improved delineation of tumor and surrounding critical structures. Novel techniques capitalize on an improved definition of tumor volumes, allowing clinicians to decrease the dosages delivered to critical structures while maintaining or increasing the dose to tumor. The advent of other technical advances such as multileaf collimation, digitally reconstructed radiographs, and electronic portal imaging have contributed to the integration of conformal radiation delivery. Intensity-modulated radiation therapy (IMRT) has the potential to reduce morbidity (e.g., spare the inner ear in posterior fossa treatment).

CT images are analyzed jointly by radiation oncologists, diagnostic radiologists, and occasionally by other treating clinicians, such as pediatric oncologists and pediatric neurosurgeons. The treatment volume is dictated by the natural history of the tumor. GTV is defined by physical examination and imaging studies, and encompasses the macroscopic extent of the tumor, as defined by preoperative MRI contrast and fluid-attenuation image recovery (FLAIR) MRI images. Clinical target volume (CTV) contains both the GTV and areas at risk for microscopic spread of disease. Planning target volume (PTV) is defined as the CTV surrounded by adequate margin to account for variation in patient position, organ motion, and other movement.

Once target volumes and critical structures are defined, beam geometry and weighting are defined and dose distribution is calculated. Selection of beam angles can be done by referencing axial images or by using beam’s-eye view (BEV). BEV allows visualization of the relationship of tumor volumes to the volumes of critical normal tissues as if looking from the origin of the beam. This allows beam angles and beam shaping to be selected more intelligently. Once an initial plan has been developed, the resulting dose distributions are calculated and evaluated by the clinician. The plan can then be altered to improve on initial results, if necessary. The beam directions as well as their relative weights and shapes are modified finally to optimize the three-dimensional (3-D) plan.

The last decade has seen rapid development of novel technical approaches to radiotherapy and its application to pediatric CNS malignancies. These include 3-D conformal radiation therapy (CRT), IMRT, proton-beam radiotherapy, intraoperative radiotherapy, radiosurgery, and temporary or permanent interstitial brachytherapy.

Interstitial brachytherapy allows for the delivery of high doses of radiation to a tumor region. One retrospective study reports the largest series of pediatric brain tumors treated with iodine-125 (I-125) brachytherapy.¹⁷ Twenty-eight children were treated with temporary, high-activity 125I brachytherapy for recurrent or persistent supratentorial tumors. The study is most useful in its documentation of acute and late toxicities. No grade 3 or grade 4 acute or late toxicities occurred. However, 22 patients (79% of 28 total patients) required at least one repeat operation following brachytherapy, and 17 of these 22 patients had evidence of necrosis in the resected specimen. Furthermore, little improvement was found compared with conventional methods.

Proton-beam radiotherapy has emerged as an exciting modality that may reduce long-term toxicities of radiation. Physical properties of proton beams differentiate them from photon beams and offer potentially superior dose distributions. Salient among these physical characteristics are a finite range in tissue corresponding to the energy of the incident beam and a sharply defined lateral beam edge that together produce a steeper falloff dose than can be achieved with photon-beam radiotherapy. These advantages must be weighed against proton beam contamination by neutrons that may contribute significantly to risks of second malignancies, particularly in children. Passive scatter techniques, currently used in the United States, are likely to be replaced in the future by active scanning approaches that offer better conformity of highest doses, potentially lower doses to normal structures, and reduced beam contamination by neutrons.

To date, outcome data with use of proton beam radiotherapy for CNS tumors is limited, and advocated mostly on theoretical grounds. Merchant and colleagues compared models of photon and proton dose characteristics and their predicted relationship to cognitive function in children treated for brain tumors.¹⁸ They found that small critical normal structures such as the cochlea and hypothalamus, which were anatomically separated from the PTV, received substantially less radiation using protons compared with photons. Proton radiotherapy would therefore be expected to reduce the risks of endocrine deficits and hearing loss. In addition, protons decreased the low (0-20 Gy) and intermediate (20-40 Gy) doses to the cerebrum in patients receiving focal radiation. Using longitudinal models of radiation dose-cognitive effects, their data indicate that proton radiotherapy would mitigate intellectual decline from radiation treatment.

The benefit of proton beam radiotherapy in children may be best exemplified by its use for craniospinal irradiation (CSI). Comparisons of proton beam, conventional 3-D radiation, and IMRT for treatment of the posterior fossa and spinal column suggest superior sparing of normal structures by protons. In particular, protons are likely to mitigate long-term toxicities related to hearing, endocrine, and cardiac functions. For example, 90% of the cochlea received 101.2% of posterior fossa boost dose with conventional radiation techniques, 33.4% with IMRT, and only 2.4% with protons. Similarly, 50% of the heart received 72.2%, 29.5%, and 0.5% of the posterior fossa boost dose for conventional x-ray, IMRT, and protons, respectively.¹⁹

Toxicity of Radiation Therapy

A wide range of potential toxicities complicates the implementation of radiation therapy in the treatment of tumors of the craniospinal axis. These toxicities can be severe and debilitating, particularly in pediatric patients. Care should be taken to minimize these effects. Treatment of intracranial tumors can result in damage to the eye, ear structures, brain, and hypothalamic-pituitary axis, as well as growth abnormalities. Treatment of the spine can result in growth deficits and damage to the spinal cord. Specific potential acute side effects of radiation to the CNS include epilation, skin reactions, otitis, hematopoietic depression, and somnolence. Specific late toxicities of such radiation include radionecrosis, myelopathy, leukoencephalopathy, vascular injury, neuropsychologic sequelae, endocrine dysfunction, bone and tooth abnormalities, ocular complications, ototoxicity, and induction of second primary tumors. Table 53-4 delineates the radiation doses associated with late toxicities that may result from radiation therapy to the CNS.

Table 53-4 Late Toxicities of Central Nervous System Irradiation