Etiology And Pathogenesis

Central nervous system tumors represent approximately 20% of all childhood cancers with 2.5 to 4 cases diagnosed per 100,000 children per year. There is a slight male predominance (male : female ratio, 1.29) at all ages younger than 20 years, and infratentorial location is more common in children 1 to 15 years of age.

The etiology of most childhood brain tumors is unknown. Specific genetic syndromes, such as neurofibromatosis (NF1 and NF2), tuberous sclerosis, and Li-Fraumeni and Turcot’s syndromes, are associated with a higher incidence of tumors, but this group represents fewer than 10% of pediatric brain tumors. The only known environmental risk factor related to the development of brain tumors is exposure to ionizing radiation. Other exposures such as maternal diet during pregnancy, viral infections, cell phone use, and exposure to magnetic fields have been studied extensively with limited and conflicting data for an association with brain tumor risk.

Understanding the origin of brain tumors has been enhanced by the ability to detect specific molecular genetic alterations in tumor samples and the association of brain tumor development with inherited genetic disorders in which the gene defect is known. This has contributed to our understanding of the underlying biology of brain tumor initiation and progression and has led to the identification of therapeutic targets for drug development.

Clinical Presentation

The presenting symptoms of a brain tumor are determined by tumor location rather than histology. Brain tumors may present with either generalized or localizing symptoms. Generalized symptoms are caused by obstruction of cerebrospinal fluid (CSF) with associated hydrocephalus and increased intracranial pressure (ICP). Increased ICP is more common with fourth ventricular or posterior fossa, pineal, suprasellar, and tectal tumors. Symptoms include headache (particularly in the morning), nausea, vomiting, and fatigue. On examination, paresis of upgaze, sixth cranial nerve palsies, and papilledema are often seen. In infants, macrocephaly, tense fontanelle, failure to thrive, developmental delay, and paresis of upgaze with downward eye deviation (“sun setting”) are common. Posterior fossa tumors, such as cerebellar astrocytomas, often present with increased ICP (Figure 57-1).

Figure 57-1 Clinical presentation of brain tumors.

Localizing symptoms depend on tumor location. Cerebellar tumors commonly present with ataxia and dysmetria. Brainstem tumors may cause cranial nerve deficits (diplopia, facial weakness, swallowing deficits), unsteadiness, and weakness (see Figure 57-1). Symptoms from hemispheric cortical tumors include seizures, hemiparesis, visual field deficits, and changes in behavior or school performance. Tumors in the suprasellar region often present with bitemporal visual field loss, decreased acuity, and hormonal dysfunction. Pineal region tumors frequently compress the tectal region of the brainstem and result in Parinaud’s syndrome, characterized by paresis of upgaze, convergence nystagmus, pupils that respond better to accommodation than light (light-near dissociation), and eyelid retraction. Tumors of the spinal cord (primary or metastatic) may cause back pain, extremity weakness, sensory dysfunction, and bowel or bladder dysfunction. The most common presenting signs and symptoms are outlined in Table 57-1.

Table 57-1 Signs and Symptoms Associated with Intracranial Tumors

Differential Diagnosis

The clinical presentation can aid in localizing a brain tumor, and the anatomic location of a mass often narrows the differential diagnosis of the tumor type. Histologic confirmation is necessary in nearly all brain tumor cases with the exception of diffuse intrinsic brainstem (pontine) glioma, tectal glioma, and optic pathway gliomas in patients with NF1, in which neuroimaging alone can be sufficient for diagnosis. The differential diagnosis of brain tumors according to intracranial location is presented in Table 57-2.

Table 57-2 Differential Diagnosis of Brain Tumors by Location

PNET, primitive neuroectodermal tumor.

Evaluation And Management

When a brain tumor is suspected, neuroimaging is the initial diagnostic test to obtain. Computed tomography (CT) is often the first imaging obtained because of its speed and availability and will detect nearly 95% of brain tumors. CT is useful as a rapid study to evaluate for hydrocephalus, hemorrhage, or the presence of calcifications in the tumor. However, because of its higher resolution, magnetic resonance imaging (MRI) with and without gadolinium is the established standard for diagnosis. Children with a brain tumor confirmed by MRI should be stabilized and referred to a tertiary hospital with experienced pediatric subspecialists in neurosurgery, neuro-oncology, and neuroradiology. The management of brain tumors depends on histology, tumor location and extent, and patient age but typically involves surgery, chemotherapy, and radiation therapy. Surgery for histology and to attempt maximal tumor debulking by an experienced pediatric neurosurgeon is required in most cases.

After surgery and histologic diagnosis, further studies are needed to stage the tumor. A postoperative MRI with and without gadolinium should be done within 24 to 48 hours after surgery to determine if residual tumor remains. The MRI must be repeated within this time frame so postoperative inflammatory changes are not confused for residual tumor or vice versa. For tumors with a high likelihood of spread via the CSF, complete multiplanar spine MRI and large-volume lumbar puncture for cytology should be performed. Medulloblastoma, the most common malignant tumor in children, must be evaluated in this fashion (Figure 57-2). CSF and serum for the tumor markers α-fetoprotein and quantitative β-HCG should be sent if a germ cell tumor is diagnosed. Last, laboratory assessment of the hypothalamic–pituitary axis should be evaluated for any tumor involving the suprasellar region. Panhypopituitarism, including life-threatening diabetes insipidus, can be a relatively common postoperative complication in these children.

Figure 57-2 Brain tumors in children.

Treatment is tailored to specific tumor type and patient age. In general, regardless of tumor type, radiation therapy is avoided in infants and very young children because they are especially vulnerable to radiation-associated toxicities and neurocognitive deficits. Alternative therapies for this population include intensified chemotherapy followed by autologous stem cell transplant. For some brain tumors (e.g., low-grade gliomas), complete surgical resection may be the only therapy indicated. Common pediatric tumors with their relative incidences and prognoses are outlined in Table 57-3.

Table 57-3 Common Pediatric Brain Tumors: Incidences, and Prognoses

PNET, primitive neuroectodermal tumor; XRT, radiation therapy.

Most children with tumors of the CNS also require some form of supportive care in addition to tumor-directed therapy. This includes hormonal replacement for patients with neuroendocrine dysfunction; antiepileptic drugs for patients with seizure disorders; physical, occupational, and speech therapy; and individualized educational planning for patients with learning challenges related to tumor or treatment.

Future Directions

Improvement in the long-term survival of children with brain tumors has come with a cost. Late effects of radiotherapy include neuropsychological and neurocognitive disorders (especially in young children who received large doses of radiation), endocrinologic disorders and growth delay, and the risk of secondary malignancies. The late effects of chemotherapy include prolonged bone marrow suppression, hearing loss, renal insufficiency, and risk of secondary malignancies such as leukemia. Individualized therapies targeted to specific patient populations, tumor types, and risk groups are being studied to minimize the risks of treatment-related toxicities while continuing to improve long-term survival.