The past 2 decades have witnessed a revolution in the management of childhood brain tumors, with the establishment of multidisciplinary teams and national and international consortiums that led to significant improvements in the outcomes of children with brain tumors. Unprecedented cooperation within the pediatric neuro-oncology community and sophisticated rapidly evolving technology have led to advances that are likely to revolutionize treatment strategies and improve outcomes.
Key points
- •
The past 2 decades have witnessed a revolution in the management of childhood brain tumors, with the establishment of multidisciplinary teams and national and international consortiums.
- •
Unprecedented cooperation within the pediatric neuro-oncology community and sophisticated rapidly evolving technology have led to advances that are likely to revolutionize treatment strategies and improve outcomes.
Brain tumors in children represent the second most common malignancy in children. The number of children, adolescents, and young adults (0–19 years) with a diagnosis of a brain tumor is approximately 4350 per year. The cause for most of these tumors is unknown, but there are some predisposing conditions that give rise to certain types of brain tumors. Turcot syndrome, Li-Fraumeni syndrome, and Gorlin syndrome are examples that can give rise to high-grade glioma (HGG) and medulloblastoma.
Management of children with brain tumors requires a multidisciplinary approach, and these children are best served at pediatric hospitals, which are equipped with the necessary resources and personnel. Pediatric neurosurgeon, oncologist, neuropathologist, neuroradiologist, radiation oncologist, endocrinologist, and physical rehabilitation services among others should be available.
These children present most commonly with symptoms related to increased intracranial pressure or one or several of the following: cranial nerve palsies, incoordination, seizures, loss of vision, and short stature.
A few of the more common brain tumors and recent advances in their management are discussed in the following sections.
Medulloblastoma
Medulloblastoma is the most common malignancy in children and represents approximately 20% of all malignant brain tumors that affect children between the ages of 0 and 14 years. There is a bimodal distribution peak between 3 and 4 years and again between 8 and 10 years of age. It can occur in teenagers and young adults, but less frequently.
The cause of medulloblastoma is unknown. However several familial syndromes like Gorlin syndrome, Turcot syndrome, and Li-Fraumeni syndrome, which have a genetic predisposition to development of medulloblastoma, offer clues to the molecular pathologic mechanisms that can lead to growth of medulloblastoma. About 3% to 5% of children with Gorlin syndrome develop medulloblastoma. Gorlin syndrome is characterized by an inherited germline mutation of the PATCHED1 gene on chromosome 9, which encodes the sonic hedgehog (SHH) receptor PTCH1 and normally suppresses SHH signaling by inhibiting the SMO receptor. Approximately 40% of medulloblastomas show evidence of mutations in the PTCH1, and these tumors are mostly associated with the desmoplastic variant of medulloblastoma. Children with Turcot syndrome have mutations in the adenomatosis polyposis coli gene (type 2) or mutations in the DNA mismatch repair genes HPS2 and MLH1 (type 1). Patients with type 2 disease are at increased risk for developing medulloblastoma. Approximately 10% of children with medulloblastoma have a favorable prognosis and have abnormalities in the WNT molecular pathway, which is also aberrant in Turcot syndrome. Patients with Li-Fraumeni syndrome with germline mutations in the TP53 gene can develop medulloblastoma, particularly of the SHH subtype, although gliomas are more common in this syndrome.
Clinical Presentation
The symptoms at presentation caused by medulloblastoma are related to obstruction of cerebrospinal fluid (CSF) pathways and direct involvement of the cerebellum or the brainstem. Headaches and vomiting as a result of raised intracranial pressure, constant features later in the course of the disease, are often nonspecific in the early stages. Unsteadiness, mostly truncal, is present in about 50% to 80% of children with medulloblastoma. Esotropia in 1 or both eyes and papilledema are common. Clumsiness, dropping things frequently, and declining academic performance are other symptoms that can indicate the presence of a cerebellar lesion like medulloblastoma. Macrocephaly, unexplained lethargy, and head tilt are more common in infants.
Diagnosis
The diagnosis of medulloblastoma is initially suspected based on imaging studies, which include MRI of the brain. A typical radiographic presentation is the presence of a solid midline posterior fossa mass that seems to arise from the cerebellum and occupies the fourth ventricle. It shows variable and heterogeneous enhancement pattern. Occasionally, it may arise from the lateral aspect of either cerebellar hemisphere and often indicates a specific subtype of medulloblastoma that shows activation of the SHH pathway. The differential diagnosis of a midline posterior fossa mass includes ependymoma and pilocytic astrocytoma. The former is a solid tumor, which tends to spread toward the cerebellopontine angle via the foramen of Luschka or toward the spinal cord via the foramen of Magendie. The latter consists of solid and cystic components, with often a uniform enhancement of the solid component. In the younger child, the differential diagnosis includes atypical teratoid rhabdoid tumor, which may show involvement of the cerebellopontine angle. A complete MRI evaluation of the full length of the spinal cord and the thecal sac is strongly recommended before surgical intervention for the primary tumor. A lumbar puncture to assess the involvement of CSF should be performed at least 2 weeks after surgical removal of the primary tumor. Attempts at lumbar puncture at the time of diagnosis before alleviation of increased intracranial pressure are strongly contraindicated. In the absence of peripheral blood count abnormalities, bone marrow evaluation is not indicated. It is rare for bone metastases to be present at the time of diagnosis.
Clinical Staging
Most treatment strategies have used the modified Chang system for classification of medulloblastoma into standard-risk (average-risk) or high-risk categories. A gross total resection (GTR) or near total resection of the primary (with ≤1.5 cm 2 of residual tumor) and the absence of metastases renders a patient as having average-risk disease. Residual tumor greater than 1.5 cm 2 or evidence of metastases indicates high-risk disease.
Management of Medulloblastoma
A multidisciplinary team is essential for optimal management of a child with medulloblastoma. Primary intervention consists of complete removal of the primary tumor and is commonly achieved at most pediatric centers in the United States. Postoperatively, one of the main complications of surgery is the appearance of posterior fossa syndrome or cerebellar mutism, which occurs approximately 72 hours after surgery. This complication is characterized by inability to speak with or without accompanying neurologic deficits. The cause of this complication is unclear. Disruption of long white matter tracts is implicated. There is no evidence that this complication can be avoided by modifying surgical technique. In 1 retrospective study of more than 400 patients, approximately 25% of patients were affected by posterior fossa syndrome. Most of these patients suffer long-term severe to moderate neurocognitive deficits. There is no evidence that the course of this syndrome can be modified by medical intervention.
Radiation therapy is an important component of adjuvant therapy and was the mainstay of therapy after surgery until the early 1990s. After early reports of increased failures after radiation volumes that did not include the whole craniospinal axis, improved outcomes of approximately 70% were achieved using a standard CSI dose of 36 Gy with a posterior fossa boost to 54 Gy in patients with average-risk disease. To reduce the long-term adverse neurocognitive effects of a craniospinal radiation dose of 36 Gy, a randomized trial was initiated within the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) comparing 36 Gy to 23.4 Gy for craniospinal irradiation (CSI) with a posterior fossa boost up to 54 Gy. The results of this intergroup trial showed a trend toward a better outcome with those who received 36 Gy to CSI. However in the interim, a multi-institutional study clearly showed a benefit with the use of multiagent chemotherapy (chloroethylnitrosourea [CCNU], cisplatin, and vincristine) after radiation therapy (23.4 Gy to CSI) in patients with average-risk disease. The sequence of surgery followed by reduced dose of CSI and multiagent chemotherapy became the standard of care for children with medulloblastoma with average-risk disease, with an expected 5-year event-free survival (EFS) of approximately 80%. Variation of this treatment schema with decrease in duration and an increase in dose intensity of chemotherapy agents produced similar results. Substitution of CCNU with cyclophosphamide in the multiagent regimen yielded similar results. Tumors with anaplastic histology have a poorer outcome, especially those that have either MYC or MYCN amplification. Success in improving outcomes in average-risk disease comes at a price. Significant neurocognitive effects have been described, even with CSI dose of 23.4 Gy. Ninety percent of patients develop growth hormone deficiency, and many develop deficiencies of other hormones, requiring lifelong supplementation, which carries its own risks as a result of lack of adherence, especially in the teenage years. Sensorineural deafness as a result of radiation therapy and cisplatin can also be debilitating. The current Children’s Oncolgy Group (COG) trial is testing whether the use of 18 Gy to CSI can achieve the same outcome as 23.4 Gy and decrease the severity and incidence of long-term effects mentioned earlier.
The role of chemotherapy after radiation therapy in patients with medulloblastoma with high-risk disease was clearly established, with a 5-year EFS of 46% with chemotherapy. Data from POG trial 9031 showed that patients with high-risk disease had a 5-year EFS of 70% with higher doses of radiation therapy and chemotherapy, including cyclophosphamide and cisplatin. Similar results were obtained with more intensive chemotherapy with stem cell rescue. A current trial within the COG is testing whether the use of carboplatin as a radiosensitizer and a differentiating agent (retinoic acid) can further improve the outcome in patients with high-risk disease.
Children younger than 3 years present a unique challenge. The developing brain is highly susceptible to devastating effects of radiation therapy, and therefore, clinical trials had centered on the use of chemotherapy alone and delaying the use of CSI until the patient is 3 years of age. This strategy had resulted in a poor outcome in infants, except in those infants who have nonmetastatic disease, undergo GTR, and have a particular type of histopathology, described as nodular desmoplastic or medulloblastoma with extensive nodularity. The use of higher doses of systemic methotrexate and concomitant use of intrathecal methotrexate has obviated radiation therapy in infants but still resulted in leukoencephalopathy in 19 of 23 patients tested; this could lead to long-term significant neurocognitive deficits.
Recent Advances
Until recently, medulloblastoma was considered one disease and was treated uniformly with the same regimen. Northcott and colleagues, along with others, showed that medulloblastoma can be categorized into 4 groups. Tumors displaying WNT pathway activation with resultant nuclear accumulation of β-catenin and monosomy 6 constitute about 10% of all children with medulloblastoma and have a favorable prognosis. Efforts are under way to significantly reduce radiation therapy or chemotherapy or both for this subtype. Approximately 30% of patients with medulloblastoma have evidence of activation of the SHH pathway as a result of mutations in the PTCH1 or the SMO genes. Survival rate in this subgroup is approximately 75%. SMO inhibitors are in clinical trials, and one such trial was recently published. Group 3 constitutes tumors that have a poor prognosis, with survival rate of approximately 50%; survival rate of group 4 is approximately 70%. Newer and more effective agents are needed to improve outcomes in these groups. Genomic sequencing data offer further clues to the biology of these tumors and potentially new targets. With the burgeoning data, there is increased hope for more effective and targeted therapies, which could lead to improved outcomes with lesser toxicities.
Medulloblastoma
Medulloblastoma is the most common malignancy in children and represents approximately 20% of all malignant brain tumors that affect children between the ages of 0 and 14 years. There is a bimodal distribution peak between 3 and 4 years and again between 8 and 10 years of age. It can occur in teenagers and young adults, but less frequently.
The cause of medulloblastoma is unknown. However several familial syndromes like Gorlin syndrome, Turcot syndrome, and Li-Fraumeni syndrome, which have a genetic predisposition to development of medulloblastoma, offer clues to the molecular pathologic mechanisms that can lead to growth of medulloblastoma. About 3% to 5% of children with Gorlin syndrome develop medulloblastoma. Gorlin syndrome is characterized by an inherited germline mutation of the PATCHED1 gene on chromosome 9, which encodes the sonic hedgehog (SHH) receptor PTCH1 and normally suppresses SHH signaling by inhibiting the SMO receptor. Approximately 40% of medulloblastomas show evidence of mutations in the PTCH1, and these tumors are mostly associated with the desmoplastic variant of medulloblastoma. Children with Turcot syndrome have mutations in the adenomatosis polyposis coli gene (type 2) or mutations in the DNA mismatch repair genes HPS2 and MLH1 (type 1). Patients with type 2 disease are at increased risk for developing medulloblastoma. Approximately 10% of children with medulloblastoma have a favorable prognosis and have abnormalities in the WNT molecular pathway, which is also aberrant in Turcot syndrome. Patients with Li-Fraumeni syndrome with germline mutations in the TP53 gene can develop medulloblastoma, particularly of the SHH subtype, although gliomas are more common in this syndrome.
Clinical Presentation
The symptoms at presentation caused by medulloblastoma are related to obstruction of cerebrospinal fluid (CSF) pathways and direct involvement of the cerebellum or the brainstem. Headaches and vomiting as a result of raised intracranial pressure, constant features later in the course of the disease, are often nonspecific in the early stages. Unsteadiness, mostly truncal, is present in about 50% to 80% of children with medulloblastoma. Esotropia in 1 or both eyes and papilledema are common. Clumsiness, dropping things frequently, and declining academic performance are other symptoms that can indicate the presence of a cerebellar lesion like medulloblastoma. Macrocephaly, unexplained lethargy, and head tilt are more common in infants.
Diagnosis
The diagnosis of medulloblastoma is initially suspected based on imaging studies, which include MRI of the brain. A typical radiographic presentation is the presence of a solid midline posterior fossa mass that seems to arise from the cerebellum and occupies the fourth ventricle. It shows variable and heterogeneous enhancement pattern. Occasionally, it may arise from the lateral aspect of either cerebellar hemisphere and often indicates a specific subtype of medulloblastoma that shows activation of the SHH pathway. The differential diagnosis of a midline posterior fossa mass includes ependymoma and pilocytic astrocytoma. The former is a solid tumor, which tends to spread toward the cerebellopontine angle via the foramen of Luschka or toward the spinal cord via the foramen of Magendie. The latter consists of solid and cystic components, with often a uniform enhancement of the solid component. In the younger child, the differential diagnosis includes atypical teratoid rhabdoid tumor, which may show involvement of the cerebellopontine angle. A complete MRI evaluation of the full length of the spinal cord and the thecal sac is strongly recommended before surgical intervention for the primary tumor. A lumbar puncture to assess the involvement of CSF should be performed at least 2 weeks after surgical removal of the primary tumor. Attempts at lumbar puncture at the time of diagnosis before alleviation of increased intracranial pressure are strongly contraindicated. In the absence of peripheral blood count abnormalities, bone marrow evaluation is not indicated. It is rare for bone metastases to be present at the time of diagnosis.
Clinical Staging
Most treatment strategies have used the modified Chang system for classification of medulloblastoma into standard-risk (average-risk) or high-risk categories. A gross total resection (GTR) or near total resection of the primary (with ≤1.5 cm 2 of residual tumor) and the absence of metastases renders a patient as having average-risk disease. Residual tumor greater than 1.5 cm 2 or evidence of metastases indicates high-risk disease.
Management of Medulloblastoma
A multidisciplinary team is essential for optimal management of a child with medulloblastoma. Primary intervention consists of complete removal of the primary tumor and is commonly achieved at most pediatric centers in the United States. Postoperatively, one of the main complications of surgery is the appearance of posterior fossa syndrome or cerebellar mutism, which occurs approximately 72 hours after surgery. This complication is characterized by inability to speak with or without accompanying neurologic deficits. The cause of this complication is unclear. Disruption of long white matter tracts is implicated. There is no evidence that this complication can be avoided by modifying surgical technique. In 1 retrospective study of more than 400 patients, approximately 25% of patients were affected by posterior fossa syndrome. Most of these patients suffer long-term severe to moderate neurocognitive deficits. There is no evidence that the course of this syndrome can be modified by medical intervention.
Radiation therapy is an important component of adjuvant therapy and was the mainstay of therapy after surgery until the early 1990s. After early reports of increased failures after radiation volumes that did not include the whole craniospinal axis, improved outcomes of approximately 70% were achieved using a standard CSI dose of 36 Gy with a posterior fossa boost to 54 Gy in patients with average-risk disease. To reduce the long-term adverse neurocognitive effects of a craniospinal radiation dose of 36 Gy, a randomized trial was initiated within the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) comparing 36 Gy to 23.4 Gy for craniospinal irradiation (CSI) with a posterior fossa boost up to 54 Gy. The results of this intergroup trial showed a trend toward a better outcome with those who received 36 Gy to CSI. However in the interim, a multi-institutional study clearly showed a benefit with the use of multiagent chemotherapy (chloroethylnitrosourea [CCNU], cisplatin, and vincristine) after radiation therapy (23.4 Gy to CSI) in patients with average-risk disease. The sequence of surgery followed by reduced dose of CSI and multiagent chemotherapy became the standard of care for children with medulloblastoma with average-risk disease, with an expected 5-year event-free survival (EFS) of approximately 80%. Variation of this treatment schema with decrease in duration and an increase in dose intensity of chemotherapy agents produced similar results. Substitution of CCNU with cyclophosphamide in the multiagent regimen yielded similar results. Tumors with anaplastic histology have a poorer outcome, especially those that have either MYC or MYCN amplification. Success in improving outcomes in average-risk disease comes at a price. Significant neurocognitive effects have been described, even with CSI dose of 23.4 Gy. Ninety percent of patients develop growth hormone deficiency, and many develop deficiencies of other hormones, requiring lifelong supplementation, which carries its own risks as a result of lack of adherence, especially in the teenage years. Sensorineural deafness as a result of radiation therapy and cisplatin can also be debilitating. The current Children’s Oncolgy Group (COG) trial is testing whether the use of 18 Gy to CSI can achieve the same outcome as 23.4 Gy and decrease the severity and incidence of long-term effects mentioned earlier.
The role of chemotherapy after radiation therapy in patients with medulloblastoma with high-risk disease was clearly established, with a 5-year EFS of 46% with chemotherapy. Data from POG trial 9031 showed that patients with high-risk disease had a 5-year EFS of 70% with higher doses of radiation therapy and chemotherapy, including cyclophosphamide and cisplatin. Similar results were obtained with more intensive chemotherapy with stem cell rescue. A current trial within the COG is testing whether the use of carboplatin as a radiosensitizer and a differentiating agent (retinoic acid) can further improve the outcome in patients with high-risk disease.
Children younger than 3 years present a unique challenge. The developing brain is highly susceptible to devastating effects of radiation therapy, and therefore, clinical trials had centered on the use of chemotherapy alone and delaying the use of CSI until the patient is 3 years of age. This strategy had resulted in a poor outcome in infants, except in those infants who have nonmetastatic disease, undergo GTR, and have a particular type of histopathology, described as nodular desmoplastic or medulloblastoma with extensive nodularity. The use of higher doses of systemic methotrexate and concomitant use of intrathecal methotrexate has obviated radiation therapy in infants but still resulted in leukoencephalopathy in 19 of 23 patients tested; this could lead to long-term significant neurocognitive deficits.
Recent Advances
Until recently, medulloblastoma was considered one disease and was treated uniformly with the same regimen. Northcott and colleagues, along with others, showed that medulloblastoma can be categorized into 4 groups. Tumors displaying WNT pathway activation with resultant nuclear accumulation of β-catenin and monosomy 6 constitute about 10% of all children with medulloblastoma and have a favorable prognosis. Efforts are under way to significantly reduce radiation therapy or chemotherapy or both for this subtype. Approximately 30% of patients with medulloblastoma have evidence of activation of the SHH pathway as a result of mutations in the PTCH1 or the SMO genes. Survival rate in this subgroup is approximately 75%. SMO inhibitors are in clinical trials, and one such trial was recently published. Group 3 constitutes tumors that have a poor prognosis, with survival rate of approximately 50%; survival rate of group 4 is approximately 70%. Newer and more effective agents are needed to improve outcomes in these groups. Genomic sequencing data offer further clues to the biology of these tumors and potentially new targets. With the burgeoning data, there is increased hope for more effective and targeted therapies, which could lead to improved outcomes with lesser toxicities.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
