Epidemiology

Malignant brain tumors are the most common solid tumors in childhood; they account for 20% to 30% of all childhood cancers and are the leading cause of cancer-related death in this age group.^1,5 In this chapter, we provide a general overview of the important clinical, diagnostic, and treatment-related considerations in pediatric brain tumors as a reference for practicing clinicians faced with caring for these patients. The annual incidence has been reported to be 2.4 to 6.3 per 100,000, which has actually risen over the past several decades because of better diagnostic modalities and reporting practices.^3,5,7–10 Incidence rates for the pediatric population show that brain tumors are more common in white children than in black ones.³ In both, however, there is an overall slight male preponderance, with studies consistently showing a male-to-female ratio of about 1.5.^11,12 More favorable histologic subgroups have repeatedly been found to occur in adolescents, whereas tumors with higher grade, more unfavorable locations, and poorer prognosis have generally occurred in younger children, particularly those younger than 3 years.¹¹

The central nervous system (CNS) tumors that occur most frequently in childhood are vastly different from those in adulthood with regard to both histology and tumor location.¹² In contrast to adults, in whom most CNS tumors are located supratentorially, approximately 50% to 55% of all childhood CNS tumors are infratentorial.⁸ In the first 6 months of age, supratentorial tumors are actually more common; however, by 2 years of age this location reverses, with up to 60% being infratentorial.⁸ This is in contrast to the third decade of life and beyond, where only 25% to 35% of intracranial tumors are infratentorial.⁸

The overall 5-year survival rate of children with brain tumors has improved considerably over the past several years. Because of earlier diagnosis and better therapies, survival rates are now between 35% and 65%, depending on several factors, including tumor histology and location.⁹ Age is also an important prognostic indicator for children with CNS tumors in general. Data consistently show that 10- to 15-year-olds have the longest survival whereas those younger than 2 years have the shortest.¹¹

Classification

Classification schemes are important for all types of cancers because they allow physicians to make accurate predictions regarding the natural history of the disease. The response to certain therapies and prognosis can also be derived from a classification scheme.¹³ Classification schemes for CNS tumors are categorized according to the cell type from which the abnormal tissue originated.^1,12 Subclassifications of tumors derived from a specific cell type exist as well, and such tumors can differ in their histologic, cytologic, and behavioral characteristics.^12,13 CNS tumors can also be more broadly categorized into those that occur in certain age groups or locations.¹²

The cells of the nervous system can roughly be categorized as nerve cells and a variety of supporting cells called neuroglia. Glial cells greatly outnumber nerve cells by approximately 3 : 1 and include astrocytes, oligodendrocytes, ependymal cells, and microglia.¹ As a whole, gliomas and, more specifically, astrocytomas are the most common CNS tumors of childhood and account for up to 50% in some series.^1,4,11 Astrocytomas vary greatly in their histology, cytology, and behavioral characteristics and occur in several locations in the pediatric population. Pilocytic astrocytomas are the most common and represent up to 25% of pediatric CNS tumors. These tumor are considered benign and typically occur in the posterior fossa but can also be found elsewhere.¹¹ However, other common locations for pediatric gliomas include the hypothalamic and optic pathway regions. The histology of these lesions is typically low grade, but they are difficult to treat surgically as a result of their location.¹¹ Brainstem gliomas are not resectable because of their diffuse infiltrative nature, and their natural history and poor prognosis are similar to glioblastoma multiforme, which is the most common primary supratentorial tumor in adults. Focal lesions of the brainstem may have a better prognosis and can be monitored by serial surveillance with magnetic resonance imaging (MRI). Other focal lesions of the brainstem may have a dorsally exophytic portion that is amenable to surgical debulking.

The second most common CNS tumor in the pediatric population is medulloblastoma, which arises from neural stem cell precursors in the fourth ventricle and accounts for approximately 15% to 20% of tumors in this age group.^10,14 Other common CNS tumors in this population are of neuroepithelial origin and include ependymomas, which account for 10% of pediatric CNS tumors; primitive neuroectodermal tumors (PNETs), 1.9%; ganglioglioma, 2.5%; dysembryoplastic neuroepithelial tumors, 0.6%; desmoplastic infantile astrocytomas, 0.6%; and mixed tumors.^7,11

Non-neuroepithelial neoplasms consist of germ cell tumors (2.5%) of the pineal or other regions and include germinomas, teratomas, choriocarcinomas, and yolk sac tumors, as well as atypical teratoid/rhabdoid tumors (AT/RTs) (1.3%), choroid plexus tumors (0.9%), and craniopharyngiomas (5.6%).^7,11

Overall, the most common CNS tumors seen in childhood are astrocytomas, medulloblastomas, ependymomas, craniopharyngiomas, and germ cell tumors.¹² The incidence of these tumors, however, varies greatly within age groups among the pediatric population, and there is a tendency for certain tumors to occur at particular times during a child’s life (Table 194-1).^3,11 In infancy (0 to 2 years old), choroid plexus papillomas, desmoplastic infantile astrocytomas, teratomas, PNETs, and AT/RTs predominate. By childhood (3 to 11 years of age), these tumors are rare and astrocytomas and craniopharyngiomas are much more frequently seen. By adolescence (≥12 years), germ cell tumors are commonly encountered, whereas craniopharyngiomas are less commonly seen.¹¹

TABLE 194-1 Statistical Report: Primary Brain Tumors in the United States, CBTRUS, 2000-2004

CBTRUS, Central Brain Tumor Registry of the United States; NOS, not otherwise specified.

Published by the Central Brain Tumor Registry of the United States, 2008.

The distribution of astrocytomas also varies by age. As mentioned previously, pilocytic astrocytomas predominate overall and particularly in the childhood and early adolescent age groups. However, the incidence of pilocytic astrocytoma falls, and World Health Organization grades III and IV astrocytomas become more common in children older than 15 years (Fig. 194-1).^3,11

FIGURE 194-1 Statistical report: Primary brain tumors in the United States, 2000 to 2004.

(Published by the Central Brain Tumor Registry of the United States [CBRTUS], 2008.)

Oncogenic Factors

Although population studies have failed to confirm any significant environmental factors associated with the development of CNS malignancies, several syndromes and genetic markers have been shown to be associated with their development.¹ Such syndromes include neurofibromatosis types 1 and 2 (NF1 and NF2), tuberous sclerosis, and von Hippel-Lindau (VHL) syndrome, as well as many others. These disorders are associated with specific chromosomal abnormalities and lead to alterations in oncogenes and tumor suppressor genes, which typically regulate normal cell growth but, when altered, lead to tumor genesis. NF1 is associated with genetic alterations on chromosome 17 and predisposes individuals with this disorder to optic gliomas and malignant nerve sheath tumors.^1,7,12 The genetic alteration in NF2 is located on chromosome 22 and is associated with the development of meningiomas and vestibular schwannomas.^1,7 Tuberous sclerosis is caused by an abnormality on chromosome 9 that predisposes these patients to the development of astrocytomas.⁷ VHL syndrome is associated with multiple systemic malignancies secondary to an alteration on chromosome 3, including cerebellar hemangioblastomas.^1,7

Although not associated with specific syndromes, several common CNS malignancies are linked to certain genetic tumor markers that are prognostic and continue to direct research for therapy. Examples include a strong association between overexpression of the oncogene p53 in childhood gliomas. p53 mutations are found in approximately 40% of malignant gliomas in children older than 3 years, which is much higher than the frequency seen in adult gliomas.^1,12,15 In addition, the presence of the p53 mutation is associated with a poor prognosis independent of both the clinical and histologic prognostic features of the tumor at initial evaluation.¹⁵ Studies have also shown a relationship between AT/RTs and the INI1 gene on chromosome 22.¹² This has become an important diagnostic tool because AT/RTs cannot be distinguished from medulloblastoma by clinical features or neuroimaging.¹⁶ Microscopically, these tumors can also be difficult to distinguish as a result of several similar features. Antibody staining for the INI1 gene for immunohistochemical analysis has now been used to differentiate these two entities because inactivating mutations of the INI1 gene located on chromosome 22 are a crucial step in the molecular pathogenesis of AT/RTs.¹⁶ Interestingly, choroid plexus tumors, called choroid plexus papillomas and carcinomas, which are intraventricular epithelial tumors arising from the choroid plexus, may also stain for the INI1 gene.

In addition, multiple genetic markers have been linked to medulloblastoma, including Trk-C, whose presence correlates with a good prognosis, whereas overexpression of epidermal growth factor receptor 2 and c-MYC have high predictive power for a poor prognosis.^14,15 OTX2 overamplification has also been appreciated in medulloblastomas.¹⁷ OTX2 is a transcription factor that plays a role in normal cerebellar development.¹⁷ Expression of OTX2 has correlated with higher grade tumors, a poorer prognosis, and medulloblastomas that more frequently localize to the vermis of the cerebellum.^17,18 OTX2 may become important in the treatment of this disease as well, inasmuch as a recent study demonstrated that OTX2-expressing medulloblastomas were responsive to all-trans-retinoic acid in vitro.¹⁷

Clinical Features

Because CNS malignancies account for approximately a quarter of childhood cancers, it is imperative that health care professionals be able to recognize the signs and symptoms at initial encounter.⁵ The signs and symptoms at diagnosis are typically a result of tumor location but are most often secondary to the raised intracranial pressure (ICP) that occurs with 40% of all intracranial tumors in childhood.⁵ Hydrocephalus is principally seen with infratentorial tumors and is due to obstruction of the ventricular system from mass effect by the tumor. The most common symptoms of elevated ICP are headache, nausea, and vomiting, which occur especially in the morning, and lethargy.^8,10,12 Less commonly, macrocephaly and a bulging fontanelle can be seen in younger patients whose sutures have not yet closed.¹⁰ Infratentorial tumors causing compression on the brainstem can also be manifested as cranial nerve palsies.¹² A common example is Parinaud’s syndrome, which is seen with compression of the midbrain tectum from a mass effect or increasing hydrocephalus. Features of Parinaud’s syndrome include paralysis of upgaze, paresis of accommodation, and convergence nystagmus. Additionally, a local mass effect from cerebellar tumors can cause ataxia and subsequent gait disturbances.⁵