Pediatric Brain Tumors

David L. Kaye

Patricia K. Duffner

Michael E. Cohen

Background

Intracranial tumors are the second most common malignancy in childhood (exceeded only by leukemia) and are the leading cause of cancer-related deaths in this age group. In 1992, when the first edition of this book was published, the incidence of malignant brain tumors in children younger than 15 years (Third National Cancer Survey) was 2.4 per 100,000 (1). In the period 1990 to 1994 the Central Brain Tumor Registry of the United States (CBTRUS) reported an incidence of brain tumors in children 0 to 19 years as 3.77 per 100,000, and most recently, the incidence in the same age group had risen to 4.3 per 100,000 (2). CBTRUS reported that in 2005 the number of newly diagnosed nonmalignant and malignant brain tumors in children 0 to 19 in the United States was 2,590. This overall increase in reported cases has been reflected in individual tumor types, including a rise in the incidence of ependymomas in children younger than 2 years and in astroglial tumors in children younger than 4 years (3). Part of the increase in the reported incidence may reflect enhanced neuroimaging of benign tumors, which might previously have been misdiagnosed on computed tomography (CT) scan as encephalomalacia. The possible role of environmental factors in the increasing incidence of brain tumors is being explored.

Although the incidence of brain tumors may be rising, the survival of children with certain types of brain tumors is also increasing. Today children with average-risk medulloblastomas have an 80% progression-free survival, those with high-risk medulloblastomas have progression-free survivals of 60% to 80%, and children with cerebral low-grade gliomas have 80% progression-free survivals (4). In general, children have significantly better survivals than adults. Five-year survival of children 0 to 19 years reported by the SEER (Surveillance Epidemiology and End Results) registries was 64.8%, compared with 10.7% for patients 55 to 64 years of age (2).

Brain tumors occur more commonly in children 0 to 4 years, in whom the incidence is 5.0 per 100,000, compared with children in the 10- to 14-year and 15- to 19-year age groups, in whom the incidence is 3.9 per 100,000. There is also a difference according to gender, as brain tumors are more common in boys than in girls (4.5 vs. 4.0 per 100,000), and they are also more common in white children than black children (4.5 vs. 2.9 per 100,000) (2).

The current World Health Organization classification of brain tumors is based on site, histologic type, and degree of malignancy. One fourth of all brain tumors in children are benign, a much lower percentage than in adults. Gliomas, the most common histological grouping in children, refer to any neoplasm deriving from interstitial tissue cells of the
nervous system and include such diverse tumors as astrocytomas, oligodendrogliomas, ependymomas, and glioblastoma multiforme among others. Medulloblastomas are the next most common histopathological grouping. Among children 0 to 14 years of age, the most common histopathological groupings are pilocytic astrocytomas (21%) and embryonal tumors, including medulloblastomas (17%). In contrast among the 15- to 19-year group, pilocytic astrocytomas represent 15% of tumors, whereas embryonal tumors, including medulloblastomas, represent only 6%. The most common sites for brain tumors in children 0 to 19 years are the brainstem and cerebellum (31%), followed by the cerebral hemispheres (25.6%) (2).

The survivals of children with certain types of brain tumors have steadily increased over the past 20 years. The most striking increase has been in children with standard-risk medulloblastomas whose current survivals are approximately 80% (5). These improved survivals, however, are by no means found in all children. Children with diffuse intrinsic pontine gliomas still face almost certain death within 2 years. Most of the improved survivals are due to advances in surgery, anesthesia, radiation techniques, and the advent of chemotherapy. As a result, there are now an increasing number of long-term survivors who are at risk for sequelae including cognitive decline, endocrinopathies, second tumors, leukoencephalopathy, and vasculopathy. Most centers therefore use a multidisciplinary team approach toward these children. Members of the team include neurologists, oncologists, neurosurgeons, radiation therapists, psychiatrists, psychologists, endocrinologists, pediatricians, and social workers.

Signs and Symptoms

NONLOCALIZING SYMPTOMS

The signs and symptoms of brain tumors reflect the location and nature of the tumor, the age and development of the child, the neurological system with which the tumor interferes, and the presence or absence of increased intracranial pressure. A number of symptoms associated with brain tumors are considered nonlocalizing. For example, signs of increased intracranial pressure may result from obstruction of cerebrospinal fluid (CSF) pathways or a mass growing within a fixed volume. Symptoms of increased intracranial pressure may be delayed, however, due to the ability of the young child to expand the skull. Young children may therefore present with a biphasic pattern of illness, in which temporary relief of symptoms accompanies sutural diastasis, rather than with the relentless progression of symptoms present in older children.

The nonlocalizing symptoms of increased intracranial pressure include headache, vomiting, diplopia, and personality change. Headache is a particularly important symptom. Although most children with headaches do not have an intracranial mass lesion, certain warning signs should alert the examiner to this possibility (6, 7, 8, 9, 10) (Table 8.1).

TABLE 8.1. HIGH-RISK HEADACHE WARNING SIGNS

Headaches that wake the child from sleep or occur first thing in the morning
Persistently focal headaches
Headaches of less than 6 months’ duration
Headaches associated with nausea and vomiting (especially in the absence of a family history of migraine)
Headaches that increase with Valsalva maneuvers
Headaches that are associated with confusion, disorientation, or abnormal neurological findings

In general, most children whose headaches are due to brain tumors typically develop other neurological symptoms or have findings on neurological examination particularly involving the extraocular movements or fundi by 8 weeks following onset of symptoms, and most assuredly within 4 to 6 months (11). Chronic headaches of long duration are rarely associated with intracranial neoplasms.

Nausea and vomiting, also important nonlocalizing symptoms of intracranial mass lesions, may reflect either increased intracranial pressure or direct irritation of the vomiting center in the floor of the fourth ventricle. In general, vomiting occurs in the morning and then improves as the day progresses. As noted earlier, headaches associated with vomiting are of concern if there is no family history of migraine. Persistent or recurrent vomiting should suggest intracranial pathology and merits a neurodiagnostic evaluation.

Recent personality change occurs commonly with brain tumors and may be associated with tumors in a variety of locations, not just the supratentorial region. Lethargy, irritability, and apathy are typically present. The tendency of a child to withdraw, become indifferent to playmates, or refuse to participate in play or school activities may indicate depression, but these symptoms are also seen in the context of organic disease. A deterioration in academic functioning is also commonly observed. Although these symptoms are frequently observed at presentation, they are usually seen along with other neurological signs and symptoms. An emotional, behavioral, or school-related symptom is the first symptom noted in a small percentage (up to 10%) of children with brain tumors (8). It is the extremely rare child who presents solely with these symptoms and no other neurological sign or symptom. In addition to the frequent personality changes noted previously, children with brain tumors may present with specific psychiatric disorders. A wide range of psychiatric disorders has been reported in the medical literature in association with central nervous system (CNS) tumors. These include changes in mentation, delirium, and agitation, which may be nonspecific and reflect intracranial pressure. Other cases mimicking obsessive-compulsive disorder (12), psychosis, mania, depression, and/or anorexia nervosa (13) have also been reported in children; schizophrenia, panic, and other anxiety disorders have also been reported in adults. Anorexia, bulimia, somnolence, failure to thrive, sexual precocity, or symptoms of an autonomic nature also raise the suspicion of disease of the hypothalamic-pituitary axis. The caveat resulting from these observations is that in the assessment of a new-onset acute or subacute psychiatric illness in a child, a careful history and neurological examination are essential in excluding an organic etiology.

NONLOCALIZING SIGNS

Nonlocalizing signs of increased intracranial pressure include papilledema, sixth nerve palsy, and increasing head circumference. Papilledema should always suggest increased intracranial pressure. Early signs of papilledema are an increase in the blind spot and/or loss of color vision in the presence of normal visual acuity. In contrast, visual loss and optic atrophy may indicate long-standing increased intracranial pressure.

Sixth nerve palsy, causing an inability to abduct the affected eye, is associated with diplopia. It is considered a nonlocalizing sign, as it can develop due to compression of the nerve against bony prominences resulting from diffuse increased intracranial pressure.

Although this chapter does not focus on infants and very young children, it is still important to recognize that in young children skulls will expand to accommodate a mass lesion, and as such, attention should be paid not just to the absolute head circumference but to the changing of percentiles as well.

LOCALIZING SIGNS AND SYMPTOMS

Cerebral hemispheres

The most common tumors in this location are astrocytomas, anaplastic astrocytomas, glioblastoma multiforme, primitive neuroectodermal tumors, ependymomas, oligodendrogliomas, and meningiomas. Supratentorial tumors tend to present later, with increased intracranial pressure, than those arising in the posterior fossa. This is because with cerebral hemisphere tumors, signs of pressure reflect tumor bulk rather than obstruction of CSF pathways.

Headaches are a very common presenting symptom in patients with tumors of the cerebral hemispheres. At times a focal headache can be highly correlated with tumor location, but diffuse headaches, due to increased intracranial pressure, are more common.

Because certain supratentorial tumors, such as oligodendrogliomas and desmoplastic neuroepithelial tumors, are extremely epileptogenic in nature, seizures are frequently the presenting symptom. Those tumors located in the sensorimotor region tend to be particularly epileptogenic. Most seizures are either partial seizures with simple or complex symptomatology, with or without secondary generalization. Seizures tend to be a good prognostic sign, as they occur more commonly with low-grade rather than high-grade tumors. Although most children with seizures do not have mass lesions, tumor should be suspected in those patients with long-standing seizure disorders who undergo changes in school performance or behavior, change in type or frequency of seizure, an alteration on neurological examination, or development of a slow-wave dysrhythmia on electroencephalogram (14).

Other signs and symptoms of supratentorial mass lesions include motor, sensory, and hemianopic defects. Because most brain tumors are compressive rather than destructive, motor abnormalities can be subtle and may reveal only a pronator drift, decreased arm swing, or slight dragging of the leg as opposed to the dense hemiparesis arising from a cerebrovascular accident.

Midline tumors

Midline tumors include optic pathway tumors, hypothalamic tumors, thalamic tumors, craniopharyngiomas, pineal tumors, and ventricular tumors. Optic pathway tumors and hypothalamic tumors are typically juvenile pilocytic astrocytomas. They are commonly associated with abnormalities of the visual axis and endocrinopathies. Visual loss may reflect either direct involvement of the optic nerves or chiasm or may be due to optic atrophy arising from chronic increased intracranial pressure. The presence of nystagmus in a young child, often associated with a chiasmatic mass, may erroneously be attributed to congenital nystagmus or spasmus nutans (15). Visual field abnormalities may be a sign of a craniopharyngioma, chiasmatic tumor, or a lesion compressing the optic tracts or radiations.

Endocrine dysfunction may include weight loss or weight gain. Weight loss is typical of infants with the diencephalic syndrome due to a tumor in the hypothalamus (16), whereas older children may experience an increase in weight due to damage to the satiety center in the hypothalamus. Other endocrinopathies include diabetes insipidus, growth failure, and hypothyroidism.

Precocious puberty is another endocrinopathy that should raise the suspicion of CNS disease. Children with certain pineal tumors have excessive androgen effects. Therefore minimal testicular enlargement will be found in the presence of a large penis; axillary, inguinal, and facial hair; and increase in both bone age and longitudinal growth. In contrast, males with precocious puberty secondary to hypothalamic lesions tend to have large testes with other signs of sexual precocity.

Children with pineal region tumors may present with Parinaud syndrome (failure of upward gaze, pupils that react better to accommodation than direct light, lid retraction, and convergence or retraction nystagmus). In addition, these children may have hydrocephalus, ataxia, pyramidal signs, and obtundation.

Children with craniopharyngiomas may present with signs and symptoms of increased intracranial pressure, endocrinopathies, and visual field defects (17).

Posterior fossa tumors

The posterior fossa is the most frequent location of tumors in childhood. Cerebellar astrocytomas, medulloblastomas, ependymomas, and brainstem gliomas are the most common posterior fossa tumors that develop in childhood. Children with tumors in the cerebellum typically present with disorders of coordination. Tumors in the midline tend to be associated with truncal ataxia, whereas tumors in the cerebellar hemispheres are more likely associated with appendicular ataxia. Scanning speech, hypotonia, pendular reflexes, and skew deviation of the eyes are less common. Patients with tumors of the cerebellum typically present with signs and symptoms of increased intracranial pressure due to obstruction of the fourth ventricle or aqueduct of Sylvius. In children, cerebellar astrocytomas tend to be diagnosed later than medulloblastomas, which are more malignant.

Children with tumors in the pons have the typical triad of cranial neuropathies, cerebellar signs, and long tract signs. Because of the tumor’s location on the ventral aspect of the pons, increased intracranial pressure occurs either late or not at all. Tumors in the midbrain, in contrast, are typically associated with increased intracranial pressure due to obstruction of the aqueduct of Sylvius, whereas medullary and cervicomedullary tumors are associated with bulbar signs, spasticity, and ataxia.

Ependymomas of the fourth ventricle tend to occur in very young children. They present with signs and symptoms of increased intracranial pressure as well as cranial neuropathies arising from compression or invasion of the floor of the fourth ventricle. Truncal ataxia is also common.

Neurological Evaluation

All children presenting with histories suggestive of intracranial structural disease require a complete examination by a neurologist, including comprehensive history, physical examination, and neuroimaging studies. Although CT scans provide a good screening test for children with headaches but no warning signs on examination, magnetic resonance imaging (MRI) is the procedure of choice when a brain tumor is suspected (18).

The evaluation of a child with a brain tumor consists of MRI of the brain with and without gadolinium and, in those tumors that seed the CSF, MRI of the neuraxis. In addition, examination of the CSF for abnormal cytology as well as tumor markers (in the case of pineal region tumors) completes the initial workup in most cases (19). Because medulloblastomas can occasionally metastasize to the bone marrow and bones, bone marrow aspiration and radionuclide bone scans are performed at baseline.

MR angiography can also be helpful in identifying vascular lesions, thus eliminating the need in most cases for more invasive angiography. MR spectroscopy has been used to identify tumor, determine response to therapy, and distinguish tumor from necrosis (20).

Surveillance neuroimaging of the neuraxis in children with tumors that have the potential to seed the CSF (e.g., medulloblastomas) is typically recommended on national cancer group studies. Although it is unclear how much early identification affects survival of those children who have already received radiation therapy, most investigators believe that early identification of metastatic disease is indicated (21).

Medical-Surgical Treatment

Surgery is the first approach to the treatment of almost all brain tumors. The only exceptions are the optic pathway tumor, especially in children with neurofibromatosis, some tectal tumors, and the diffuse intrinsic pontine glioma. In all other cases, surgery permits pathological confirmation of the tumor, relief of pressure, opening of CSF pathways, and removal of tumor, allowing adjuvant treatment to be more effective. In the past 10 years it has become abundantly clear that a gross total removal of tumor is associated with significantly better survivals for children with medulloblastomas and ependymomas. In some tumors such as cerebellar astrocytomas, meningiomas, choroid plexus papillomas, and optic gliomas (in those children with complete visual loss), a complete resection is associated with a cure without need for further therapy. With the advent of the operating microscope, CT- and MRI-guided surgery, microdissection, and the laser, tumors that previously were considered too dangerous to approach due to their location can be safely biopsied and either removed or at least subtotally resected.

Radiation remains the standard therapy for brain tumors in older children and adolescents. Because of concerns about the long-term effects of radiation, however, a number of modifications have been instituted. For example, children with average-risk medulloblastoma—that is, treated with gross total resection, age older than 3 years, and no metastases—are now treated with reduced-dose radiation to the neuraxis (2400 cGy vs. 3600 cGy) coupled with chemotherapy. This approach has led to no decline in survivals. Indeed, although there are no studies in which standard-dose radiation is compared with reduced neuraxis radiation plus adjuvant chemotherapy, survivals approach 80% (5).

Another change in radiation treatment involves the volume of radiation. Three-dimensional (3-D) conformal radiation to the tumor bed is now standard for children with ependymomas and infants with medulloblastomas. Hyperfractionation, in which radiation is delivered twice daily in smaller doses, has also been used in several brain tumor trials. All of these changes reflect the concerns of the neuro-oncology community regarding the delayed neurocognitive toxicity of radiation. Recently, several studies have incorporated radiation sensitizers such as carboplatin (22).

Chemotherapy is given in an adjuvant fashion on most of the national cancer cooperative group studies today. For some tumors, such as glioblastoma multiforme and primitive neuroectodermal tumors, chemotherapy is given along with full-dose radiation. In children with average-risk medulloblastomas, the use of adjuvant chemotherapy has allowed a reduction in the dose of radiation delivered to the neuraxis. In the case of germinomas, the volume of radiation can be significantly reduced if adjuvant chemotherapy is administered. The most commonly used agents for high-grade tumors are cyclophosphamide, cisplatin, etoposide, vincristine, and the nitrosoureas (BCNU or CCNU). In addition to being given in an adjuvant role, chemotherapy is now the primary therapy for young children with low-grade tumors, that is, optic pathway and hypothalamic tumors. The most common chemotherapeutic agents for this group are carboplatinum, vincristine, etoposide, vinblastine and temozolomide. For many of these children, chemotherapy has permitted a delay of radiation therapy and, in some cases, has completely eliminated the need for it. Chemotherapy not only is given as the primary postoperative therapy for low-grade tumors but has become an important primary treatment for infants and young children with malignant brain tumors (23). In these studies, radiation therapy has been delayed, eliminated completely, or limited to small volume (conformal radiation) to the tumor bed. Most recently, very high dose chemotherapy with either bone marrow transplantation or peripheral stem cell support has become a focus of investigators.

Long-term Outcome

Children’s lives are impacted by brain tumors in multiple domains. Over time, disruptions occur in neurological, endocrinological, neurocognitive, psychosocial, and psychiatric functioning. Second primary malignancies may occur. Indeed, studies of health-related quality of life indicate that the vast majority of survivors of pediatric brain tumors have deficits in multiple domains of functioning. Of all child cancer survivors, pediatric brain tumor survivors have some of the poorest outcomes (24, 25, 26, 27).

NEUROLOGICAL STATUS

Survivors of pediatric brain tumors frequently have at least one neurological sequela in the years following recovery (25,26,28,29). Ataxia, hemiparesis and hemiplegia, epilepsy, slowed speech, and visual impairments are the most common difficulties. A number of studies suggest that many of these children experience significant pain. Perhaps up to one fourth have multiple neurological disabilities.

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