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CONGENITAL AND CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS
JAMES H. GARVIN, JR. AND NEIL A. FELDSTEIN

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Epidemiology
Symptoms
Diagnosis and Management
Congenital Tumors
Astrocytomas
Medulloblastomas/Primitive Neuroectodermal Tumors
Ependymomas
Germ Cell Tumors
Lymphomas
Meningiomas
Late Effects of Treatment and Quality of Life
Suggested Readings
EPIDEMIOLOGY
Malignant and benign tumors of the central nervous system (CNS) may occur at any time in infancy and childhood. Astrocytomas are the largest group, mostly of low-grade histology. Next are medulloblastomas, the most frequent malignant tumor. After these are congenital and acquired lesions, a diverse group that includes craniopharyngiomas, ependymomas, choroid plexus tumors, teratomas, and other germ cell tumors. Apart from occasional high-grade astrocytomas, the usual tumors of adults (glioblastoma multiforme, anaplastic astrocytoma, meningioma, oligodendroglioma, pituitary adenoma) are rarely seen. CNS metastases from solid tumors are also uncommon in children compared with adults.
Primary CNS tumors account for 20% of all childhood cancers, second only to leukemia. Approximately 2,200 cases are diagnosed annually in the United States in children under age 15 years, an incidence of 2.8 per 100,000. The reported incidence of childhood brain tumors in the United States increased by 35% between 1973 and 1994, due mainly to increased numbers of supratentorial low-grade gliomas and brainstem tumors diagnosed annually starting in the mid-1980s. This is probably related to the introduction and rapid dissemination of magnetic resonance imaging (MRI) at that time and the fact that MRI is considerably more sensitive than computed tomography (CT) for detection of focal low-grade tumors of the cerebrum and brainstem.
The causes of congenital and childhood CNS tumors remain unknown. There is a slight male preponderance. Most CNS tumors are sporadic, but some are seen in association with inherited genetic disorders. Children with neurocutaneous syndromes are at increased risk. For example, individuals with neurofibromatosis type 1 (NF-1) have a 10% chance of developing an intracranial tumor, and in childhood these may include optic pathway gliomas and astrocytomas elsewhere in the brain and spinal cord. The NF1 gene maps to chromosome 17q11.2, so it is of interest that allelic loss on chromosome 17q occurs in one-fourth of pilocytic astrocytomas, suggesting the presence of a tumor suppressor gene. In the less common neurofibromatosis type 2, there is a predisposition to bilateral vestibular schwannomas, which exhibit chromosome 22q deletion and NF2 gene mutations in at least half of cases. NF2 also predisposes to ependymomas, which commonly show chromosome 22q deletion, but analysis of the NF2 gene in ependymomas has revealed only a single mutation in a tumor that had lost the remaining wild-type allele.
Children with tuberous sclerosis may develop subependymal giant cell astrocytoma or occasionally ependymoma. Linkage studies have identified tuberous sclerosis genes on chromosomes 9q and 16p; allelic loss of 9q and 16p loci has been demonstrated in some subendymal giant cell astrocytomas, suggesting a tumor suppressor function. In the epidermal nevus syndrome, there is an increased risk of astrocytomas and primitive neuroectodermal tumors (PNETs). Hemangioblastomas of the cerebellum, medulla, and spinal cord are associated with von Hippel-Lindau disease, and choroid plexus tumors have occasionally been reported. Loss of chromosome 3p sequences has been described in one choroid plexus tumor, suggesting involvement of the VHL gene.
Combined cytogenetic and molecular studies of the common sporadic childhood brain tumors have identified certain genomic alterations that may also lead to the identification of genes contributing to tumorigenesis. For example, isochromosome 17q is found in approximately half of medulloblastomas (PNETs), suggesting the presence of a tumor suppressor gene.
Environmental risk factors for the development of CNS tumors include exposure to ionizing radiation. In children treated for acute lymphoblastic leukemia, there was a 1.39% cumulative incidence of secondary brain tumors (gliomas and meningiomas) at 20 years, and cranial irradiation was a dose-dependent predisposing factor. There is inconclusive evidence for any risk associated with electromagnetic fields (from electric blankets or other residential exposure). Several studies have shown an association between farm and animal exposures and childhood brain tumors, but dietary exposure to N-nitroso compounds, implicated in animal studies of brain tumor causation, was not a risk factor in young children. Maternal intake of folic acid in pregnancy may be protective against the development of PNETs, and a study in England found that the incidence of medulloblastoma declined after 1984, when multivitamin supplementation in pregnancy became widespread after reports that multivitamins with folate reduced the risk of neural tube defects.
SYMPTOMS
Children with brain tumors most often present with symptoms and signs of increased intracranial pressure. This results from obstruction of normal cerebrospinal fluid (CSF) pathways, leading to ventriculomegaly, and secondarily from direct mass effect of bulky tumors. Characteristic signs are headache, vomiting, and diplopia, but the onset may be gradual and nonfocal. Fatigue, personality change, or worsening school performance may be described. Symptoms in infants are particularly nonspecific and may include irritability, anorexia, persistent vomiting, and developmental delay or regression, with macrocephaly and seemingly forced downward deviation of the eyes (“sunsetting sign”). Persistent vomiting, recurrent headache (awakening the child from sleep), neurologic findings (ataxia, head tilt, vision loss, papilledema), endocrine disturbance (growth deceleration, diabetes insipidus), and stigmata of neurofibromatosis should all prompt further evaluation for the presence of a CNS tumor.
Symptoms and signs reflect tumor location, and in children (unlike adults), CNS tumors are divided about equally between supratentorial and infratentorial sites (Table 59.1). Supratentorial tumors, which predominate in infants and toddlers and also occur in older children, cause headache, motor weakness, sensory loss, and occasionally seizures, deteriorating school performance, or personality change. Frontal lobe tumors affect personality and movement. Temporal lobe tumors may cause partial complex seizures or fluent aphasias. The incidence of underlying neoplasm in children with intractable epilepsy approaches 20%, and the increased risk of having a brain tumor is noted even 10 or more years after a diagnosis of epilepsy. Parietal lobe tumors affect reading ability and awareness of contralateral extremities (hemineglect). Occipital lobe tumors cause visual field disturbance and occasionally hallucinations. Suprasellar lesions may cause both visual field defects and endocrine dysfunction. Parinaud syndrome (upgaze paresis and mild pupil dilatation with better reaction to accommodation than light, retraction or convergence nystagmus, and lid retraction) is specifically found in patients with pineal region tumors.

TABLE 59.1. LOCATION OF CETRAL NERVOUS SYSTEMS TUMORS IN INFANTS, CHILDREN, AND ADOLESCENTS

Infratentorial tumors, which predominate from ages 4 to 11 years, typically present with headache, vomiting, diplopia, and imbalance. Bilateral sixth cranial nerve palsy is a frequent sign of increased intracranial pressure. Brainstem tumors present with facial and extraocular muscle palsies, ataxia, and hemiparesis. Leptomeningeal spread occurs at diagnosis or recurrence in up to 15% of children with CNS tumors (more often in medulloblastoma/PNET) and may be asymptomatic or cause pain, irritability, weakness, or bowel and bladder dysfunction.
DIAGNOSIS AND MANAGEMENT
MRI is the preferred modality for imaging CNS tumors in the pediatric age group. Compared with CT, MRI is more sensitive (especially for nonenhancing infiltrative tumors and leptomeningeal involvement), can generate images in any plane (axial, coronal, sagittal), and is not compromised in the posterior fossa by bone artifact. Nonetheless, it can be difficult to distinguish tumor from surrounding edema or residual tumor from postoperative changes. MRI of the spine has replaced myelography as the standard procedure for evaluation of spinal cord lesions and leptomeningeal disease in cases of medulloblastoma, ependymoma, and pineal region tumors. Lumbar puncture for CSF cytology and tumor markers should be done in children with these diagnoses. Recommended baseline and surveillance studies, based on tumor aggressiveness and patterns of recurrence, are shown in Table 59.2. Positron emission tomography is potentially useful in characterizing metabolic abnormalities that could distinguish residual or recurrent tumor from cerebral necrosis. Thallium-201 single-photon emission CT may be more sensitive for recurrent tumors. Proton magnetic resonance spectroscopy offers similar capability and is more widely available.

TABLE 59.2. STAGING AND SURVEILLANCE OF CHILDREN WITH CENTRAL NERVIOUS SYSTEM TUMORS (21 MONTHS FROM END OF TREATMENT)

The mainstay of therapy is surgery, which can be curative by itself in congenital and benign tumors. Gross total resection is generally also attempted in malignant tumors, with the exception of intrinsic brainstem tumors and lesions deep in diencephalic structures such as the thalamus. The introduction of the operating microscope and ultrasonic aspirator has improved both the safety and effectiveness of surgery. Stereotactic (CT or MRI guided) techniques are used increasingly for biopsy or subtotal resection in difficult areas such as the basal ganglia. However, even a 99% resection of a lesion that is 10 cm3 in size will leave 108 tumor cells behind, and additional postoperative treatment will be necessary to prevent the lesion from regrowing. Surgery is important for establishing a tissue diagnosis and relieving obstructive hydrocephalus. With placement of an external drain or endoscopic third ventriculostomy followed by tumor resection, it may be possible to avoid the need for a permanent ventriculoperitoneal shunt in most patients. Operative mortality is generally not more than 1%, but morbidity varies according to the extent of surgery and condition of the child. Surgery may be facilitated by intraoperative monitoring of sensory and other evoked potentials. Adjunctive measures include the use of corticosteroids, which counteract tumor edema and are often used in the perioperative period but should be tapered within 1 to 2 weeks if possible. Patients undergoing surgery for supratentorial tumors are placed on anticonvulsants if they have had seizures or if the surgical approach is likely to cause seizures. Prophylactic anticonvulsants are generally continued for 3 to 12 months.
Radiation therapy is an important treatment for nearly all malignant CNS tumors and certain benign lesions as well. Standard doses used to achieve local control range from 45 to 55 Gy, in divided fractions of 150 to 200 cGy, to the tumor as localized on MR scan plus 1- to 2-cm margin. Higher doses can be given, often in smaller twice-daily doses (“hyperfractionated technique”), but with very high total doses there is increased risk of toxicity to the surrounding normal brain. The volume irradiated depends on tumor histology and may include an involved field or whole brain and spine. Presymptomatic craniospinal irradiation is almost always given for medulloblastoma, because of its propensity to disseminate throughout the neuraxis. Doses of 36 Gy have been used conventionally, but lower doses may be adequate if adjuvant chemotherapy is given.
Newer radiotherapy techniques may increase the effective tumor dose and limit toxicity to the surrounding brain. Stereotactic irradiation techniques in conjunction with rigid head fixation systems include single high-dose delivery (“radiosurgery”), fractionated convergence therapy, and three-dimensional conformal therapy. Interstitial radioactive implants (brachytherapy) may be appropriate in some cases. Alternative radiation sources such as neutron beam and the use of radiation sensitizers are also under study. Acute side effects of radiation therapy include headache, nausea, alopecia, skin hyperpigmentation and desquamation, and a transient “somnolence syndrome” occurring 4 to 8 weeks after treatment.
Chemotherapy is used increasingly as an adjunct to radiotherapy, as primary postsurgical treatment in infants, and in recurrent tumors. There is evidence that chemotherapy increases survival for children with medulloblastoma and high-grade astrocytoma (see below) and may be effective in delaying the need for radiotherapy in infants and young children with malignant CNS tumors. Effective agents include the nitrosoureas (carmustine, lomustine), vincristine, cisplatin, carboplatin, etoposide, and cyclophosphamide. Newer agents such as temozolomide appear promising. Chemotherapy is generally given systemically and in combination because of complementary mechanisms of action of different agents and to subvert potential tumor resistance. Regional delivery of drugs (intraarterial, intrathecal, intratumor), although potentially affording higher concentration within the tumor, has not yet been shown to be effective in childhood CNS tumors. The dose intensity of conventional systemic chemotherapy can be increased with the use of hematopoietic growth factors, which shorten the period of myelosuppression and permit use of higher doses and/or shorter intervals between treatments. A related approach is the use of extremely high doses of chemotherapy supported by autologous hematopoietic stem cell rescue for recurrent tumors or as an intensive consolidation therapy for infants.
CONGENITAL TUMORS
Craniopharyngiomas originate from rests of embryonic tissue located in the Rathke pouch, which later forms the anterior pituitary gland. They may appear clinically at any age, even later adulthood, and constitute 6% to 10% of intracranial tumors in children. They vary from small, well-circumscribed, solid nodules to huge multilocular cysts invading the sella turcica. The cysts are filled with turbid fluid that may contain cholesterin crystals. Craniopharyngiomas are histologically benign and may be categorized as mucoid epithelial cysts, squamous epitheliomas, or adamantinomas. Total surgical removal may be difficult because the tumor may invade the hypothalamus or third ventricle and adhere to optic nerves or blood vessels. Presenting signs may include short stature, hypothyroidism, and diabetes insipidus, with vision loss and signs of increased intracranial pressure. Although CT is useful for demonstrating calcification and bony expansion of the sella, MRI is preferred because of better definition of the tumor“s relationship to vessels, optic chiasm and nerves, and the hypothalamus (Fig. 59.1). A conservative approach is to drain the cyst and resect nonadherent tumor and then administer radiation therapy to the involved area. Alternatively, gross total resection can be attempted, avoiding irradiation. Recurrence rates are similar (20% to 25%), and radical surgery is likely to be accompanied by panhypopituitarism necessitating lifelong hormonal replacement therapy, whereas irradiation has lesser hormonal sequelae but causes cognitive deficits, especially in younger children. Focused treatment by stereotactic radiosurgery (“gamma knife”) may be advantageous in this regard.

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