Roger J. Packer, MD and Elizabeth M. Wells, MD
Roger J. Packer, MD | Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington DC, Departments of Neurology and Pediatrics, The George Washington University, Washington, D.C.
Dr. Roger J. Packer is Senior Vice-President, Center for Neuroscience and Behavioral Medicine, Gilbert Distinguished Professor of Neurofibromatosis, and is Director of both the Gilbert Neurofibromatosis Institute and the Brain Tumor Institute of Children’s National Health System (CNHS), Washington, DC. Dr. Packer’s present academic titles include Professor of Neurology and Pediatrics at The George Washington University and Clinical Professor of Neurosurgery at the University of Virginia in Charlottesville, Virginia.
Throughout his career, Dr. Packer has been heavily involved in clinical and applied basic science research. His clinical research has touched on various aspects of child neurology and neuro-oncology, including pediatric brain tumors, neurofibromatosis type 1, and the neurologic aspects of childhood neurogenetic diseases. His research has focused on the development and performance of clinical and translational trials for children with neurologic, neuro-oncologic, and neurogenetic disorders, and he has received peer-reviewed grant support for these efforts.
Presently, Dr. Packer is principal investigator at CNHS for the Pediatric Brain Tumor Consortium (PBTC); Chair of the PBTC Low-Grade Glioma Committee; Principal Investigator (CNHS) of the Neurofibromatosis Clinical Trials Consortium; and Chair of the Medulloblastoma Committee of the Children’s Oncology Group. He is P.I. for CNHS NINDS-sponsored Neuro-NEXT Clinical Trials Consortium and Scientific Director of the NBTS-sponsored Defeat Pediatric Brain Tumor Consortium. He has worked closely with the NCI and NINDS, and has served on multiple committees setting the directions for neurologic clinical and basic science research for the future. The majority of the studies now being coordinated by Dr. Packer are evaluating innovative agents aimed at the molecular underpinnings of neurologic disease. He has published over 350 original articles and 300 reviews and chapters.
Elizabeth M. Wells, MD | Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children’s National Medical Center, Washington DC, Departments of Neurology and Pediatrics, The George Washington University, Washington, D.C.
Dr. Wells is a pediatric neurologist specializing in neurologic effects of cancer treatment. Her research focuses on characterizing and mitigating late effects and adverse neurologic sequelae in patients with pediatric brain tumors. She is the Medical Director of Inpatient Neurology at Children’s National.
Tumors of the brain and spine arising in patients less than 18 years of age are, at times, a bewildering array of different tumor types which are challenging for both families and physicians to understand. In total, pediatric central nervous system tumors are infrequent, arising in 3 to 4 out of 100,000 children each year. However, childhood brain tumors are second only to leukemia in incidence of all types of pediatric cancer. Due to the improvements in the treatment of children with leukemia, childhood brain tumors are now the leading cause of pediatric cancer-related deaths, as well as the tumor-type resulting in the greatest physical, neurobehavioral and psychosocial damage. Unlike the situation in adults, in which the majority of brain tumors are secondary to metastatic deposits from systemic cancer, such as cancer which originally arose in the lung, colon, breast or skin, childhood brain tumors develop in the brain and send deposits to other organs. Furthermore, childhood brain tumors arise in different areas of the brain than adult brain tumors and frequently arise deeper in the brain or in the back portion of the brain the posterior fossa, which contains the brain stem, cerebellum and the fluid space which separates the brain stem from the cerebellum, the fourth ventricle. Even the types of primary central nervous system tumors which arise in childhood are different from those occurring in adults, as the majority of adult brain tumors are high grade gliomas or meningiomas, whereas pediatric brain tumors are more likely to be lower grade glial tumors or tumors arising from primitive, embryonal cells of the central nervous system.
The treatments of pediatric brain tumors have improved over the past decades. Over 70% of children with a primary central nervous system tumors are alive 5 to 10 years following diagnosis, many cured of their disease. The likelihood of survival is dependent on the type of brain tumor and global statements about survival have little meaning. The diagnosis of a brain tumor for many patients is far from a death sentence and aggressive, prompt therapy can result in long term disease control. However, at times, the price paid for such disease control is steep due to the complications caused by the therapies required such as surgery, radiation therapy and chemotherapy. Sequelae of the tumor or its treatment may include both short term and long term irreversible neurologic and intellectual damage. Treatment often becomes a balancing act between what the brain, especially the developing brain, can tolerate and what is needed to cure the child.
For decades, it has been accepted that the majority of childhood brain tumors occur without a definitive cause. Other than exposure to radiation, no other clear cut cause of childhood brain tumor has been proven. Environmental factors, such as pesticide exposure or electromagnetic waves, have been associated with higher occurrence of brain tumors in some studies, but not in others.
The genetic contributions to the development of brain tumors were believed to be minimal except for rare tumor predisposition syndromes. The exceptions to this rule were two conditions:
- Neurofibromatosis type 1
- Tuberous Sclerosis Complex
Recent studies have demonstrated that up to 10% of children who develop cancer in the pediatric ages may have predispositions due to germ-line mutations, including recognized syndrome such as the Li Fraumeni syndrome. Mismatch repair syndrome is now being diagnosed and there is little doubt that over time more genetic causes, crucial in the development of these tumors, will be identified. Blood testing to identify germ-line mutations is being improved and recommended.
Children with brain tumors may come to attention in a variety of ways. The tumor can cause direct damage to the brain and result in localizable symptoms and signs. Because of the midline location of many childhood brain tumors, cerebrospinal fluid may be blocked, causing secondary hydrocephalus and symptoms which include headaches, vomiting and lethargy. The classical headache of increased intracranial pressure is one which is worse in the morning, symptoms associated with morning nausea and improves during the day. Headaches which awaken children in the middle of the night are also worrisome, but also occur in patients with migraines. Although headaches are quite frequent in pediatrics, a change in headache pattern or an acute onset of headaches is a warning sign of a mass in the brain.
Tumors which arise in the posterior fossa often result not only in headaches and vomiting, but imbalance, motor impairment and cranial nerve deficits. Tumors which arise in the suprasellar region, an area behind the eyes and near the hormonal center of the brain, will often result in visual impairments which can be difficult to initially diagnose, such as loss of vision in one or both peripheral fields and endocrinologic difficulties. Another relative hotspot for pediatric brain tumors is the pineal region, an area behind the upper part of the brain stem. Disease in this area results in abnormal eye movements which include eyes which dart inward or seem to contract into the globe (retraction and/or convergent nystagmus), pupils which do not react well to light but react better to accommodation, and inability to move the eyes upward. This has been termed the Parinaud’s syndrome and it is also often associated with blockage of cerebrospinal fluid flow and signs of increased intracranial pressure.
Early diagnosis can be problematic in infants and young children. For infants, a slowing or delay in developmental milestones can be an early symptom of a brain tumor, especially for those with large, midline low-grade tumors. Signs of such tumors can be subtle, as visual changes can be difficult to diagnose in infants; fine shimmering nystagmus can be seen in children with chiasmatic tumors. Tumors in some areas may cause an abnormally steep increase in head circumference, due to blocking of cerebral spinal fluid flow (hydrocephalus), and this change may be detected by measurements at regular pediatrician visits. Tumors of the hypothalamus may cause the diencephalic syndrome manifested by difficulty in maintaining weight despite apparent adequate caloric intake. The euphoric components of this syndrome discussed in the literature are absent and infants are excessively irritable. In school-age children, large midline or frontal lesions may result in falling school performance and associated behavioral changes.
Diagnosis has been simplified by the greater availability of Magnetic Resonance Imaging (MRI) which is 99% sensitive in the detection of a brain tumor. Computerized tomography (CT) scans are almost of the same sensitivity, but do not demonstrate the tumor as well as MRI. Other tests such as Positron Emission Tomography (PET) scans can be helpful, but are usually reserved for later evaluations, such as determination of the aggression of the tumor or distinguishing the tumor from inflammation. Since brain tumors in childhood, especially the embryonal ones, spread to other sites within the nervous system, most patients require an MRI of the entire neuro-axis (including the spine) for appropriate evaluation prior to surgery. Lumbar puncture may disclose spread of the tumor not seen on MRI; however, lumbar puncture is reserved for those tumors that have a high likelihood of spread and is done after surgery has relieved increased intracranial pressure.
Childhood brain tumors have a tendency to spread to other central nervous system sites early in the course of illness. Spread to the spinal cord and other parts of the brain are most frequent in the embryonal tumors, but may occur in almost any form of childhood malignant or benign tumors. For these reasons, with the possible exception of craniopharyngiomas and low grade circumscribed pilocytic astrocytomas, neuroimaging of the entire neuro-axis (brain and spine) is required before final treatment planning. As noted previously, in most cases lumbar cerebrospinal fluid analysis is also required for full staging.
Following staging evaluation, for treatment purposes, childhood brain tumors are often placed into risk groups, with the goal of modifying treatment based on risk classification. Other factors, such as amount of residual tumor after resection and histopathologic/immunohistochemical/molecular aspects of the tumor, are incorporated into staging systems. Risk stratification is a critical component of management of medulloblastoma and other embryonal tumors. The discovery of distinctive molecular genetic abnormalities in other tumor types will increase the utility of stratification for other forms of childhood central nervous system tumors.
For the vast majority of childhood brain tumors, surgery is the first step in management, not only to confirm the type and the molecular subtype of the tumor, but also to remove as much tumor as can be safely removed. The degree of resection, or more specifically the amount of tumor left after surgery (dependent on the type of tumor present), may be an important determinant of survival. Therapy is not undertaken until there is pathologic confirmation, with notable exceptions such as characteristic low grade tumors in children with neurofibromatosis type I and germ cell tumor with elevated cerebrospinal fluid protein markers. Increasingly, in the areas where tumor resection is impossible, such as the brain stem, stereotactic biopsies are being employed to confirm the presence of the tumor; these small samples may also be useful in supplying critical molecular information.
Improvements in anesthesia and surgical navigation have made surgery safer and in many cases have allowed more aggressive resections. However, neurologic morbidity after brain tumor surgery remains a significant problem. Any type of brain injury may occur. A common surgical complication is the “posterior-fossa mutism syndrome”, also known as the “cerebellum mutism syndrome”. In this circumstance, after surgery for a posterior fossa tumor (primarily in those with medulloblastomas but also after surgery for any type of midline cerebellum tumor), the child classically slowly awakens and within 24-48 hours is noted to have poor word output or complete mutism. This mutism is not an isolated finding and is often associated with:
- extreme irritability
- difficulties in swallowing
- supranuclear cranial nerve palsies
- low muscle tone
- cerebellum deficits
In most cases the patient slowly improves over days to weeks, but is often left with residual speech and balance difficulties. This syndrome has to be distinguished from direct damage to the brain stem, which may also occur during tumor removal. Children with direct brain stem damage do not have the same degree of poor word output or irritability, but may have similar cerebellum deficits often associated with selective cranial nerve abnormalities including sixth and seventh nerve palsies and swallowing difficulties. The diagnosis of the posterior fossa mutism syndrome is a clinical one, as there are no specific immediate MRI abnormalities. The posterior fossa mutism syndrome is due to disruption of critical pathways from the cerebellum (dentate nuclei) through the upper brainstem and projecting to the thalamus and cerebral cortex.
For decades, following surgery for high grade tumors and some low grade tumors, the only proven effective means of adjuvant treatment was radiation therapy. Radiation therapy can be delivered in different ways, as radiation can be given with the use of various energy particles, different delivery systems and variable dose schedules. The most common form of radiation is photon beam radiation. Photon beam radiation is usually delivered in daily fractions of 1.5-1.8Gy over a 4-6 week period. The total dose to the primary tumor site, with some degree of planned exposure to the area surrounding the tumor site to control infiltrating or residual tumor, ranges between 45Gy and 59.6Gy. For tumors that have a high propensity to spread to other central nervous system early in the course of illness, additional radiation is given to the entire brain and spine (craniospinal radiation) at a lower dose (18Gy-36Gy); dosing is dependent on whether there is frank evidence of dissemination at the time of diagnosis, the type of tumor and the age of the child. Craniospinal radiation may result in significant long-term sequelae including intellectual difficulties and hormonal deficiencies and the likelihood and severity of such difficulties are affected by the dose of craniospinal radiation employed, the age of the child and other still poorly understood host-factors.
To limit the amount of scattered radiation, a variety of different techniques are utilized to deliver local radiation therapy more precisely, such as intensity modulated radiation therapy (IMRT) and other means of conformal radiotherapy. More recently, proton beam radiation has become available. Proton beam radiation results in less scatter radiation and for this reason may result in decreased damage to other organs such as the heart, lung, and ovaries. It may also cause less hearing difficulties and hormonal deficits. However, its early use has been associated with a possibly higher incidence of focal brain damage, especially to the brain stem in young children.
Chemotherapy is increasingly employed for children with brain tumors. It initially was utilized in addition to radiation therapy after surgery in an attempt to increase tumor control. Chemotherapy has also been utilized to reduce the amount of radiation therapy needed and in selected cases, delay or obviate the need for radiation therapy.
With the notable exception of methotrexate-associated leukoencephalopathy, chemotherapy does not cause acute or subacute structural brain injury. Chemotherapy may cause selective forms of neuropathy, especially both vincristine and cisplatin. Vincristine most commonly causes a length dependent sensory and/or motor neuropathy. Cisplatin can result in progressive, often irreversible hearing loss, as well as a “large-fiber” peripheral neuropathy.
Despite these risks, chemotherapy for selective tumors is quite effective and its use has changed the treatment of medulloblastoma and other embryonal tumors. It is also now a major component of treatment for children with low grade gliomas and germ cell tumors.
Molecular Targeted Therapy
The goal of all cancer treatment, including the treatment of childhood brain tumors, is to utilize therapy which will selectively kill or stop the growth of tumor cells without affecting normal tissues. Over the past decade, with increased molecular knowledge of the underpinnings of many forms of tumors, “molecular-targeted therapy” has been developed and employed. Although such “personalized” or “precise” treatments are still in their infancy, agents which target specific molecular characteristics of the tumor have shown some early promise and are being incorporated into treatment of both children with recurrent and newly diagnosed brain tumors. These include:
- drugs which interrupt tumor blood vessel development (antiangiogenic agents)
- agents which inhibit growth factors
- other drugs which aim to interrupt aberrant intracellular signaling
Molecularly targeted therapy, although potentially of extreme utility, carries the risk of interrupting signaling pathways which are critical for normal brain development. The neurotoxicity of these agents, if any, is unknown.
Specific Tumor Types
The classification and therapy of pediatric embryonal tumors are undergoing significant change. In total, such tumors comprise 20-25% of all childhood brain tumors and a higher percentage of those tumors arising in infants and young children. The most common is medulloblastoma and less common are tumors that are termed CNS primitive neuroectodermal tumors and atypical theratoid/rhabdoid tumors.
Medulloblastoma, the most common embryonal tumor occurring in children, may also occur in adults. By definition this histologically small round cell, aggressive tumor only arises in the posterior fossa, usually but not always emanating from the floor of the fourth ventricle. It is now recognized that medulloblastoma is comprised of at least four and probably more molecular subtypes. These subtypes tend to arise at stereotyped ages and the identification of the specific molecular tumor type present is of increasing importance in guiding treatment. A variety of different techniques can be utilized to identify these molecular subtypes including immunohistochemistry and FISH analysis. Fluorescence in situ hybridization (FISH) is a cytogenetic method that employs fluorescent probes that bind to chromosomes.
However, increasingly molecular genetic platforms studying tumor DNA, RNA and DNA methylation are being employed for more comprehensive genomic characterization. It was believed that molecular parameters would supplant clinical staging criteria, but it is likely that the combination of molecular testing and clinical staging will yield the most robust means to guide therapy. Another major determinant of treatment of children with medulloblastoma is the age of the child. Although craniospinal radiation remains a component of treatment for most children with medulloblastoma, because of its potential sequalae is not usually utilized in children less than three years of age and in some studies children less than four or five, as immediate post-operative treatment.
The care of children with medulloblastoma of all ages is changing and patients are best treated on multicentered trials which utilize molecular information to guide treatment. For children three years of age or greater, patients with a medulloblastoma diagnosis have for decades been split into average-risk and high-risk patients.
Those children with average-risk disease include children whose tumors have been totally or near totally resected and have no evidence of spread at the time of diagnosis. Treatment for the average-risk grouping of patients consists of craniospinal radiation (23.4Gy) with local boost radiotherapy (54-59Gy) and chemotherapy during and after radiation therapy. Various chemotherapeutic approaches have been employed and one of the most effective is vincristine combined with radiation followed by vincristine, cisplatin, cyclophosphamide and lomustine. Another approach utilizing similar doses of radiation therapy and higher dose of chemotherapy supported by stem cell rescue with less vincristine has also been used. After either treatment, 70-80% of children can be expected to be alive and free of disease five years after diagnosis, the majority cured of their illness.
For children with high-risk disease, either those whose tumors that could not be fully resected and have greater than 1.5 cm2 of residual disease and/or tumor dissemination, survival rates with similar therapy are not as high. Reported survival rates in this “higher-risk “group ranges between 50-65% at five years. Usually radiation for children with such poor-risk disease is given a higher craniospinal dose (3.6Gy) and is coupled with more aggressive chemotherapy given during and/or post-radiation. Chemotherapy before radiation has also been employed in high risk patients with the hope of improved survival, although no study has clearly demonstrated the benefits of pre-radiation chemotherapy.
Utilizing immunohistochemical and now genomic analysis, the most discrete molecular subset of medulloblastoma are WNT tumors. “WNT” (pronounced wint) is the name of a proto-oncogene, and this tumor type is now being called WNT by doctors and patients, showing how important the molecular descriptions have become. Comprising approximately 10% of all children with medulloblastoma, WNT tumors tend to arise in older children and adolescents. With standard treatment, these patients have an excellent prognosis and there are multiple studies now underway attempting to either utilize less craniospinal radiation therapy and/or less chemotherapy to decrease sequelae, while maintaining the 95-100% survival rate.
The sonic-hedge-hog (SHH) subgroup is a complicated subgroup. Patients in this subgroup have aberrant signaling in the SHH pathway. Infants and adults are more likely to have an upstream SHH pathway mutation and an overall relatively good prognosis. In childhood, the presence of downstream SHH pathway mutations connote poor prognosis and survival rates as low as 20-30% at five years have been observed. To assess the likelihood of disease control and to develop more effective therapies, identifying a patient being in the SHH subclass by immunohistochemistry is no longer adequate and gene sequencing is required to identify the specific pathway mutation present. Some children with SHH tumors also have an underlying p53 germ-line mutation, diagnosable by blood analysis.
MYC Elevated Tumors
Still another group which has been separated by molecular genetic testing are children with amplification or possibly overexpression of MYC (pronounced “mick”), a transcription gene, in their tumors. Again, while this term seems technical, it is now part of the vocabulary for doctors and patients with medulloblastoma. MYC patients carry a poor prognosis and a high likelihood of dissemination, either at the time of diagnosis or at the time of relapse. More aggressive therapeutic approaches are being developed for these high-risk patient, classified by some as MYC elevated group 3 tumors and by others MYC-elevated non WNT, non SHH tumors.
Infants and Young Children
For infants and children less than three years of age (in some studies less than four or five years of age) with medulloblastoma, craniospinal radiation is known to have such severe intellectual sequalae that treatment is undertaken with chemotherapy alone. It has been recognized that a subgroup of these younger children have a different histological appearance, having large areas of the tumor demonstrating desmoplasia and nodularity. These same children harbor tumors which have been found to have molecular evidence of SHH mutations, predominantly upstream mutations. Infants and young children in this SHH/desmoplastic/extensive nodularity subgroup carry an excellent prognosis and recent studies have demonstrated that many can be effectively treated with chemotherapy alone. Survival rates ranging are as high as 80% after 5-years chemotherapy alone have been noted. There is some concern that late local relapse may occur. For infants with more classical or anaplastic forms of medulloblastoma, therapy is not as effective. With multiagent chemotherapy alone less than 50% of such children are cured, even fewer if the tumor is disseminated at the time of diagnosis and/or cannot be totally resected.
Following treatment, predominantly because of the whole brain radiation utilized as part of the craniospinal radiotherapy for most patients, children with medulloblastoma are high-risk for permanent intellectual, hormonal, psychosocial and behavioral sequelae. The intellectual sequelae may be complicated by chemotherapy related toxicities, including hearing loss. Survivors of childhood medulloblastoma also are likely to suffer from obesity and short stature. Multidisciplinary follow-up of survivors is mandatory.
Late relapses are uncommon in children with medulloblastoma, but may occur. An underdiagnosed and underappreciated long-term risk is the development of secondary tumors, either because of cancer pre-disposition syndromes or the treatment (especially radiation) employed or both. Some of these tumors may mimic tumor relapse. Any child “relapsing” greater than three years following diagnosis should be carefully evaluated for a secondary treatment induced tumor, such as a malignant glioma.
CNS Primitive Neuroectodermal Tumors (PNETs) and Pineoblastoma
The present WHO classification of embryonal tumors occurring outside the posterior fossa groups classifies embryonal tumors as primitive neuroectodermal tumors (PNETs). The atypical theratoid/rhabdoid is a distinct tumor and embryonal tumors arising in the pineal region are termed pineoblastomas. PNETs, composed of undifferentiated or poorly differentiated cells which by definition cannot arise in the posterior fossa (except in the brainstem), occur in the cerebral hemispheres and rarely in the spinal cord. Although classification of these tumors has been difficult, new molecular genetic findings demonstrate that these tumors are composed of distinct molecular subtypes. Nomenclature for these tumors, also utilizing terms such as medulloepithelioma and ependymoblastoma, is being changed and the molecular genetic mutations found in these tumors are being built into classification schema.
Despite these molecular differences, the overall treatment approach for PNETs has been similar. They have been treated as medulloblastomas with older children receiving craniospinal and local boost radiotherapy and similar chemotherapy as outlined for children with medulloblastomas. Younger children have been treated on infant medulloblastoma protocols. Outcome has been variable, however, in general, older children who can receive radiation therapy have had better overall survival rates. In some studies, children with pineoblastomas (especially after aggressive resections), also had fairly good survival rates in the range of 30-50% at five years. Young children and infants have fared less favorably and new treatment approaches are being explored in multicentered studies.
Atypical Teratoid/rhabdoid Tumor
The atypical teratoid/rhabdoid tumor has only been separated from other embryonal tumors, especially medulloblastoma, over the past quarter century. The tumor has a distinctive pathologic appearance, characterized by areas that look embryonal intermixed with areas of larger cells with eosinophilic cytoplasm and “rhabdoid” cells. The tumor also has a characteristic immunohistochemical profile. Diagnosis is dependent on determining the loss of a specific tumor suppressor gene termed SMARCB1 also known as INI1 or HSNF5.
A percentage of patients with atypical teratoid/rhabdoid tumors of the brain will harbor similar tumors in the kidney. It is believed that between 40 and 60% of patients with atypical teratoid/rhabdoid tumors will have a germline abnormality which predisposes to these tumors.
Treatment of atypical teratoid/rhabdoid tumors has evolved over the past decade. This tumor was considered a tumor of infancy and although it arises most in infancy, it is diagnosed in older children. Also, it is now thought to be comprised of two, if not more, molecular subtypes.
For infants and very young children, a variety of different chemotherapeutic regimens have been employed. For those patients with extensive tumors that cannot be totally resected, especially those with disseminated disease, such treatment is infrequently successful. For older children, treatment with craniospinal radiation therapy coupled with chemotherapy pre- and post-radiation therapy has been more successful, especially in those older children who do not have tumor dissemination at diagnosis and whose tumor has been totally or near totally resected.
Gliomas are the single most common form of childhood brain tumor and their classification can be confusing and often subjective. Gliomas are graded on a 1 to 4 scale with grade 1 and 2 tumors considered benign and grade 3 and 4 tumors considered aggressive or malignant. This type of classification, like other classifications of pediatric brain tumors, is undergoing reassessment. It is now understood that the most frequent type of grade 1 tumors, pilocytic astrocytomas, differs molecularly from grade 2 to 4 tumors. Pilocytic astrocytomas tend to act benignly and carry a better prognosis than other forms of glioma. In adults, grade 2 gliomas often mutate into grade 3 and 4 tumors with 75% of adults showing such progression over a 3 to 5 year period of observation. Grade 2 gliomas occurring in children often stay grade 2 for many years and may not mutate. Biologically, although not sharing characteristics with grade 1 tumors, tumors graded as 2 to 4 in pediatrics are biologically different than adult tumors.
In addition, pediatric low-grade tumors, especially pilocytic astrocytomas, have been further subdivided on the basis of their location of origin in the central nervous system. The rationale for this type of separation is suspect. Confusing the issue even more are the possible congenital origins of many childhood low-grade gliomas. Congenital tumors are often difficult to classify as they may contain different histological elements. Pediatric low-grade gliomas with intermixed neuronal elements, such as gangliogliomas, are common in pediatrics and categorization can be arbitrary.
There is no doubt that immunohistochemical analysis has aided in the diagnosis of pediatric low-grade gliomas and mixed neuronal-glial tumors. However, biologic insights garnered over the past decade have changed how pediatric low-grade gliomas and, for that matter, high-grade gliomas are conceptualized. The majority of pediatric pilocytic astrocytomas have abnormalities in the BRAF gene (pronounced “Bee-Raff”)and dependent on location of origin of the tumor, a specific type of BRAF mutation (a BRAF fusion abnormality), occurs in as high as 80 to 90%. It has been suggested by some that diagnosis of pilocytic astrocytoma should be in question unless a BRAF fusion abnormality is found. A smaller component of pilocytic astrocytomas have a specific mutation in BRAF (the v600e mutation) and it is unclear whether such tumors should be considered pilocytic astrocytomas or actually are grade 2 tumors. Some grade 3 tumors will also have a v600e mutation. Molecular genetic testing for the presence or type of BRAF mutation is becoming important in the diagnosis, categorization and management of children with low-grade gliomas.
Pilocytic astrocytoma is the most common form of childhood low-grade glioma and, as noted above, often have mutations in the BRAF gene. The most common location for pilocytic astrocytomas is the cerebellum. Although cerebellar pilocytic astrocytomas may be midline, they are more likely to be laterally placed cerebellar tumors and amendable to gross total resection. Cerebellar pilocytic astrocytomas may have a protracted clinical course prior to diagnosis and may or may not be associated with obstructive hydrocephalus. Gross total resection of the tumor is the treatment of choice and after such treatment between 90 and 95% of patients can be expected to be cured of their disease. For those tumors that cannot be totally resected, a period of observation is indicated before additional therapy is undertaken as some lesions will stay stable after partial resection for many years.
The chiasm and hypothalamus are the second most common sites for pediatric pilocytic astrocytomas. Tumors in this region may arise early in life and, when the predominant site is the hypothalamus, may cause the diencephalic syndrome. Patients with chiasmatic tumors have visual deficits at the time of diagnosis. However, the visual field deficits can be complex and are not particularly stereotyped. In addition to the chiasm, one or both optic nerves may be involved. Approximately 50% of patients with visual pathway gliomas have neurofibromatosis type 1.
Biopsy is required in the majority of patients with chiasmatic/hypothalamic tumors without neurofibromatosis type 1 to confirm the presence of a glioma, its grade, and to gather molecular information which might aid treatment decisions. In children with neurofibromatosis type 1 and characteristic radiographic findings, diagnosis and treatment planning are made without biopsy.
The treatment of chiasmatic and hypothalamic pilocytic astrocytomas is dependent on the size of the lesion and the age of the patient. In most cases, surgery is primarily a diagnostic tool. Although radiotherapy can be used and is often quite effective, it may result in significant hormonal and frequent cognitive sequalae, especially in very young children. For this reason, children less than 5 years of age and even somewhat older are initially treated with chemotherapy. A variety of different chemotherapeutic approaches are effective and the greatest experience has been with the combination of carboplatin and vincristine. After carboplatin and vincristine chemotherapy, 90% of the patients will experience tumor control with the tumor radiographically responding in 50% or more of patients. In children without neurofibromatosis type 1, tumor control decreases over time with the majority requiring some alternative form of treatment, either a different chemotherapy regimen or radiation, within 5 years of initial treatment. Children with neurofibromatosis type 1 are diagnosed on screening examination, at times being asymptomatic or with apparently non-progressive symptoms or findings. A period of observation, before initiation of treatment, is often indicated. Because of the potential detrimental effects of radiation in children with neurofibromatosis type 1, radiation is infrequently used. After initial chemotherapy many children with neurofibromatosis type 1 will require no further treatment as long-term control is achieved in is high at 70% of patients.
Biologic therapy can also be quite effective in children with pilocytic astrocytomas. As the majority harbor a mutation of the BRAF gene, the BRAF gene has been targeted as a means of treatment and a variety of drugs either inhibiting the gene or blocking its downstream signaling are being tested. The MEK inhibitors are a class of drugs which has shown early efficacy in blocking the abnormal activation of the RAS-MAPK intracellular signaling pathway distal to the BRAF gene.
For pilocytic astrocytomas that occur in the cerebral cortex, the treatment of choice is surgical resection. Other means of treatment are only indicated in those patients who develop progressive disease following resection.
Grade 2 (Diffuse/Infiltrating Low Grade Gliomas)
The management of grade 2 or diffuse/infiltrating low grade gliomas is more problematic than for the pilocytic tumors. After total resection, many patients will experience long-term disease control and some are cured of the tumor. However, outcome is more variable and some patients will relapse despite gross total resections. Following surgery, for those patients undergoing a partial resection, observation is undertaken before alternative means of treatment are utilized.
For those children with progressive disease following resection, treatment with chemotherapy may be effective. These children tend to be somewhat older and often are also good candidates for local radiation therapy. Molecular genetic abnormalities in patients with diffuse infiltrating gliomas are less well characterized; some may have a BRAF point mutation (the v600e mutation) and may be candidates for treatment with drugs which inhibit the v600e or BRAF downstream signaling.
The treatment of children with grade 3 and grade 4 gliomas is problematic. Although carrying a somewhat better prognosis than adults with such tumors, disease control for the majority of children cannot be maintained. If possible, patients should be treated on multicentered prospective clinical studies. There is general acceptance that prognosis is better after a total or near total resection of the tumor. Following resection, the majority of patients will receive radiotherapy and then go in remission. However, 50% or less of patients with grade 3 tumors and likely 20% or less of patients with grade 4 tumors will maintain disease control for five years. Often chemotherapy is given after radiotherapy, although the efficacy of chemotherapy remains questionable. Drugs such as CCNU and temozolomide are often utilized with some evidence that they may result in a greater proportion of children surviving. However, clearly better treatments are needed.
New molecular agents are being studied for high-grade gliomas. The anti-angiogenesis agent bevacizumab has been utilized in adults and confers a slight progression-free survival advantage. However, its use has not been proven to be effective in prolonging survival in children with high-grade gliomas. Immunotherapeutic approaches, including vaccine trials, are presently under active study in children with high-grade gliomas.
One of the most virulent forms of childhood brain cancer, if not the most devastating, are brainstem gliomas. The majority of gliomas that infiltrate the brainstem in children are high-grade lesions. Although they can involve any portion of the brainstem, they most ofteninvolve the pons and a term utilized for these tumors are “diffuse intrinsic pontine gliomas ”(DIPGs). The prognosis for patients with DIPGs is dismal, as nearly 90% of children succumb to their disease within 18 months of diagnosis. Treatment with radiation for these patients will, in the majority, result in transient clinical benefit and for this reason radiation therapy is given to most patients. To date, the addition of chemotherapy, either prior to, during and/or after radiotherapy, has not improved survival.
The majority of patients with DIPGs can reliably be diagnosed based on neuroradiographic findings. For this reason, biopsy of these tumors (the tumor cannot be safely resected) was often limited to those patients with atypical radiographic features. More recently, it is been shown that DIPGs are biologically composed of different biologic subsets of tumors which may respond to therapy, especially molecularly-targeted therapy, differently. Abnormalities of genes which are involved in chromatin remodeling have been shown in the majority of patients with DIPGs and such genetic abnormalities are potential biologic targets. Other biologic abnormalities have been identified. For these reasons there is increasing interest in biopsying brainstem glioma at the time of diagnosis, not only to confirm the presence of a high-grade glioma, but also to identify the underlying biologic abnormalities of the tumor. Studies are underway attempting to utilize biopsy-derived biologic information to direct therapy. Also, it has been shown that stereotactic biopsy performed by neurosurgeons experienced in these types of procedures can be done with relative safety.
Other types of tumors may occur in the brainstem. Approximately 10% of brainstem gliomas will arise in the upper midbrain, especially in the region of the tectum. Such tectal gliomas are often quite indolent. They often present with hydrocephalies due to obstruction of the cerebral aqueduct. Cerebrospinal fluid diversion will result in long-term disease control and less than one-third of patients will require treatment in the first five years from diagnosis. Low-grade gliomas, especially pilocytic astrocytomas, may emanate from the brainstem. They are radiographically different and seem to extend exophytically dorsally from the brainstem and the upper cervical cord. Rarely, focal pilocytic astrocytomas will also arise within the pons. Primitive neuroectodermal tumors may also arise within the brainstem and mimic more diffuse intrinsic tumors.
Ependymomas are another type of childhood brain tumor that is comprised of different molecular subtypes. Categorized as grade 1 (subependymomas and myxopapillary ependymomas), grade 2 (cellular ependymoma, papillary ependymomas and clear cell ependymomas) and grade 3 (anaplastic ependymomas), this classification and grading does not take into account molecular differences. Supratentorial ependymomas differ from posterior fossa tumors in their molecular make up. In addition, there are at least two subgroups of ependymomas which occur in the posterior fossa. The prognostic significance of anaplasia is unclear but most, but not all, studies suggest that those patients with anaplastic lesions fare less well.
In pediatrics, especially in infants and young children, ependymomas of the posterior fossa are more frequent than supratentorial lesions. The treatment for ependymomas that arise in the cortex is surgical resection. Following total surgical resection of grade 2 tumors, no further treatment may be required. For partially resected grade 2 or any grade 3, radiation therapy to the tumor bed is indicated.
The management of infratentorial ependymomas is more complex. After total or subtotal resection, focal radiation therapy is usually recommended, even in children as young as one year of age at time of diagnosis. Higher survival rates have been noted in children after “total” resections, but since ependymomas often arise in the lateral portions of the brain stem (the cerebellopontine angle) complete resection can be difficult to impossible without damage to intertwined cranial nerves such as the sixth, seventh and eighth and often lower cranial nerves. Near total resections may result in similar survival rates with less short and long-term neurologic sequalae. In very young children, chemotherapy alone has been used with some success. A variety of different chemotherapeutic regimens have been employed and the most favorable outcome has been after multi-agent chemotherapy. There has been no survival advantage noted after the use of higher dose of chemotherapy with stem cell rescue.
The prognosis for patients with ependymomas is variable. Survival rates between 70-80% have been noted in supratentorial tumors, with and without the use of radiation therapy. In the posterior fossa tumors, it is becoming clear that survival differs depending on which molecular subtype is present. For the favorable cluster of patients survival in the 60-80% has been noted after radiation therapy, while overall survival is considerably less for those patients with unfavorable molecular genetic findings.
Myxopapillary ependymomas are rare tumors which can be difficult to manage. Most arising in the lower part of the spinal cord in the region of the cauda equine, “encapsulated” myxopapillary ependymomas may be amenable to gross total resection. In those patients whose tumors have spread or when total resection is impossible, radiation therapy is usually the next step in management. The volume of radiation required for myxopapillary ependymoma disease control is not well established. Some investigators recommend radiation only to areas of disease while others recommend full spine and, in rare cases, craniospinal radiation. As in other forms of ependymomas, there is no evidence for the benefit of chemotherapy during or after radiation therapy.
Craniopharyngiomas are complex tumors that arise in the suprasellar region. The tumor frequently has both cystic and solid elements and may have a significant amount of calcification. Craniopharyngiomas are histologically benign tumors, but may be difficult to manage and their treatment is often associated with significant morbidity.
Management options include total removal of the cystic and solid elements, partial removal followed by focal radiation therapy or the installation of chemotherapy (bleomycin) or radiolabelled particles into the cyst to collapse it, followed by focal radiation therapy. After gross total resection, 75% or more patients are cured of their disease. However due to surgically-related sequealae, such patients often suffer hypopituitarism, behavioral and cognitive sequalae and obesity. Radiation therapy may also cause damage in the suprasellar and hypothalamic region and disease control has been more variable with some centers reporting overall survivals similar to those after total resection, while others have found a higher incidence of later relapse. Chemotherapy has no role in the management of craniopharyngiomas with the possible exception of interferon for those with recurrent disease.
Pineal Region Tumors
Tumors of the pineal are infrequent, comprising only 2-4% of childhood brain tumors; management is challenging. Because of the anatomic complexities of this region, extensive surgical resection is difficult and surgery should only be undertaken by those surgeons who are experienced in operating in this region. Even biopsy of these lesions can cause significant neurologic compromise, especially if there is post-surgical vascular injury. Multiple tumor types occur in the pineal region including germ cell tumors (40%) pineal parenchymal tumors (pineoblastomas and pineocytomas-40%) and astrocytomas. Complicating the situation to a greater extent is that there are multiple different kinds of germ cell tumors and each carries a different prognosis and requires different forms of treatment.
Germ Cell Tumors
Some germ cell tumors do not need histological confirmation for the diagnosis. The tumor cerebrospinal fluid protein markers, alpha-fetoprotein and beta-HCG, can be diagnostic. Blood sampling is usually less useful. Germinomas may secrete low levels of beta-HCG into the cerebrospinal fluid although one variant, the syncytiotrophoblastic germinoma, secretes high levels. Mixed germ cell tumors have elevations of both beta-HCG and alpha fetoprotein, whereas the choriocarcinoma variant results in high levels of beta-HCG.
Pure germinomas carry an excellent prognosis after treatment with radiation alone or radiation plus chemotherapy. Chemotherapy has been used to reduce the dose and volume of radiation required for disease control. Chemotherapy alone is curative in no more than 60 to 70% of patients. After focal radiation alone or with chemotherapy, as high as 20% of patients will relapse and develop disseminated disease; for this reason either craniospinal radiation therapy or, in patients with non-disseminated germinomas at the time of diagnosis, whole ventricular radiation therapy is recommended. Ninety percent or more of patients with pure germinomas can be expected to be alive and free of disease five years of diagnosis, the vast majority cured of their tumor.
Outcome for patients with mixed germ cell tumors and other rare variants, such as the yolk sac tumor and the embryonal carcinoma, carry a poorer prognosis and radiation therapy plus chemotherapy is required for disease control. Some recent series suggest improved survival after the use of aggressive pre-radiation chemotherapy; as high as 65% of patients have been noted to be free of disease five years of diagnosis. Mature teratomas are treated with surgery alone. Treatment for immature teratomas is more variable and often consists of both extensive surgical resection followed by focal radiation therapy.
Pineoblastomas and Pineocytomas
Pineal parenchymal tumors are pineoblastomas or pineocytomas. Pineoblastomas are treated as other supratentorial primitive neuro-ectodermal tumors and survival after resection followed by radiation and chemotherapy has varied between series. It has been reported to be as low as 20% and as high as 50% five years from diagnosis. Pineocytomas may be anaplastic, but are more likely to be benign tumors. Treatment options for patients with pineocytomas include surgery alone or surgery followed by focal radiation therapy.
Choroid Plexus Tumors
Choroid plexus tumors are rare and although occurring predominantly in infant and young children, they may arise in older patients. Choroid plexus papillomas usually presenting with marked hydrocephalus are best treated with surgery, although surgery may have significant morbidity due to the degree of hydrocephalus and the very young age of patients. After total resections, long-term disease control and cure usually occurs.
The management of choroid plexus carcinomas is more complex and unsettled. Gross total resection alone has been associated with long-term survival, although some recommend chemotherapy and/or radiation therapy after total resections. Treatment of partially resected choroid plexus carcinomas usually consist of some combination of radiation and chemotherapy. Outcome is suboptimal, as majority of patients will develop progressive disease.
- Adjuvant treatment – Cancer treatment beyond surgery; typically refers to radiation and chemotherapy but may also include molecularly-targeted agents.
- Craniospinal radiation – Radiation to the brain and spinal cord; this type of radiation may be necessary for more malignant tumors especially those that have spread in the central nervous system; it often results in more adverse effects than local radiation and is therefore avoided in children age 3 and under.
- Degree of resection – Amount of tumor removed by surgery.
- Diencephalic syndrome – A syndrome that develops in patients with damage to the hypothalamus and includes difficulty in maintaining weight despite apparent adequate caloric intake.
- Dissemination – Tumor spread beyond the primary site.
- Germ-line mutations – Detectable and heritable variations in the lineage of germ cells. Mutations in these cells are transmitted to offspring while, on the other hand, those in somatic cells are not.
- Grade of tumor – The description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope. It is an indicator of how quickly a tumor is likely to grow and spread.
- Hydrocephalus – A condition in which the primary characteristic is excessive accumulation of fluid in the brain. The excessive accumulation of cerebrospinal fluid (CSF) results in an abnormal widening of spaces in the brain called ventricles.
- Immunohistochemical analysis – A method for demonstrating the presence and location of proteins in tissue sections.
- Leukoencephalopathy – Brain dysfunction, usually cognitive impairment and excessive sleepiness, resulting from damage to the cerebral white matter; may result from chemotherapy (particularly methotrexate) or from radation.
- Li Fraumeni – A rare cancer predisposition hereditary disorder that is autosomal dominant.
- Mismatch repair syndrome – A cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome.
- Molecular-targeted therapy – Therapy that precisely attacks the molecular biochemical pathways causing a tumor to grow.
- Multicentered studies – Research studies where multiple hospitals agree to treat children similarly, to pool research data. These are often run by cooperative groups.
- Neurofibromatosis type 1 – A multisystem genetic disorder that is characterized by cutaneous findings, most notably café-au-lait spots, by skeletal dysplasias, and by the growth of both benign and malignant nervous system tumors.
- Nystagmus – Describes when the eyes move involuntarily from side to side in a rapid, swinging motion rather than staying fixed on an object or person.
- Parinaud’s syndrome – Abnormal eye movements including eyes darting inward or seeming to contract into the globe (retraction and/or convergent nystagmus), pupils which do not react well to light but react better to accommodation and inability to move the eyes upward.
- Peripheral neuropathy – Dysfunction of the nerves of the face, arms or legs; may be caused by certain chemotherapy (e.g., vincristine and cisplatin) and may result in numbness, tingling, pain, or weakness.
- Pineal region – An area behind the upper part of the brainstem. Tumors in this area may result in Parinaud’s syndrome, blockage with cerebrospinal fluid flow and signs of increased intracranial pressure.
- Posterior fossa – Area of the brain which contains the brain stem, cerebellum and the fluid space which separates the brain stem from the cerebellum, the fourth ventricle; common place for development of pediatric brain tumors. Tumors in this area of the brain cause headaches, vomiting, imbalance, motor impairment and cranial nerve deficits.
- Primary central nervous system tumors – Tumors that develop within brain or spinal cord, rather than in other parts of the body.
- Proton beam radiation – A newer radiation technique that results in less scatter radiation beyond the target site; may result in decreased hearing loss and hormonal effects. Short and long term possible adverse effects are still being studied.
- Suprasellar region – An area behind the eyes, near the hormonal center of the brain. Tumors here result in loss of vision in one or both peripheral fields and endocrinologic difficulties.
- Tuberous Sclerosis Complex (TSC) – Rare, multi-system genetic disease caused by defects in the TSC genes that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease.
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