Chapter 25. Brain Tumors

Pediatric brain tumors represent the second most common form of pediatric cancer and the most common solid malignancy. The most recent statistics available report findings from 2004, and they show that the incidence of pediatric brain tumors is approximately 1100 per year, representing 20% of all childhood cancers. These neoplasms also represent the second leading cause of cancer death in US children, and the sixth leading cause of death in US children overall.1,2 Survival for children with central nervous system (CNS) neoplasms, however, has dramatically risen over the past 30 years, with 5-year survival rates of 74%, up from 57% in 1977. Most of these results are due to a combination of improved chemotherapeutic regimens, more accurately targeted and dosed radiation, and safer, more accurate surgical resection techniques.1,3

The location of childhood tumors differs from those in adults. Most pediatric tumors occur in the posterior fossa, with medulloblastoma, juvenile pilocytic astrocytoma (JPA), and ependymoma making up the majority of these lesions.1-4

The etiology of childhood tumors is poorly understood. Although certain genetic syndromes are responsible for an increased risk of tumorigenesis (Table 25-1), the majority of tumors arise de novo. Certain environmental exposures have also been implicated in the development of tumors, including toxic chemicals, cigarette smoke, radiation, medications, home microwave ovens, cellular telephones, and electromagnetic fields. Of these, the only exposure that has a proven link to tumorigenesis is ionizing therapeutic radiation.5

Brain tumors arise from multiple different cell lineages, and thus are a heterogeneous population of tumors. In this review, we will examine the following lesions: low-grade glioma, high-grade glioma, medulloblastoma, ependymoma, juvenile pilocytic astrocytoma, brainstem glioma, craniopharyngioma, and pineal region tumors (usually germ cell).

Pediatric brain tumors appear to arise from a different set of circumstances than do similar adult lesions. Craniopharyngiomas represent remains of embryonic cells that slowly differentiate over time, leading to growth of large lesions. Medulloblastomas are primitive neuroectodermal tumors (PNETs) that arise from similar but more aggressive embryonic rests. High- and low-grade gliomas are derived from newly differentiated glial cells that undergo multiple different genetic mutations, leading to malignant transformation.6

Presentation of pediatric brain tumors can differ depending on location and vary from subtle changes to fulminant coma with the need for emergent neurosurgical treatment (Table 25-2). The most common symptom of mass lesions is headache. This can be difficult to localize, and headache in the absence of other neurological signs is not an indication for neuroimaging. Other signs and symptoms include seizures, nausea/vomiting, ataxia/dysmetria, visual disturbances, macrocephaly/hydrocephalus, weakness (focal deficit), altered level of consciousness, and endocrine disturbances (including weight loss/gain, precocious puberty, amenorrhea, hypothyroidism, and diabetes insipidus).7

History and Physical Examinations

Diagnosis of pediatric brain tumors starts with a detailed clinical history and physical examinations. A combination of findings from the list of symptoms described in the earlier section will often lead to an imaging study.7 In the vast majority of cases, neuroimaging will lead to discovery and, often, diagnosis of a lesion. For emergency situations, computed tomography (CT) scanning is the study of choice. CT scanning, however, has low soft-tissue resolution, which can limit its ability to identify intrinsic brain lesions. CT also has the disadvantage of using ionizing radiation. Thus, if there is appropriate clinical suspicion, magnetic resonance imaging (MRI) is indicated. MRI allows for multiplanar imaging and much more sensitive and subtle differentiation of normal and abnormal tissues. MRI is especially suited for posterior fossa imaging, where beam hardening artifact from CT often makes accurate diagnosis of a lesion difficult or impossible. Enhanced MRI with the administration of gadolinium increases sensitivity and reveals areas of breakdown of the blood-brain barrier. This accurately depicts the tumor nidus, although this does not necessarily imply tumor grade.8

Postoperatively, enhanced MRI is the gold standard for evaluation of residual tumor. Other more specialized imaging techniques, including MR-spectroscopy and positron-emission tomography (PET) scanning, may give additional information regarding brain lesions. These technologies, however, are currently reserved for monitoring tumor response to therapy and differentiating tumor regrowth versus treatment effects such as radiation necrosis.9 The specific imaging characteristics of different types of tumors will be discussed with each separate lesion.

Medulloblastoma

Medulloblastoma is a highly aggressive form of childhood brain tumor and is the most common malignant central nervous system tumor in children. The term "medulloblastoma" is actually a misnomer, derived from the idea that these tumors arose from multipotential cells known as medulloblasts. These tumors have since been reclassified as PNETs and thus can be referred to interchangeably as PNET-MB, medulloblastoma, or infratentorial PNET. MB represents about 20% of all pediatric brain tumors and 30% of posterior fossa tumors. There is a 2 to 1 male predominance. These tumors present with a classic posterior fossa syndrome, including headache that is worse in the morning, nausea, vomiting, and a fairly rapid decline over 1 to 2 months. Occasionally presentation can be related to spinal pathology from drop metastases, including back pain, leg pain, or paraparesis. Physical examination findings include papilledema, sixth-nerve palsies, lethargy, or ataxia. The diagnostic evaluation of these lesions begins with imaging. CT can be used for emergent symptoms, but contrasted MRI is the study of choice. CT shows hyperdensity in the area of the vermis, often with speckled calcifications, ± cyst formation (Figure 25-1). MRI will show T1 iso- to hypodensity and T2 hyperintensity, as well as avid enhancement with contrast (Figures 25-2, 25-3, and 25-4). Diffusion-weighted imaging can also help differentiate these tumors from others, as it will often reveal restricted diffusion as a consequence of the lesions' hypercellularity (Figures 25-5 and 25-6). Due to the propensity of these tumors to spread through the neural axis, MR imaging of the entire neuraxis to assess for drop metastases is also indicated (Figure 25-7).10,11

Initial treatment is aimed at stabilizing the patient, often with the administration of steroids. Occasionally, emergent cerebrospinal fluid diversion such as external ventricular drain placement or endoscopic third ventriculostomy is performed. This should be followed by surgical evaluation. Tumor resection is the treatment of choice and allows for relief of mass effect, cerebrospinal fluid (CSF) diversion/drainage, and tissue diagnosis. Due to the location of these tumors and their adherence to critical brain structures, morbidity is fairly high, on the order of 25% to 40%. Complications include cranial nerve deficits, swallowing/breathing difficulties, cerebellar mutism, gaze abnormalities, hydrocephalus, and infection.12

After surgical resection, the next step in treatment is adjuvant, in the form of chemotherapy and radiation. For children older than 3 years, radiation to the tumor bed and the craniospinal axis, followed by chemotherapy alone, is the current standard.13,14 For those considered to be high risk (age less than 3 years, >1.5 mL of residual tumor, tumor dissemination) are offered chemotherapy alone if younger than 3 years, and either concurrent chemotherapy/irradiation followed by chemotherapy, or induction chemotherapy with stem cell rescue if the patient is older than 3 years. Five-year survival for low-risk tumors is as high as 80%, and recent data for recurrent and progressive disease indicates 5-year survival of almost 70% with a stem cell rescue strategy.15 Overall, however, continued research is ongoing and is attempting to focus not only on survival, but also on the morbidity, especially neurocognitive, of these treatments.

Ependymoma

Ependymomas represent about 10% of pediatric brain tumors and 15% of posterior fossa tumors.2,16 They are the third most common pediatric brain tumor behind medulloblastoma and cerebellar astrocytoma. These tumors arise from ependymal cells that line the ventricular system. The presentation of posterior fossa ependymoma is similar to that of medulloblastoma, although rarely as rapid. Signs and symptoms of hydrocephalus, compression of the brainstem, and cranial neuropathies are the most common. Classically, it is not uncommon for these patients to have gastrointestinal (GI) problems including nausea, vomiting, and poor appetite that have gone on for a prolonged period, resulting in a prolonged gastrointestinal workup prior to eventual neuroimaging that reveals a brain tumor.16-20 The best diagnostic study is contrasted MRI. These tumors will be iso- to hypointense on T1 and T2 and show heterogeneous enhancement (Figures 25-8, 25-9, and 25-10). The tumor can often be seen arising from the floor of the fourth ventricle and also exiting through the foramina of the fourth ventricle, including Luschka and Magendie (Figures 25-10 and 25-11). The extrusion of ependymomas out of the fourth ventricle is often referred to as plastic ependymoma. Imaging of the entire spinal axis is also indicated due to the rare (<10 %) occurrence of drop metastases. This imaging preoperatively is also important to distinguishing between new tumor spread and expected postoperative changes.8,9

Surgical treatment of these tumors is the first option. This allows for pathologic diagnosis, tumor gross total resection if possible, and reestablishment of CSF flow channels. Following diagnosis, the current mainstay of adjuvant therapy is conformal local radiation therapy. This currently includes conformal radiotherapy to the tumor bed in a variety of fractions and total doses ranging from 54 to 59.4 Gy.21-24 Chemotherapy also has a role in this disease, and multiple different regimens have been used, with cisplatin appearing to be the most effective agent, with approximately a 40% response rate.25-28 Overall, 5-year survival for patients with ependymoma is approximately 55% in historical studies, with some improvement recently to as high as 70% with gross total resection followed by adjuvant local involved field radiation.

Juvenile Pilocytic Astrocytoma

Juvenile pilocytic astrocytoma (JPA) is another of the most common pediatric brain tumors and is most often located in the posterior fossa. It is the second most common posterior fossa tumor, representing approximately 20% to 35% of these lesions.1,2 These tumors can also be found in the hypothalamus (Figure 25-12), optic nerves (Figure 25-13), thalamus, and the cerebral hemispheres. Pilocytic tumors are also associated with neurofibromatosis type I, and the optic nerve and hypothalamic lesions are more common in this setting. Pathologically, the classic finding with JPA is fibrillar astrocytes against a microcystic background and the presence of eosinophilic intracytoplasmic inclusions called Rosenthal fibers. Signs and symptoms of these tumors are similar to other posterior fossa lesions, including headaches, ataxia, and hydrocephalus. Optic nerve lesions can lead to visual loss.29 The diagnostic workup for these tumors is contrasted MRI. Often, these tumors have a cystic appearance with an enhancing mural nodule. Solid lesions can also have varying degrees of contrast enhancement. In spite of this enhancement, however, these tumors are often benign in their course.8 Surgical removal, when possible, is the treatment of choice.29-31 For WHO grade I tumors, survival exceeds 90% at 10 years with gross total resection. Adjuvant therapy for JPA is usually reserved for subtotally resected lesions that show signs of continued growth or for recurrent lesions after gross total resection. Radiotherapy has not been shown to affect overall survival in the nonrecurrent setting, although it has shown some efficacy in preventing disease progression.32 Chemotherapy has also not been greatly effective for these lesions in the posterior fossa, although multiple trial regimens are available.29

Craniopharyngioma

Craniopharyngiomas represent 3% to 5% of pediatric brain tumors. These tumors also occur in a bimodal distribution and are also represented in the sixth decade of life (Table 25-3). The greatest incidence in children is in the ages of 6 to 10 years.2 These tumors are benign histologically, but can cause severe morbidity due to their location. The two histologic subtypes are adamantinomatous and squamous papillary. The adamantinomatous variety is that which occurs in childhood. These tumors arise from embryologic remnants of Rathke pouch, located in the region stretching from the sella turcica through the pituitary and hypothalamus up to the third ventricle (Figures 25-14 and 25-15). They often contain epithelial remnants, and have large amounts of epithelial cells and keratin, and have associated oily cysts that can calcify. Craniopharyngiomas present with headaches in 60% to 75% of cases. Other symptoms include visual loss, hormonal changes including delayed sexual maturation, weight gain, diabetes insipidus, or growth failure; and for larger lesions, problems with cognition or seizures. Radiologically, craniopharyngiomas appear as cystic lesions arising from the sella with variable amounts of calcification. CT scanning can also show erosion or remodeling of the skull base and sella. MR imaging will also show a cystic lesion with the solid portions being hypointense on T1 and avidly enhancing with contrast (Figures 25-16 and 25-17). Cyst fluid will usually be hyperintense on T2 and have variable intensity on T1 due to the heterogeneity of the cyst contents. Sagittal MRI can also be used to distinguish these lesions from pituitary adenoma by visualizing the normal pituitary gland (Fig. 25-18).33,34 Treatment of craniopharyngioma has evolved over the years due to the nature of these tumors. As stated previously, the benign nature and location make the gross total resection of these tumors possible. However, the proximity and involvement of the hypothalamus may make gross total resection a highly morbid procedure in many instances. Complete resection of tumors with significant hypothalamic and third ventricular extension may result in severe disturbance of thirst and hunger inhibition as well as cognitive impairment. Virtually all patients have panhypopituitarism following aggressive resection. Complete resection, however, does result in 10-year progression-free survival rates around 80%. Thus, this area remains an area of considerable dispute among pediatric neurosurgeons. Surgery remains necessary to remove mass effect, treat hydrocephalus, establish a diagnosis, and decompress the optic apparatus. Alternative treatment strategies have moved toward a less aggressive surgical technique, sparing the hypothalamus and using adjuvant therapies such as intracystic or external beam radiotherapy. Morbidity of treatment is still significant, but overall survival for craniopharyngioma is 70% to 100% at 5 years, and 60% to 90% at 10 years.35-40

Supratentorial Low-Grade Glioma

Supretentorial low-grade glioma (SLGG) is a heterogeneous group of glial tumors that can include astrocytoma, oligdendroglioma, dysembryoplastic neuroepithelial tumors (DNT), ganglioglioma, and pleomorphic xanthoastrocytoma (PXA). These tumors are located anywhere in the supratentorial space and represent about 10% to 15% of pediatric tumors (Figures 25-19, 25-20, 25-21, 25-22, 25-23, 25-24, 25-25, 25-26, 25-27, 25-28, 25-29, and 25-30).1 Focal neurological findings can be seen, depending on tumor location, but headaches and seizure are the most common presenting complaints.41 The lesion types also appear different on imaging. Plain head CT is often nondiagnostic, so contrasted MRI is again the primary diagnostic modality. This will show a variety of findings, including hypo- to isointensity on T1, very minimal contrast enhancement, and iso- to hyperintensity on T2. FLAIR imaging is often better able to differentiate between normal and pathologic brain. Ganglioglioma, DNT, and PXA can also be associated with cyst formation.8 Treatment for these tumors is variable. Initially, if symptoms are nonspecific, they can be followed with neuroimaging. Surgery offers the option for tissue sampling, removal of mass effect, therapeutic treatment of seizures, and in many cases, cure. For astrocytoma and oligodendrogliomas in accessible locations, gross total resection offers increased progression-free survival.41,42 Adjuvant treatment of SLGG is variable, depending on the pathology and extent of surgical resection. For tumors that are nonresectable, especially in the hypothalamus or optic nerves/pathways, chemotherapy and radiotherapy, either separately or in combination, allow for slowed time to progression and 5- and 10-year survival rates in the range of 60% to 80% and 55% to 70%, respectively.43-45 Ganglioma and DNT typically present with seizures and are commonly cured with complete excision.

Supratentorial High-Grade Glioma

Supratentorial high-grade glioma (SHGG) tumors are similar histologically to those found in adult patients and are represented by anaplastic astrocytoma, anaplastic oligodendroglioma, and glioblastoma multiforme. SHGG are relatively rare in the pediatric population, representing about 20% of all supratentorial gliomas and 5% to 10% of all pediatric tumors.2-5,46 Their presentation varies, but includes similar symptoms such as headache, seizure, or focal neurological deficit, depending on tumor location. On imaging, these tumors are more likely to show surrounding edema, central necrosis, and ring enhancement on T1 MR with contrast. Treatment begins with diagnosis via tissue sampling. For lesions that are easily accessible, gross total resection has been shown to improve outcome and overall survival.46-51 However, for more deep-seated lesions and those in eloquent cortex, resection may not be feasible. For these lesions, as well as postoperatively, chemotherapy and radiation are indicated to slow progression of the disease. Multiple different chemotherapeutic and radiation delivery methods have been used and newer methods of targeted chemotherapy for specific genetic markers are in development. Survival rates for these more aggressive lesions, however, remain low, with 5-year survivals from 6% to 40%.49-53

Brainstem Glioma

Brainstem gliomas represent about 10% of pediatric brain tumors. These tumors can be divided into diffuse intrinsic tumors (also known as diffuse pontine tumors) representing 75% to 80% of brainstem tumors and the remaining heterogeneous group of lesions, which include tectal lesions, cystic tumors, and exophytic cervicomedullary tumors (Figures 25-31, 25-32, 25-33, 25-34, 25-35, 25-36, and 25-37).3,54 Brainstem gliomas present with symptoms of cranial neuropathies, long-tract signs such as spasticity and ataxia, and occasionally with headache or hydrocephalus.54 These symptoms are usually rapid in onset for diffuse tumors. Diagnosis of these tumors is usually by imaging only, as radical resection of diffuse brainstem tumors is not an option, and biopsy is often not indicated, unless imaging is not classic or there has been a prolonged clinical course with some question as to the nature of the lesion.55,56 MR imaging will show diffuse pontine enlargement with T1 hypointensity, T2 hyperintentsity, and little contrast enhancement. Treatment for diffuse tumors is usually supportive or with radiation therapy. Chemotherapy trials have had little success.57 The subset of tumors that are not diffuse can have some benefit from surgical resection, although morbidity rates for these types of procedures remain high.58 Overall, survival for diffuse lesions is poor, with less than 25% at 2 years. The remaining lesions have different survival rates depending on extent of resection and tumor histology.54,55,59,60

Pineal Region Tumors

The pineal region is home to multiple different types of tumors, including germ cell tumors (germinoma, embryonal cell carcinoma, endodermal sinus tumors, choriocarcinoma, teratoma), astrocytomas, pineoblastoma, and pineocytomas (Figures 25-38, 25-39, 25-40, 25-41, 25-42, 25-43, 25-44, and 25-45). They make up 5% to 8% of pediatric brain tumors. The majority of germ cell tumors are germinomas (~70%).61 Pineal tumors present with signs of mass effect, including hydrocephalus, headaches, and nausea and vomiting. A classic finding is that of Parinaud syndrome, which is upgaze palsy, light-near dissociation on pupillary examination, convergence retraction nystagmus, and eyelid retraction. This is all due to compression of the superior colliculus and tectal plate.7 Germinomas may be associated with endocrinopathies, specifically diabetes insipidus primary or metastatic lesions occur in the pituitary stalk. The diagnostic workup for these lesions begins with neuroimaging. Any tumor found in the pineal region should initiate MRI with and without contrast of the entire craniospinal axis. MRI characteristics of germinoma are usually hypointense on T1 with iso- to hyperintensity on T2 and avid contrast enhancement. Non-germinomatous lesions are more likely to be irregular in shape and enhancement, and may have evidence of calcification or cyst formation.8 Blood and cerebrospinal fluid sampling for tumor markers (alpha-fetoprotein, beta-hCG, and placental alkaline phosphatase [PLAP]) are also helpful in the diagnosis of germ cell tumors. At this time, biopsy of the lesion, either endoscopically or stereotactically, can be carried out. Once a diagnosis is made, the mainstay of treatment for germinoma is chemotherapy and radiotherapy.61-64 A variety of chemotherapeutic and radiotherapeutic options are available for non-germinomatous tumors, and for non–germ-cell tumors. Surgical resection is usually reserved for those tumors that recur or are nonresponsive to medical treatment.65 Other treatment strategies designed to limit the total dose of radiation with the use of adjuvant chemotherapeutic regimens have been examined, with the goal to limit treatment-related morbidity.66,67 Overall survival for germinomas is greater than 90% at 5 years. The other tumors in this location, however, are much more difficult to control, with average survival lesser than 50% overall.

In conclusion, tumors of the pediatric CNS are relatively common, although each particular subtype is rare. The most common presenting signs and symptoms of these lesions are headache, seizure, or focal neurological deficit. Increasing head circumference or failure to meet developmental milestones are also important indications of CNS pathology. Prompt referral for neuroimaging, in most cases MRI scanning, and referral to a neurosurgeon are of paramount importance. With aggressive treatment, the majority of children with CNS neoplasms can survive into adulthood. Rates of treatment-related morbidity and long-term cognitive and developmental side effects, however, remain high. Newer therapies, imaging modalities, surgical techniques, radiation and chemotherapy, as well as molecular and genetic diagnostic methods, will likely only improve not only survival but quality of life for future patients.3,4,6,46,68