Neurofibromatosis

Probably the most common genetic syndrome associated with development of primary central nervous system tumors is neurofibromatosis type 1, which is an autosomal-dominant disorder due to mutation of the NF1 gene [Burger et al., 1987; Cawthon et al., 1990; Listernick et al., 1999; Wallace et al., 1990]. The NF1 gene on the long arm of chromosome 17 encodes the neurofibromin protein, which, among other actions, is a tumor suppressor gene [Burger et al., 1987; Listernick et al., 1999; Pollack and Mulvihill, 1997]. Its absence allows ras activation and subsequent downstream intracellular signaling through the RAS/MAPK (MAP kinase) pathway. The gene is large, spanning 350 kb, and a mutation in the initially unaffected (wild-type) NF1 gene is thought to result in the development of a host of tumors. In the central nervous system, the most common are low-grade, most often pilocytic astrocytomas, which early in life have a marked predilection for the optic nerves and other parts of the visual pathway. Later in childhood, gliomas may develop in other central nervous system sites, especially midline areas, including the brainstem and corpus callosum.

Separation of low-grade tumors from areas of brain dysplasia, also common in neurofibromatosis type 1, can be difficult [Listernick et al., 1997]. These areas of abnormal signal on T2-weighted MRI are at least partially developmental, and many disappear as the child enters into puberty. Other central nervous system tumors, such as ependymomas and possibly medulloblastomas, are more common in patients with neurofibromatosis type 1. Neurofibromatosis type 1 occurs in as many as 1 in 3500 patients at risk, and brain tumors may occur in as high as 20 percent of patients, although, for unclear reasons, many affected patients do not require specific treatment.

Children with neurofibromatosis type 1 are also prone to development of neurofibromas, of which the most problematic in prepubertal patients are plexiform neurofibromas [Listernick et al., 1999; Packer and Rosser, 2002; Packer et al., 2002a]. Plexiform neurofibromas are congenital and may cause significant cosmetic disfigurement, organ dysfunction, and, dependent on location, neurologic compromise, including spinal cord compression. A percentage of plexiform neurofibromas, possibly as high as 10 percent, will undergo malignant transformation, although in the vast majority of patients this occurs after puberty, especially in the early adult years. Since patients with neurofibromatosis type 1 have an increased predilection for the development of other malignancies, including myelogenous leukemia and sarcomas, treatment of patients with neurofibromatosis type 1-associated brain tumors can be quite challenging. Chemotherapeutic alkylating drugs and radiation therapy may increase the risk of developing secondary tumors.

Neurofibromatosis type 2, which is also an autosomal-dominant disorder affecting approximately 1 in 25,000 to 1 in 400,000, is due to a gene abnormality on the short arm of chromosome 22 [Pollack and Mulvihill, 1997; Rouleau et al., 1993; Trofatter et al., 1993]. Patients with this condition are predisposed to developing schwannomas of the cranial nerves, spinal nerves, and peripheral nervous system. Bilateral acoustic schwannomas are essentially pathognomonic of the illness and are usually present by early adulthood. Gliomas and ependymomas, especially spinal ependymomas, also occur with increased frequency.

Tuberous Sclerosis and Other Autosomal-Dominant Conditions

Other autosomal-dominant neurogenetic diseases are related to specific tumor types. Tuberous sclerosis is associated with the development of subependymal giant cell astrocytomas, which tend to occur in the subependymal ventricular zone and most commonly cause obstructive hydrocephalus early in illness [Kandt et al., 1992; van Slegtenhorst et al., 1997]. Cerebellar gangliocytomas are associated with Cowden’s syndrome, caused by a germline mutation of the PTEN gene [Liaw et al., 1997]. The occurrence of dysplastic gangliocytoma of the cerebellum is also known as Lhermitte–Duclos disease. Caused by a mutation of the VHL gene, von Hippel–Landau syndrome is associated with the development of hemangioblastomas in the cerebellum, spinal cord, and retina [Duan et al., 1995; Latif et al., 1993].

Li–Fraumeni Syndrome

Li–Fraumeni syndrome is caused by a germline mutation in the multifunctional TP53 gene [Malkin et al., 1990; Srivastava et al., 1990]. The protein encoded by the gene has a role in cell-cycle control and in DNA integrity and repair. Gliomas, both high-grade and low-grade, are most common in patients with Li–Fraumeni syndrome, and such tumors may be multifocal. Other central nervous system tumors that occur in increased incidence in this syndrome include medulloblastomas, supratentorial neuroectodermal tumors, and choroid plexus tumors.

Gorlin’s Syndrome

Gorlin’s syndrome, also known as the nevoid basal cell carcinoma syndrome, accounts for probably less than 1 percent of all patients with medulloblastoma, but the relationship between this condition and the development of medulloblastoma has led to a better understanding of the molecular pathogenesis of a larger subset of patients with medulloblastoma [Amlashi et al., 2003; Stavrou et al., 2001; Taylor et al., 2000]. It has been estimated that 3–5 percent of patients with Gorlin’s syndrome will develop medulloblastoma. Gorlin’s syndrome is caused by an inherited germline mutation of the PATCHED 1 (PTCH1) gene on chromosome 9, which encodes the sonic hedgehog (SHH) receptor. PTCH1 normally suppresses sonic hedgehog signaling [Taylor et al., 2000]. The syndrome may be diagnosed early in life by characteristic dermatological and skeletal features, including odontogenic keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcification of the falx. The basal cell carcinomas tend to occur later in life. Mutations of the PTCH1 gene can be demonstrated in 20–40 percent of medulloblastomas, especially in the desmoplastic variant in infants. Since patients with Gorlin’s syndrome are predisposed to the development of basal cell carcinomas later in life, the use of craniospinal radiotherapy, which is the backbone of treatment for most patients with medulloblastoma, is problematic, as basal cell carcinomas may occur in large numbers in the radiation fields. The diagnosis of Gorlin’s syndrome is often made later in life, when the basal cell tumors become evident.

Turcot’s Syndrome

Turcot’s syndrome is another autosomal-dominant disorder due to mutations in the adenomatous polyposis coli (APC) gene (type 2), or secondary to mutations in DNA mismatch repair genes HPS2 and MLH1 (type 1) [Attard et al., 2007; Foulkes, 1995; Hamilton et al., 1995; Ng et al., 2005]. Patients with mutation of a mismatch repair gene are prone to developing colorectal carcinomas and gliomas. Patients with type 2 disease are at increased risk for developing medulloblastomas. Mutations in the APC gene result in abnormalities of the Wnt molecular pathway. This pathway has been noted to be abnormal in up to 15 percent of patients over 3 years of age with medulloblastoma, especially older patients, and may constitute a different, more favorable form of the disease.

Environmental Exposures, Including Radiation Therapy

Of the environment exposures that predispose to the development of brain tumors, the best documented is ionizing radiation [Bakhshi et al., 2003; Kimball Dalton et al., 1998; Rimm et al., 1987; Ron et al., 1988]. This association was demonstrated in children treated with radiation for tinea capitis during the 1940s and 1950s, who were found to have an increased incidence, later in life, of meningiomas, gliomas, and nerve sheath tumors [Ron et al., 1988]. Secondary brain tumors have been reported after cranial irradiation for leukemia, head and neck tumors, and primary brain tumors [Kimball Dalton et al., 1998; Kleinerman, 2009; Neglia et al., 1991; Rimm et al., 1987; Thierry-Chef et al., 2008]. The most common form of malignant brain tumor occurring after radiation is malignant gliomas, which tend to appear 5–15 years after radiation and are highly resistant to therapy. Meningiomas are the most common radiation-induced tumors, increase in frequency with time after radiotherapy, and do not begin to peak until ten years after exposure [Neglia et al., 1991; Rimm et al., 1987]. Other tumor types that have been reported include lower-grade gliomas, medulloblastomas, and ependymomas.

The effects of a multitude of environmental exposures, including maternal diet, on the occurrence of childhood brain tumors have not been conclusively shown [Bunin, 2000; Preston-Martin, 1996]. Factors that have been associated with a higher incidence of medulloblastoma in some, but not all, studies include maternal farm residence during pregnancy and pesticide exposure [Connelly and Malkin, 2007; Norman et al., 1996; Preston-Martin, 1996; Robison et al., 1995]. In some studies, mothers’ multivitamin use and food consumption during pregnancy have been found to be potentially protective against of the development of tumors, especially medulloblastoma. Initial studies suggested an association between significant exposure to electromagnetic waves or the use of cell phones in the development of gliomas, but other studies have not been able to confirm this relationship [Ali Kahn et al., 2003; Connelly and Malkin, 2007; Hardell et al., 2002]. Similarly, initial studies suggested that patients exposed to simian virus 40 (SV40), through immunizations, may have a higher incidence of developing medulloblastoma [Hayashi et al., 2001; Kim et al., 2002]. Subsequent studies could not confirm this association. Immunosuppression, either due to an underlying disorder of the immune system or after treatment with chronic immunosuppressive agents in situations such as organ transplantation, has been associated with an increased incidence of central nervous system lymphoma [Kuijten and Bunin, 1993; Penn, 1998].

Biology

With the advent of technology that allows for high-throughput genetic screening, the pathogenesis of childhood CNS tumors is rapidly becoming better defined. These studies have started not only to uncover the underlying molecular heterogeneity that exists between the different types of pediatric brain tumors, but also to place tumors within a histological subtype or a specific histologic subtype occurring in different anatomical locations. The emerging molecular signatures should continue to have a profound impact on the diagnosis, prognosis, stratification, and future treatment of childhood brain tumors.

Medulloblastoma and Supratentorial PNET

Isochromosome 17q, often in combination with loss of 17p, is the most common cytogenetic alteration in medulloblastoma, occurring in up to 50 percent of tumors [Biegel, 1999]. A clear association with clinical outcome has not been confirmed; however, recent evidence suggests that isochromosome 17q is an unfavorable prognostic indicator [Pan et al., 2005]. Supratentorial primitive neuroectodermal tumors (sPNET) display a unique set of genomic alterations that rarely include isochromosome 17q, indicating that sPNET are molecularly distinct from medulloblastoma, despite sharing a similar histological appearance [Bayani et al., 2000; Pfister et al., 2007].

High expression of the neurotrophin-3 receptor, TRKC, was the first molecular alteration identified as an independent predictor of favorable outcome in medulloblastoma [Grotzer et al., 2000; Segal et al., 1994]. Increased expression of ErbB2, a member of the epidermal growth factor receptor (EGFR) family, and MYCC oncogene independently correlates with a poor outcome [Gilbertson et al., 1995; Grotzer et al., 2001]. High-level amplifications of MYC family members are also seen in 5–15 percent of medulloblastomas, and are associated with the aggressive anaplastic medulloblastoma variant and unfavorable outcome [Herms et al., 2000].

Aberrant signaling through the developmental pathways, Hedgehog (Hh), Notch, and Wnt, has been linked to medulloblastoma formation and growth (Figure 83-3). The relationship between Hh and medulloblastoma was deduced from the observation that medulloblastomas arise in patients with nevoid basal cell carcinoma syndrome (Gorlin’s syndrome), a condition caused by a somatic mutation of the PATCHED (PTCH) gene [Wicking and Bale, 1997]. PTCH is an important regulator of the Hh mitogenic signaling pathway. Gorlin’s syndrome accounts for 1–2 percent of all medulloblastomas, most commonly of the desmoplastic subtype [Amlashi et al., 2003]. Mutations in Hh pathway genes have been identified in approximately 25 percent of sporadically occurring medulloblastomas, predominantly of the desmoplastic subtype [Dong et al., 2000; Pomeroy et al., 2002; Raffel et al., 1997].

Fig. 83-3 Aberrant signaling pathways in medulloblastomas.

APC, adenomatous polyposis coli protein; Frz, frizzled; GSK-3β, glycogen synthase kinase-3β; IGF, insulin-like growth factor; P1/3K, phosphatidylinositol-3-Kinase; P1/JK, phosphatidylinositol/Janus Kinase; PTCH, patched; SHH, sonic hedgehog; SMO, smoothened.

Increased copy numbers of Notch and mutations in the Wnt signaling pathway have each been detected in up to 15 percent of medulloblastomas. Expression of the Notch pathway target gene Hes1 is associated with shorter survival time, while nuclear immunoreactivity for beta-catenin, a marker of Wnt pathway activation, is associated with a highly favorable outcome [Ellison et al., 2005; Fan et al., 2004]. A more recent integrative genomic study identified five distinct molecular subtypes of medulloblastoma, including a Wnt signaling group associated with classic histology tumors in older children, and an Hh signaling group associated with desmoplastic tumors in younger children [Kool et al., 2008]. Both tumor groups shared increased expression of Notch and platelet-derived growth factor (PDGF) pathway genes.

Astrocytoma

Perhaps the most significant discovery to date for this group of tumors is the identification of BRAF oncogene-activating mutations in association with juvenile pilocytic astrocytoma (JPA) [Jones et al., 2008]. BRAF mutations appear to be rare in other types of pediatric low-grade glial tumors, and are associated primarily with JPA of the cerebellum and optic pathway [Jacob et al., 2009]. Low-grade gliomas, usually JPA of the optic nerves and chiasm, also occur in about 15 percent of children with neurofibromatosis type 1; however, BRAF mutations have not been identified in neurofibromatosis type 1-associated JPA [Jacob et al., 2009].

Evidence shows that childhood and adult malignant gliomas are molecularly distinct. Overexpression of EGFR is seen in 60–80 percent of high-grade gliomas in both children and adults; however, amplification of EGFR is found in 40 percent of adult tumors, but only rarely seen in childhood gliomas [Bredel et al., 1999]. TP53 is mutated in 12 percent of malignant gliomas in children aged less than 3 years, compared to 40 percent of the tumors in children older than 3 years [Pollack et al., 2001]. The 5-year survival is 17 percent in patients with high TP53 expression, and 44 percent in those with tumors that have low TP53 expression [Pollack et al., 2002]. PTEN mutations occur in only 8 percent of high-grade lesions in children, compared to 30 percent of adult high-grade tumors; however, expression of activated PDGF receptors and PTEN deficiency are associated with increasing malignant histology and decreased survival, respectively, among children with high-grade gliomas [Cheng et al., 1999; Raffel et al., 1999; Thorarinsdottir et al., 2008].

Other Childhood Brain Tumors

One of the most important molecular genetic alterations in childhood brain tumors is the discovery of hSNF5/INI1 gene mutations in association with atypical teratoid/rhabdoid tumors (AT/RT) [Biegel et al., 2002a]. AT/RT has sometimes been confused with medulloblastoma and PNET, but now screening for hSNF5/INI1 mutations can confirm the molecular diagnosis of AT/RT, which has important prognostic and therapeutic implications.

In ependymoma, chromosome 17p deletions have been found in 50–80 percent of tumors, but TP53 mutations have not been found to date [von Haken et al., 1996]. An integrative genomic study of ependymoma also revealed that supratentorial, posterior fossa, and spinal tumors have distinguishable molecular signatures, and that genes of supratentorial and spinal tumors are similarly expressed in mouse radial glial cells in the corresponding region of the CNS [Taylor et al., 2005].

Diffusion Imaging

Diffusion imaging (DI) investigates molecular translational movements (i.e., Brownian motion) of water molecules. Brownian motion produces signal loss proportional to the degree of molecular translation/diffusion. Within the cerebral milieu, cellular membranes and other macromolecular structures restrict water diffusion, which results in increased signal on DI. (Less diffusion means less signal loss secondary to spin dephasing.) Thus, signal on diffusion images can reflect cellular density and microarchitecture. The apparent diffusion coefficient (ADC) is a measure of the ability of tissue to restrict water diffusion. ADC adversely correlates with the grade of tumor and the cellular proliferation Ki-67 labeling index [Higano et al., 2006]. Increase in ADC, reflecting decrease in cellularity, has been observed as tumors respond to treatment.

In the intracellular and extracellular spaces of the brain, macromolecular proteins, intracellular organelles, cell walls, and myelin sheaths restrict or slow diffusion in certain directions. The most significant determinant of the preferred diffusion direction is the myelin sheath within cerebral white matter [Miller et al., 2003]. DI can therefore assess the microscopic structural integrity of white-matter tracts as the movement of water occurs preferentially along the long axis of the myelin sheath surrounding the axon. Anisotropy is an aggregate measure of the magnitude of displacement across all three dimensions; using information gleaned from the size, shape, orientation, and distribution (or spatial pattern) of diffusion ellipsoids within an imaged volume, one can characterize features of water diffusion within a voxel – the diffusion tensor. A voxel by voxel analysis of anisotropy can be performed, resulting in diffusion tensor imaging (DTI). Connectivity maps (i.e., tractography) can also be generated, which demonstrate the long association (axonal) pathways that convey cortical connections as tracklike structures.

DTI tractography is used to plan the surgical approach to a focal tumor. Important association pathways (e.g., pyramidal, optic tracts) can be localized in relation to a tumor; this helps the surgeon to avoid injury to these white-matter tracts. DTI also shows promise as a tool to evaluate for the presence and extent of tumoral invasion; whereas focal (well-marginated) tumors should displace but not disrupt axons outside of their borders, the microscopic tumor extension of infiltrative tumors is expected to disrupt local axonal structures [Helton et al., 2006; Talos et al., 2007].

Magnetic Resonance Spectroscopy

MR spectroscopy provides information about the presence and amount of hydrogen molecules attached to different cerebral molecular compounds. Hydrogen atoms located on different molecular compounds display intrinsic differences in resonant frequencies due to their differing molecular environment. Spectra are represented by a series of peaks, with positions expressed in parts per million (ppm) – a histogram of nuclei with different precession frequencies.

The four most relevant compounds identified within cerebral tissue include N-acetyl-aspartate (NAA, a marker of neuronal and axonal integrity), choline (a marker of cell membrane), creatine and phosphocreatine (energy metabolites), and lactate (a by-product of cerebral metabolism). Concentration of NAA within a tumor is decreased compared to normal brain tissue as tumor cells either replace or disrupt normal neuronal and glial populations. Concentration of choline reflects cell membrane turnover and is elevated in tumors, demyelination, and inflammation.

Spectroscopy can be performed with single-voxel or multivoxel techniques. Tissue composition within a voxel must be homogeneous, otherwise partial volume averaging of tissue of various compositions (e.g., normal, tumor, and necrotic tissue) occurs and the spectrum has little value. Single-voxel studies have improved spectral resolution over multivoxel techniques, though minimal voxel size for good signal to noise is about 4 cm³; further, in single-voxel imaging, the prescription (i.e., the determination of the voxel location) of the voxel is totally operator-dependent – and therefore not very reproducible. Spectroscopic analysis of a large volume of cerebral tissue is feasible with multivoxel techniques (i.e., two- or three-dimensional chemical shift imaging [CSI]), in which several subcentimeter voxels can be examined simultaneously. CSI is very helpful in the evaluation of small or heterogeneous tumors; in the evaluation of the extent infiltrative tumors where the tumor/normal brain boundary may be difficult to determine with conventional techniques; and to distinguish recurrent tumor from radiation necrosis. MR spectroscopy may be of help to monitor tumor response versus progression [Tzika et al., 2004]; prognosticate overall survival [Warren et al., 2000]; and improve preoperative identification of tumor type [Panigrahy et al., 2006].

Perfusion Imaging

Perfusion imaging can be performed with techniques based on dynamic susceptibility contrast (DSC) or on vascular permeability. DSC techniques assess cerebral tissue perfusion following a dynamic injection of gadolinium. During the first-pass transit of contrast through cerebral capillaries, which lasts anywhere from 5 to 15 seconds, gadolinium is (normally) restricted to the intravascular space. This intravascular restriction gives rise to signal inhomogeneity within image voxels (i.e., a susceptibility effect), which is reflected as signal loss on susceptibility-sensitive T2 (T2*) imaging techniques. A curve showing concentration of gadolinium over time can be generated. This enables a time versus signal intensity curve to be drawn, from which a variety of parameters can be inferred. These include mean transit time (MTT); time-to-peak; area under the curve, a measure of relative cerebral blood volume (rCBV); and relative cerebral blood flow (rCBF). rCBV corresponds to the volume of blood within brain tissue and can reflect the neovascularization associated with tumor growth (tumor angiogenesis). Perfusion imaging is therefore useful for the study of neovascularization and angiogenesis inhibition; for evaluation of tumor grade [Schmainda et al., 2004]; for targeting a lesion for biopsy; and to differentiate hypervascular tumors from tissue necrosis. DSC perfusion imaging may also be able to identify low-grade tumors that progress rapidly, and low-grade gliomas that have a propensity for malignant transformation [Law et al., 2006].

DSC perfusion studies do not consistently generate usable data. First, a larger-bore intravenous catheter must be placed for safe delivery of the injection of 3–4 cc/sec of gadolinium necessary to generate a well-defined first-pass curve; that is not always easy, especially in children with poor intravenous access. (Recent commercial introduction of ports and central lines that are safe to use with power injectors may alleviate this issue.) Second, susceptibility artifacts are not negligible, as DSC perfusion utilizes an echo planar technique (echo planar images are prone to image distortion by susceptibility artifacts); studies performed on children with dental braces or in the presence of significant amounts of intracranial/intratumoral hemorrhage are often useless. Finally, gadolinium contrast can leak through tumor capillaries; such leakage can result in an underestimation of rCBV, as the computations performed to process the susceptibility T2* signal assume that the contrast remains confined to the capillary [Cha et al., 2002].

Permeability-based perfusion techniques take advantage of leakage of gadolinium through tumor vessel walls. In healthy cerebral capillaries, the blood–brain barrier prevents gadolinium leakage into the interstitium. Tumor capillaries have disrupted or absent blood–brain barriers, which allows contrast to leak outside the vessel. The rate of leakage is proportional to the permeability of the capillary wall. Permeability imaging, also known as relaxivity imaging, is a T1-weighted technique in which a curve of dynamic signal intensity (i.e., enhancement) versus time is generated. The slope of enhancement reflects the degree of permeability of capillaries. The intensity of initial enhancement reflects tissue vascularity; fractional blood volume (fBV) can be extrapolated [Roberts et al., 2000]. fBV is a fairly good estimate of the rCBV data obtained with susceptibility perfusion [Haroon et al., 2007].

Positron Emission Tomography

Positron emission tomography (PET), with use of ^(18)F-fluorodeoxyglucose (FDG), allows for the evaluation of regional cerebral glucose metabolism. PET is useful in the determination of tumor metabolism/grade and of tumor extent, and to distinguish persistent or recurrent tumor from radiation necrosis [Pirotte et al., 2007]. Metabolic changes can be measured with a spatial resolution approaching 2–3 mm in the newer scanners. Images can be co-acquired with a CT scan (CT-PET), or can be co-registered with MR images using fusion software. Metabolic activity of tumor sites can be determined with quantitative, as well as qualitative (comparing FDG uptake in a tumor to uptake of normal gray or white matter), assessment. Higher-grade tumors tend to be more glucose-avid than lower-grade tumors, except for juvenile pilocytic astrocytomas, which show very high glucose uptake. For lesions that do not show abnormal glucose uptake, of ^(11)C-methionine PET scanning is helpful to differentiate neoplastic from non-neoplastic types. Thallium-201 single-photon emission CT (SPECT) now has a decreasing role in evaluation of pediatric brain tumors, given its more limited anatomic resolution.

Nonlocalizing Signs and Symptoms

Nonlocalizing signs and symptoms predominate early in the course of illness in almost all types of childhood nervous system tumors. This is due to a variety of factors, including the predilection of childhood brain tumors to arise in the posterior fossa and cause obstruction of cerebrospinal fluid early in the course of illness, resulting in the nonspecific symptoms of headaches, nausea, vomiting, and lethargy. Separation of headaches caused by neoplasms, as opposed to the more common headaches children develop, can be extremely difficult [Glaser et al., 1971; Honig and Charney, 1982]. The majority of children with brain tumors, especially those with posterior fossa tumors and large supratentorial tumors, will have headaches by the time of diagnosis. However, headaches are notoriously nonspecific early in the course of illness. A change from a nonspecific headache pattern to morning headaches should raise concern that a mass lesion is present. Headaches that wake a child from sleep also suggest the possibility of increased intracranial pressure. Although this is true in general terms, recognizing such changes, in practicality, can be quite difficult for the child or family, and migraine headaches can wake a child from sleep. Headaches are especially difficult to characterize in very young children.

Localizing Symptoms

Supratentorial Tumors

The diagnosis of primary central nervous system tumors is usually easier when there are associated localizing signs and symptoms (Table 83-1). Supratentorial tumors present with symptoms and signs similar to those seen in older patients and adults. Headaches are the most common initial complaint and are often nonlocalizing early in the course of illness [Hirsch et al., 1989]. Seizures are the second most common symptom encountered and approximately one-quarter of children with supratentorial tumors will have seizures as their initial symptom. This is especially true with tumors of the frontal or temporal lesion. Slower-growing cortical tumors, especially gliomas, are more likely to result in convulsions early in the course of illness. Although patients with more aggressive cortical gliomas may have seizures, focal neurologic deficits, such as hemiparesis or, in a patient amenable to careful examination, hemisensory loss or visual field loss, are more common.

Table 83-1 Differential Diagnosis: Supratentorial Tumors

An increasing diagnostic dilemma, probably secondary to better neuroimaging and the increasing utilization of epilepsy surgery, has been the diagnosis of children with long histories of complex partial or other seizures and low-grade glial or mixed neuronal glial lesions, especially gangliogliomas and dysembryoplastic neuroepithelial tumors. In patients with epilepsy, features associated with an increased risk of a neoplasm include change in the character of the seizure type, status epilepticus at the onset of the seizure, prolonged postictal paralysis, and resistance to medical control.

Lesions that arise in the “silent” areas of brain, especially the frontal lobes in children, often have long presentations prior to diagnosis. This is especially true for lower-grade tumors, which may present with a long history of nonspecific behavioral problems, executive functioning difficulties, and even attention difficulties. The specific relationship between such symptomatology and the presence of the tumor is often difficult to confirm.

Posterior Fossa Tumors

Five tumor types are most likely to occur in the posterior fossa, as noted in Table 83-2. Since cerebellar astrocytomas are more laterally placed and are slower-growing tumors, their symptoms tend to be more indolent than those of medulloblastomas, which fill the fourth ventricle early in the course of illness and result in obstructive hydrocephalus. However, midline cerebellar astrocytomas may mimic medulloblastomas [Packer et al., 1999a]. Brainstem gliomas are an insidious lesion and are likely to cause cranial nerve neuropathies associated with motor, cerebellar, and sensory deficits. Ependymomas are the great mimickers of other tumor types in the posterior fossa and may present as slow-growing, medulloblastoma-like tumors or, if the tumor involves the cerebellopontine angle, can mimic brainstem gliomas and result in multiple cranial neuropathies, especially sixth, seventh, and eighth nerve palsies.

Table 83-2 Differential Diagnosis: Infratentorial Tumors

Symptoms caused by obstructive hydrocephalus may overwhelm these more subtle signs and deficits. Inability to abduct one or both eyes, secondary to sixth nerve involvement, may be a false localizing sign related to increased intracranial pressure rather than to direct brainstem dysfunction. However, the presence of a gaze palsy or the inability to abduct one eye properly on attempted lateral gaze with jerk nystagmus of the abducting eye, representing an intranuclear ophthalmoplegia, implies an intrinsic brainstem disorder. When the latter ophthalmologic findings are coupled with other cranial neuropathies, such as a facial palsy or lower cranial nerve deficits, the presence of a diffuse infiltrating brainstem process, most likely a brainstem glioma, is likely. Crossed hemiparesis, with a peripheral facial palsy on one side and contralateral weakness that may also involve the lower portion of the face, also strongly suggests an intrinsic brainstem tumor. Ipsilateral ptosis and miosis, with or without increased redness or warmth on the side of the ptosis and miosis (Horner’s syndrome), suggests brainstem or upper cervical cord compromise, but it can also occur in tumors extrinsic to the upper cervical cord compressing the sympathetic ganglions.

Surgery

Surgery remains the initial step in the treatment for the overwhelming majority of childhood central nervous system tumors, and the degree of resection, even for malignant neoplasms that require other forms of adjuvant therapy, is often an important factor in determining outcome [Albright et al., 1995; Campbell et al., 1996; Chen et al., 2007; Horn et al., 1999; Packer et al., 1999a; Roujeau et al., 2007]. As regards diagnosis, attainment of a representative portion of the neoplasm for histological and increasingly biological analysis is crucial. Exceptions to the need for tissue for diagnosis include neuroradiographic characteristic diffuse intrinsic brainstem tumors; chiasmatic/hypothalamic infiltrating gliomas in children with neurofibromatosis type 1 and possibly for those without; and germ cell tumors, predominantly mixed germ cell tumors, which secrete diagnostic proteins into cerebrospinal fluid and blood.

For some tumor types, surgery is curative and complete resection obviates the need for alternative therapies [Schneider et al., 1992]. This is primarily true for low-grade gliomas, especially pilocytic astrocytomas of the cerebellum or cerebrum, gangliogliomas, other mixed neuronal-glial tumors, and possibly supratentorial low-grade ependymomas [Poussaint and Rodriguez, 2006]. For other, more aggressive tumor types, surgery may be a crucial component of multimodality treatment, as outcome is statistically better for patients with nondisseminated medulloblastomas, posterior fossa ependymomas, and cortical malignant gliomas if total or near-total resection can be obtained [Albright et al., 1989; Packer et al., 1992; Wisoff et al., 1998]. For those tumors that located in eloquent areas of brain or are disseminated, the preoperative assessment of whether “total” resection or an attempt at total resection provides a survival benefit is usually the prime determinant of whether aggressive tumor removal is tried or less aggressive approaches, including open or stereotactic needle biopsy, will suffice. Stereotactic biopsy techniques, be they CT- or MRI-guided, are highly accurate in targeting deep-seated lesions and are associated with morbidities of less than 5 percent and mortalities of less than 1 percent [Broggi et al., 1983]. The advent of biologic therapies, often requiring fresh frozen tissue for molecular analysis, has resulted in the need, in certain circumstances, for additional tissue that cannot be obtained by needle biopsy alone.

Radiation Therapy

Radiation therapy is an integral component of treatment for many forms of childhood brain tumors. For children with benign tumors, its use is usually limited to those tumors that are not amenable to gross total resections. For children with more aggressive or malignant tumors, radiation therapy has been the backbone of most curative and palliative therapies, even in those patients whose tumors are totally resected. For medulloblastoma, other embryonal tumors, and germ cell tumors, delivery of radiotherapy to the entire neuroaxis (craniospinal radiotherapy), supplemented with boost radiotherapy to the primary tumor site, is routinely employed to treat neuroaxis sanctuary disease and prevent exoprimary disease relapse, even in patients without evidence of tumor dissemination [Packer et al., 1999b]. Craniospinal radiotherapy has been associated with improved survival, but also significant long-term endocrinologic, growth, and cognitive sequelae. In very young children, especially infants, radiotherapy may result in even more severe sequelae and attempts have been made to delay, if not obviate, the need for radiotherapy by the use of chemotherapy. Chemotherapy is often utilized with radiotherapy in older patients, not only to increase survival, but also to decrease the dose or volume of radiation therapy required for disease control or cure.