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Tumors of the Brain and Spinal Cord
Tumors of the central nervous system (CNS) account for approximately 25% of pediatric cancer but are now the leading cause of cancer-related mortality in children. The complexities of tumors in this site are related to the large number of different histologies within the CNS and a historic nomenclature that is confusing, even to those in this field. With the need to modify therapies to spare important neurocognitive function in the youngest patients and the presence of the blood-brain barrier (BBB), which restricts the delivery of effective therapies, improvement in outcome has lagged well behind that of many other cancers, especially childhood leukemia. The molecular revolution offers the chance to begin classifying tumors by the signals that drive their phenotype rather than by their appearance under the microscope. In this chapter we will discuss the different types of brain tumors in children, their diagnoses, and their treatments, while incorporating the expanding knowledge of tumor biology.
Although clinical studies often focus on progression-free survival (PFS) and overall survival (OS), successful therapy incorporates much more. Accepting a lower overall cure rate but preserving neurocognitive function is the norm for many types of brain tumors, especially those of infants and young children. Optimization of outcome requires expertise in multiple subspecialties that play a role in the care of these children. The skill of the neurosurgeon, the sophistication of the radiation planning, and the safe administration of chemotherapy are all important factors in improving the long-term outcome for these patients. In fact, many centers now use neurooncologists who have completed additional training in outcome optimization. When combined with a large number of subspecialty services (e.g., endocrinology, neurology, neuropsychology, social work, back to school, and physical and occupational therapy), truly optimal care is now possible for this patient population. Needs of the family continue to evolve as patients transition from diagnosis to treatment to posttherapy follow-up. A comprehensive understanding of pediatric neurooncology and the delivery of comprehensive care to these patients and their families will be the focus of this chapter.
To assist the reader, a number of important review articles summarizing different aspects of the care of children with CNS tumors are referenced.
Epidemiology
Primary CNS (PCNS) tumors rank second behind leukemia as the most common pediatric cancer diagnosed in the United States each year ( Fig. 57-1 ). Brain tumors are the most common form of solid tumors in children and are now the leading cause of death from solid tumors in children. The spectrum of adult brain tumors based on location, histology, and outcome differs significantly from that in pediatrics, suggesting that the causative events are different from those for pediatric brain tumors. No single standard classification system has been implemented for pediatric brain tumors, although development of a standardized platform for epidemiologic studies has been attempted. The 2013 Central Brain Tumor Registry of the United States Statistical Report included primary nonmalignant (1.93 per 100,000 children) and malignant (3.33 per 100,000 children) pediatric brain and CNS tumors with a total incidence of 5.26 per 100,000 children. Similarly in the 2013 National Cancer Institute Surveillance Epidemiology and End Results (SEER) Cancer Statistics Report, the annual age-adjusted incidence rate of pediatric malignant brain and other nervous system tumors was listed as 3.1 cases per 100,000 children. The rate is higher in males (3.2 per 100,000) compared with females (2.9 per 100,000). Approximately 4100 new cases of childhood PCNS tumors are diagnosed in the United States each year. Of these, an estimated 3007 will be in children younger than 15 years. The incidence for all brain tumors is highest among 0- to 4-year-olds (5.77 per 100,000) and lowest among 10- to 14-year-olds (4.78 per 100,000), results that are similar to those reported in 2005. The age-adjusted mortality rate for pediatric CNS tumors in 2010 was 0.6 per 100,000 children, resulting in an estimated 500 deaths per year in the United States for those aged 0 to 19 years. The prevalence rate for all malignant and benign pediatric CNS tumors (ages 0 to 19 years) is estimated at 9.5 per 100,000, with more than 26,000 children estimated to be living with this diagnosis in the United States in 2000. However the prevalence rate for patients with only malignant brain tumors was 7.9 per 100,000, with more than 21,000 children estimated to be living with a diagnosis of primary malignant CNS tumor in the United States in 2000. The distribution of pediatric brain tumors by site is presented in Figure 57-2 . Different brain tumor histologies have different age distributions ( Fig. 57-3 ). The most common histologies in the younger age group (ages 0 to 14 years) include pilocytic astrocytomas (PAs) and medulloblastomas, which account for 20% and 16% of cases, respectively. The broad category of glioma accounts for 56% of tumors in children younger than 15 years. The most common histologies in adolescents ages 15 to 19 years include PA and pituitary tumors, which account for 15% and 14% of cases, respectively. The broad category of glioma accounts for 45% of tumors in adolescents ages 15 to 19 years. The rates among boys are slightly higher than those in girls, and brain tumors are more common in whites (4.7 per 100,000) than in blacks (3 per 100,000).
The histologic-specific differences in brain and CNS tumor distribution by age and gender suggest that childhood tumors have different mechanisms whereby normal cells, possibly somatic CNS stem cells, are susceptible to oncogenic mutation. Although certain histologic subtypes can also differ by race, the overall concordance of tumor histologies among different ethnic groups and different locations suggest that specific local environmental factors are not the cause of most cancers in children. The incidence of common pediatric brain tumors such as medulloblastoma, malignant gliomas, and diffuse pontine glioma do not differ significantly in industrialized versus nonindustrialized countries, in vegetarian versus meat-eating societies, and in areas where smoking and drinking are permitted versus where they are not permitted. Similarly death rates for children with CNS tumors between different ethnic groups within the United States (Hispanics, Asians, blacks, and whites) do not differ significantly for most CNS tumor types.
In the mid 1990s an increase in the incidence of childhood brain cancer appeared to occur compared with that in the previous two decades. This increase is now thought to reflect the introduction and widespread use of magnetic resonance imaging (MRI) technology in the mid 1980s, resulting in improved detection and reporting of pediatric brain tumors. More precise classification of brain tumors and diagnostic capabilities, such as stereotactic biopsy, also may have contributed to the increase in incidence. The rise in incidence was followed by the establishment of a new baseline that has remained stable. Mortality rates have not mirrored the increase in incidence.
PCNS tumors develop from an accumulation of genetic changes. Such changes can result from inherited mutations or develop from exposure to chemical, physical, or biologic agents that damage deoxyribonucleic acid (DNA). Unlike in adults, for whom lifetime exposure is significant, most pediatric tumors are believed to be the result of random genetic mutations that occur during normal cellular proliferation. Today molecular biologic techniques are used to unravel the complex genetic errors that lead to the development of CNS tumors. To date most pediatric brain tumors have demonstrated a limited number of mutations, even in highly aggressive tumors, suggesting that their presence during development or within the stem cell compartment is an important aspect of tumorigenesis in pediatric patients.
The search for causative factors that place children at risk for developing CNS tumors has not yielded clear answers. Numerous epidemiologic studies have evaluated potential risk factors. Similar to most pediatric cancers, no specific risk factor explains more than a small proportion of tumors. Factors studied but not conclusively found to increase risk include exposure to tobacco and smoke, alcohol, traffic-related air pollution, electromagnetic fields, pesticides, and occupational and industrial chemicals; diet; drugs and medications; infections and viruses; epilepsy; and consumption of cured meats during pregnancy. The dramatic increase in the use of cellular telephones has generated concerns about the potential risk for the development of brain tumors. A meta-analysis of nine case-control studies concluded that cellular phone users have no overall increased risk of brain tumors. The potential risk after long-term cellular phone use awaits analysis in future studies. A seasonal variation unique to medulloblastoma incidence by month of birth may provide evidence for an environmental exposure cause, although further studies are needed. An association between atopic disease and a reduced risk of glioma has been observed in adult epidemiologic studies, with the implication that heightened immune surveillance decreases the risk of brain tumor development. Prenatal multivitamin use has been associated with a protective effect in the development of pediatric brain tumors in a large meta-analysis. Confirmation of this result in a prospective trial is needed.
The role of viruses in the pathogenesis of tumors has been documented in experimental animals, and adenovirus serotypes have been shown to induce tumors in rodents. Adenoviral sequences were evaluated in more than 500 tumors derived from 17 different pediatric cancer entities. Although most leukemias and solid tumors were negative for the presence of adenoviral sequences, tumor material from 25 of 30 glioblastomas, 22 of 30 oligodendrogliomas, and 20 of 30 ependymomas, as well as normal brain, were positive by polymerase chain reaction assay for adenoviral gene sequences. This finding raises important questions about the contribution of this infectious agent to pediatric brain tumorigenesis. In contrast, tests for polyomavirus sequences in adult and pediatric CNS tumors were rarely positive.
Ionizing radiation, immunosuppression, and certain hereditary genetic disorders are the only factors that have been proven thus far to increase a child's risk for CNS malignancy. Ionizing radiation exposure is a well-documented cause of brain tumors. Children who undergo therapeutic irradiation to the CNS for the treatment of malignancy are at risk for development of a second tumor, specifically meningioma, high-grade glioma (HGG), or sarcoma. Since its introduction in the 1970s, computed tomography (CT) has become an essential tool in the diagnosis and monitoring of disease. The growing use of CT scans has raised concerns about potential risks. Pediatric CT scans may result in a small but not negligible increased lifetime risk for cancer mortality.
Immunocompromised children are at increased risk for PCNS lymphoma. The risk for developing CNS lymphoma is 1% to 5% higher for adults and children undergoing transplantation and for those with congenital immunodeficiencies. The risk is 2% to 6% higher for persons with acquired immunodeficiency syndrome (AIDS). This risk will probably increase with longer survival because of improved AIDS treatment.
In summary although a few environmental factors are associated with an increased risk of developing a pediatric CNS tumor, the vast majority of patients have no easily identifiable risk factors. For a small percentage, inherited genetic mutations contribute to the onset of these tumors, but for the remainder, CNS tumors are likely the result of spontaneous mutations.
Neurodevelopment
Our understanding of the steps in hematopoietic development, together with the pathways and markers that distinguish precursors along each blood cell lineage, has been instrumental in allowing better classification and subsequently better treatment of leukemias. In the same way that leukemias can be viewed as deregulated expansion of hematopoietic precursor cell pools, pediatric brain tumors may similarly be considered as the proliferation of neuropoietic precursors. Thus knowledge of the steps and intermediates in neural development may help us understand and treat pediatric brain tumors. A current schema for neuropoiesis relies heavily on models for hematopoiesis but introduces two additional aspects of developmental regulation, the first of which is the importance of regionalization. During neural development a rostral-caudal gradient delineates distinct zones for proliferation and differentiation, while the orientation of proliferating cells relative to the dorsal-ventral axis provides the basis for determining the progeny of each proliferative event.
The second aspect of neuropoiesis is the concept of mitogenic niches. Although hematopoietic stem cells can proliferate and give rise to the entire array of blood cell types when exposed to the environment of the immature or mature bone marrow, neural stem cells use a number of distinct niches, some of which are eliminated before birth, some that persist through early childhood, and some that remain extant into adult life. These niches provide important cues for proliferation and differentiation but may also provide an environment that fosters the growth of tumor cells.
Neural Tube
The nervous system develops as a specialized zone of the epithelium. In the third week after fertilization, the midline zone of the epithelium becomes specialized as the neural plate. This distinctive zone extends from the caudal to the rostral portion of the embryo. While the embryo turns, the neural plate grows and folds ( Fig. 57-4 ). Subsequent fusion of the folds creates a discrete neural tube that zips up from both the top and bottom. The two last places where the fold fuses are the hindbrain (the incipient cerebellum) and the lumbar spine. Cells at the crest of the developing neural tube are the neural crest cells, which give rise to the peripheral nervous system, including sympathetic ganglia, dorsal root ganglia, and Schwann cells, as well as to melanocytes in the developing skin. The neural crest cells are the precursors to neuroblastomas, neurofibromas, and melanomas.
After the neural tube fuses, rapid expansion of cell number continues, but this expansion occurs very differently along the rostral-caudal axis. The dramatic expansion of cell number in the rostral neural tube provides the building blocks for the brain, whereas the more caudal regions undergo more limited growth and engender the spinal cord.
Development of Brain Structures
Along the rostral-caudal axis of the neural tube, three outpouchings can be seen at the end of the fourth week after fertilization—the forebrain, midbrain, and hindbrain ( Fig. 57-5 ). Subsequent branching of the forebrain forms two lateral protrusions that are destined to become the left and right cortex, and the midline portion of the forebrain gives rise to the thalamus. The midbrain does not undergo much expansion, but the hindbrain undergoes massive proliferation to give rise to the cerebellum and underlying pons, as well as the medulla. Cerebral cortical tumors, including supratentorial primitive neuroectodermal tumors (CNS PNETs) and cortical and subependymal astrocytomas, all derive from the forebrain. Posterior fossa tumors, including the distinctive pontine gliomas, medulloblastomas, and cerebellar PAs, all derive from the hindbrain. Thus the areas of the brain that undergo rapid expansion in early life engender most pediatric brain tumors. Along the dorsal-ventral plane of the neural tube, greater proliferation of neural tube precursors occurs in the dorsal part of the tube than in the ventral tube. Proliferation of more dorsal precursors gives rise to the multilayer structures of the cerebral and cerebellar cortex; these areas are also the regions that give rise to many pediatric brain tumors.
Forebrain and Cerebral Cortex
In the forebrain the open spaces within the lateral outpouchings of the neural tube become the lateral ventricles, and proliferation largely occurs adjacent to the ventricular zone (VZ) in the medial and lateral ganglionic eminences, in the subventricular zone (SVZ) or subependymal zone. Early in development, neural stem cells/precursors divide extensively to provide the cellular elements of the cerebral cortex, thalamus, and basal ganglia (see Fig. 57-5, A ).
Although the VZ in the forebrain initially contains the dividing neural stem/progenitor cells, during development the size of the VZ progressively decreases while the adjacent SVZ increases in size. The early generated cells migrate radially from the VZ and SVZ to become the neurons of the innermost cortical layer (layer VI), and later mitoses give rise to neurons that also migrate radially and occupy increasingly superficial layers. Inhibitory neurons are derived from precursors in the medial ganglionic eminence. They migrate tangentially throughout the cortex. Thus the cortex develops in an inside-out pattern. Toward the end of the prenatal neurogenic phase, the precursors of the VZ and SVZ generate glial cells, including astrocytes, oligodendrocytes, and ependymal cells.
A small population of precursors remains in the SVZ, just above the ependymal cells, throughout life. These neural stem cells continue to generate glial cells and oligodendrocytes and also continue to give rise to a limited number of neuronal cells through adult neurogenesis. An additional zone of adult neurogenesis is located in the hippocampus, adjacent to the granular zone. Thus the neural stem cell represents a common precursor for glial and neuronal cells. Accumulating data suggest that many, if not most, brain tumors arise from such stem cells or their early derivatives.
Cerebellar Cortex
The cerebellar cortex develops in a way that has some similarities to, but some differences from, the pattern in the cerebral cortex. The hindbrain is the site where the neural tube closes last. While closure occurs, the neural folds pucker to form the rhombic lips. These two protrusions will give rise to many cell types of the cerebellum and pons. Cells in the VZ of the upper rhombic lip proliferate and then begin an unusual migration pattern. The precursor cells of the rhombic lip migrate over the top of the rhombic lip and disperse by moving from the caudal aspect of the pucker to cover the rhombic lip or incipient cerebellum. The rhombic lip–derived precursors settle in a zone that covers the developing cerebellum, which is called the external granule cell (external germinal cell [EGL]) layer. This layer constitutes a site of extensive postnatal proliferation and is a specialized mitogenic niche where precursors divide and give rise almost exclusively to cerebellar granule cells, the most numerous neuronal cells in the brain. This secondary proliferative zone may be necessary to generate this vast number of granule cells. To generate the 60 to 80 billion granule cell neurons, the granule cell precursors in the EGL undergo many rounds of cell divisions, beginning in the ninth week after fertilization and continuing through the first 18 months of life in humans. Other stem/precursors in the VZ follow distinct differentiation paths. Radial glia adjacent to the cerebellum provide one source of these multipotential stem/precursors. Some VZ stem/precursors migrate toward the cerebellar white matter, where they can give rise to cerebellar interneurons and glia. Others migrate past the cerebellar white matter and form the Bergmann glia of the cerebellar cortex.
It has been suggested that four distinct subtypes of cerebellar stem/precursors each give rise to a distinct subtype of medulloblastoma. A great deal of evidence has indicated that the granule cell precursors of the EGL are a cell of origin for the sonic hedgehog (SHH) subtype of medulloblastoma. First, in very young children, medulloblastomas are often continuous with the EGL, and an intermediate zone of dysplastic cells can sometimes be seen to join the EGL and tumor tissue. Second, the appearance and pattern of gene expression of the granule cell precursors resemble those of SHH-type medulloblastoma. Finally, SHH signaling pathways that normally regulate proliferation of granule cell precursors are constitutively active in one type of medulloblastoma (discussed later).
The precursor cells adjacent to the ventricle that resemble radial glia have been suggested to be the cells of origin of Wingless (Wnt)-subtype medulloblastomas. In mouse models, activation of the Wnt pathway and/or activation of phosphoinositide 3′ kinase (PI3K) in these radial glial precursors can mimic this group of medulloblastomas.
The cellular origin and the oncogenic mutations responsible for initiating other medulloblastoma subtypes have also been identified. For example, it has been suggested that the stem cells of the white matter and earlier stem cells may provide the cellular origin for group III and IV medulloblastomas, respectively. It has been suggested that less specialized stem cells can give rise to medulloblastomas. Indeed molecular characterization of medulloblastomas suggests that genetically distinct tumor types exist that may represent the oncogenic transformation of cerebellar precursor cells at different locations and stages. This scenario would be analogous to leukemias, in which oncogenic transformation of hematopoietic precursors at distinct developmental stages leads to distinct types of leukemias.
Cancer Stem Cells
Brain tumors have predominantly been classified as neuronal or glial in nature. The neuronal tumors include CNS PNETs, pineoblastomas, and medulloblastomas, as well as ganglion cell tumors. Glial tumors include many different gliomas, such as juvenile PA, subependymal giant cell astrocytoma, other low-grade astrocytomas, pontine glioma, malignant astrocytoma (including glioblastoma multiforme), and tumors that resemble other glial cell types, such as oligodendroglioma and ependymoma. Although this classification schema remains useful, it appears that many brain tumors are generated by oncogenic mutations in neural stem–precursor cells, rather than more mature cell types. Furthermore although cancers traditionally have been viewed as clonal, increasing evidence indicates that this is not the case. Instead the concept of the existence of a subpopulation of cancer stem cells has developed—distinctive cells within the tumor that are uniquely capable of regenerating the cancer. Recent studies of brain tumors have identified cluster of differentiation (CD)-133–positive cells as radioresistant, slowly proliferating cancer stem cells that are particularly prevalent in high-grade tumors, such as glioblastoma multiforme. The ability of these cancer stem cells to survive surgical resection, radiation, and cytotoxic chemotherapy is a major reason for the difficulty in curing high-grade brain tumors.
Genetic and Signaling Pathways Implicated in Development and in Pediatric Tumors
Inherited disorders that cause a familial propensity for brain tumors have provided an important method for identifying genetic pathways that contribute to these cancers. Neurofibromatosis, tuberous sclerosis, Gorlin syndrome, Turcot syndrome, Cowden syndrome, and the SMARCB1 (switch/sucrose nonfermentable [SWI/SNF]–related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1) mutation all represent heritable disorders associated with an increased risk of brain tumors ( Table 57-1 ).
TABLE 57-1
Common Chromosomal Abnormalities Associated with Pediatric Central Nervous System Tumors
| Chromosomal Abnormality | Tumor |
|---|---|
| Monosomy 22 | Atypical teratoid-rhabdoid tumor |
| Acoustic neuromas | |
| Meningioma | |
| Ependymoma | |
| 1p and/or 22q loss | Oligodendroglioma |
| Isochrome i17 | Medulloblastoma |
| 9q22 loss ( PTCH1 gene) | Medulloblastoma |
| Loss of chromosome 10, 9p, 17p | Progression to high-grade glioma |
Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF-1) is an autosomal-dominant neuroectodermal disorder characterized by café-au-lait spots and fibromatous tumors of the skin. Additional clinical features that can be seen in NF-1 ( Box 57-1 ) include Lisch nodules in the iris, scoliosis, cognitive problems, and epilepsy. Several tumors occur with greater frequency in persons with this disorder, including pheochromocytoma, ependymoma, meningioma, and glioma; this characteristic may relate to dysregulation of specific stem cell populations. Among these tumors, gliomas of the optic pathway are the most common tumors seen. The unique biology of these tumors is slowly being elucidated through studies of the role of NF-1 in the development of the optic pathway in animal models. Neurofibromatosis is caused by heterozygous mutations in neurofibromin, and the cancers observed in this disorder result from loss of heterozygosity at chromosome 17q11.2, leaving only the mutant NF-1 allele. Although this disorder is inherited as an autosomal-dominant disease, as many as 50% of patients represent new germline mutations and therefore do not have a family history of the disorder.
Box 57-1
Diagnostic Criteria of Neurofibromatosis Type 1 *
* The diagnosis of neurofibromatosis type 1 requires any two or more of these criteria.
-
Six or more café-au-lait spots ≥1.5 cm in postpubescent individuals or >0.5 cm in prepubescent individuals
-
Two or more neurofibromas or one or more plexiform neurofibromas
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Freckling in the axillae or groin
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Optic glioma
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Two or more Lisch nodules
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Dysplasia of the sphenoid bone or dysplasia or thinning of the cortex of long bones
-
A first-degree relative with neurofibromatosis type 1
The neurofibromin protein is a 250-kD tumor suppressor that functions as a guanosine triphosphatase activator for the small G protein Ras. In this way, active neurofibromin decreases the ratio of guanosine triphosphate–bound (active) to guanosine diphosphate–bound (inactive) Ras or Ras-like protein. While activated Ras stimulates mitogen-activated protein kinases (MAPKs) and PI3Ks, the change in Ras activity leads to unregulated proliferation and survival ( Fig. 57-6 ). Although the incidence of brain tumors, particularly optic nerve gliomas, is significantly increased in persons with NF-1 (approximately 5% to 15%), the tumors that develop in these patients tend to be less aggressive than other gliomas. These tumors are more susceptible to chemotherapeutic interventions and thus can be treated differently than other gliomas. In fact many tumors stop growing spontaneously. The unique developmental environment of the optic pathways may account for the differential occurrence of these tumors in patients with NF-1, as well as their increased responsiveness. In addition to optic pathway gliomas (OPGs), non-OPGs occur at frequencies 100 times greater than expected, with the most common sites being the brainstem (49%), cerebral hemispheres (21%), and basal ganglia (14%). Other MRI signal abnormalities within the brain are often observed in patients with NF-1. The most characteristic abnormality is the unidentified bright object. Unlike low-grade gliomas (LGGs), these lesions are bright on T2-weighted imaging, do not demonstrate contrast enhancement, and usually produce neither mass effect nor symptoms. They often come and go and should not be biopsied or treated. The varied intracranial localization of lesions and variable need for neurosurgical intervention in a subset of children with NF-1 suggests that radiologic surveillance should be based on careful and regular neurologic and ophthalmologic examinations. Patients with NF-1 appear to be at increased risk of moyamoya syndrome, and this risk becomes especially high after cerebral radiation therapy. Patients with NF-1, even in the absence of a brain tumor, are also affected by a number of other problems as a result of their disease, in particular neurocognitive impairment, which can range from mild to severe.
Neurofibromatosis Type 2 (Merlin)
Neurofibromatosis type 2 (NF-2) is characterized by familial, bilateral acoustic neuromas and is caused by mutations in the gene that encodes merlin, or schwannomin, localized to chromosome 22q12.2. Merlin interacts with cytoskeletal components and appears to be important in adhesion-dependent growth control. Persons with germline mutations also have skin tumors with both peripheral schwannomas and neurofibromas and have a propensity to develop intracranial meningiomas or, more rarely, gliomas and spinal tumors. The onset of symptomatic tumor growth is uncommon in childhood, and in most patients the condition is identified in adulthood.
Tuberous Sclerosis
A third neurocutaneous disorder associated with an increased propensity for brain tumors is tuberous sclerosis (TS). This condition can be caused by mutations in either of two genes, TSC1 (hamartin, at chromosome 9q34) or TSC2 (tuberin, at chromosome 6p), and it is characterized by hamartomata in multiple organs. The most common clinical manifestations include epilepsy, cognitive and behavioral problems, and characteristic skin lesions. The white leaf-shaped skin lesions can best be seen under a Wood light; adenoma sebaceum (facial angiofibroma) can also be seen. Renal manifestations include angiomyolipomas, renal cysts, and, more rarely, renal cell cancer. Brain tumors develop in between 5% and 14% of patients, the most common being the subependymal giant cell astrocytoma (SEGA); other gliomas and ependymomas are also relatively frequent. Careful serial evaluations are required because of the possibility of additional tumor development in this patient population. Cortical tubers can cause seizures and require specialized neurosurgical approaches in children. Resection of tubers does not always control seizures and suggests that extratuberal epileptogenic brain abnormalities may be present that require more specialized imaging.
The phenotypic similarity of mutations in Tsc1 and Tsc2 is explained by the finding that these two proteins interact directly with one another. This complex acts as a guanosine triphosphatase–activating protein for Ras homolog enriched in brain (Rheb). The decreased activity of Rheb inhibits the mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase–1. As a result there is diminished translation by eukaryotic translation initiation factor 4E-binding protein–1 (EIF4EBP1; 602223). The hamartin-tuberin complex thereby regulates growth and proliferation of subependymal and subventricular neural stem cells. The Tsc-mTOR pathways may normally be regulated by Wnt and insulin-like growth factor (IGF) ligands during development. Patients with TS who have SEGA or LGGs have demonstrated responses to mTOR inhibitors, confirming the clinical relevance of these findings.
Gorlin Syndrome
Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome) is characterized by multiple basal cell carcinomas or basal cell nevi before the age of 30 years, odontogenic keratocysts or polyostotic bone cysts, and palmar and plantar pits. Other manifestations include rib or vertebral anomalies, large head circumference with frontal bossing, cardiac or ovarian fibroma, and lymphomesenteric cysts. Gorlin syndrome is caused by mutations in PTCH1 (chromosome 9q22.3), the receptor for the SHH ligand. Medulloblastoma develops in approximately 4% to 10% of persons with Gorlin syndrome. This syndrome also predisposes to other tumors, such as rhabdomyosarcoma and meningioma.
The PTCH1 gene product functions as both a receptor and negative regulator of signaling initiated by SHH or the related ligands, Indian hedgehog and desert hedgehog. These ligands initiate an unusual and incompletely understood signaling pathway ( Fig. 57-7 ). When a hedgehog ligand binds to Ptc, this alters the activation state of smoothened, or Smo, a seven-transmembrane protein. Normally Ptc represses the activity of Smo; however, when a ligand binds to Ptc, this derepresses Smo activity. Active Smo translocates to a distinctive subcellular organelle known as a primary cilium. Here active Smo enables the dissociation of a signaling complex containing suppressor of fused homolog (SUFU) and Glioma-associated Oncogene Homolog (Gli) transcription factors. The dissociation of this complex results in the nuclear relocalization of Gli family members and increased expression of Gli family members, as well as the expression of v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), D-type cyclins, and the stem cell–associated chromatic complex component, B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1). The active pathway thereby potentiates proliferation and inhibits apoptosis.
Good evidence indicates that constitutive activity of the SHH pathway can cause medulloblastoma. Gorlin syndrome is associated with increased incidence of medulloblastoma, as is the analogous mutation in mice. Activating mutations in Smo, or mutations in suppression of fused (SuFu), can also lead to these brain tumors. Recent studies have suggested that specific inhibitors of Smo may provide valuable biologic therapies for medulloblastoma.
The value of understanding developmental pathways that normally regulate neural precursor proliferation to decipher the mechanisms that cause pediatric brain tumors is reinforced by data showing that SHH ligand stimulates and regulates proliferation of granule cell precursors and neural stem cells. Thus it is perhaps not surprising that SHH-responsive genes are also expressed in gliomas, including diffuse intrinsic pontine gliomas (DIPG) and glioblastoma. Thus inhibitors of SHH signaling may play a role in treating several types of brain tumors.
Turcot Syndrome
Turcot syndrome is characterized by familial polyposis of the colon, together with malignant brain tumors. This disorder can be caused by mutations in the adenomatous polyposis coli gene ( APC , on chromosome 5q21) or in the mismatch repair genes MLH1 (120436) or PMS2 (600259). The distinction between the clinical entities that result from mutations in APC and mutations in repair genes include the nature of the brain tumors seen; the characteristic brain tumors seen are medulloblastomas or astrocytomas, respectively. APC is a large protein whose activity is critical in the Wnt signaling pathway. Therefore inactivating mutations of APC result in the aberrant accumulation of β-catenin and increased transcription of transcription factor 4 (Tcf4)-dependent genes, including c-myc . Mutations in β-catenin and in APC have also been reported in sporadic medulloblastoma, highlighting the importance of this pathway for this malignant cerebellar tumor.
Wnts constitute a family of ligands that can act through two distinct signaling pathways. The canonical Wnt pathway is initiated when Wnt proteins bind to cell-surface receptors of the Frizzled family. This binding leads to activation of Dishevelled (DSH) family proteins. When DSH becomes activated, it inhibits a protein complex that includes axin, glycogen synthase kinase–3 (GSK3), and APC ( Fig. 57-8 ). The axin–GSK3–APC complex promotes the proteolytic degradation of β-catenin. After this β-catenin destruction complex is inhibited, cytoplasmic β-catenin becomes stabilized and β-catenin is then able to enter the nucleus. Nuclear β-catenin interacts with TCF-LEF (lymphoid enhancer-binding factor 1) family transcription factors to promote the expression of a gene program that includes c-myc , N-myc , and cyclin D1 and thereby stimulate cell cycle progression ( Fig. 57-9 ). It is not clear whether the noncanonical Wnt pathway, which does not involve APC, also contributes to brain tumors.
As is the case for SHH signaling, the ability of the deregulated Wnt pathway to cause medulloblastomas highlights the relevance of understanding neurodevelopment. In the absence of Wnt1, the cerebellum does not form properly. The Wnt and SHH pathways cooperate during normal development to generate normal cerebellar neurons. It is likely that these pathways also synergize in tumor formation, particularly during medulloblastoma oncogenesis.
Lhermitte-Duclos Disease, Cowden Syndrome, and PTEN Mutation
Activation of PI3K results in phosphorylation of phospholipids at the 3′ position; this phosphorylation is removed by the phosphatase and tensin homolog (PTEN) phosphatase. Therefore mutations in PTEN result in excess and/or incorrectly localized activation of the PI3K pathway. PI3K is critical in several signaling pathways that regulate proliferation, survival, migration, and cell size. The multiplicity of functions explains the diverse spectrum of disorders seen in PTEN mutations, including neurologic, cutaneous, and oncologic syndromes.
Molecular studies on Lhermitte-Duclos disease (LDD) tissue have revealed PTEN gene mutations in 83% of cases, with immunostaining showing lost or reduced PTEN expression in 78% of cases. As a consequence, Akt phosphorylation is increased. Initially Cowden syndrome was described as a familial predisposition for breast cancers, thyroid cancers, brain tumors, and other neoplasia. This syndrome was subsequently recognized as a spectrum of disorders that includes LDD and Bannayan-Ruvalcaba-Riley syndrome. The diagnosis of LDD depends on characteristic hamartomas of the cerebellum. These lesions in the cerebellar cortex exhibit thickened cerebellar folia, with misplaced cerebellar granule cells and enlarged size of the cerebellar neuronal cell bodies. In addition to cerebellar ataxia, these hamartomas can cause hydrocephalus and herniation. Another manifestation of the PTEN mutations is seen in Bannayan-Ruvalcaba-Riley syndrome, with macrocephaly, seizures, cognitive dysfunction, and autistic behaviors. Different manifestations of the mutation can be observed even within a family, and thus a careful consideration of family history is warranted.
RB1 Mutations
The retinoblastoma gene was the first tumor suppressor gene identified. In addition to the retinal tumors seen in persons with germline mutations in Rb1 , “trilateral” retinoblastoma has been described. In these persons, bilateral retinoblastoma is accompanied by a pineal tumor (pineoblastoma) with similar characteristics to retinoblastoma. The other secondary tumors that occur in patients with retinoblastoma are osteosarcomas. The Rb1 protein is required for the G1 checkpoint, and studies on this pathway have provided key insights into the mechanisms of growth regulation.
Atypical Teratoid Rhabdoid Tumor
Mutations in the sucrose nonfermentable 5/integrase interactor 1 (SNF5/INI1) component of the SWI-SNF DNA remodeling complex cause rhabdoid tumors. These tumors include renal and soft tissue tumors and brain tumors. In the CNS, these brain tumors, called atypical teratoid rhabdoid tumors (ATRTs), are characteristically found in the cerebellopontine angle or in supratentorial locations. Prior to the identification of deletions or mutations of the SMARCB1 gene on chromosome 22, these tumors were historically grouped with medulloblastomas and PNETs. However their histology is distinct, with a mixture of atypical spindle cells, poorly differentiated small round blue cells, and rhabdoid cells with prominent cytoplasmic inclusions, large eccentric vesicular nuclei, and adjacent whorls of intermediate filaments. The nature of the cell of origin for these tumors, and why they predominantly arise in very young children, is as yet poorly understood.
Conceptual Organization of Pediatric Brain Tumors
Leukemias are considered in the context of their lineage and stage of development, whereas neuroblastoma is evaluated by the extent of spread, age of the child, and molecular phenotype. Neither of these approaches is well suited to CNS tumors. Although brain tumors share an anatomic site, a number of unique cell types, significant heterogeneity in distribution, and differences in the consequence of therapy differ according to the age of the patient and location within the CNS. These factors, combined with a complicated historic nomenclature, require a different approach to understanding these tumors.
The CNS is made up of three major elements, and therefore three major groups of tumors are commonly observed:
- 1.
Glial cells—responsible for structural support and maintenance of the CNS, and composed of three cell subtypes:
- a.
Astrocytes—structural support for the CNS → astrocytoma
- b.
Ependymocytes—help regulate homeostasis of the CNS → ependymoma
- c.
Oligodendrocytes—myelination for the neural axons → oligodendroglioma
- a.
- 2.
Neurons—electrical activity → medulloblastoma, pineoblastoma, CNS PNETs
- 3.
Choroid plexus—production of cerebrospinal fluid (CSF) → choroid plexus carcinoma (CPC)
Tumors arising from glia, neurons, or the choroid plexus account for approximately 90% of all pediatric CNS tumors. The remaining 10% of pediatric brain tumors arise from cells that are derived from extracranial sources but become entrapped in the developing CNS during embryogenesis ( Fig. 57-10 ).
- 4.
Germ cells, which arise in the primordial gonadal ridge and normally migrate down to their final resting place in the abdomen (ovaries) or scrotum (testes), can occasionally migrate upward and become enveloped in the developing brain → germinoma, nongerminomatous germ cell tumor (NGGCT)
- 5.
Cells from the Rathke pouch, which normally gives rise to structures of the head and neck, can become trapped within the developing brain → craniopharyngioma
Two additional tumor types that are rare in children but account for approximately 80% of CNS tumors in adults include metastatic carcinoma, especially of the breast, colon, lung, and prostate. Metastatic lesions to the brain in pediatric patients are exceptionally rare, and when they occur, they are usually in the context of end-stage disease. Meningiomas are the other common adult brain tumor that is rarely observed in children.
The five primary cell types of the brain are not evenly distributed in the CNS ( Fig. 57-11 ):
- 1.
Glia.
- a.
Astrocytes are found throughout the entire brain and spine.
- b.
Ependymocytes line each of the ventricles, and hence these cells are most predominant in the 4th ventricle > 3rd ventricle.
- c.
Oligodendrocytes are found around the junction of the gray-white matter.
- a.
- 2.
Neural tumors are defined by location rather than histology; molecular characterization indicates that these distinctions based on location are biologically important.
- a.
Medulloblastoma is found within the posterior fossa.
- b.
Pineoblastoma is found within the pineal region.
- c.
CNS PNETs can be found anywhere in the brain or spine.
- a.
- 3.
Choroid plexus is predominantly located in the lateral ventricles.
- 4.
Germ cell tumors (GCTs) are localized to the suprasellar region, the pineal area, or both.
- 5.
Craniopharyngiomas are found within the suprasellar region.
Brain tumors tend to spread in one of two ways, by direct invasion into adjacent regions with focal expansion of the primary mass, or by dissemination (seeding) of cells through the CSF, with resultant multifocal disease. Of the five tumor types listed, glial tumors and craniopharyngiomas tend to grow by direct extension and the other three tend to grow by seeding cells into the CSF. The workup of patients with newly diagnosed brain tumors will therefore require MRI of the involved area for glial tumors and craniopharyngioma, and craniospinal imaging and CSF cytology will be needed for seeding tumors (neural, choroid plexus, and germ cell).
Three major treatment strategies are considered for all CNS tumors: (1) surgery, (2) radiotherapy, and (3) chemotherapy. Certain general principles can be applied to their use ( Table 57-2 ):
- 1.
Surgery is important for making the diagnosis, achieving rapid reduction in tumor size, and relieving elevated pressure from obstructive hydrocephalus.
- 2.
Radiotherapy is effective for a wide range of tumors but has significant morbidity on the developing CNS, which frequently limits its applicability. In general focal tumors (gliomas and craniopharyngiomas) are treated with focal radiation therapy, whereas seeding tumors (medulloblastomas, pineoblastomas, CNS PNETs, CPCs, and GCTs) are treated with craniospinal radiotherapy with a boost to the primary site and areas of metastatic disease, particularly in children 3 years and older.
- 3.
Chemotherapy is effective for most seeding tumors and has become part of the initial therapy for these tumors (neural, choroid plexus, and germ cell). By contrast chemotherapy has had limited success for most focal tumors (malignant gliomas and craniopharyngiomas).
TABLE 57-2
Common Types of Treatment for Pediatric Central Nervous System Tumors *
| Type of Tumor | Method of Spread | Attempted Surgery | Type of Radiation Therapy † | Chemotherapy |
|---|---|---|---|---|
| Glial | Local | Yes | Focal | No ‡ |
| Neuronal | Seeding | Yes | CSI | Yes |
| Choroid | Seeding | Yes | CSI | Yes |
| Germ cell | Seeding | Yes | CSI | Yes |
| Cranio | Local | Yes | Focal | No |
CSI, Craniospinal irradiation.
* Tumors that exhibit focal growth receive attempted resection and focal radiation therapy. Tumors that are at high risk for early dissemination are treated with focal surgery, CSI, and chemotherapy.
† Radiation therapy is often deferred in children younger than 3 years.
‡ Symptomatic unresectable low-grade gliomas are treated with chemotherapy to delay radiation therapy.
The classification of tumors based on their histologic characteristics is important to provide prognostic information, although the unique environment of the brain makes the classification of benign versus malignant less important than for most other sites in the body. The brain and spine are critical for the control of basic autonomic response, as well as higher order function, and therefore limit the ability to obtain complete resection with a wide margin in most cases. Even benign tumors located in critical and inoperable structures may result in death if their growth cannot be stopped or slowed. Conversely many highly malignant World Health Organization (WHO) grade IV brain tumors (defined histologically) that are responsive to radiation treatment (CNS germinoma) or radiation and chemotherapy (medulloblastoma) have an excellent prognosis. Because patients and their parents have preconceived notions about the importance of benign versus malignant, clarifying these terms early can be important.
The presenting symptoms for patients with CNS tumors can usually be categorized into one of two patterns: (1) direct compression of nerves or (2) obstructive hydrocephalus. The location of the tumor, histologic subtype, and age of the patient are major determinants in the length of clinical symptoms before the diagnosis is made. Although dependent on the location and rapidity of growth, the time to diagnosis for many children may range from 3 to 8 months, and multiple visits to primary care providers is not infrequent. For younger children who cannot verbalize their symptoms and for whom fine motor coordination, speech, and gait are still developing, even greater delays may result.
Symptoms related to the direct compression of adjacent nerves by a tumor will cause a unique constellation of symptoms that can be localized to an area as a result of the highly organized structure of the CNS.
-
The posterior fossa contains the brainstem, 12 cranial nerves, and the descending and ascending fibers connecting the upper and lower aspects of the CNS, in addition to the cerebellum, which is responsible for movement and balance. Tumors in this area result in cranial nerve dysfunction such as diplopia, choking, or facial asymmetry. Tumors of the brainstem can compress the descending motor tracts, resulting in lower motor deficits. Compression of the cerebellum will lead to ataxia or dysmetria.
-
The thalamus is the major relay station of coordinated function from the motor strip and other areas of the cortex. Tumors in this area will often lead to significant hemiparesis.
-
The frontal lobe regulates mood and behavior and contains the motor cortex. Patients with tumors in this area will often present with changes in behavior (more aggressive or more passive), worsening school performance, or specific motor deficits (except those controlled by the cranial nerves). In some patients, more subtle signs of frontal lobe dysfunction such as fatigue, lack of interest, or decreased energy can be mistaken for the behaviors frequent in adolescence.
-
The parietal lobe possesses the centers for sensory function. Tumors in this area can often compress a specific area of the sensory cortex, resulting in a focal sensory deficit that does not follow classic dermatomal or peripheral nerve patterns.
-
The hypothalamus and suprasellar regions contain the area that coordinates endocrine function (i.e., growth hormone, regulation of salts, pubertal development, and stress hormones). This area is near the optic nerves and chiasm. Tumors in this area often present as a change in growth (accelerated or delayed), hormonal dysfunction, or change in vision.
-
The occipital lobe organizes and interprets vision. Tumors in the occipital lobe will present with homonymous defects in vision.
-
The pineal area sits adjacent to the centers of upward gaze (supranuclear tectal or pretectal areas). Lesions in this area can result in Parinaud syndrome (paresis of upward gaze, enlarged pupils that are poorly reactive to light, and poor or limited convergence).
-
The spinal cord possesses all the ascending and descending tracks for sensory and motor function to all areas innervated from that segment of the cord and below. Mass lesions in this area will reduce the motor and/or sensory activity of those areas below the lesion and can consist of motor, sensory, temperature, position, and vibration abnormalities.
-
Gray matter is where neuron bodies are concentrated. Lesions in the gray matter of the frontal, parietal, temporal, and occipital lobes can result in seizure activity. Although initially focal in nature, seizures can rapidly become generalized, obscuring the initial presenting focality.
-
White matter tracts are the myelinated axons of neurons. Lesions in white matter tracts typically result in focal neurologic deficits that correspond to the tracts compressed.
The differential diagnosis of a new tumor of the CNS should be developed using the preceding information. Symptoms will help localize the probable site of the tumor. In turn the site will assist in developing a limited differential diagnosis of possible tumors at that site. Staging and treatment can then be considered in the context of focal versus seeding tumors. Although this exercise will not obviate the need for a definitive biopsy, it can help organize the large array of CNS tumors and ensure that appropriate presurgical planning and staging have been completed.
Obstructive Hydrocephalus and Raised Intracranial Pressure
The brain and spinal cord are supported in the cranium and spinal canal by the CSF, which is largely localized to the subarachnoid space. CSF is initially made by the choroid plexus in the lateral ventricles and, to a lesser degree, in the third and fourth ventricles. The production of CSF is not linked to its passage from the lateral and third ventricles to the fourth ventricle and, finally, through the foramen of Magendie or foramen of Luschka, where it is eventually reabsorbed by the arachnoid villi ( Fig. 57-12 ). The ventricles hold approximately 50 mL of CSF and, with approximately 500 mL of CSF produced each day, any failure to remove old CSF in the context of continued production will cause the fluid-filled ventricles to expand like water balloons in the closed cranium. Obstruction anywhere above the exit from the ventricles to the subarachnoid space (posterior fossa or above) will therefore result in obstructive hydrocephalus. The speed with which the accumulation of fluid occurs will in part determine the rapidity of the symptoms, as well as their severity. Obstructive hydrocephalus is considered a medical emergency because progressive expansion of the ventricular volume will force the brain to be compressed in all directions, including downward, resulting in tonsillar herniation.
The three common symptoms of obstructive hydrocephalus include headaches, often severe in nature, that are thought to arise as a result of stretching of vessels and the pial surfaces. These headaches can often be worsened by changes in body position or head motion. They can be dull, aching, or stabbing in nature. Because of the prevalence of headaches in the general population, it is their persistence and worsening in the context of other symptoms (e.g., morning vomiting and focal neurologic deficits) that usually trigger further investigation. Patients will often have vomiting (often associated with a headache), especially early in the morning upon wakening. Whether this symptom results from hydrostatic pressure changes when first getting up, resulting in compression of the area postrema, or changes in CNS homeostasis upon wakening as a result of more rapid breathing and carbon dioxide release is unknown. Unfortunately the significance of morning vomiting is often overlooked and thought to be related to school avoidance or the flu. Many patients present with prolonged histories of intermittent morning vomiting and headache, suggesting that this process can be partial and relieved by the vomiting, which itself causes raised intraabdominal pressure and equilibration of the CSF pressure gradient. A third common symptom in children with hydrocephalus is blurring of the optic discs, related to the increase in intracranial pressure (ICP). Patients often report blurring or double vision, as well as difficulty in upward gaze. These symptoms likely result from a constellation of factors, including compression of the brainstem and cranial nerves, as well as edema and swelling of the optic discs (papilledema) and pathways leading to vision. The final common symptom of obstructive hydrocephalus is the presence of lower motor deficits, likely because of compression of motor tracts within the brainstem and difficulties with balance and gait related to pressure on the cerebellum.
The symptoms of obstructive hydrocephalus differ in infants, in whom the presence of open sutures permits the head to expand. This expansion relieves the buildup of pressure and thus the associated symptoms. While their head size expands, infants may begin to show some signs of delay in gaining milestones. Careful attention to head circumference changes will help identify these infants early, independent of the cause of the obstruction.
CT imaging of the brain is a rapid method for confirming the presence of obstructive hydrocephalus. Images (without the need for contrast material) will demonstrate enlargement of the ventricles above the area of obstruction. Increasing concerns of radiation dose regarding repeat CT imaging in young children has resulted in a shift to rapid-sequence MRI vent checks. These images are performed without contrast material and are not useful for assessing changes in the tumor. However they have the advantage of assessing changes in fluid within the CNS and without exposure of the child to ionizing radiation. MRI will show large ventricles on T1- and T2-weighted images. Best seen on fluid-attenuated inversion recovery (FLAIR) sequences, the presence of a bright signal around the ventricles is suggestive of transependymal flow, which is thought to result from the backward transduction of pressure from the ventricle to the brain parenchyma ( Fig. 57-13 ). Obstructive hydrocephalus is a surgical emergency and requires urgent intervention. For posterior fossa tumors such as medulloblastoma, ependymoma, or low-grade astrocytoma, relief from obstruction can be achieved with resection of the tumor in most patients, thus avoiding the need for a separate CSF diversion procedure.
Imaging Studies
Neuroimaging
Imaging of brain tumors entails determining the size and site of origin of the lesion, establishing primary diagnosis, and planning treatment. Neuroimaging is critical for the appropriate placement of catheters for stereotactic biopsy, resection, planning of radiation, guided application of experimental therapeutics, and delineation of tumor from functionally important neuronal tissue. After treatment, imaging is used to quantify response and the extent of residual tumor. At follow-up imaging helps determine tumor progression and differentiate recurrent tumor growth from treatment-induced tissue changes, such as radiation necrosis.
Imaging brain tumors in children presents unique challenges not encountered in adult imaging, including the need for sedation and consideration of the long-term effects on a growing child. Cranial CT and MRI remain the main modalities for the primary diagnosis of brain tumors. However several other techniques are being increasingly used in the evaluation of this patient population, including positron emission tomography (PET), MR perfusion and diffusion, and MR spectroscopy (MRS). Assessment of response in pediatrics is a critical component in the appropriate treatment of patients, as well as in identifying active regimens. Recently adult neurooncologists have adopted a new series of guidelines (developed by the International Radiologic Assessment in Neuro-Oncology Committee) to aid in better differentiating tumor progression from pseudoprogression and similarly tumor response from pseudoresponse. Although some of these adult criteria will be useful in pediatrics, the types of tumors common in the pediatric population will require some modifications to the adult approach. Currently an international working group is developing recommendations for children with brain tumors (Radiologic Assessment in Pediatric Neuro-Oncology).
CT is a rapid and inexpensive modality for assessing fluid, blood, and calcification in the central CNS. As such it has typically been the first imaging procedure in children with a presumed intracranial bleed or raised ICP that might require immediate neurosurgical intervention. Other than for lesions arising from the skull vault and to assess calcified tumors, CT scans are used less frequently for routine surveillance of pediatric patients because of an increase in long-term cancer risk caused by CT imaging.
MRI is currently the modality of choice for localization and assessment of the size of brain tumors. MRI provides valuable information about secondary phenomena such as mass effect, edema, hemorrhage, necrosis, and signs of increased ICP. In addition MRI provides excellent tissue contrast and high spatial resolution. Standard T1- and T2-weighted MRI sequences detect brain tumors with high sensitivity. Varying acquisition parameters such as T1 or T2 weighting, techniques such as diffusion- and perfusion-weighted images, and FLAIR sequences reveal a characteristic pattern of each tumor, depending on tumor type and grade. Susceptibility-weighted MRI is useful for detecting areas of hemorrhage, calcifications, and increased vascularity associated with brain tumors. Recently rapid-sequence MRI for the assessment of bleeds or hydrocephalus has been developed, which can avoid the radiation doses associated with CT scans and, like CT scans, can be performed without sedation, even in young children. However it should be noted that these studies are limited in evaluation of the tumor burden and should only be used to assess for acute findings.
MRS can also be helpful for the initial characterization of tumors ; it can also be used to differentiate tumor tissue from other tissue in children with CNS tumors in certain circumstances. MRS has continued to evolve, and the development of multivoxel and two-dimensional techniques has resulted in improved spatial resolution, thereby supplying additional information regarding tumor heterogeneity and intratumoral metabolite distribution. Although MRS is a sensitive technique, it still lacks specificity as a stand-alone technique in the clinical setting. In a recent study, brain proton MRS biomarkers were shown to predict survival of children with CNS tumors better than standard histopathology. More accurate prediction using this noninvasive technique represents an important advance and may suggest more appropriate therapy, especially when a diagnostic biopsy is not feasible. In general, decreased N -acetylaspartate (NAA) and creatine concentrations and increased choline concentrations correlate with tumor grade. Reduction of NAA is likely because of neuronal death or damage, although the reduction in creatine is likely to be a result of changes in cell energetics. The increase in choline is believed to reflect increased membrane synthesis. Increases in lipid and lactate concentrations have been observed in some gliomas. Lactate accumulation is believed to be a result of central tumor necrosis.
Diffusion-weighted MR pulse sequences enable a quantitative and reproducible assessment of the diffusion changes, not only in areas exhibiting signal abnormality in conventional MRI but also in areas of normal signal. MR diffusion using predominantly echoplanar techniques has been useful in the characterization of tissue, tumor cellularity, tumor grading, tumor response to treatment, and distinction of tissue types. Diffusion tensor imaging (DTI) provides visualization of fiber bundle direction and integrity, with in vivo characterization of the rate and direction of white matter diffusion. DTI is useful for presurgical planning or coregistration of tractography data with radiosurgical planning and functional MRI data. Fractional anisotropy using DTI may prove helpful for the assessment of treatment-induced white matter changes in children.
The usefulness of diffusion-weighted imaging (DWI) for characterizing intracranial cystic or cystlike lesions has been demonstrated in a number of studies. DWI has long been used to differentiate between epidermoid and arachnoid cysts. Arachnoid cysts are characterized by free diffusion, whereas epidermoids have an apparent diffusion coefficient similar to that of brain parenchyma, thereby demonstrating restricted diffusion. The usefulness of DWI in the distinction between ring-enhancing cerebral lesions such as brain abscesses, cystic or necrotic HGG, or metastasis has been shown in multiple studies during the past decade, although this differentiation continues to be a challenge. The ring enhancement of a brain abscess can be indistinguishable from that of a cystic or necrotic HGG or metastasis. Other lesions that may also have a similar appearance are subacute ischemic infarction, resorbing hematoma, and demyelinating disease. Abscesses demonstrate high signal on DWI and a reduced apparent diffusion coefficient (ADC) in a cystic ring-enhancing cerebral lesion. ADC values have been assessed between tumor types; however, considerable overlap exists between certain tumor types, requiring additional evaluations. Authors of a retrospective study of ADC values of 275 adult and pediatric brain tumors have reported a significant negative correlation between ADC and WHO astrocytic tumor grades II through IV. Other comparisons included a higher ADC in dysembryoplastic neuroepithelial tumors (DNETs) than in astrocytic grade II tumors (100% accuracy) or other glioneuronal tumors, a lower ADC in malignant lymphomas compared with glioblastomas and metastatic tumors, a lower ADC in CNS PNETs compared with ependymomas, and a lower ADC in meningiomas compared with schwannomas. The ADC of craniopharyngiomas was higher than that of pituitary adenomas, whereas the ADC of epidermoid tumors was lower than that of chordomas. In meningiomas the ADC was not indicative of malignant grade or histologic subtype. DWI has also been used to obtain additional information regarding tumor type and grade. The reduction in extracellular space, as well as high nuclear-to-cytoplasmic ratios of some cancer cells, causes a relative reduction in ADC values. In some studies overlap was seen in ADC values of HGGs and LGGs. The presence of glycosaminoglycans such as hyaluronan in the extracellular space of some HGGs may decrease water content and cause a reduction in ADC values. In addition, one pitfall of DWI is that high-grade tumors that may exhibit necrosis can lead to higher ADC values.
DWI and proton MRS have been evaluated as diagnostic tools, and in a study of children with posterior fossa lesions in which these techniques were combined, MRI was successful in correctly identifying the histologic diagnosis in every case. Although this approach does not replace the pathologic diagnosis, it demonstrates the increasing accuracy of biologic-based imaging. Similar results have been reported for ADC analysis. DWI may also be helpful in differentiating postsurgical changes from tumor recurrence. DWI can also detect acute changes in white matter from methotrexate administration, which must be differentiated from progressive disease.
Determination of the tumor margins is considered by many investigators to be extremely important for the management of brain tumors. Complete resection of tumors with minimal neurologic deficit is the ultimate goal of surgical resection. In some studies DWI has been shown to discriminate among tumor, infiltrating tumor, peritumoral edema, and normal brain parenchyma. However other studies have not found DWI to be helpful for evaluating tumor margins.
MR diffusion imaging has also been assessed as a biomarker for early prediction of treatment response in patients with brain tumors. Recent studies have indicated the possibility of using functional diffusion map analysis as an early biomarker for treatment response preceding decrease in tumor size. Increasingly MR perfusion imaging is being used to evaluate cerebral perfusion dynamics by analysis of the hemodynamic parameters of relative cerebral blood volume (CBV), regional cerebral blood flow (CBF), and mean transit time. CBV is the parameter most commonly quantified in brain tumors. CBV is defined as the volume of blood in a region of brain tissue, commonly measured in milliliters per 100 g of brain tissue. CBF refers to the volume of blood/unit time passing through a given region of brain tissue, measured in milliliters per minute per 100 g of brain tissue. Mean transit time refers to the average time it takes blood to pass through a given region of brain tissue and is commonly measured in seconds. Perfusion imaging techniques include T2-weighted dynamic susceptibility techniques, arterial spin labeling (ASL) techniques, and T1-weighted dynamic contrast-enhanced perfusion techniques. These techniques use exogenous tracer agents, such as paramagnetic contrast material, or endogenous tracer agents, such as magnetically labeled blood (arterial water). The most common method currently performed in the clinical setting is dynamic contrast-enhanced perfusion MRI with an exogenous tracer, such as gadopentetate dimeglumine. It is assumed that the tracer is restricted to the intravascular compartment and does not diffuse into the extracellular space. Imaging is performed dynamically (rapid imaging over time during a bolus injection) using echoplanar imaging–based spin echo or gradient echo sequences. It is thought that the spin echo sequences are more sensitive to capillary level blood vessels, whereas gradient echo techniques are more sensitive to the larger vessels. Although gradient echo sequences are associated with more magnetic susceptibility artifacts, particularly in the posterior fossa, they are the more common of the two techniques. For young children and infants, challenges exist relating to intravenous (IV) access, smaller intravenous catheters, and limitations of the contrast medium dose.
DTI is an adaptation of DWI and is performed by acquiring diffusion data in six or more directions, enabling determination of the direction and magnitude of water diffusion. Connecting the directions of diffusion in each voxel to those of neighboring voxels using a variety of mathematical algorithms enables creation of a three-dimensional (3D) white matter tract map, termed “tractography.” This technique is used to delineate important white matter tracts affected by tumor and help guide surgical resection. In conjunction with functional MRI, tractography can be used to predict possible postoperative deficits resulting from white matter tract damage.
Dynamic T1-weighted contrast imaging can be used to assess microvascular permeability (measured as the transendothelial transfer constant, or Kps) in brain tumors. Kinetic modeling of the dynamic signal changes can yield estimates of regional fractional blood volume and Kps, which is an indicator of BBB disruption and correlates with angiogenesis. This technique can be successfully performed in children, and applications of this technique may be useful for monitoring antiangiogenic therapies in pediatric patients with brain tumors. ASL is an MR perfusion technique that does not use an IV contrast agent. The perfusion contrast in the image results from the subtraction of two successively acquired images, one with and one without proximal labeling of arterial water spins, with a magnetic gradient used to invert the magnetization of inflowing blood. The signal-to-noise ratio, anatomic coverage, and shorter imaging time are currently better for the dynamic contrast perfusion techniques compared with ASL. However ASL may have a future role in the imaging of pediatric brain tumors, particularly because it relies on a noninvasive endogenous contrast agent.
The use of PET and single-photon emission CT (SPECT) imaging continues to improve and can be important in helping to differentiate treatment effect from tumor recurrence. The usefulness of PET imaging is especially evident when a baseline evaluation is performed so that postoperative changes can be evaluated in the context of the pretherapy PET avidity, thus requiring consideration of nuclear imaging early in the workup of these patients.
Standardization of neuroimaging parameters for children with CNS tumors and the testing of novel sequences that can be adapted to specific molecular inhibitors now being evaluated in this population are being developed.
A further advance in MRI of brain tumors has occurred with the availability of intraoperative scanners. These scanners enable preoperative guidance for stereotactic biopsy and for planning tumor resection, and they provide a review of the resection site for residual tumor prior to closure of the craniotomy. Intraoperative DTI has been proposed to aid in the preservation of fiber tracts and to minimize postoperative deficits.
Somatostatin receptor scintigraphy has been used to differentiate the presence of residual or recurrent tumor from scar and necrosis and is better than MRI scans for a number of pediatric tumor types. Molecular imaging is likely to play an expanding role in neurooncology as more pathway-specific inhibitors become available.
Posterior reversible leukoencephalopathy (PRES) is increasingly identified in children with brain tumors, particularly in children with episodes of hypertension. Patients present with headaches that are usually severe, mental and visual status changes, and seizures concurrent with hypertension and characteristic MRI findings, including T2 signal abnormalities. MRI findings are those of vasogenic edema with T2 and FLAIR hyperintensities involving predominantly the parietal and occipital regions bilaterally ( Fig. 57-14 ). The diffusion changes in PRES are traditionally thought to be represented by higher ADC values, consistent with vasogenic edema. Focal areas of restricted diffusion (likely representing infarction–tissue injury with cytotoxic edema) are uncommon (11% to 26%) and may be associated with an adverse outcome. Hemorrhage (focal hematoma, isolated sulcal-subarachnoid blood, or protein) is seen in approximately 15% of patients. The parietal and occipital lobes are most commonly affected, followed by the frontal lobes, the inferior temporal-occipital junction, and the cerebellum. Lesion confluence may develop as the extent of edema increases.
The mechanism of PRES remains controversial, although the hypertension-hyperperfusion theory is favored because of the common presence of elevated blood pressure and perceived response to hypertension management. Key issues remain problematic, including PRES in normotensive patients with pressures rarely reaching autoregulatory limits, and brain edema that is lower in patients with severe hypertension. Hypertensive encephalopathy animal models do not reflect the systemic toxicity that is present, and hyperperfusion has not conclusively been demonstrated in patients.
Intracranial vasospasm has been seen with conventional and MR angiography, suggesting vasospasm as a possible pathophysiologic mechanism for the observed findings. MR DWI was instrumental in establishing and consistently demonstrating that the areas of abnormality represent vasogenic edema. Prompt treatment with antihypertensive therapy or discontinuation of immunosuppressive agents can lead to complete recovery in some cases. However, if untreated, permanent neurologic deficits or even death may occur as a result of cerebral infarctions or hemorrhages, and 20% to 40% of patients with PRES can be normotensive. PRES can be associated with a number of inciting events, including chemotherapy, radiation therapy, and antiangiogenic drugs. This latter group of drugs may cause PRES as a result of their direct effect on vascular endothelial growth factor (VEGF) and raised blood pressure. Rapid recognition of this entity is critical to prevent permanent damage from occurring.
Surveillance Imaging
The role and usefulness of surveillance imaging for patients with a brain tumor remain controversial and depend on a number of factors, such as the age of the patient, histology of the tumor, time from diagnosis, and type of treatment. For example, in one study only nine of 318 imaging encounters identified an asymptomatic recurrence. Other studies have demonstrated the cost-effectiveness of surveillance imaging, recognizing that decisions are often made on the basis of insurance coverage. A common practice has been imaging every 3 months while the patient is undergoing therapy (to assess continued response while undergoing therapy), and then every 3 months for the first year after the completion of therapy. Beginning in the second year, scans are performed every 6 months for a year and then annually afterward. With time the risk of tumor recurrence will go down, although the risks of radiation-induced vasculopathy and second tumors begin to increase. Modification of these guidelines for children with tumors at low risk of recurrence (e.g., completely resected craniopharyngioma or low-grade astrocytoma) or those who did not receive radiation therapy can be made on a case-by-case basis.
Neuropathology
The neuropathologic classification of pediatric brain tumors has evolved greatly during the past century. Categorizing tumors is helpful to guide therapy and estimate prognosis. A number of outstanding reviews on the classification of CNS tumors have been written. When attempting to determine the treatment and/or prognosis of a tumor based on published reports or meeting abstracts, the classification schema used in those reports will become critical before applying this information to other patients.
Most current classification systems are based on the pioneering work of Cushing and Bailey almost 100 years ago. The major premise of this approach was to define tumors by their presumed cell of origin and cell lineage based on morphologic similarity to normal immature or mature brain cells. This system was adapted by Kernohan when he proposed that certain tumors, especially those with a glial appearance, such as astrocytomas, ependymomas, and oligodendrogliomas, could be further classified by the degree of anaplasia, which related to prognosis. Most current systems now use these two criteria—presumed cell lineage and degree of anaplasia—as the primary basis for classification of adult and pediatric CNS tumors. In spite of the usefulness of this classification schema, it is becoming progressively clear that most brain tumors do not derive from mature cell types but rather from primitive precursors or stem cells that can differentiate down many different pathways, obscuring the cell lineage. In comparison with their adult counterparts, pediatric brain tumors are exceptionally diverse in their morphologic appearance and therefore represent a particular challenge for classification by morphologic criteria alone. This diversity likely stems from the fact that pediatric brain tumors are derived from a wide spectrum of proliferative cell types at many developmental stages not present in adult brains.
Significant advances have been made in the field of neuropathology. The WHO classification of CNS tumors has been recently revised, with a number of important modifications based on histopathologic recognition of new pediatric brain tumors. A synopsis of the WHO 2007 classification system is provided in Table 57-3 . Increasingly the field has begun to include use of molecular alterations for many tumors and the use of highly specific immunohistochemical markers. When combined with immunohistochemical analysis and the increasing use of cytogenetic classification and molecular profiling, the classification of tumors continues to become more reproducible and predictive of clinical outcomes. A simplified overview of the chromosomal abnormalities associated with pediatric brain tumors is presented in Table 57-1 . For many large consortium-based studies in both Europe and North America, molecular profiling of tumors to ensure proper classification is now required, especially for medulloblastoma and ATRTs.
TABLE 57-3
Simplified World Health Organization Classification of Pediatric Central Nervous System Tumors
| Type | Subtype | Example(s) | Grade |
|---|---|---|---|
| Glial tumors | Astrocytic tumors | Pilocytic astrocytoma | I |
| Subependymal giant cell astrocytoma | I | ||
| Pilomyxoid astrocytoma | II | ||
| Pleomorphic xanthroastrocytoma | II | ||
| Diffuse (fibrillary) astrocytoma | II | ||
| Anaplastic astrocytoma | III | ||
| Glioblastoma multiforme | IV | ||
| Gliosarcoma | IV | ||
| Gliomatosis cerebri | III-IV | ||
| Oligodendroglial tumors | Oligodendroglioma | II | |
| Oligoastrocytoma | II | ||
| Anaplastic oligodendroglioma | III | ||
| Anaplastic oligoastrocytoma | III | ||
| Ependymal tumors | Subependymoma | I | |
| Myxopapillary ependymoma | I | ||
| Ependymoma | II | ||
| Anaplastic ependymoma | III | ||
| Neural/embryonal tumors | Medulloblastoma | IV | |
| Pineocytoma | I | ||
| Pineal parenchymal tumor of intermediate differentiation | II-III | ||
| Papillary tumor of the pineal region | II-III | ||
| Pineoblastoma | IV | ||
| Primitive neuroectodermal tumor (medulloepithelioma, ependymoblastoma) | IV | ||
| Atypical teratoid-rhabdoid tumor | IV | ||
| Choroid plexus tumors | Choroid plexus papilloma | I | |
| Atypical choroid plexus papilloma | II | ||
| Choroid plexus carcinoma | III | ||
| Germ cell tumors | Germinoma | III | |
| Nongerminoma | Embryonal carcinoma | III | |
| Yolk sac tumor | III | ||
| Choriocarcinoma | III | ||
| Mature teratoma | 0 | ||
| Teratoma | I | ||
| Immature teratoma | III | ||
| Teratoma with malignant transformation | III | ||
| Craniopharyngioma | Craniopharyngioma | Adamantinomatous | I |
| Papillary | I | ||
| Other | Mixed glial neuronal tumor | Ganglioglioma | I |
| Gangliocytoma | I | ||
| Anaplastic ganglioglioma | III | ||
| Dysembryoplastic neuroepithelial tumor | I | ||
| Desmoplastic infantile astrocytoma | I | ||
| Central neurocytoma | II | ||
| Extraventricular neurocytoma | II | ||
| Neuroepithelial | Astroblastoma | — | |
| Nerve tumors | Schwannoma | I | |
| Neurofibroma | I | ||
| Malignant peripheral nerve sheath tumor | II-IV | ||
| Meningeal | Meningioma | I | |
| Atypical meningioma | II | ||
| Anaplastic meningioma | III | ||
| Hemangioblastoma | I |
The immunohistochemical patterns used to classify CNS tumors require considerable experience on the part of the neuropathologist, as well as appropriate control subjects. Most markers lack specificity and can be identified in a wide array of histologies, requiring correlation with other clinical or molecular data. Common markers used to classify pediatric CNS tumors are provided in Table 57-4 . Four commonly used immunohistochemical markers are the oligodendrocyte lineage transcription factor 2 (OLIG2) and glial acidic fibrillary protein (GFAP), which stain glial cells ( Fig. 57-15 ); synaptophysin, which stains neurons ( Fig. 57-16 ); and Ki-67, which stains cells that have left G0 cell cycle and are at some stage of cellular division ( Fig. 57-17 ).
TABLE 57-4
Immunohistochemical Markers of Pediatric Central Nervous System Tumors
| Marker | Tumor |
|---|---|
| Glial fibrillary acidic protein | Astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, PNET, ATRT |
| Synaptophysin/NeuN | PNETs, ganglial tumor, neurocytoma |
| MIB1/Ki-67 | Measures all cells not in G0 |
| Mitotic rate | Measures cells in mitosis |
| Neurofilament proteins | Ganglial tumor, PNET, neurocytoma, subependymal giant cell tumor, ATRT |
| S-100 and neuron-specific enolase | Normal and neoplastic glial and neuronal in origin |
| Retinal S-antigen | Pineal parenchymal tumor, PNET, retinoblastoma |
| Desmin | Muscle tumor, teratoma, PNET |
| Smooth muscle actin | Muscle tumor, ATRT |
| Cytokeratin | Chordoma, choroid plexus tumor, meningioma, some malignant gliomas, nongerminomatous germ cell tumor, PNET, ATRT |
| Epithelial membrane antigen | Meningioma, ependymoma, teratoma, ATRT |
| Vimentin | Mesenchymal tumor, meningioma, sarcoma, melanoma, ependymoma, astrocytoma, chordoma, schwannoma, PNET, ATRT |
| Alpha-fetoprotein | Embryonal carcinoma, endodermal sinus (yolk sac) tumor |
| Human chorionic gonadotropin | Germinoma, choriocarcinoma |
| Placental alkaline phosphatase | Germ cell tumor |
| INI-1 | ATRT |
ATRT, Atypical teratoid/rhabdoid tumor; PNET, primary neuroectodermal tumor.
Treatment Strategies
Neurosurgery
The neurosurgeon is often the first of the specialized team of caregivers called to see a child with a brain tumor, with the call frequently coming from the emergency department or radiology department. The initial evaluation consists of acute management—that is, assessment of the patient's clinical condition with respect to neurologic stability and the possibility of acute neurologic decompensation requiring immediate intervention, and subsequent to that the development of a plan that includes surgical interventions geared toward obtaining tissue for pathologic diagnosis, resection of tumor as part of the overall management of the tumor, and dealing with the secondary effects of the tumor.
In the field of neurosurgery remarkable advances have occurred in technology, from intraoperative microscopes, robotics, and computer-assisted navigation to intraoperative MRI, endoscopic techniques, and minimally invasive techniques. Each of these advances has been instrumental in reducing the morbidity of neurosurgical procedures while ensuring maximal surgical resections.
Acute Management Issues
Hydrocephalus.
Hydrocephalus is the most common clinical presentation of posterior fossa brain tumors, which are the most common pediatric brain tumors. Historically the initial evaluation of children suspected of harboring a posterior fossa brain tumor has been via CT scan. However with improved technologies and more recent concerns regarding the long-term effects of radiation exposure, there is a trend toward less utilization of CT scans. If possible the initial assessment should be an MRI of the brain, which can provide the dual information regarding the brain tumor and the extent of hydrocephalus. The cause of the hydrocephalus is obstruction to the CSF flow as a result of the tumors in and around the fourth ventricle. The evaluation should consist of assessing the severity of the hydrocephalus (via the presence of periventricular capping/edema and tonsillar herniation) and the need for immediate intervention. High-dose steroids will often produce significant relief in symptoms as peritumoral edema is suppressed, and they are often utilized as a temporary measure for symptom relief. In infants, hydrocephalus can be asymptomatic and only evidenced by a rapidly enlarging head circumference. Supratentorial brain tumors can also produce hydrocephalus by causing mass effect on the ventricles, as well as by obstructing CSF flow through the ventricular system. Patients with suprasellar tumors can also have inadequate cortisol production or electrolyte disturbances, which need to be addressed as quickly as possible and often in concert with preparation for surgery.
Raised ICP is a medical emergency. Immediate relief can be accomplished by temporary placement of a catheter (drainage tube) in the ventricles, although this step is rarely needed, primarily because of the fact that steroids in the preoperative period followed by surgery to remove the tumors within 24 to 48 hours after diagnosis usually relieves the obstruction. Permanent techniques of hydrocephalus treatment include the placement of a ventriculoperitoneal (VP) shunt that drains CSF around the obstruction into the peritoneal space via a permanently implanted tube and more recently via an endoscopic third ventriculostomy (ETV). The latter has become the treatment of choice in the management of obstructive hydrocephalus and is not associated with the long-term complications of shunt revisions and infections. Most pediatric centers with sufficient expertise now routinely perform ETVs as the primary management of hydrocephalus in children with brain tumors. In addition the overall incidence of shunting for brain tumors has decreased during the past two decades. Like all complex procedures, rare but significant neurologic risks are associated with this procedure in approximately 1% of cases. The possibility of closure of a third ventriculostomy and resultant acute hydrocephalus requires long-term follow-up with neurosurgery, as with all children who have had placement of shunts for the management of the hydrocephalus.
Visual and Endocrine Evaluation.
Children with tumors in the sellar and suprasellar area can present with blindness, which rarely can be acute in onset. In those circumstances, although extremely rare, it is possible to obtain some recovery of vision by immediate treatment of the tumor. If a large mass or cyst is causing compression, acute drainage in conjunction with steroid administration can lead to some recovery of vision. Tumors in this location can also interfere with endocrine function and may lead to electrolyte disturbances and decreased steroid production, and these effects can be critical if they are unrecognized, especially if acute surgical intervention is indicated.
Surgical Management
Surgical management after treatment of hydrocephalus consists of obtaining tissue for diagnosis and resecting the tumor. The decision to perform these procedures depends on the location of the tumor, the known biology, and the goals of treatment management.
Certain tumors do not require routine biopsy or attempted resection at diagnosis (e.g., diffuse pontine gliomas, classic optic pathway tumors in children with NF-1, and some suprasellar or pineal lesions with positive serum or CSF tumor markers). Tectal gliomas are rare tumors centered in the tectum with a classic radiographic appearance and presentation of hydrocephalus and, rarely, neurologic deficits. Their management consists solely of treatment of the hydrocephalus via ETV and radiographic and clinical follow-up.
The leading factor in the outcome of a child with a brain tumor is not the presenting symptoms, age of the child, or the final disease. Rather it is the experience of the neurosurgeon performing the operation and the number of similar procedures performed during the prior few years. With increasing cure rates in children with CNS tumors, careful consideration of the neurosurgical morbidity, which can often be lifelong, needs to be taken into account while a treatment plan is developed.
Advances in Surgical Techniques.
Recent advances in image-guided neurosurgical techniques have been considerable. Endoscopic procedures provide minimally invasive techniques to address not just obstructive hydrocephalus but also biopsy or resection of intracranial masses, with minimal morbidity in experienced hands. New techniques using intraoperative ultrasound have been developed and are being used in pediatric patients. 3D laser-guided maps can assist in the orientation and surrounding environment of the tumor during a procedure. More recently intraoperative MRI facilities now allow surgeons to use MRI procedures with the same magnet strength as that used for diagnostic imaging while operating. Real-time MRIs can assist the neurosurgeon in the detection of residual disease or hemorrhage before closure of the resection site.
The surgical approach used by the neurosurgeon will depend on a number of factors that must balance the need for diagnosis with the potential risks of operating in a given area. While the relative risks of general anesthesia and neurosurgical procedures continue to diminish with improving techniques, it is now common to perform staged operations in which a limited resection is performed to confirm the diagnosis. Based on the pathologic results obtained, decisions about more complicated or risky surgery can be considered for lesions in which complete resection is a critical component of improved outcome and can be deferred in lesions in which additional resection would not significantly alter prognosis but could cause significant morbidity. Specialized techniques such as endonasal endoscopic approaches can allow a minimally invasive approach, with excellent outcome in centers that have expertise in this approach.
The need of neurosurgeons to be aware of the evolving treatment strategies for children reinforces the role of the multidisciplinary team. During the past 5 years this need has become even more important, because many pediatric brain tumors now require molecular classification to guide therapy. For example in spite of their similar appearance, the treatment of posterior fossa medulloblastoma now differs significantly from posterior fossa ATRT. Treatment on national protocols therefore requires submission of fresh-frozen material obtained at the time of surgery for proper stratification on the basis of therapy protocols. As our molecular classification of pediatric brain tumors expands and newer and better molecular inhibitors of specific pathways become available, the role of the neurosurgeon and neuropathologist in ensuring the proper processing of these samples will continue to expand.
Perioperative Issues.
A number of factors must be considered for a child after a tumor-based procedure has been completed. The rate of weaning steroids after an operation will depend on many factors, including the histology, degree of resection, postsurgical edema, and patient status. Although most patients can be weaned off steroids rapidly after an operation, it is important that the members of the team have a coordinated structure so that as children pass from neurosurgical care to the radiation therapist or oncologist, overall management of these issues is seamless. A similar discussion holds true for anticonvulsant agents. Whereas many patients will receive preoperative or perioperative anticonvulsant therapy, most can be weaned rapidly, and communication among team members will therefore be required.
Seizures can be a presenting symptom for many patients with brain tumors or a result of electrolyte disturbances in the perioperative period. Management includes anticonvulsant agents and surgical resection geared not only toward the tumor but also toward dealing with the seizures. Intraoperative electrocorticography is particularly useful in the management of temporal and frontal lobe tumors with seizures and requires a multidisciplinary approach, which can lead to excellent overall outcomes. Choices of antiepileptic drugs (AEDs) are important because some may interfere with metabolism of chemotherapeutic agents, which requires a comprehensive approach toward the management of the patient's seizures and tumor.
Hyponatremia is a common problem that can occur after neurosurgical intervention and requires immediate recognition. Two common conditions, both resulting in hyponatremia but needing different interventions, can occur. Cerebral salt wasting (CSW) occurs because of excess renal loss of sodium with volume depletion and has been associated with abnormally high atrial natriuretic peptide or brain natriuretic peptide levels, which block all stimulators of zona glomerulosa steroidogenesis, resulting in mineralocorticoid deficiency. CSW usually occurs 1 to 2 days after neurosurgical intervention, and patients typically demonstrate polyuria, dehydration, a serum sodium level less than 130 mEq/L, and excess urine sodium or urine osmolarity. Duration of CSW was 1 to 9 days in a study of 12 pediatric patients. CSW is generally treated with salt repletion, although fludrocortisone supplementation has also been successful. Syndrome of inappropriate diuretic hormone (SIADH), by contrast, results when water is preferentially retained, causing dilution of serum sodium. Patients present with hyponatremia and an elevated urine sodium level. The major clinical difference between CSW and SIADH is that in the former, dehydration is common, whereas in SIADH, symptoms of dehydration are lacking. SIADH is treated with water restriction. CSW was much more common than SIADH in one study of 30 patients.
Posterior fossa syndrome (or cerebellar mutism syndrome) is a complex and heterogeneous disorder that tends to occur 24 to 48 hours after resection of a posterior fossa tumor, usually medulloblastoma, ependymoma, or low-grade astrocytoma. Posterior fossa syndrome will develop in up to 25% of patients undergoing surgical resection in the posterior fossa and, in most patients, it will be severe. The pathophysiologic basis for this syndrome is unclear, with many hypotheses proposed. It is likely related to pressure effects on the deep cerebellar nuclei and is more frequently associated with large tumors extending into those areas. Gross total resection (GTR) of most posterior fossa brain tumors is associated with better long-term outcomes, and it is thought that the more aggressive surgical resections for those reasons are associated with the perceived increase in the frequency of this syndrome. The exact clinical patterns of posterior fossa syndrome can vary among patients both in constellation and severity. Usually the disorder includes loss of speech in patients who were capable of talking immediately after surgery. Other symptoms include irritability, which may relate to difficulties in communication, emotional withdrawal, and motor difficulties with ataxia. In a review of 450 children from two large Children's Cancer Group (CCG) protocols for high-risk and standard-risk medulloblastoma, 107 patients (24%) had posterior fossa syndrome. It was classified as severe in 43%, moderate in 49%, and mild in 8%. As with many neurologic insults, most patients demonstrated significant improvement, although neurologic abnormalities persisted in a large proportion of patients. No uniform diagnostic criteria exist for posterior fossa syndrome, and radiologic imaging with SPECT has failed to define a specific controlling neurologic region.
Venous thrombosis in adults with brain tumors is common, especially when compared with adults undergoing operations for causes not related to brain tumors, and typically requires therapy. A similar predilection to significant symptomatic thrombosis in children with CNS tumors has not been identified. Because of the risks of spontaneous hemorrhage in patients taking anticoagulants, their routine use is discouraged for pediatric patients. When thromboses in this patient population are identified, other precipitating factors such as the presence of a central venous access device are usually evident. CNS hemorrhage is rare in pediatric patients undergoing tumor resection. Use of recombinant factor VIIa has been used successfully when bleeding was difficult to control.
Long-Term Follow-Up
Long-term follow-up is extremely important because neurosurgical sequelae of the treatment of brain tumors exist. The management of hydrocephalus is lifelong, and all survivors of childhood brain tumors who have treated hydrocephalus should undergo frequent evaluations by a neurosurgeon and radiographic evaluation of the patency of the ETV (via specialized MRIs) or of their shunt systems.
A relatively rare but significant complication of radiation therapy and surgery for tumors in the sellar/suprasellar area is moyamoya disease. This condition is manifested by the development of occlusive vascular disease at the base of the skull with subsequent ischemic events and stroke. The management includes surgical revascularization, which is effective in stopping the clinical symptomatology and preventing new ischemic events and is performed in centers with specialized interest in this condition and expertise in the surgical procedure.
Radiotherapy
A detailed section on the fundamentals of radiation oncology is included elsewhere in this text (see Chapter 48 ). The primary goal of this brief discussion is to focus on radiation therapy issues that are specific to pediatric neurooncology. An understanding of the basic principles of radiation therapy is critical because it remains one of the most effective, albeit toxic, therapies for this patient population.
Like chemotherapy, radiation therapy targets dividing cells, one of the hallmarks of cancer therapy. Unlike chemotherapy, however, delivery of radiation therapy is not limited by the BBB. The biologic effects of ionizing radiation are the result of damage to cellular DNA, primarily through irreparable double-strand breaks. Photon radiation can cause damage through direct interaction with DNA or through the formation of free radicals, which damage the DNA. Charged particles can cause damage through direct interactions with the nucleus. This damage results in complex cascades of molecular events, affecting cell cycle checkpoints, apoptosis, DNA damage response, and DNA repair. Tumor cells have lost the regulation required to repair DNA damage before entering cell replication. In contrast normal adjacent cells that receive radiation therapy will repair the damage between fractions. After weeks of continued radiation therapy, normal cells will have repaired themselves, although the repair process is not perfect and accounts for the toxicity to normal brain caused by radiation therapy. Tumor cells, on the other hand, will have accumulated significant damage, leading to cell death. The concept of fractionation is the hallmark of radiation therapy.
Technical Aspects of Radiation Therapy
Radiation therapy technology has advanced continually since the discovery of x-rays. The most commonly used modalities in the treatment of CNS tumors are photon radiotherapy and proton radiotherapy. Both these forms of irradiation provide the same treatment dose to the tumor tissue, and therefore their differences are not related to efficacy. Rather the differences in the therapeutic beams and the physical properties associated with them result in different dose distributions. The major clinical difference between the two techniques relates to potential toxicities to the normal brain.
Photon Therapy.
Photons are packets of high energy that enter tissue, depositing their energy as they pass through both normal tissue and the tumor, eventually exiting the brain. The presence of an exit dose is one of the major differences between this modality and proton therapy. The generation of photon beams is easily achieved with a large array of commercially available machines and, with more than 60 years of clinical experience, photon radiotherapy remains the most widely used form of radiation therapy. Significant advances in this modality have occurred through the development of better imaging (MRI and functional imaging such as PET and metaiodobenzylguanidine), planning algorithms, and machine delivery that has allowed the radiation oncologist to target tumors more accurately and to minimize the dose delivered to normal tissue.
Opposed Lateral Fields.
Used largely before 1990, opposed lateral fields typically rely on two wide beams, usually one from the left and the other from the right. This approach is no longer considered the standard of care in children with a brain tumor because of excessive toxicity to normal brain tissue. At a minimum conformal fields should be used.
Conformal Radiation Therapy.
The conformal radiation technique uses the principle of tumor volume definition through MRI and CT scans. In the treatment of CNS tumors, the anatomic localization of the bony structures of the skull using CT scans are fused to the MRI with specialized fusion software. This technique allows accurate tumor definition and submillimeter accuracy in treatment. Radiation therapists choose beam placement to maximize tumor coverage while avoiding normal brain tissue. With 3D conformal radiation therapy, conformal beams are used to shape the dose delivered to the target, and wedges or compensators can be used to optimize the dose distribution. With 3D conformal radiation therapy, variable field weighting and use of different energies (higher beam energies are more penetrating) are additional tools that enable optimization of the dose distribution. With the development of more rapid and powerful computers, the ability to generate a large number of different beam orientations has allowed for diffusion of the radiation dose over normal tissue, thus reducing long-term damage while ensuring complete coverage of the tumor volume.
Stereotactic Radiotherapy.
Stereotactic radiotherapy is a further improvement on 3D conformal therapy by ensuring improved head immobility so that beam configuration may be further reduced without having to worry about head position and tumor location. In the normal delivery of the radiation beam, some head movement may occur; therefore, the target volume must be expanded in all directions to ensure that at no time is part of the tumor outside the targeted area. To overcome this difficulty, a series of techniques have been developed that use head immobilization to ensure less head movement and consequently smaller target volumes. Options for such immobilization include frames bolted to the skull and then fixed to the radiation device, which is the standard procedure for stereotactic radiation surgery (discussed later). The major limitation of this procedure, however, is that radiation therapy is delivered over approximately 6 weeks, and bolting screws into the skull for this length of time is not practical. A second option is the use of a head mask made for each patient, which fits around the face and skull and can sometimes use the ear canals or palate to ensure exact and reproducible fits. A new development is the use of real-time CT scans that constantly reevaluate the position of the skull, with computer software that corrects for changes in head position to reset the beams accordingly. In children the additional dose of radiation therapy from CT scans is not trivial and needs to be considered in the choice of method.
Intensity-Modulated Radiation Therapy.
Intensity-modulated radiation therapy (IMRT) gives radiation therapists the opportunity to modulate the intensity of a radiation beam so that instead of uniform dosing throughout a volume, areas of decreased intensity may spare critical structures. For example if a critical nerve runs through or adjacent to a tumor, IMRT allows the radiation therapist to spare the middle, like a doughnut, while still treating the entire surrounding tumor. IMRT is a device that fits onto the gantry of a radiation machine and moves small metal slots in and out of the beam path as it moves in arcs to deliver the required fields. Large metal (macroleaf) and small metal (microleaf) pieces are available. The microleaf collimators allow for a more refined shaping of the field. An important limitation of this technique is the development of hot spots in areas within the field. As a general rule this technique can be added to 3D conformal and stereotactic radiation therapy treatment plans.
Stereotactic Radiosurgery.
Stereotactic radiosurgery (SRS) techniques (e.g., gamma knife, cyber knife, or X-knife) use a single fraction (or occasionally several fractions) rather than the prolonged treatment courses that are standard with radiation therapy. As the names imply in these techniques, all develop a focused beam of energy that covers a tight volume and causes the cells within the volume to die. Unlike traditional radiation therapy, in which normal cells recover between successive doses while tumor cells do not, the principle for this technique is similar to focusing sunlight with a magnifying glass to burn a small area. Because of the significant toxicities possible with a technique designed to kill a targeted area, a specific volume that excludes normal adjacent structures is critical. To achieve this requirement, after induction of general anesthesia, the head is often bolted into a metal head frame, and then the metal frame is bolted to the radiation device. In this way no additional or unintended movement can occur that would result in the targeted beam missing part of the tumor and damaging uninvolved adjacent normal brain tissue. New methods that can avoid the need for fixed head localization are being developed.
Proton Radiotherapy.
The use of proton beam radiation therapy as an alternative to high-energy x-rays (photons) has the potential to limit some of the late effects of radiation therapy by reducing the exposure of normal tissue to the radiation. Physically, photon beams deliver their maximum radiation dose near the surface, followed by a continuously reducing dose with increasing depth. Tissues outside the target area receive an exit dose of the radiation beams. For example when a single posterior field is used to treat the spinal axis, critical organs along the path such as the heart, lung, bowel, and ovaries may receive significant exposure. In contrast in proton beam radiotherapy, while the charged particles—namely, protons—move through tissue, they ionize particles and deposit their radiation dose along the path. The maximal dose, called the Bragg peak, occurs shortly before the point of greatest tissue penetration, which is dependent on the energy of the proton beam. Because the energy can be precisely controlled, the Bragg peak can be placed within the tumor targeted to receive the radiation dose. Because the protons are absorbed at this point, normal tissues beyond the target receive little irradiation. Proton beam radiotherapy is becoming more readily available but remains a more limited and costly modality. Children most likely to benefit from proton beam treatment are those with favorable or curable brain tumors such as craniopharyngiomas, medulloblastomas, LGGs, ependymomas, and GCTs. With the increasing complexity of radiation planning, a dedicated pediatric radiation oncology team is required to ensure appropriate care for the pediatric patient.
Toxicity of Radiation Therapy
Even with the significant advances in the highly precise delivery of radiation therapy, a number of circumstances limit its usefulness for children. Humans achieve their maximum number of brain cells shortly after birth. From that time forward, a steady loss of cells continues throughout life. While we age our neurocognitive development is related to the development of new connections and interactions between cells, not the addition of cells. For reasons that are poorly understood, irradiation can affect not only the proliferation of new cells in infancy but also the ability of cells already present to form or maintain connections in children and adolescents.
Late effects of radiotherapy in the treatment of children with brain tumors include neurocognitive sequelae, ototoxicity, hormonal dysfunction, vascular complications, growth disturbance, and secondary malignancies. The severity of these effects depend upon many factors. The three major factors that determine the severity of the impairment after radiation therapy are the age of the patient, the volume of the brain to be irradiated, and the dose of radiation therapy required.
- 1.
Age . Because the age of the patient at diagnosis is not mutable, simply withholding radiation therapy until a child has had an opportunity to grow older would reduce the long-term morbidity, but this approach may allow a tumor to recur. As such, the decision between accepting toxicity or foregoing efficacy is not uncommon in pediatric practice.
- 2.
Volume . Although neurocognitive development is most active from birth until the age of 3 years, significant development occurs up to the age of 10 years and even into adulthood, which implies that radiation therapy to large parts of the brain can cause detrimental effects on cognition throughout life. Because the volume of brain to be irradiated is determined by the extent of tumor spread, radiation therapists must treat the required volumes with all the associated long-term morbidity or reduce the volume to be treated with a corresponding reduction in the efficacy that radiation provides.
- 3.
Dose . The third factor related to radiation toxicity is the dose used. Because most brain tumors require the use of maximal tolerated doses to have a significant clinical impact on outcome, reducing the dose would again require a tradeoff between toxicity reduction and efficacy reduction.
Further discussion of the toxicities of radiation therapy is found in Chapter 47 .
Chemotherapy
The approach and use of chemotherapy, like radiation therapy, does not differ significantly for most children with brain tumors when compared with children with other cancers. Similarly the effects of antiseizure medications on chemotherapy mirror those of other patient populations, and agents susceptible to altered metabolism by enzyme-inducing anticonvulsants, such as irinotecan, require appropriate dose adjustments or a switch to a nonenzyme-inducing anticonvulsant. This requirement has resulted in the development of many pediatric treatment regimens modified from adult studies. The increasing recognition of the unique nature of pediatric tumors in general and pediatric brain tumors specifically has led to the development of pediatric-specific preclinical models of cancer. Incorporation of information from these models is likely to be slow as different combinations of chemotherapy, biologic therapies, and radiation therapy undergo evaluation. The need for drugs to cross into the brain raises questions about agents that showed no activity in prior clinical trials. Although the routine approach was to discard such agents as inactive, the ability to modify such agents to improve their CNS penetration has resulted in the need to retest some of these chemotherapeutic classes.
Blood-Brain Barrier
The BBB results from the tight junctions of endothelial cells and astrocytic projections surrounding the brain that limit the penetration of substances, especially infections and inflammatory responses, from gaining access to the CNS. A slightly different barrier exists between the blood and CSF (called the blood-CSF barrier), although the primary role of the two systems remains the same—to isolate the brain from the entry of as many foreign chemicals and pathogens as possible.
While tumors develop, they grow and invade normal structures, which can disrupt the BBB. Tumors also need to secure a blood supply, which can be achieved through the secretion of a large number of cytokines, of which the best characterized is VEGF. Before its discovery in stimulating angiogenesis, this molecule was initially discovered as vascular permeability factor (VPF) because of its ability to open up endothelial junctions, allowing for changes in fluid shifts. The secretion of VEGF (VPF) by tumors is responsible for significant peritumoral edema and leakage of the BBB. For reasons that remain poorly understood at present, many tumors, or areas within tumors, do not demonstrate disruption of the BBB, making their detection on contrast-enhanced MRI scans more difficult.
General principles of chemotherapy administration in tumors of the CNS are similar to those of other tumors of the body. The CNS lacks a lymphatic system and, because of the presence of the BBB, extraneural metastases are uncommon. Thus the goal of treatment remains focused on the brain and spine. Some agents may not fully penetrate through the BBB, depending on the characteristics of the drug and local breakdown of the BBB. Although the chemical structure of compounds should be an important consideration in their predicted ability to penetrate the BBB, and thus have the potential for clinical activity, many hydrophilic drugs have demonstrated activity in brain tumors. However some hydrophobic agents, which should easily traverse the BBB, do not traverse it. Even with extensive knowledge of the hydrophobicity of a drug, one cannot predict with certainty whether it will have activity in CNS tumors. The platinum drugs, for example, which would not be predicted to penetrate into the brain significantly, are active agents for various tumors in the brain and spine. This outcome may in part relate to the breakdown of the BBB around tumors, resulting in penetration of drugs into restricted areas. One important variable that can significantly affect BBB penetration is the degree of protein binding. To overcome this problem of drug delivery, direct application of drugs into surgical cavities or cysts is possible. Hydrostatic pressure gradients moving from tissue into an empty cavity draw most of the drugs away from the tumor and likely account for the limited activity of chemotherapeutic agent–impregnated wafers along the resection margin.
Intrathecal or Intra-Ommaya Chemotherapy
Intrathecal administration of chemotherapy can overcome the blood-CSF barrier and is of importance in tumors with a predilection to seeding of the brain and spine. This technique is not safe in patients with obstructed CSF flow, but for patients without this problem who also lack diversional shunts that would draw the drugs out of the CSF spaces, high concentrations can be delivered. Because repeated access to the lumbar spine can be uncomfortable, insertion of an Ommaya or Rickham reservoir may reduce the difficulties of repeated administration. To assist in the delivery of chemotherapeutic agents into the CSF, insertion of reservoirs that sit on top of the skull or in the subcutaneous tissue of the abdomen or flank can make repeated administration more practical. Although a number of new agents have been investigated for intrathecal or intra-Ommaya/Rickham administration, including busulfan, etoposide, and mafosfamide, overall a limited number of agents may be safely administered to this compartment, including standard intrathecal agents used in leukemia (e.g., methotrexate and cytarabine), etoposide, topotecan, and liposomal cytarabine.
An important approach to increasing the penetration of chemotherapy into the brain has been the use of high-dose systemic therapy followed by stem cell rescue. The efficacy of this approach and management of the associated toxicities continue to be an area of significant study (discussed later).
Newer methods of targeting penetration of drugs into the CNS include BBB disruption agents. These agents are in clinical trial and are designed to temporarily open up the tight junctions protecting the CNS. They are typically administered just before the active anticancer agent is administered. Although this approach is promising and deserving of additional evaluation, a common problem to date has been the opening of the BBB in normal areas of the brain, resulting in greater toxicities to uninvolved areas. In a similar approach new lipophilic carrier molecules have been designed to help transport drugs across the BBB, and further advances in these areas are expected.
Convection-Enhanced Delivery
With the movement of fluids away from areas of high interstitial pressure to areas of low interstitial pressure, passive diffusion of drugs deep into tumors is unlikely to occur in sufficient concentrations to be effective. To overcome this problem developments in convection-enhanced delivery have been reported. These techniques require the implantation of small catheters that can be tunneled under the scalp, which then penetrate the solid tumor parenchyma or adjacent brain. By injecting drugs under high pressure, these agents move through the interstitial space between cells, giving the drugs an opportunity to kill tumor cells, even in critical areas of the CNS such as the pons. Because tumors usually penetrate along the pathway of least resistance, similar to fluids under pressure, this technique allows the drug to spread out in a fashion similar to that of the infiltrating tumor. A number of candidate molecules designed for convection-enhanced delivery are being developed. This technique should be equally well suited to small-molecule inhibitors, chemotherapeutic agents, biologic drugs (including large protein molecules), and gene vectors. Advances in drug packaging may permit control of drug delivery, improving the activity of this approach.
Novel Chemotherapeutic and Biologic Agents
The revolution in the molecular classification of adult and pediatric tumors has significantly advanced our understanding of pathways implicated in tumor initiation, progression, and metastases. These pathways have also become important targets for new therapy approaches that are included in the realm of chemotherapy but differ in many fundamental ways. The unique mechanism of action of these inhibitors, and their lack of typical chemotherapy-related toxicity (e.g., myelosuppression) make them ideally suited for combination with traditional chemotherapy and radiation therapy. In addition to classic cytotoxic agents, the use of agents that modulate the epigenome, such as histone deacetylases, which modify DNA methylation, a process critical in gene regulation, may allow apoptotic or differentiation genes to be reactivated while turning off proliferative pathways.
The development of new formulations of old drugs also deserves comment. Many drugs that were tested in children with tumors of the CNS did not demonstrate activity, which may have been the result of poor penetration or unknown pharmacokinetics. Modifications to older agents such as doxorubicin by pegylation and liposomal encapsulation will require additional clinical testing. Even vincristine, which is commonly used in pediatric patients with CNS tumors despite a lack of clear data demonstrating its activity in these diseases, is being redeveloped to improve its potential activity.
Numerous targeted agents are now available, and each will require some early pediatric clinical experience regarding dosing and tolerability. Unfortunately most biologic agents are unlikely to possess significant single-agent activity or resistance will develop, although some exciting responses have been observed in a number of different pathways, including SHH and BRAF. Many of these drugs may be better at slowing tumor progression and will need to be used in combination with other molecular inhibitors, radiation therapy, and chemotherapy. These targets may also have important roles as prognostic markers, as well as therapeutic targets.
Small-Molecule Inhibitors.
The sequencing of the human genome and the identification of a number of critical signaling pathways, especially the receptor tyrosine kinases, have provided the basis for a whole new class of anticancer agents. Normal cells transmit signals from the external environment to the nucleus via receptor tyrosine kinases. These molecules sit on the cell surface and homodimerize or heterodimerize in the presence of ligand, which results in a conformational change in the intracellular domain of the receptor. This process allows a phosphorylation event on the cytoplasmic component of the receptor that begins a complex cascade that results in the alteration of cell function. Many tumors use these receptors or their pathways to drive cell proliferation and migration, as well as decouple cell repair and apoptosis.
The activation of receptor tyrosine kinases results from the phosphorylation of a tyrosine residue in the intracellular domain of the receptor. This process can be blocked by the steric interference of small molecules designed to fit into the phosphorylation pocket. By carefully designing the shape of these molecules, the ability to define the specificity of these drugs to related receptors means that some inhibitors can disrupt only a single receptor or entire families of receptors. A number of experimental studies of these inhibitors have been tested in children with brain tumors, including those targeting the platelet-derived growth factor receptor (PDGFR) and ras pathways. One problem with small-molecule inhibitors, as with other agents targeting the CNS, is the need to get drugs across the BBB; small molecules are ideally suited for this purpose, but efflux pumps are present that may expel the agents, resulting in limited activity. Unfortunately this mechanism must be evaluated on a drug-by-drug basis.
Immunotherapy
Although the brain and spine are considered immunologically privileged sites, the presence of lymphocytic infiltrates in many brain tumors suggests that activation of the immune system is possible. Significant attempts to activate the immune system against these tumors, especially malignant gliomas, have followed two main approaches. Some groups have attempted to increase the immune activation of lymphocytes by cytokine stimulation of the innate immune system. In the second approach a patient's own tumor is required to generate tumor-specific immune-activated cells. While more is learned about how immune cells interact with and are activated by tumors, opportunities to develop immunotherapies may become more feasible, and some early encouraging results are already being reported.
Gene Therapy
The use of gene vectors for the treatment of brain tumor allows for the expression of a large array of different molecules. Many experimental approaches have focused on modulators of the immune response. An important component in the expansion of these approaches will be the identification of different vectors, as well as improvement in direct delivery of large molecules directly into the brain to bypass the BBB.
Antiangiogenic Agents
During the past few decades the role of angiogenesis in the development of cancer has evolved from a novel hypothesis to a fundamental area of research and therapeutic intervention. Although not brain tumor–specific, angiogenesis has been a hallmark of the progression of malignant gliomas. A large number of antiangiogenic inhibitors are now in clinical trials and have focused on targeting the cytokine vascular endothelial growth factor, ; other inhibitors of the angiogenic cascade are being tested as well. Although bevacizumab has been extensively tested in adults with malignant gliomas, its role in pediatric tumors remains unclear. A developing area ideally suited for pediatric patients has been the use of oral antiangiogenic chemotherapy. The principle behind this approach is the use of very-low-dose chemotherapy that targets dividing endothelial cells rather than tumor cells. A number of low-dose chemotherapy approaches are being tested, and preliminary results are encouraging.
Suppression of Tumor Resistance
The innate resistance of many tumors to cytotoxic agents, especially those of glial origin, is well documented by the near-complete and rapid progression of HGGs after upfront radiation and chemotherapy. Tumors can use a number of pathways to avoid cell death when confronted with DNA-damaging agents. Temozolomide has become widely used in conjunction with radiation therapy in adults and has demonstrated clear activity in these patients. Although this combination has demonstrated prolongation in time to progression of the disease, in the vast majority of patients the disease will eventually progress as resistance mechanisms are activated. To help overcome this problem recent clinical trials have begun testing molecules that can bind and inactivate the enzymes responsible for resistance. One such example is O(6)-benzylguanine (O(6)-BG), a small molecular compound that can bind the enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which functions to remove the methyl group on the O(6) position of guanine after temozolomide treatment. By treating the patient in advance with O(6)-BG, all free MGMT can be consumed, at which point administration of temozolomide can damage the DNA. Although still early in pediatric testing, this approach offers considerable opportunity. Additional resistance pathways have been identified in pediatric and adult brain tumors that may guide therapeutic approaches, as well as the development of new inhibitors of the resistance pathways. For example mutations within the PMS2 mismatch repair gene, which can lead to tumorigenesis and treatment resistance, may be influenced by the addition of retinoic acid.
High-Dose Chemotherapy with Stem Cell Rescue
The principles of high-dose chemotherapy and stem cell rescue are similar to those for other malignant diseases. Many brain tumors, especially those of primitive neuroectodermal origin, such as medulloblastoma and CNS PNETs, have demonstrated dose-dependent chemotherapy responses. This technique has therefore been used extensively in children with relapsed disease after standard upfront therapy and in young children and infants. In light of the long-term neurocognitive effects of radiation therapy for young children, particularly for diseases that require craniospinal radiation therapy, high-dose chemotherapy with autologous stem cell rescue (ASCR) currently serves as the backbone treatment in many infant protocols around the world. Although the conditioning regimens, disease histologies, and patient characteristics have differed across multiple clinical trials and retrospective studies, this approach has demonstrated positive results in patients who could achieve minimal residual disease prior to transplant. The addition of this modality with other therapies remains to be tested and may influence the utility of this approach in persons without minimal residual disease or the ability to maintain the disease-free state. The role of high-dose chemotherapy with stem cell rescue is debatable, however, in the recurrent setting. The evaluation of patients after transplantation can be complicated by the presence of therapy-related signal changes on MRI scan, including heterogeneously enhancing lesions, often causing clinical symptoms related to their location. Although these lesions can appear consistent with disease progression early after transplantation, they do not progress and need to have long-term follow-up with regard to their clinical significance.
Pediatric Brain Tumors
Gliomas
Glial tumors are usually classified according to the type of glial cell that constitute the tumors—astrocytomas, ependymomas, and oligodendrogliomas. Each is further divided by morphologic features, degree of invasiveness, and location and is assigned a grade ranging from I to IV as the features of malignancy increase. In pediatrics, the grading of astrocytomas has been defined by the WHO or St. Anne-Mayo system and is predictive of patient survival. In pediatrics, the modified WHO classification of CNS tumors has become the standard classification system (see Table 57-3 ). Astrocytomas can be classified as low grade (WHO grades I and II) or high grade (WHO grades III and IV). LGGs may consist of relatively pure tumors such as a juvenile pilocytic (grade I) or fibrillary (grade II) astrocytoma or mixed populations of both glial and neuronal lineages, such as ganglioglioma or glioneurocytoma. The classification of several other subtypes is still being debated. Although the differentiation of HGG from LGG is universally used and based on degree of atypia, mitoses, necrosis, and vascular proliferation, with greater molecular definition of astrocytic tumors, the need to separate grade I from II and grade III from IV tumors regarding treatment and prognosis is increasing. Pediatric gliomas can also be discussed in the context of location, rather than grade. This approach recognizes some of the unique aspects of the environment in which tumors of similar histologies can grow and its effect on treatment and prognosis ( Box 57-2 ).
Box 57-2
Histologic Classification of Low-Grade Gliomas
-
Astrocytic tumors
-
Pilocytic astrocytoma
-
Pilomyxoid astrocytoma
-
Diffuse astrocytomas (fibrillary, protoplasmic, gemistocytic)
-
Pleomorphic xanthoastrocytoma
-
Subependymal giant cell astrocytoma
-
-
Oligodendroglial and mixed glial tumors
-
Oligodendrocytoma
-
Oligodendroglioma
-
Oligoastrocytoma
-
-
Mixed glial-neuronal tumors
-
Gangliocytoma
-
Ganglioglioma
-
-
Dysembryoplastic infantile astrocytoma and dysembryoplastic infantile ganglioglioma
-
Dysembryoplastic neuroepithelial tumor
-
Special locations that are often not biopsied
-
Optic pathway gliomas
-
Tectal gliomas
-
-
Cervicomedullary gliomas
Low-Grade Glioma
Supratentorial, Cerebellar Pilocytic, and Other Low-Grade Astrocytomas.
LGGs represent the most frequent group of brain tumors that develop during childhood. According to the latest statistical report from the Central Brain Tumor Registry of the United States, the annual incidence of pediatric LGGs in the United States is 2.1 per 100,000 persons. PAs, which make up the majority of LGGs, are well-circumscribed tumors classified as WHO grade I. These tumors were formally referred to as juvenile PAs but are now classified simply as PAs. Grade I tumors are the most common LGGs found in children, representing 20% to 30% of all childhood brain tumors. PAs typically appear in the first two decades, with no clear gender predominance. They usually grow slowly, although their presentation can occur as acute deterioration as a result of obstructive hydrocephalus. NF-1 is the best example of a condition associated with an increased risk of PA in up to 15% of these patients. The localization of PAs in the context of NF-1 and their improved long-term prognosis is well established, although the molecular basis for this difference is unclear. Other predisposing factors such as common cytogenetic abnormalities are uncommon. Low-grade astrocytomas typically lack epidermal growth factor receptor (EGFR) amplification, although defects in the BRAF pathway have recently been reported and are present in the majority of cases.
Clinical Presentation.
Low-grade astrocytomas in children have a varied course, ranging from dissemination and persistent recurrence to spontaneous regression without therapy, and they behave differently from low-grade astrocytomas in adults. The biologic factors that account for these differences remain investigational, although telomere length may play an important role. PAs commonly occur throughout the brain, including the optic pathways, optic chiasm–hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brainstem (dorsally exophytic brainstem glioma). PAs of the spinal cord are less common.
The spectrum of clinical manifestations of a PA depends on the site of origin, its size, the age of the patient, and the presence of raised ICP. Cerebellar PAs and dorsally exophytic brainstem PAs usually present with symptoms of increased ICP, such as headache, nausea, and vomiting. Children may also present with a relatively long history of progressive focal neurologic deficits, including gait disturbance, and infants may present with progressive secondary macrocephaly. Signs of chronicity such as bone remodeling, scoliosis, or hemihypertrophy may be present, depending on the primary tumor location. The diencephalic syndrome is unique to low-grade astrocytomas, both PA and pilomyxoid astrocytoma, is typically seen in infants whose tumors arise from the hypothalamus or optic pathways, and consists of emaciation, emesis, euphoria, and normal linear growth. Although many other deep-seated low-grade glial tumors cannot be resected, patients with diencephalic syndrome appear to have a worse prognosis, suggesting that subtle biologic differences among these tumors and other PAs may exist. Leptomeningeal dissemination is associated at diagnosis in 3% to 5% of cases.
Imaging and Histology.
The typical MRI appearance of a grade I astrocytoma is that of an intensely homogeneous, well-circumscribed, contrast-enhancing lesion with minimal surrounding edema. Lesions are typically bright on both T1- and T2-weighted images. Tumoral cysts are more prevalent in the cerebellum than in the cerebrum ( Fig. 57-18 ) and often possess a contrast-enhancing mural nodule. Apparent diffusion coefficient imaging may be useful in differentiating PAs from higher grade astrocytomas. Imaging characteristics can help with the differential diagnosis of low-grade lesions preoperatively but are not specific enough to be used without biopsy confirmation.
Histologic examination reveals a biphasic pattern, with a compacted component containing bipolar cells ( Fig. 57-19 ) and Rosenthal fibers and a loose cellular array containing microcysts and eosinophilic granular bodies. Rosenthal fibers and eosinophilic granular bodies are pathologic hallmarks of pilocytic astrocytomas, although they can be observed in other diseases of the CNS. Rosenthal fibers are brightly eosinophilic, hyaline masses composed of alpha-B-crystalline and are best seen on tumor smear preparations ( Fig. 57-20 ). Eosinophilic granular bodies are globular aggregates within astrocytic processes and are also best visualized with smear preparations. PAs stain intensely with the GFAP immunoreagent. Invasion of the overlying meninges and adjacent brain parenchyma is commonly observed. Mitoses are rare, and the MIB1 labeling index is usually lower than 4%. Although the pathologic criteria for anaplastic astrocytoma include the identification of mitoses, their presence in PAs does not indicate a higher grade. Inexperienced pathologists can often misinterpret these mitoses, resulting in a diagnosis of a malignant rather than an LGG. Similarly PAs can have vascular proliferation, a hallmark of glioblastoma multiforme (grade IV astrocytoma), although, again similar to that of the presence of mitoses, this does not indicate transformation to a more malignant phenotype. Rarely PAs can present with diffuse leptomeningeal dissemination, especially in the variant of pilomyxoid astrocytoma. Characteristic of the unique biology of PAs, each of the metastatic lesions continues to behave as a low-grade astrocytoma with a slow, indolent course. These tumors therefore are not difficult to treat as a result of their metastatic phenotype but rather as a result of their slow, persistent recurrences.
Molecular and Genetic Characteristics of Pediatric LGGs.
Recent efforts in the characterization of genomic alterations in pediatric LGGs have significantly expanded our understanding of the biology of those tumors. Genomic alterations of the BRAF gene, resulting in alteration of the MAPK pathway, are prominent in pediatric but not adult LGGs. Other genomic alterations affecting PI3K/AKT, EGFR, PDGFRa, FGFR1, TrkB, MybL1 and VEGF signaling pathways have been described in a subset of pediatric LGGs.
Importantly pediatric LGGs present distinct molecular alterations compared with adult LGGs. Tumor protein p53 (TP53) mutations are frequent in adult LGGs (up to 60% to 70%) but are rare in pediatric LGGs. Deletion of 1p and 19q is the most frequent copy number alteration in adult oligodendrogliomas. In contrast very few 1p-19q codeletions have been reported in pediatric LGGs. IDH1 and IDH2 mutations occur in about 70% of adult LGG, whereas these mutations are very rarely described in the pediatric population.
BRAF Truncation-Duplication.
The high incidence of LGGs in patients with NF-1 prompted initial investigation into the role of the MAPK pathway in pediatric LGG tumorigenesis. Early comparative genomic hybridization studies performed on pediatric LGGs, especially PAs, identified a significant recurrent gain of the 7q34 region containing the BRAF locus. This region is amplified in 50% to 90% of pediatric PAs, with the highest frequency in tumors of the posterior fossa and of the hypothalamic/chiasmatic region and less frequently in fibrillary astrocytomas and oligodendroglial tumors, and they are thought to have a better prognosis than other LGGs. Further genomic studies found that the 7q34 gain corresponded to a BRAF duplication and KIAA1549 insertion. In vitro validation showed that this gene product is constitutively active, leading to downstream upregulation of effectors of the MAPK pathway, MEK and ERK. One short form of the KIAA1549-BRAF fusion induces anchorage independent growth in vitro. Also short-term cultured pediatric LGG lines showed significant diminution of cell proliferation rate using pharmacologic inhibitors of MEK1 and MEK2. Other partners of BRAF fusion have recently been identified that involve either SRGAP3 or FAM131B, all causing MAPK pathway activation. Although break points between BRAF genes differ in those variants, they all result in the loss of the N-terminal inhibitory domain of BRAF , leading to the constitutive activation of the BRAF kinase. Recent functional studies using BRAF fusion variants have highlighted the importance of the context in which this genomic alteration drives tumor growth. Kaul et al and colleagues demonstrated that in vivo transfection of the BRAF fusion transcript in mature astrocytes was not able to induce glioma tumors, whereas transfected neural stem cells were able to develop tumors. Another recent study comparing the overexpression of the BRAF-KIAA transcript in neural stem cells of different regions within the brain showed that tumors appeared only in neural stem cells located in the third ventricular region.
BRAF V600E Point Mutation.
BRAF V600E mutation has been described in a variety of cancer subtypes including melanoma, colorectal cancers, papillary thyroid carcinoma, non–small-cell lung carcinoma, and leukemia. This mutation enhances BRAF kinase activity and leads to the constitutive activation of the MAPK pathway. In contrast to BRAF truncation-duplication, which is strongly associated with grade I histology, the BRAF V600E mutation occurs more frequently in grade II pediatric LGGs (PLGGs), especially fibrillary astrocytomas, gangliogliomas, pilomyxoid astrocytomas, and pleomorphic xanthoastrocytomas (PXAs). V600E mutation was also described as transforming fibroblasts in vitro, suggesting that this specific genomic alteration drives cell proliferation in a subset of PLGGs. Interestingly a recent study showed that BRAF V600E mutation promotes neural stem cell transformation followed by senescence, which may parallel the natural history of PLGGs.
Other Genomic Alterations Affecting Key Pathways.
In addition to the MAPK pathway, other pathways such as PI3K/AKT/mTOR, EGFR, SHH, and VEGF have been described to be altered in PLGGs. Although PTEN deletions and p16 deletions were previously identified in anaplastic astrocytomas and therefore associated with a more aggressive phenotype of astrocytic tumors, a recent study of 32 PLGGs showed that 44% had PI3K/Akt/PTEN/mTOR activation, mostly through PTEN promoter methylation. Additionally BRAF fusion transcript transfection in vivo is associated with mTOR pathway activation through the S6-kinase cascade. EGFR amplification, assessed by genomic hybridization and fluorescence in situ hybridization, was described in a subset of disseminated PLGGs, suggesting that the EGFR pathway may play a role in a fraction of invasive LGGs. Evidence of WNT pathway activation in a subset of PAs, especially in young children, has been highlighted by a recent study showing that the patched (PTCH1) gene, coding for the PTCH receptor, was highly expressed in a subset of PAs, especially in patients younger than 10 years. PAs might also carry abnormal function of the VEGF pathway, supported by the observation that vessel architecture of those tumors is often immature and unstable, comparable with that of HGGs. The active phosphorylated forms of the VEGF receptors 1, 2, and 3 have been shown to be highly expressed in tumor vasculature in PAs.
Recently genomic alterations of the transcriptional activator MYB, a known oncogene in other tumor subtypes, especially T-cell acute lymphoblastic leukemia, have been identified in PLGGs. MYB amplification and focal deletions have been described in fibrillary astrocytomas and in angiocentric gliomas, respectively.
Management.
Surgery is the mainstay of therapy for most pilocytic and other low-grade astrocytomas. GTR is often curative, even though residual microscopic disease may often be left behind. Radiation therapy and chemotherapy are typically not required as part of upfront therapy after a complete resection. Surgery is also an effective method of seizure control in patients with LGGs, especially those of the temporal lobes. PLGGs in more eloquent areas may not be amenable to surgical resection. Because the OS even of nonresectable PLGG is very high, surgical resection should not be attempted when a significant risk of morbidity exists. Unfortunately even in patients with complete resection, the presence of a tumor and surgical intervention can be associated with some long-term adverse effects. PAs of the optic pathway in patients with NF-1 do not require surgical confirmation unless atypical radiographic or clinical features are present. Patients with tectal gliomas require CSF diversion but do not benefit from biopsy; they can be diagnosed on the basis of the presence of hydrocephalus and MRI appearance of the lesion alone. In the largest prospective series of patients with PLGG stratified to observation, chemotherapy, or radiation therapy, the overall outcome of these patients was similar to that of patients reported in other independent series and is an important milestone in the assessment of more than 1000 patients with PLGG.
Progressive or unresectable PAs, or those arising in infants or children that cause alterations of vision or other neurologically relevant symptoms, may require adjuvant treatment. Chemotherapy is assuming an increasingly important role in the management of unresectable and/or progressive LGGs, diencephalic LGGs in younger patients, and other unresectable tumors ( Table 57-5 ). Various combination regimens, such as carboplatin and vincristine or thioguanine, procarbazine, lomustine (CCNU), and vincristine (TPCV) have produced consistent, durable responses, reviewed by Perilongo. Monthly carboplatin is more easily administered but may have less activity and requires additional study.
TABLE 57-5
Chemotherapy for Pediatric Low-Grade Gliomas
Modified from Perilongo G: Considerations on the role of chemotherapy and modern radiotherapy in the treatment of childhood low-grade glioma. J Neurooncol 75:301–307, 2005.
| Treatment | No. of Patients | Objective Response, % (CR + PR) | Overall Response, % (CR + PR + SD) | EFS or OS |
|---|---|---|---|---|
| Carboplatin | 80 | 2 CR, 17 PR | 2 CR, 17 PR, 4 MR, 46 SD | 72% 3-yr EFS in patients with NF-1; 62% 3-yr EFS in patients without NF-1 |
| Carboplatin | 12 ND | 4 PR | 4 PR, 6 SD | |
| Carboplatin | 4 ND, 2 PD | 6 SD | ||
| Carboplatin | 13 ND/PD | 1 CR/PR | ||
| Iproplatin | 15 ND/PD | 1 CR/PR | 1 CR/PR, 9 SD | |
| Cyclophosphamide | 15 ND | 1 CR | 1 CR, 9 SD | |
| Cyclophosphamide | 1 PD, 3 ND with leptomeningeal dissemination | 2 PR/MR, 2 SD | ||
| Ifosfamide | 6 | 1 PR | 1 PR, 3 SD | |
| Temozolomide | 21 PD | 1 PR | 1 PR, 20 SD | |
| Temozolomide | 13 PD | 2 CR, 3 PR | 2 CR, 3 PR, 3 MR, 4 SD | 57% 3-yr EFS |
| Temozolomide | 10 ND, 20 PD | 3 PR | 3 PR, 1 MR, 25 SD | 51% 2-yr PFS and 17% 4-yr PFS |
| Temozolomide | 2 PD | 2 SD | ||
| Methotrexate | 10 PD | 2 PR | 2 PR, 5 SD | |
| Topotecan | 2 PD | 1 PR | 1 PR, 1 SD | |
| Topotecan | 11 PD | 5 SD | ||
| Etoposide | 14 PD | 1 CR, 4 PR | 1 CR, 4 PR, 3 SD | |
| Etoposide | 12 ND | 6 PR/SD | ||
| Vincristine–actinomycin-D | 24 ND | 3 PR | 3 PR, 6 MR, 15 SD | |
| Vincristine-carboplatin | 123 ND | 105/123 CR, PR or SD | 61% 5-yr PFS | |
| Vincristine-carboplatin | 78 ND | 4 CR, 22 PR | 4 CR, 22 PR, 18 MR, 29 SD | 68% 3-yr PFS |
| Vincristine-carboplatin | 24 PD | 7 PR | 7 PR, 5 MR, 5 SD | |
| Carboplatin-etoposide | 13 ND | 1 CR | 1 CR, 3 MR, 6 SD | 69% patients alive at mean of 30 mo |
| Cisplatin-etoposide | 31 ND, 3 PD | 1 CR, 11 PR | 1 CR, 11 PR, 12 MR, 11 SD | 3-year PFS 100% in patients older than 5 yr, 66% in patients younger than 5 yr |
| Vincristine-etoposide | 11 ND, 9 PD | 1 PR | 1 PR, 4 MR, 9 SD | |
| Tamoxifen-carboplatin | 12 ND, 1 PD | 2/13 PR | 2/13 PR, 9/13 SD | 47% 3-yr PFS, 69% 3-year OS |
| 6-Thioguanine, vincristine, CCNU, dibromodulcitol, procarbazine (TPDCV) | 15 ND (4 patients were treated with other therapy and are not included), 42 ND | 11 PR, 15 CR/PR | 11/15 PR, 15 CR/PR + 25 SD | Median TTP not reached at 79 wk, median TTP at 132 wk |
| Procarbazine, carboplatin, vincristine, etoposide, cisplatin, cyclophosphamide | 85 ND | 36/85 | 74/88; 36 CR or PR, 15 MR, 23 SD | 34% 5-yr PFS, 89% 5-yr OS |
| Carboplatin, etoposide, cyclophosphamide, vincristine, CCNU, procarbazine | 7 ND, 3 PD | 2/10 | 70% CR + PR + MR; 100%, including SD | 70% PFS at 5.6 yr |
| 5-Fluorouracil, vincristine, cyclophosphamide, etoposide | 13 (12 ND, 1 PD) | 6/13, 1 CR, 5 PR | 8/13, 1 CR, 5 PR, 2 SD | 6-yr PFS 67% |
| Vinblastine | 9 (ND with carboplatin allergy; nonprogressive at time of therapy) | 2/9 | 9/9; 1 CR, 1 PR, 5 MR, 2 SD | Median follow-up of patients, 10 mo |
| Thioguanine, procarbazine, CCNU, vincristine | 9 (5 ND with carbo allergy; nonprogressive at time of therapy, 4 PD) | 0/9 | 7/9; 7 SD | 78% progression-free at 13 mo |
| Cisplatin, etoposide, vinblastine | 16 ND | 4/16 4 PR | 9/16 4 PR, 5 SD | 5-yr PFS 56% |
CR, Complete remission; EFS, event-free survival; MR, minor response; ND, newly diagnosed; NF-1, neurofibromatosis type 1; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial remission; SD, stable disease; TTP, time to progression.
With multiagent combinations, stabilization of tumor occurs in almost 50% of patients, and radiographic response is observed in an additional 40%. Median time to progression is approximately 3 years, and up to 60% of patients will eventually demonstrate tumor growth. The Children's Oncology Group (COG) recently completed a prospective randomized phase III clinical trial examining outcomes of children younger than 10 years treated with vincristine and carboplatin versus TPCV. The TPCV arm showed a trend toward a superior 5-year event-free survival (EFS) compared with the vincristine and carboplatin arm (52% vs. 39%, respectively), although no statistically significant difference was found. The ability to retreat these patients with multiple regimens has allowed most patients to avoid radiation therapy, especially early in life when the long-term morbidity of this modality is greatest. Although the time to progression may appear short and the overall progression rate of 50% to 60% appears high, these chemotherapy regimens are well tolerated, with few long-term complications. This outcome is in contrast to radiation therapy, which demonstrates a significantly improved response rate (85% response or stable disease) and duration of disease control (longer than 10 years) ; however, radiotherapy also entails significant long-term morbidities, such as neurocognitive, vascular, hormonal, and second tumor risks. Because most children with LGGs will be long-term survivors, this is exactly the population that would benefit from the avoidance of the late effects of radiation therapy. To reduce the volume of normal tissue, stereotactic conformational external radiotherapy, stereotactic radiosurgical techniques, and proton radiotherapy have been evaluated in the treatment of recurrent and progressive PLGG tumors. However more focused delivery of radiation in patients with PLGGs only marginally mitigates the long-term sequelae, which include malignant transformation and second malignancy, vascular injury, and, depending on location, neurocognitive decline, endocrinopathies, and other neurologic deficits. These significant and largely irreversible iatrogenic sequelae, conferred in the treatment of a disease whose natural history is self-limiting in most cases, provide an argument in favor of a radiation-avoidance strategy for children with PLGG.
The overall improved outcome for patients with NF-1 has also been confirmed, indicating that these tumors may have a unique biologic phenotype. Temozolomide (TMZ), an orally active alkylating agent with a favorable adverse effect profile, has been shown to have some activity as monotherapy for adult LGGs. Although it has not been widely studied, it appears to have a low response rate in LGGs in children, with a median time to progression of 6.7 months, although many patients appear to have prolonged stable disease. Responses with TMZ in disseminated low-grade astrocytomas have also been reported, although another alkylator, cyclophosphamide, when given every 3 weeks, lacked significant activity. The role of TMZ in combination with vincristine and carboplatin for PLGGs is currently being investigated. Other investigators have successfully used novel combinations containing 5-fluorouracil. The metronomic application of vinblastine, a mitotic inhibitor, has resulted in some clinical responses or stable disease in children with LGGs who are unable to tolerate carboplatin. Vinblastine is also being evaluated alone and in combination with carboplatin in newly diagnosed patients. Although more information on the activity of these approaches is needed, responses in refractory LGGs have been reported with other metronomic-based chemotherapy approaches, suggesting that angiogenesis may be an important pathway in these tumors. Antiangiogenic approaches, such as bevacizumab, have also been tested with some responses, which is also consistent with the presence of vascular proliferation observed in these tumors. Chemotherapy may also allow for improved surgical resection of previously unresectable lesions and therefore should be continuously reevaluated as a therapeutic option. Tumors treated with chemotherapy, even if they are not smaller, can be easier to resect because of less bleeding and a firmer texture at the time of the procedure. The recent identification of BRAF mutations in the majority of PLGGs offers the potential for targeted approaches to these patients. Phase II studies of the downstream inhibitor of mTOR, called everolimus, have recently been completed in this patient population with encouraging activity. In addition BRAF V600E small-molecule inhibitors are also being evaluated for patients with this specific mutation. Importantly the majority of patients with LGGs have the truncated fusion of BRAF (often referred to as the KIAA1549 fusion because this is the most common translocation). Treatment with a BRAF drug such as sorafenib or other V600E targeted agents would be expected to stimulate tumor growth as a result of a complex feedback loop, not to inhibit tumor growth. Patients with truncated fusions will require therapy that accounts for this biologic pathway, and MEK inhibitors are just entering clinical trials for this patient population.
Although most chemotherapy regimens for LGGs have been reserved for children younger than 10 years, older children seem to derive equal benefit with the use of these regimens, potentially avoiding radiation therapy and the risks of second tumors, vasculopathy, and hormonal dysfunction. The use of dose-intensive chemotherapy has been pilot tested in a small series of children, with results similar to those observed using standard doses.
Radiotherapy is considered to be contraindicated in children with NF-1 and is usually deferred in children with PAs and other LGGs, especially in diencephalic and optic pathway tumors. Even highly focused radiation therapy in these locations cannot avoid the potential cognitive, endocrine, or vascular risks associated with radiation therapy. In spite of this highly focused radiation therapy is effective for LGGs and is without significant marginal failures, suggesting that these lesions have not deeply penetrated into surrounding brain. Long-term concerns about second tumors, hormone dysfunction, and cognitive impact, however, still make this approach questionable for children. Additional late effects of radiation therapy when used in younger children with diencephalic gliomas may include strokes related to a moyamoya-like syndrome.
Prognosis.
The prognosis for surgically resectable tumors is excellent after GTR. For patients with PAs whose tumors can be completely surgically resected, depending on location, the 10-year PFS approaches 90%. Even in patients with incompletely resected lesions, treatment is not always required and, depending on the patient and clinical scenario, observation can be considered unless tumor or symptom progression is documented. The most critical variable in the treatment of PAs is the anatomic location of the tumor. Complete resections are most difficult for tumors located in the brainstem, spinal cord, optic pathways, thalamus, and hypothalamus. As such, the PFS of children with centrally located tumors (e.g., in the optic chiasm, thalamus, or hypothalamus) is less than 50%. Given the favorable toxicity profile of chemotherapy versus radiation therapy in young children, chemotherapy is preferred as the first therapeutic modality in young patients with tumors not amenable to gross total resection. The use of chemotherapy as initial treatment in patients with centrally located or unresectable lesions allows for the delay of radiation therapy until the child is less likely to incur the serious developmental and neuropsychological sequelae of radiation therapy. Patients demonstrating radiographic response to chemotherapy have PFS similar to those whose tumors remained stable. Ultimately the quality of survival depends on multiple factors, including the tumor location, the extent to which the tumor can be resected, timing of any radiotherapy, and adverse effects of surgery, chemotherapy, and radiotherapy. Transformation of PAs into higher grade malignant gliomas is highly unusual.
Optic Pathway Gliomas
Optic pathway gliomas (OPGs) represent approximately 4% to 6% of all primary pediatric brain tumors; the incidence is higher when asymptomatic lesions in patients with NF-1 are also included. OPGs are evenly distributed between boys and girls. These tumors may involve various parts of the optic pathway, such as the optic nerves, chiasm, optic tract, and optic radiations. They may also infiltrate the adjacent hypothalamus and temporal lobes. Optic nerve gliomas are strongly associated with NF-1, although sporadic lesions are not uncommon. OPGs in patients with NF-1 have a more indolent course than those arising in patients without NF-1 and likely represent a different biology than sporadic tumors. Although OPGs may be considered a subset of PAs, their unique features and management necessitate a separate discussion.
Clinical Presentation.
Most OPGs consist of PAs (WHO grade I). The clinical course of OPGs can vary considerably, from an indolent mass in a child with NF-1 to a relatively aggressive, invasive, and expansile diencephalic tumor. Unilateral optic nerve gliomas often present with the classic triad of visual loss, proptosis, and optic atrophy. Optic nerve tortuosity, which can be present alone or in the context of OPGs in children with NF-1, does not necessarily define the presence of disease or the need for therapy. Chiasmatic involvement may lead to unilateral or bilateral visual loss, a bitemporal visual field defect, and obstructive hydrocephalus as the tumor grows dorsally to obstruct CSF flow in the third ventricle. Further invasion into brain parenchyma may result in more pronounced visual field deficits, as well as hemiparesis. Chiasmatic tumors in infants present as large suprasellar masses that may also extend into the hypothalamus and third ventricle, producing hydrocephalus and endocrine abnormalities. In cases of hypothalamic extension, in addition to nystagmus, visual loss, and hydrocephalus, the diencephalic syndrome may occasionally be seen. This syndrome consists of hyperkinesia, euphoria, and emaciation, with preserved normal linear growth. Failure to thrive is a common presentation of this syndrome, but in the context of a number of other conditions that may also cause failure to thrive during infancy, a delay in diagnosis of a brain tumor is not uncommon. Endocrine deficiencies commonly accompany PAs in this location, and these tumors are more likely to have CSF dissemination in association with diencephalic syndrome, in spite of their histopathologic classification as benign. Many patients with NF-1 will have long-standing, subtle ophthalmologic abnormalities, and thus regular visual evaluation is required. For these patients routine surveillance MRI scans are not indicated because many asymptomatic and clinically irrelevant tumors will be diagnosed, creating a treatment dilemma.
Imaging and Histology.
The clinical diagnosis of an OPG is suspected when a child presents with visual impairment, nystagmus, and/or optic atrophy. MRI of the brain or orbits typically shows a solid, cystic, or mixed type of tumor, with strong gadolinium enhancement. The imaging characteristics of LGGs of the optic pathway are similar to those of low-grade astrocytomas in other locations. The typical MRI appearance of a grade I astrocytoma is an intensely homogeneous, well-circumscribed, enhancing lesion with minimal surrounding edema ( Fig. 57-21 ). Lesions are typically bright on both T1- and T2-weighted images. A higher ADC may predict a greater chance of progression. MRI studies and clinical presentation may distinguish an OPG from other childhood tumors that arise in the suprasellar location, such as a GCT or craniopharyngioma. Histologically OPGs are usually grade I PAs or, less frequently, grade II fibrillary astrocytomas. Mixed LGGs have been reported in this region, but the overall therapeutic approach is not altered, because most of these lesions are not resectable at diagnosis. Tumors with an elevated MIB1 labeling index of more than 1% and p53 expression were more likely to be WHO grade II and had a worse outcome compared with tumors with an MIB1 and p53 labeling index less than 1%, all of which were PAs. PAs with a more aggressive behavior had an MIB1 labeling index of 2% to 3% but retained a low p53 labeling index of less than 1%. Like LGGs in other locations, patients with sporadic OPGs have both BRAF V600E and truncated fusion KIAA1549 abnormalities. BRAF abnormalities are rare in patients with NF-1 because of the existence of constitutive activation of the ras/raf/mek/MAPK pathway.
Management.
The unpredictable clinical course of patients with optic pathway tumors has led to controversy regarding the optimal management of these tumors. The clinical course, age of onset, severity of symptoms, size and extent of the tumor, and presence of NF-1 may all affect management decisions. Treatment is frequently started promptly in younger patients, in patients with progressive symptoms, and in those with more extensive CNS involvement, with the paramount concern being preservation of vision. Although progression can be easily quantified on an MRI scan, correlation between MRI findings and visual outcome is poor. The initial treatment of choice is chemotherapy (see Table 57-5 ), which may cause stabilization or regression even in older children and adolescents and is not associated with the neurocognitive decline observed with radiation therapy. Surgery can be used upfront in selected cases, but the tumor may not be removed from the optic nerve without sacrificing vision. Combination therapy with carboplatin and vincristine or with TPCV has been considered to have comparable beneficial effects. TPCV should not be used in children with NF-1 because of the increased risks of secondary tumors associated with alkylator-based treatment. When progression of the tumor occurs after treatment with vincristine and carboplatin, vincristine and actinomycin can be considered for patients with NF-1 to avoid further risks of alkylator therapy. As for other LGGs, a number of new chemotherapy regimens are being developed (see Table 57-5 ) and can include bevacizumab and irintoecan, vinblastine, metronomic therapy, and low-dose cisplatin and etoposide. Current clinical trials targeting the mTOR pathway are under way, as is a phase II trial of lenalidomide. Although delaying radiation therapy is paramount in young children, older patients may also benefit from these chemotherapy approaches and from delaying or avoiding radiation therapy.
A randomized phase III COG study comparing the two regimens, carboplatin and vincristine versus TPCV for the treatment of progressive low-grade astrocytoma in children younger than 10 years, closed to accrual in 2005. The results have shown that both regimens are well tolerated and can delay or obviate the need for radiation therapy in most patients, and that some patients will show improvement in vision with therapy. Newer chemotherapy clinical trials for OPGs combine a number of agents such as TMZ with vincristine and carboplatin, and vinblastine and carboplatin. Although a definitive role for radiotherapy exists for the management of OPG, current trends in treatment favor a delay in the initiation of radiotherapy in young patients. Newer surgical techniques with direct administration of radiotherapy are also being explored and have demonstrated usefulness for selected patients. Unlike LGGs in other areas, optic pathway tumors affect vision directly, and changes in visual fields and acuity can be a better determinant of both disease response or progression than are changes on MRI. Recent consensus criteria for the assessment of visual function in patients with NF-1 have been reported, and these criteria should provide a useful platform for the assessment of therapies that target OPGs.
Prognosis.
Although optic pathway tumors are almost always of low-grade histology, their location often results in serious morbidity. In patients with significant visual deterioration, progressive vision loss can continue for many years after the tumor has become stable on routine surveillance imaging. The growth rate of these tumors, however, often slows during late childhood so that by adulthood, tumors may become quiescent and do not require further therapy. Children with NF-1 have been shown to have a better PFS, although an age of younger than 1 year is clearly associated with a higher risk of tumor progression. Patients with NF-1 appear to be at high risk for the development of moyamoya disease, as well as radiation-induced second malignancies. Patients with NF-1–associated optic nerve gliomas may remain stable for several years. Close observation and symptomatic management are recommended for these patients.
Low-Grade Astrocytomas of the Brainstem
Although most brainstem tumors are DIPGs, approximately 20% of brainstem tumors are low-grade astrocytomas involving the medulla, midbrain, tectum, or cervicomedullary, pontomedullary, or midbrain-pontine junction. Although 20% of nonpontine tumors in these locations can be classified as grade III or IV malignant gliomas, 80% are low-grade glial lesions with a much better prognosis. These lesions differ from diffuse pontine gliomas by their clinical presentation and their imaging characteristics. Early identification of the type of brainstem lesion is critical in the workup, especially for consideration of neurosurgical intervention.
Presentation.
Patients with brainstem lesions can present with various clinical symptoms, depending on the location of the tumor. Medullary tumors are more common than midbrain tumors, and the male to female ratio is approximately 1 : 1. In spite of the eloquent function of the brainstem, most patients with low-grade astrocytomas in this location have an indolent course with subtle neurologic findings. Most commonly patients present with cranial nerve dysfunction or head tilt. Lower motor weakness with subtle hemiparesis is also seen. Most parents have difficulty defining the start of the symptoms and refer to their child as having always been clumsy or weak. Rarely these tumors can be multifocal in nature.
Histology and Imaging.
Most low-grade brainstem tumors are either grade I or II astrocytomas; fewer than 20% are malignant astrocytomas. Imaging characteristics are similar to those of other LGGs; PAs (grade I) tend to be bright on T1- and T2-weighted images and enhance after administration of contrast material. Edema tends to be minimal. Fibrillary astrocytomas (grade II), by comparison, enhance to a lesser degree after administration of contrast material. The considerable overlap and variability in the imaging characteristics of grade I versus grade II astrocytomas, however, prevents accurate diagnosis based on MRI characteristics alone. The histologic features of brainstem low-grade astrocytomas are identical to grades I and II astrocytomas in other locations.
Management.
Brainstem low-grade astrocytomas that remain focal can often be surgically resectable if they possess a plane between the brainstem and tumor. If the tumor is completely resected, these patients are unlikely to need additional therapy. Given the good long-term outcome of this patient population, aggressive surgery should not risk damage in areas with poor tumor boundaries. Incompletely resected brainstem low-grade astrocytomas have a high recurrence rate, and most of these patients will need additional therapy, usually chemotherapy rather than radiation therapy, given the good long-term prognosis of these patients (see Table 57-5 ). White matter tracts are often displaced by these tumors, and preoperative DTI can assist the neurosurgeon regarding the optimal approach to maximize resection while minimizing morbidity in this patient population. Although postsurgical morbidity such as problems with swallowing can be significant, many patients eventually recover function, although this process can take many months and requires extensive physical and occupational therapy. The chemotherapy options for these tumors are identical to those for low-grade astrocytomas in other locations and include vincristine and carboplatin or TPCV chemotherapy. Recurrence and need for retreatment are common, but most tumors will eventually stop growing while these patients enter adulthood.
Prognosis.
Because most patients with a low-grade brainstem glioma will be long-term survivors, it is important that the workup and treatment of these patients be adapted with this likely outcome in mind. Differentiation from DIPGs is usually easily made on the basis of imaging and clinical criteria. Surgical intervention must be based on the expectation that minimal long-term morbidity will result, given the large number of other treatment options available for these patients.
Low-Grade Thalamic Astrocytomas
Thalamic tumors are rare in pediatric patients, accounting for fewer than 5% of intracranial tumors. Most thalamic tumors are unilateral, and approximately 50% are low-grade astrocytomas. Thalamic tumors occur at a slightly older age than do many other LGGs of childhood. Low-grade thalamic tumors present as unilateral or bithalamic in location, which appears to have prognostic significance.
Clinical Presentation.
Thalamic tumors can present with a number of different clinical findings. Raised ICP, tremors, motor deficits, seizures, and mood changes are the most commonly observed presenting symptoms. Unlike in adult tumors, dementia is a rare presenting symptom.
Imaging and Histology.
Imaging characteristics of thalamic tumors are similar to those of gliomas in other locations ( Fig. 57-22 ). Low-grade and high-grade histologies are approximately equally distributed, although pathologic classification of these tumors can be influenced by sampling error from small biopsy specimens. The use of PET or SPECT imaging can help identify areas to be biopsied. Although astrocytic histologies predominate, oligodendroglial tumors have also been identified.
Management.
The presence of tumor in the thalamus presents a number of management difficulties. Because of their location, complete resection is difficult, although surgery can result in symptom improvement in selected cases. Even attempts at biopsy can result in significant morbidity. The small amount of surgical material often raises concerns of sampling error in attempting to determine the histopathologic grade of the tumor. Biopsy of the most malignant component of these deep-seated lesions can be guided with PET imaging. This guidance is particularly important for astrocytic tumors, for which samples of sufficient size and content are needed to define the elements of tumor grade. In the analysis of children with thalamic lesions, most tumors are unilateral in nature, and approximately 50% to 60% are low-grade astrocytomas; the remaining 40% are high-grade lesions. Some tumors are amenable to significant resection. The response of low-grade thalamic tumors to chemotherapy and radiation is not known to be different from that of similar tumors in other locations. Thus younger patients are often treated initially with chemotherapy used for other low-grade astrocytomas ( Table 57-5 ). In those with rapid progression or histologic verification of high-grade features, radiotherapy can be used, although a significant portion of the brain will receive a substantial dose, resulting in long-term toxicity for survivors.
Prognosis.
Contrary to some reports of very poor outcome for bithalamic astrocytomas of any grade, five of nine patients were long-term survivors in one retrospective series. Part of the difficulty in assigning an accurate prognosis to these tumors is the limited biopsy material available for assessment. With a number of reports of survivors now available, even in the context of bilateral disease, all young patients should be given a trial of chemotherapy.
Low-Grade Diencephalic Astrocytomas (Diencephalic Syndrome)
Diencephalic tumors remain a unique and poorly understood subtype of PLGGs. They typically occur in young infants, although a few patients have presented late in the first or second decade of life. A high incidence of dissemination throughout the neural axis has been recognized and may relate to the increased frequency of the pilomyxoid variant in this location. The presence of failure to thrive in infants often leads to an extensive and prolonged workup for gastrointestinal abnormalities before the correct cause is identified. The presence of diencephalic tumors with early age of onset and the propensity to disseminate suggest that unique biologic differences may exist among these tumors and other low-grade astrocytomas, although no specific abnormalities have yet been documented.
Clinical Presentation.
Diencephalic low-grade astrocytomas are differentiated from other LGGs in children by their presence around the hypothalamus–optic chiasm and a unique constellation of symptoms, including the three “E's”—emaciation, emesis, and euphoria. In spite of severe failure to thrive that is often seen, most infants retain normal growth rates and maintain normal pituitary secretion prior to surgical resection. Although an accurate clinical picture for these patients continues to be defined, because many lack the typical constellation, their management is difficult because of the deep-seated nature of these lesions and the frequent presence of leptomeningeal dissemination at diagnosis. As such, these patients require full craniospinal imaging at diagnosis, along with CSF analysis. Any patient presenting with symptoms of spinal disease needs to undergo immediate restaging.
Imaging and Histology.
The imaging characteristics of diencephalic LGGs do not differ from those of low-grade astrocytomas in other locations. Lesions are centered around the hypothalamus and chiasm, are bright on T2-weighted images, and usually show homogeneous enhancement after administration of contrast material. The lesions are typically PAs or fibrillary astrocytomas, although the pilomyxoid variant can also be observed in this location. These tumors cannot be differentiated by mutational status of BRAF because some patients have the BRAF V600E mutation, some have the BRAF truncated fusion KIAA1549, and other patients have neither.
Management.
The approach to therapy follows that used for other low-grade astrocytomas. Because of the young patient age and deep location of these tumors, radiation therapy is usually contraindicated and will result in significant cognitive impairment over the long term. Most patients undergo maximal safe surgery, followed by chemotherapy with vincristine and carboplatin or TPCV (see Table 57-5 ). Radiographic response or stable disease accompanied by weight gain is common. High-dose chemotherapy has also been used successfully as an investigational approach. Radiographic responses and improvement is weight have also been reported with bevacizumab and irinotecan.
Prognosis.
In spite of the low-grade nature of diencephalic tumors, patients with these tumors do less well than do patients with similar tumors located in the optic pathway, brainstem, or cerebellum. In addition to the continued progression of these tumors, which leads to compression of vital structures, patients are at high risk for surgery-induced hypothalamic damage resulting in obesity.
Fibrillary Astrocytomas
Fibrillary (WHO grade II) astrocytomas are low-grade astrocytomas that are distinct from PAs. Precise determination of the incidence of fibrillary astrocytomas is difficult because many tumors, particularly those in deep structures of the diencephalon or brainstem, cannot be resected sufficiently to provide the material required to classify the tumor accurately. Thus the terms “fibrillary astrocytoma” and “low-grade astrocytoma” are often used interchangeably. Although all fibrillary astrocytomas are LGGs, most LGGs are PAs. Many tumors are classified as grade II astrocytoma with piloid features because a biopsy specimen may have been too small to identify all the elements required for classification as a grade I PA. Similarly the histologic term “pilocytic astrocytoma with fibrillary features” is used to indicate tumors that have all the components of grade I pilocytic astrocytomas but with areas of infiltration suggesting that they could be grade II. Other LGGs include pilomyxoid astrocytomas, oligodendrogliomas, and gangliogliomas. Fibrillary astrocytomas localized to the posterior fossa represent 3% to 15% of cerebellar tumors ; their incidence is lower in the remainder of the brain and spine. No gender predilection exists, and the peak age at diagnosis is 6 to 10 years. Genetic abnormalities in LGGs are uncommon. The reported incidence of LGGs has increased during the past several years. Although an association with paternal workplace exposure in the chemical and electrical industries is purported, a more likely explanation is the increased use and availability of MRI and the diagnosis of presymptomatic lesions.
Clinical Presentation.
The initial symptoms of fibrillary astrocytomas vary, depending on the location of the tumor. Patients with medullary tumors may present with a long history of dysphagia, hoarseness, ataxia, and hemiparesis. Cervicomedullary tumors may cause medullary or upper cervical symptoms such as neck discomfort, weakness or numbness of the hands, and an asymmetrical quadriparesis. Patients with midbrain tumors such as a tectal glioma often present with signs and symptoms of raised ICP. Other symptoms include diplopia and hemiparesis. In children with dorsally exophytic brainstem glioma, a component of the tumor arises in the medulla and expands in a dorsal direction, resulting in noncommunicating hydrocephalus. Supratentorial fibrillary astrocytomas more commonly present with seizures, although thalamic lesions present with motor deficits. Hypothalamic lesions can present as diencephalic syndrome. Low-grade astrocytomas in the brainstem are usually focal rather than diffuse. They tend to arise in the midbrain, cerebellar peduncles, medulla, or cervicomedullary region. Because of the slow rate of progression of these lesions, most patients have subtle neurologic changes that only become evident over a long period. Unlike adult fibrillary astrocytomas, with which degeneration to malignant gliomas is common, pediatric fibrillary astrocytomas remain low grade, even after multiple recurrences. Symptoms may exist for months to years prior to the diagnosis of a low-grade astrocytoma.
Imaging and Histology.
Most low-grade fibrillary astrocytomas appear isodense on CT without significant contrast enhancement. The tumors are hypointense on T1-weighted and hyperintense on T2-weighted MRI, with minimal or no gadolinium enhancement ( Fig. 57-23 ) except for dorsally exophytic brainstem tumors. This appearance is in contrast to that of most PAs, in which homogeneous contrast enhancement is common. Pathologic examination may demonstrate some cellular pleomorphism, but no mitoses, necrosis, or endothelial proliferation are present (i.e., no histologic features of malignancy are present). Although PAs are usually well-circumscribed lesions with a biphasic pattern of areas of bipolar cells and Rosenthal fibers and other areas with microcysts, fibrillary astrocytomas have greater cellularity and infiltrating boundaries. In contrast to grade III or IV astrocytomas, fibrillary astrocytomas must lack features of malignancy, such as significant atypia and pleomorphism, mitoses, vascular proliferation, and palisading necrosis. A number of other subtypes of grade II astrocytomas have been identified, including the lipoastrocytic, protoplasmic, gemistocytic, and xanthomatous types. These subtypes are much less common in pediatric patients compared with adults, and may have a worse outcome compared with fibrillary astrocytomas and PAs. The rarity of these lesions prevents formal studies of these subtypes.
Management.
Management of most fibrillary astrocytomas is similar to that of PAs and depends on the clinical prodrome, age, and location of the primary tumor. Rapidly evolving clinical symptoms in the setting of an operable tumor usually warrant prompt neurosurgical intervention. On the other hand, a lesion with a long history of indolent and mild symptoms is often managed with close MRI and clinical surveillance. In patients who subsequently show progressive neurologic symptoms and for whom MRI studies suggest tumor growth, therapeutic intervention is required. Diffuse fibrillary astrocytomas in eloquent locations such as the thalamus or motor regions are often biopsied to confirm the diagnosis and to exclude higher grade glial tumors. They do not lend themselves to radical resections, as is commonly performed for PAs. However in certain cases, such as dorsally exophytic brainstem astrocytomas, radical resection can often confer a long symptom-free outcome. In cases in which resection is not feasible, chemotherapy or radiotherapy may be indicated. As in the case of progressive or unresectable PAs, chemotherapy is the preferred first approach for patients (see Table 57-5 ). Patients respond well to either vincristine and carboplatin or TPCV chemotherapy. A recent randomized clinical trial of grades I and II astrocytomas has been completed in which these two treatment regimens were compared. Although recurrences occur in most patients, necessitating retreatment with other chemotherapeutic agents, the overall prognosis remains good. Experience with novel combinations of agents or high-dose chemotherapy is limited. Radiotherapy is reserved for older children or younger patients whose tumors progress and are refractory to chemotherapy. Reduced radiation doses to adjacent normal tissue, with equivalent tumor control to that of standard photon therapy, can be achieved with conformal proton therapy. Radiation therapy delivered at the time of initial diagnosis does not appear to provide additional benefit for OS.
Prognosis.
The long-term survival rate for completely resected pediatric supratentorial low-grade astrocytomas is excellent, especially when compared with similar tumors in adults. Even partially or unresected fibrillary astrocytomas may remain stable for many years. An example of this is the focal midbrain or tectal glioma, which is rarely biopsied or resected. Response to chemotherapy appears to be similar to that observed in PAs, although most patients will experience one or more episodes of progression, requiring retreatment with additional chemotherapy. However children with primary tumors arising in the pons or thalamus have a worse prognosis. The presence of a gemistocytic component characterized by a predominance of large astrocytes, with thick processes and dramatic accumulation of GFAP, represents a histologic variant of low-grade fibrillary (grade II) astrocytoma. This variant may be associated with p53 mutations and may also convey a higher predisposition to malignant transformation.
Although most patients with low-grade astrocytomas will survive, patients with fibrillary astrocytomas have a poorer outcome than patients with grade I astrocytomas. Because PAs are more focal and easier to resect than are fibrillary astrocytomas, prognosis may be related to the ease of resection rather than to biologic differences between these histologic variants. Overall survival after chemotherapy of children and adolescents with low-grade astrocytomas at 10 years is 70% to 80%. The role of MIB1 expression in the prognosis of low-grade astrocytomas is not established as a prognostic factor, after age and degree of resection are excluded. Survivors of low-grade astrocytomas still have a number of limitations. Future treatment efforts for these tumors therefore will need to combine effective therapy with improved quality of survivorship in these patients.
Tectal Gliomas
Tectal gliomas are typically hamartomas or low-grade astrocytomas, and patients present with acute hydrocephalus in most cases. These tumors appear to represent a unique variant of low-grade tumors, based on their positive long-term outcome, with relief of hydrocephalus as the sole therapeutic intervention. Because biopsy or surgical resection of these lesions is rarely required, little is known about the pathways that drive their activation. No known genetic syndromes give rise to these tumors.
Presentation.
Most patients with tectal gliomas present with the symptoms of obstructive hydrocephalus because of expansion of these lesions adjacent to the periaqueductal space. When the presence of these tumors is picked up incidentally, many patients will demonstrate prolonged periods of stability and do not require treatment.
Imaging and Histology.
The radiographic appearance of most tectal gliomas is similar to that of other LGGs. Most tumors lack contrast enhancement ( Fig. 57-24 ). Based on their location and presenting symptoms, histologic verification is not required to make the diagnosis and can cause significant morbidity if attempted.
Management.
Biopsy or resection of tectal gliomas is usually not required. Rather, most patients require immediate CSF diversion through a third ventriculostomy. Failures of third ventriculostomies have been reported, even many years after the initial procedure, necessitating the proper education of families regarding symptoms that should precipitate immediate evaluation. Reduction in ventricular size is often incomplete and the ventricular size continues to change during the first year after diversion. Rarely tectal gliomas larger than 10 cm at presentation will continue to progress over time and may require surgical debulking and chemotherapy. Tumors that have atypical radiographic features, rapid progression, or repeated recurrence may require a biopsy. Tumors with asymptomatic progression can often be observed carefully. When treatment is required, approaches similar to those used for other low-grade astrocytomas are recommended. Chemotherapy is usually initiated. Radiation therapy is not required for most patients, and continued progression of these lesions into adulthood is rare.
Prognosis.
The long-term outcome for patients with tectal gliomas remains excellent, which is surprising given the unresectable nature of the lesion and the absence of therapy for most patients. Overall survival approaches 100% in this population, and thus avoidance of unnecessary surgical or radiation-related long-term morbidity is critical.
Pilomyxoid Astrocytomas
Pilomyxoid astrocytomas are a newly stratified group of grade II pediatric tumors in the 2007 WHO classification that were previously grouped together with PAs. Although no specific molecular pathway responsible for these tumors has yet been identified, the presence of defects in the BCR gene on chromosome 17 provides possible clues that require further analysis. Other chromosomal aberrations have also been identified. Pilomyxoid astrocytomas are found most commonly in the midline of the brain and spine. These tumors are usually identified in infants and young children, although their presence in adults has been reported. At recurrence, tumors can appear as classic PAs, suggesting a developmental relationship between the two types of tumors.
Clinical Presentation.
Although pilomyxoid astrocytomas present in a manner similar to that of other LGGs, the incidence of metastatic disease at presentation appears higher and requires a full workup, including spinal MRI and CSF for cytologic evaluation. Patients with pilomyxoid astrocytomas may be at greater risk for spontaneous hemorrhage at the time of diagnosis or resection or during follow-up.
Imaging and Histology.
On MRI pilomyxoid astrocytomas appear similar to PAs, with well-circumscribed margins and little peritumoral edema. They are usually found in the midline, including the brainstem and spine, and can be solid or solid and cystic. They are usually bright on T1- or T2-weighted and FLAIR sequences, and they enhance with administration of contrast material. In approximately 50% of cases, the contrast enhancement is heterogeneous. Adjacent areas of brain can demonstrate elevated choline-to-creatinine ratios suggestive of an infiltrative margin. Although their location, young patient age, and increased presence of dissemination provide clues to the diagnosis before a biopsy is performed, imaging characteristics do not clearly differentiate these tumors from other LGGs in the pediatric population. Histologically these lesions lack many features of PAs, such as Rosenthal fibers and a biphasic pattern. Rather a monophasic pattern and myxoid background is seen, with strong GFAP and synaptophysin staining. Like other glial tumors, mixed lineages may also be possible for pilomyxoid astrocytoma. The variable histologic appearance compared with PAs, MRS signal changes, and a higher incidence of progression and dissemination support their distinction from PAs. A predilection for younger age appears to exist when the tumor is localized to the pituitary-hypothalamic region.
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