Clinical manifestations

Presentation and course

Clinical presentation typically is dependent on the location of the tumor in the brain and can include focal motor, sensory, and speech deficits. However, symptoms could also be nonlocalizing due to increased intracranial pressure. Headaches were the leading symptom (60; 89; 08) and may be part of the classic triad of increased intracranial pressure, lethargy, and vomiting. The headaches are usually worse when waking up and improve during the day. School-aged children more commonly report vague intermittent headaches and fatigue. They may have a declining academic performance and exhibit personality changes. Infants may present with irritability, failure to thrive or anorexia, developmental delay, or regression (81). On physical examination, raised intracranial pressure is best appreciated as papilledema on fundoscopic evaluation; however, this may present only as optic pallor in infants with open cranial sutures.

Although brain tumors are found in 1% to 3% of children with new-onset seizures, seizures occur in approximately 20% of patients with supratentorial malignant gliomas (60) and even up to 30% in a study (96). Supratentorial tumors were more commonly associated with seizures than infratentorial tumors. Delayed seizure onset, lesser seizure frequency with focal weakness, and signs of increased intracranial pressure were noted more in malignant tumors (96). Hypothalamic tumors may be associated with neuroendocrine abnormalities, growth hormone deficiency, diabetes insipidus, and precocious pubertal development. These tumors may also impinge on the optic chiasm, resulting in optic atrophy and visual deficits. Patients with diencephalic tumors may present with the classic diencephalic syndrome (emesis, emaciation, and unusual euphoria), but the syndrome is rare in children older than 3 years. Gliomas of the visual pathways, which are typically not malignant, may be brought to medical attention because of strabismus, proptosis, nystagmus, or developmental delay. Infants more frequently display head tilt, head bobbing, and nystagmus.

Prognosis and complications

The outcome of children with supratentorial malignant gliomas remains poor. The 5-year survival rate in combined series ranges from 16% to 46% with the use of postoperative radiotherapy and chemotherapy (91; 23). However, the consensus is that as a group, supratentorial malignant gliomas have less than 30% 5-year survival rate (100). A statistically superior 5-year progression-free survival has been found for patients with grade III anaplastic astrocytoma versus grade IV glioblastoma multiforme that have undergone radical resection (44% ± 11% vs. 26% ± 9%) or less than radical resection (22% ± 6% vs. 4% ± 3%) (98; 68). A comprehensive review of Surveillance, Epidemiology, and End Results (SEER) data consisted of 6212 patients younger than 20 years of age at diagnosis of glioma (1973 to 2005) in 4 age categories: less than 1 year, 1 to 3 years, 3 to 5 years, and 5 to 20 years (77). Tumor grade emerged as the most significant independent prognostic factor in all age groups except the youngest age group, in which extent of resection was most significant. In this report, surgery other than gross total resection was an adverse prognostic factor, and age less than 3 years predicted a greater likelihood of survival. Children aged less than 1 year received less radiotherapy than older patients (P < .0001) and were less likely to undergo gross total resection (P < .0001). A more recent SEER data review on 302 pediatric patients with glioblastoma reveals an overall median survival of 20 months and 2-year survival rate at 46.9%. When broken down into age categories, those aged 0 to 4 years had the highest median survival of 59 months; 5 to 9 years was 12 months (24.5% 2-year survival rate), 10 to 14 years was 19 months (35.8% 2-year survival rate), and 15 to 19 years was 23 months (48% 2-year survival rate). Those with supratentorial tumors had better survival outcomes compared to infratentorial tumors (median overall survival 22 months, 45.4% 2-year survival rate, vs. 14 months, 13.5% 2-year survival rate). There was no statistically significant difference in overall survival between those receiving radiation after surgery versus no radiation (49).

Patients with other malignant gliomas such as anaplastic oligodendroglioma and mixed malignant gliomas also appear to have a better outcome than patients with malignant astrocytomas (23). Whether these differences diminish over time, as has been observed in prior comparisons, remains uncertain. One study found a significant association between overexpression of p53 and outcome (72). In this study, the rate of progression-free survival at 5 years was 44% in the group of 74 patients whose tumors had low levels of expression of p53 and 17% in the group of 41 patients whose tumors had overexpression of p53 (p < 0.001). Promoter methylation of the O6 methylguanine-DNA methyltransferase repair enzyme, resulting in epigenetic silencing of the gene, has been associated with increased overall survival in adult patients with high-grade glioma; however, its significance in pediatric high-grade glioma has been inconsistent.

The report from the Children’s Oncology Group indicates that the level of tumor expression of methylguanine-DNA methyltransferase (MGMT), which functions to counteract the cytotoxic effects of alkylating agents, such as temozolomide, has a significant impact on survival. In this study, immunohistochemical assessment of MGMT expression revealed that 12 of the 109 samples analyzed demonstrated overexpression of MGMT compared with normal brain and that the 5-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017) (74). However, methylation of the MGMT promoter, which results in decreased MGMT expression, was found to be low in pediatric patients (50). Interestingly, pediatric malignant gliomas with methylated promoters correlated with increased median event-free survival of 5.5 months versus 0.9 months (86), and an average overall survival of 13.7 months versus 2.5 months when compared to patients with nonmethylated MGMT promoters (20). However, in other studies, there was no significant difference between the overall survival based on MGMT methylation (38; 31).

Adult glioblastoma cells with reduced expression of matrix metalloproteinases such as TIMP-1 have shown increased overall patient survival; however, this has not been observed in the pediatric population (01). Activation of matrix metalloproteinases have been associated with higher grade gliomas and worse survival outcomes (33). In addition, PTEN deletions and EGFR amplifications are more commonly detected in adult glioblastomas and rarely in pediatric glioblastomas. Loss of PTEN expression is associated with poor outcome in pediatric gliomas, and this may explain the difference of survival between these 2 groups (70).

Patients who survive are often left with significant neurocognitive, neuroendocrinologic, and other neurologic deficits as a result of the tumor’s location within the central nervous system. Furthermore, secondary effects can result from the surgery, irradiation, and chemotherapy (99). Complications that may arise as a result of either direct tumor effect or the treatment administered include obstructive hydrocephaly, neurologic impairment, radiation-induced effects (neurocognitive decline, endocrinologic dysfunction, mineralizing microangiopathy with ischemia or infarct, secondary CNS malignancies, transient headaches, fatigue, nausea, vomiting, and anorexia), and chemotherapy-induced effects (myelosuppression, infection, nausea, vomiting, anorexia, renal damage, hepatic damage, hearing damage, neurotoxicity, and secondary malignancies). Investigational chemotherapy may also cause complications such as fever, neutropenia, or suspected infection. Therefore, hospitalization may be necessary. Infertility and impairment of growth may also be long-term sequelae of therapy (29).

Clinical vignette

A 17-year-old male in previous good health initially presented to his physician with a 1- to 2-month history of headaches and early morning vomiting. The patient denied having fever, weight loss, night sweats, sinus congestion, cough or other upper respiratory symptoms, diarrhea, constipation or abdominal pain, urinary frequency or dysuria, and joint or bone pain. Appetite, activity level, and school performance remained unchanged. The patient was taking no medications, and he denied alcohol or drug use. He denied that he was sexually active. Physical examination was unremarkable. Laboratory studies done, including a complete blood count, electrolytes, and a chemistry panel with liver and renal function tests, were all within normal limits. An abdominal x-ray was normal. The symptoms were thought to be migraine headaches precipitated by psychosocial stress or eye strain due to worsening nearsightedness. He was referred to an ophthalmologist for formal evaluation. Fundoscopic examination by the ophthalmologist identified papilledema. A CT scan of the head was subsequently obtained, which revealed a large solid and cystic mass with heterogeneous contrast-enhancement in the region of the right thalamus extending into the velum interpositum and right periventricular white matter. Peritumoral edema with moderate midline shift was also noted.

The patient was immediately started on intravenous dexamethasone for control of cerebral edema and intravenous phenytoin for seizure prophylaxis. A preoperative MRI of the head was consistent with the findings on CT scan. An MRI of the spine was obtained preoperatively, which was negative for tumor dissemination. The following day he underwent a craniotomy and gross total surgical resection of the tumor mass. A lumbar puncture was also performed while the patient was under anesthesia. Pathology was consistent with a World Health Organization grade III malignant glioma (anaplastic astrocytoma). CSF was negative for the presence of tumor cells. Postoperative physical examination was significant for a new left visual field deficit, decreased upgaze, a mild left pronator drift, decreased rapid alternating movements on the left, and mild left upper extremity dysmetria. Two weeks following surgery, the patient underwent a 6-week course of local irradiation to the tumor cavity and extension of 2.5 cm around the margin of the tumor cavity to a total dose of 5940 cGy. One week after the completion of radiotherapy, the patient presented with grand mal seizures while on therapeutic levels of phenytoin. MRI revealed that there had developed a cystic enlargement with mass effect and recurrence of a small enhancing nodule at the primary tumor site. The patient underwent surgical resection of the recurrent tumor mass and drainage of the cyst with resolution of the mass effect and good control of the seizure activity on therapeutic phenytoin. He then received adjuvant chemotherapy with oral temozolomide. Routine follow-up MRI after 2 cycles of chemotherapy (8 weeks) showed filling in of the operative site with tumor and a new metastatic lesion in the third ventricle. Temozolomide was discontinued and an experimental phase I chemotherapy given intravenously twice weekly was initiated. Follow-up MRI after 8 weeks of this therapy again revealed progressive tumor disease. This medication was discontinued and a different experimental phase I chemotherapy was administered intravenously every 3 weeks. On this medication, the tumor was shown to shrink by more than 75% with resolution of the metastatic tumor deposits. After 18 months of this therapy, a PET scan was obtained to evaluate the metabolic activity of the residual mass and this was found to be consistent with absence of tumor activity. The patient’s physical examination had also significantly improved, with diminished upgaze being the only residual deficit. This treatment was completed and the patient is off of all medications. He currently remains in continuous complete remission 2 years from the end of this therapy.

Biological basis

Etiology and pathogenesis

Epidemiologic studies investigating parental and patient occupational exposure, environmental exposure, and nutritional intake have failed to identify linkages with the development of supratentorial malignant gliomas (18). Ionizing radiation to the head for the treatment of prior malignancies (leukemia or brain tumor) has been associated with the development of secondary supratentorial malignant gliomas in a small number of patients (14). Glioma is also the most frequent CNS tumor in people with the Li-Fraumeni syndrome, which is characterized by a germline mutation of the p53 tumor suppressor gene on the short arm of chromosome 17 (Rickert and Paulus 2001). Polymorphisms in codon 72 of the p53 tumor suppressor gene have been most recently associated with susceptibility to human cancer. In a study that includes pediatric gliomas, the genotype distributions of the P53 Arg72Pro between all brain tumors and controls were statistically significant (P < 0.001) as well as their variant allele frequencies between cases and controls (P < 0.001). There was a significant increase in the Arg/Pro heterozygous genotype among high-grade astrocytomas compared with non-astrocytomas (P = 0.002); and there was a significant increase in the Arg/Pro heterozygous genotype among high-grade astrocytomas containing transdominant as well as recessive p53 mutations compared with controls (P = 0.002), suggesting a possible association between P53 Arg72Pro polymorphisms and susceptibility to brain tumors, particularly high-grade astrocytomas (66).

Malignant gliomas are thought to arise from differentiated glial cells (astrocytes and oligodendrocytes) or precursor cells committed to glial differentiation through a complex process involving the accumulation of alterations in genes that normally regulate the pathways of cell proliferation, differentiation and death. Mutations that result in increased gene dosage (amplification) or constitutive activation of dominantly acting oncogenes typically overproduce proteins that serve to promote dysregulated cell growth. Mutations that result in absent gene dosage (deletion) or constitutive inactivation of recessively acting tumor suppressor genes typically reduce proteins that serve as key inhibitors of cell growth. For example, the most common genetic alterations in adult malignant gliomas include amplification or overexpression of epidermal growth factor receptor and mouse double minute 2 homolog (MDM2), deletion of chromosome p16, loss of heterozygosity 10p and 10q, and mutations of the phosphatase and tensin homolog, p53 and retinoblastoma tumor suppressor genes (44).

At present, the precise inciting mutational events that are necessary for the development of childhood malignant gliomas are not known. Interestingly, some investigations have shown that the frequency of p53 and phosphatase and tensin homolog mutations, epidermal growth factor receptor amplification, and loss of heterozygosity at 17p13.1, 9p21, and 10q23-25 is different in pediatric and adult malignant gliomas, suggesting that the development of these tumors in children may follow pathways different from the primary or secondary paradigm of adult malignant gliomas (16; 90; 47). For example, epidermal growth factor receptor amplification is usually observed in approximately 40% and 15% of adult grade IV and grade III gliomas, respectively. In contrast, a study of 27 pediatric supratentorial malignant gliomas treated consecutively at a single institution between 1975 and 1992 showed elevated immunoreactivity for epidermal growth factor receptor in 80% of tumors, but only 2 of the cases had gene amplification (11). Similarly, extensive characterization of 10 pediatric anaplastic astrocytomas and 18 glioblastomas revealed EGFR amplification in only 3 cases, no amplification of PDGFR-alpha, and LOH on 1p/19q and 10p/10q less common than in adults, but the frequency of LOH on 22q was comparable, occurring in 40% to 60% of pediatric malignant gliomas (62). In another series, epidermal growth factor receptor amplification was not detected in any pediatric case (80). However, with the advent of newer genomic arrays allowing for greater sensitivity, more alterations that have been previously unrecognized are being reported. For example, data have shown an elevated frequency of EGFR amplification (11%) and EGFRvIII deletion (17%) in pediatric malignant gliomas than previously reported (05). Interestingly, some studies showed overexpression of EGFR protein in up to 85% of pediatric tumors tested, but only 7% of the cases were EGFR expressed, suggesting another mechanism other than amplification was responsible for EGFR overexpression in pediatric high-grade glioma (11; 94).

Furthermore, mutation of the p53 gene has been reported in 50% to 60% of adult malignant gliomas. Yet, in a multiinstitutional cohort of the Children's Cancer Group Study 945, the largest cohort of childhood malignant gliomas at that time, only 26 of 77 tumors (33.8%) had p53 mutations and mutations were observed in only 2 of 17 tumors (11.8%) from children less than 3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children (p = 0.04) (69). The association between age and frequency of p53 mutations among pediatric malignant gliomas indicates the probable existence of 2 distinct pathways of molecular tumorigenesis in younger versus older children, with the latter perhaps resembling more the evolution of these tumors in adults. Another study compared the status of the p53/MDM2/p14ARF or Rb/CDK4/p16INK4a tumor suppressor pathways in pediatric malignant gliomas. This study found preferential inactivation of the p53 tumor suppressor pathway of pediatric gliomas versus inactivation of the retinoblastoma tumor suppressor pathway in the same tumors (94). Another study retrospectively analyzed 54 pediatric glioblastoma multiforme patients (age range 9 months to 15 years) for expression of p53, epidermal growth factor receptor (EGFR), bcl-2 and retinoblastoma proteins (pRb) by immunohistochemistry and found p53 immunoreactivity in 53.7% of the cases, predominantly in thalamic (75%) and cerebral lobar (62.2%) but absent in cerebellar tumors. P53-positive tumors had a higher MIB-1 index compared to p53-negative tumors (p=0.003). EGFR and bcl-2 overexpressions were observed in 25.9% and 33.3% of cases, respectively, and loss of pRb expression was evident in only 7.4% of cases, indicating that loss of this gene function is not significantly involved in pediatric glioblastoma multiformes. P53 and bcl-2 expression were maximally noted in patients with poorer outcome (26).

Comprehensive molecular profiles have identified key changes in signaling pathways of pediatric malignant gliomas, especially the expression of receptor tyrosine kinase pathways. The first published report of microarray gene profiling of childhood astrocytomas demonstrated that malignant tumors are distinguished from their benign counterparts by the differential overexpression of the angiogenesis-associated genes, EGFR, FKBP12, and HIF2-alpha (42). Subsequent studies have better defined the protein immunopositivity rate in malignant gliomas for p53 (35%) and PTEN (67%) (52), as well as the activated forms of PDGFR-alpha, PDGFR-beta, and EGFR (85%, 79%, and 47%, respectively) and have shown that PDGFR is distinctly associated with malignant histology and that loss of PTEN is associated with worse outcome (95). A series of genomic profiling studies have validated these findings and confirmed key differences between pediatric and adult malignant gliomas. Most notably, pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% vs. 9%, respectively), lower frequency of chromosome 7 gain (13% vs. 74%, respectively), and 10q loss (35% vs. 80%, respectively), whereas PDGFRA amplification and 1q gain occurred at a significantly higher frequency in irradiation-induced pediatric malignant gliomas, suggesting that these are initiating events in childhood gliomagenesis (06; 67; 79).

Whole genome DNA sequencing has identified specific histone modifications in pediatric malignant gliomas. Histones have complex regulatory roles and are important in gene expression and telomere length and stability. Lys27Met mutations in histone 3.3 have been shown to be specific particularly to diffuse intrinsic pontine gliomas and as a result are used to define a specific subgroup (53). Gly34Arg mutations in histone 3.3 are thought to be exclusively found in supratentorial malignant gliomas (102). In addition, H3.3G34R/V in pediatric high-grade glioma tend to cosegregate with ATRX mutations and can be found in 20% of pediatric high-grade glioma (58; 59; 34).

Isocitrate dehydrogenase (IDH1 and IDH2) mutations, which inhibit the normal function of the IDH enzyme in converting isocitrate dehydrogenase to alpha-ketoglutarate and instead drive the conversion to 2 hydroxyglutarate, is an oncologic metabolite driving tumor growth. These mutations were detected in adult secondary glioblastoma, likely representing an early step in tumorigenesis, as such mutations are commonly seen in lower grade gliomas. However, IDH mutations are uncommon in the pediatric population (64; 83). In a study by Pollack and colleagues in 2011, the frequency of IDH1 mutation was examined in a cohort of 43 pediatric high-grade glioma patients at the time of diagnosis, and IDH1 mutations were noted in 7 of 20 (35%) of tumors from children more than 14 years of age, but 0% in younger children (71).

Advances in microarray analysis have identified key differences in pediatric malignant gliomas microRNA. miR-137 and miR-6500-3p were found to be significantly inhibited in pediatric malignant gliomas. Furthermore, over expression of these microRNAs resulted in reduced cell proliferation and survival in tumor cells (51). Targeting of microRNAs could result in potential new therapeutics.

Newer studies continue to identify aberrant pathway mutations and expression profiles that may lead to effective, personalized targeting of specific supratentorial gliomas, such as findings highlighting recurrent MET fusion genes in pediatric high-grade glioma (07) and BRAF V600E mutations (63). Advances in microarray analysis have identified key differences in pediatric malignant gliomas microRNA. miR-137 and miR-6500-3p were found to be significantly inhibited in pediatric malignant gliomas. Furthermore, overexpression of these microRNAs resulted in reduced cell proliferation and survival in tumor cells (51). Targeting of microRNAs could result in potential new therapeutics. Newer studies continue to identify aberrant pathway mutations and expression profiles that may lead to effective, personalized targeting of specific supratentorial gliomas, such as findings highlighting recurrent MET fusion genes in pediatric high-grade glioma (07) and BRAF V600E mutations (63).

In 2017, Mackay and colleagues performed an integrated analysis of over 1000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and identified cosegregating mutations in histone-mutant subgroups (58). Among the tumors not harboring either histone 3 or IDH mutation, 3 subgroups emerged, each driven by different mutations and high-level amplifications. WT-A subgroup includes tumors with mutations in BRAF, BRAF V600E, NF1, and fusions involving tyrosine-kinase receptors such as NTRK; they are mostly supratentorial. WT-B includes tumors with high level amplifications for EGFR, CDK6m, and MYCN. They can be found in all compartments, not exclusively supratentorially. Lastly, WT-C includes tumors with PDGFRA and MET amplifications and can be found mostly in hemispheric location (80%). Additionally, a hypermutant subgroup in children and adolescents/young adults was identified, with the mutations MLH1, MSH2, MSH6, PMS2, and POLE/POLD1 as oncogenic drivers (58; 34).

A summary of key molecular targets and their relevance is summarized in Table 1.

Table 1. Key Genetic and Protein Changes in Pediatric Supratentorial Malignant Gliomas

Although gross examination may reveal what appears to be a well-demarcated tumor, microscopic examination frequently shows extension of tumor for up to several centimeters beyond this margin. Grade III malignant gliomas typically show more of a distinction from the surrounding normal brain structures and a tendency to locally infiltrate without significant tissue destruction. This often leads to marked enlargement of invaded structures such as gyri and basal ganglia. Frequently there are areas of granularity, opacity, and softer consistency. With increasing anaplasia, malignant gliomas tend to invade more aggressively and become more poorly delineated. The cut surface of grade IV malignant gliomas may show variable color with peripheral grayish tumor masses, yellowish necrosis secondary to myelin breakdown and stippling with red and brown pigment indicative of prior hemorrhage. Central necrosis may occupy as much as 80% of the tumor mass (44). When present, macroscopic cysts contain a turbid fluid representing liquefaction necrosis. These tumors may be very large at the time of presentation and may occupy much of a lobe. There is a tendency for contralateral hemispheric spread through the corpus callosum creating the image of a bilateral symmetrical tumor known as a “butterfly glioma” and neuraxis dissemination may occur in as many as 25% to 50% of malignant gliomas. However, these tumors tend not to invade the subarachnoid space and, thus, rarely metastasize via the CSF. Rather, rapid spread within the internal capsule, fornix, anterior commissure and optic radiations is more likely along with extension along perivascular spaces. However, intraluminal invasion is unlikely and consequently extraneural dissemination to lung, lymph nodes, liver, and bone is exceedingly rare in children.

The principal microscopic features are marked hypercellularity, distinct cytologic and nuclear atypia, abundant mitotic activity and with increasing anaplasia the presence of necrosis, endothelial proliferation, and hemorrhage (44).

Additional signs of anaplasia may be observed, including complex nuclear morphology with increasing variations in size and shape, coarseness of chromatin, nucleolar prominence and number, nuclear inclusions, multinucleated giant cells, and abnormal and bizarre appearing mitoses. Because of the heterogeneous nature of these tumors, areas of benign appearing histology are commonly noted, particularly in small biopsy sections taken from the more superficial areas of the tumor. The mitotic labeling index MIB-1 has been shown to be a useful marker in identifying the presence of malignant lesions (73).

Epidemiology

Supratentorial malignant gliomas comprise approximately 10% to 15% of all childhood brain tumors. Data obtained from the Surveillance, Epidemiology, and End Results program from 1975 to 1995 demonstrate an annual incidence of 2.59 cases per 1,000,000 children ages 0 to 19 years (37).

Prevention

There is no known prevention of supratentorial malignant gliomas.

Differential diagnosis

The acuteness of onset, constellation of clinical signs, and symptoms described above, including the lack of an infectious or traumatic clinical history and the CT and MRI findings are generally sufficient to differentiate among these diagnoses. On CT and MRI, malignant gliomas typically show a more heterogeneous and mixed density pattern with generally more diffuse contrast enhancement than benign gliomas (44). A mass effect with peritumoral edema is also almost universal with malignant gliomas but is less frequent with benign gliomas. A surgical biopsy is essential for the definitive confirmation of the specific type of brain tumor present (88).

Diagnostic workup

Imaging studies. Head CT or MRI with and without contrast must be performed in all patients suspected of having a brain tumor. CT imaging has higher than 95% sensitivity for the detection of malignant gliomas. On CT, malignant gliomas typically appear as irregularly shaped lesions with partial contrast enhancement and peritumoral edema with or without mass effect (44). A peripheral, ring-like zone of contrast enhancement around a dark, central area of necrosis is more characteristic of glioblastoma multiforme than anaplastic astrocytoma. On T1-weighted MRI, the contrast-enhancing ring structure corresponds to the highly cellular and vascular region of the tumor. MRI is also useful by better demonstrating the anatomic origin and extent of tumor. MRI is the imaging modality of choice for detecting disseminated spinal cord lesions and should be performed in all patients with suspected supratentorial malignant gliomas. A postoperative MRI or CT is required to measure the extent of surgical resection and the detection of residual disease. Postoperative MRI or CT evaluation must be performed within 72 hours of surgery in order to delineate residual tumor from the postsurgical inflammatory changes that are visualized at this time. Exploratory studies using 2D and 3D FDG-PET imaging to estimate metabolically active tumor burden and its correlation with progression-free survival are currently underway (97).

CSF cytological examination. Lumbar puncture may be useful in malignant gliomas for the detection of microscopic leptomeningeal dissemination if clinically or radiographically suspected. CT imaging or MRI must be performed prior to the lumbar puncture to rule out the presence of hydrocephaly in those patients suspected of having a brain tumor. Hydrocephaly places the patient at risk for herniation as a consequence of the procedure. In general, the lumbar puncture is deferred for up to 2 weeks postoperatively in order to avoid identifying contaminating tumor cells that may have disseminated as a result of surgery.

Biopsy. Malignant gliomas are characterized by the histologic appearance described above and antigen markers of astrocytic or oligodendroglioma cell lineages and are distinguished from their benign counterparts by several histologic features of malignancy that include hypercellularity, cytologic and nuclear atypia, mitoses, necrosis, and endothelial proliferation.

Management

Surgery. Similar to adult malignant gliomas, gross total resection, when possible, prior to the initiation of radiotherapy or adjuvant chemotherapy, remains the most important prognostic factor for both progression-free survival and overall survival (08). The potential for radical resection depends primarily on tumor location. In 1 study, 49% of the tumors in the superficial hemisphere were amenable to radical resection, compared to only 8% of the tumors located in the deep or midline cerebrum (98). In addition, training of the neurosurgeon (pediatric vs. adult) had a significant impact on the extent of surgical resection for patients enrolled on this study. However, the benefit of radical surgery on survival should be weighed against the postoperative functional neurologic outcome (35).

Radiotherapy. Postoperative local (2 to 4 cm margin around the area of edema defined by imaging) or wide-field irradiation to 50 to 60 Gy is the mainstay of therapy for supratentorial malignant gliomas (40). The addition of radiation therapy results in improved 5-year survival rates (10% to 30%) compared to surgery alone (nearly 0%) (21; 09). All patients are, thus, considered candidates for radiotherapy following surgery, with the exception of very young children, usually 3 years and under, in whom attempts have been made to eliminate or delay the use of radiotherapy because of concern regarding neurodevelopmental morbidity. The benefit of hyperfractionated versus standard single-fraction radiotherapy for childhood malignant gliomas is uncertain. In a study, children received 50 Gy in 25 standard fractions or 3 to 40 Gy in 100 cGy hyperfractions every 3 hours to a daily dose of 400 cGy. Neither an improvement in survival nor toxicity was observed with the hyperfractionated schedule (46). However, in the SEER study data for pediatric glioblastoma patients, only 67% of patients in the study who are 4 years and older underwent radiation, which is lower than previously reported in the literature, which may reflect changing attitudes towards radiation therapy in this population due to the neurologic sequelae (49). Newer techniques, such as conformal radiation, stereotactic radiosurgery, and proton beam radiotherapy, which allow for higher doses of radiation delivered to the tumor bed while minimizing exposure to adjacent normal tissue, are currently under investigation. Combining radiation therapy with nimotuzumab, a radiation sensitizer, has shown encouraging results in clinical trials and may potentially change the treatment paradigm in pediatric glioblastoma (49).

Chemotherapy. Children with malignant gliomas appear to benefit from the addition of adjuvant chemotherapy to postoperative radiotherapy, although the extent of this benefit remains unclear. Early phase II and III trials with single-agent and multiagent chemotherapy demonstrated little or no impact on the overall survival, despite showing objective response rates as high as 45% (45).

A Children’s Cancer Group trial with prednisone, lomustine (CCNU), and vincristine following postoperative radiotherapy reported a 5-year progression-free survival of 46% versus 18% with radiotherapy alone (91). However, a subsequent trial comparing pCV to the “8-drugs-in-1-day” regimen showed no significant differences in survival between the 2 groups, and the progression-free survival associated with pCV (26%) was substantially inferior to that noted in the original study (23). Furthermore, review of the histology from the initial study with pCV suggested that a significant proportion of patients (69/250) did not fit the central consensus definition of malignant glioma. The Pediatric Oncology Group completed a study with adjuvant cisplatin and carmustine versus cyclophosphamide and vincristine following postoperative radiotherapy. The 5-year overall survival between the groups was 27% (± 9%) and 7% (± 7%) respectively.

Multiple trials utilizing neoadjuvant chemotherapy with a variety of regimens, including cisplatin and cytosine arabinoside; carboplatin, ifosfamide, or cyclophosphamide with etoposide; and procarbazine, have been uniformly disappointing (85). The report from the Children’s Oncology Group of a phase II trial (CCG 9933) randomizing between 3 separate high-dose chemotherapy regimens consisting of carboplatin/etoposide, ifosfamide/etoposide, or cyclophosphamide/etoposide prior to radiation failed to show any significant improvement in overall survival (24% +/- 5% at 5 years), and outcome did not differ between groups. The 5-year, event-free survival rate for all patients was 8% +/- 3% (55). In a report from the German study HIT-GBM-C utilizing radiation and simultaneous intensive multiagent chemotherapy, the 5-year overall survival rate for patients with complete resection was 63% +/- 12% SE, compared with 17% +/- 10% SE for the historical control group (P = .003), suggesting for the first time a therapeutic advantage with the addition of chemotherapy (101).

High-dose chemotherapy with autologous bone marrow or stem cell rescue has also been attempted in this population (22; 25; 32). In a study, objective responses were observed in 4 of 14 assessable patients treated with thiotepa and etoposide followed by autologous bone marrow rescue for malignant glioma (25). All of these patients (28%) remained free of disease at least 3 years after autologous bone marrow rescue. A study using carmustine, thiotepa, and etoposide followed by autologous bone marrow rescue for 11 patients with malignant glioma demonstrated a 46% 2-year survival rate (32). In a Children’s Oncology Group study, myeloablative chemotherapy with autologous marrow rescue produced durable remissions in children with recurrent malignant gliomas, in the setting of minimal residual tumor burden achieved surgically, and was superior to conventional chemotherapy (24).

Despite the promising response rates reported, the toxicity associated with these regimens has been excessively high (5% to 15% toxic death rate due to treatment). In an effort to reduce toxicity, investigations have used multiple cycles of somewhat lower doses of chemotherapy followed by peripheral blood stem cell support (39). To a great extent, this has decreased transplant-related complications; however, the data relating to the maintenance of treatment efficacy are still premature and the role of high-dose chemotherapy in the treatment of primary malignant gliomas remains undefined.

The alkylating agent temozolomide and biodegradable carmustine wafers impregnated with the alkylator carmustine for implantation into the surgical cavity have been FDA approved for the treatment of malignant glioma after having shown promising activity and providing longer progression-free survival in adults (12; 28). The use of temozolomide alone in pediatric patients has been less promising (48; 13). Because the use of concomitant radiation and temozolomide showed overall survival benefit in newly diagnosed adult glioblastoma patients (93), several studies have been done to see if the same results are seen in pediatric high-grade glioma but have thus far failed to demonstrate a benefit on overall survival (17; 15). Another trial by the Children's Oncology Group Phase II study of children with high grade gliomas showed that the addition of lomustine to temozolomide as adjuvant therapy improved outcome compared to patients treated with temozolomide alone (17; 38); however, the study lacked treatment randomization and there was substantial increase in hematologic toxicities (34).

An international phase 2 randomized controlled trial (HERBY) evaluated the use of concomitant and adjuvant temozolomide with/without bevacizumab (an anti-VEGF antibody) in pediatric high-grade glioma, with results showing that the addition of bevacizumab did not increase event-free survival and was associated with increased toxicity (31; 34). Currently, clinical trials are still underway to determine the most effective regimen.

Targeted therapy. Alternative treatment strategies have focused on specific biological markers that appear to play a role in malignant gliomagenesis. Of these targets, receptor tyrosine kinases, specifically epidermal growth factor receptor and platelet derived growth factor receptors, have been investigated. Both receptors are key regulator proteins involved in cell survival and proliferation. Erlotinib, an inhibitor against epidermal growth factor receptor (EGFR) had shown promise in adult malignant gliomas (76); however, it showed minimal effects after radiotherapy with 2-year progression free survival of 15 +/-7% and 19 +/-8% for anaplastic astrocytoma and glioblastoma, respectively (78). Imatinib, a platelet derived growth factor receptor inhibitor, also showed promise in adult patients; however, in pediatric patients event free survival at 12 months was 0% (75). Furthermore, increased hemorrhage has been noted in some of these patients suggesting possible toxicity. A report of the predominance of small, immature, unstable blood vessels in childhood malignant gliomas suggests a greater susceptibility to antiangiogenic therapy than previously believed (27). Although vascular endothelial growth factor receptor (VEGFR) appears to be involved in glioblastoma pathogenesis, specific inhibitors against VEGF such as bevacizumab have had minimal effect on progression free survival and overall survival (36; Narayan et al 2010; 65). The phase 2 HERBY trial did not show event-free survival or overall survival benefit; however, posthoc analyses have suggested that it may have a role in particular subtypes with MAPK pathway activation and/or enhanced CD8+ immune response (59). Targeted therapy towards integrins, involving specific proteins in cell adhesion and invasion, had shown promise in adult glioblastoma (19). However, phase I and phase II clinical trials with cilengitide, an integrin inhibitor, had minimal effect in relapsed pediatric malignant gliomas (56; 57).

Other biological-based clinical trials are also currently being investigated. Histone deacetylase inhibitors, such as valproic acid, are well tolerated and have an encouraging response rate in heavily pretreated patients (61). Other histone deacetylase inhibitors currently being investigated include vorinostat and panobinosat, as well as BET bromodomain inhibitors such as BMS-986158 (34).

Immunotherapy. One of the mechanisms of cancer cells’ proliferative growth is their ability to evade the body’s immune detection system. The advent of immunotherapy in the melanoma, lung, and other cancers has made a significant impact in the treatment of these cancers. It has been theorized that tumors with high mutational burden respond better to immunotherapy; however, pediatric cancers in general harbor a lower mutational burden. One of the few exceptions is the acquired hypermutator phenotype associated with constitutional mismatch repair deficiency, which is present in less than 5% of patients with high-grade glioma. Immune checkpoint inhibitors such as programmed cell death-1 receptor monoclonal antibody (nivolumab) have been shown to have a promising role in this subset and are being studied in children with newly diagnosed or recurrent high-grade glioma with and without ipilimumab, a human cytotoxic T-lymphocyte antigen (10).

Autologous dendritic cell vaccination has shown promise in adult glioblastoma and is currently undergoing clinical trials (02). This process involves isolating monocytes from patients, maturing them with cytokines into dendritic cells, loading dendritic cells with appropriate tumor antigens in vitro, and infusing them back into patients to activate their immune system. There are currently phase 1 and 2 trials with dendritic cell vaccines for children with newly diagnosed or relapsed high-grade glioma (34).

Viral infection directly into tumor cells such as Herpes simplex virus 1716 (29), cytomegalovirus-specific cytotoxic T cells (54), or parvovirus H-1 (41) are being investigated. New viruses being studied in pediatric gliomas are in the early phases, including recombinant polio/rhinovirus delivered by convection-enhanced delivery as well as an oncolytic adenovirus via intratumoral injection in diffuse intrinsic pontine gliomas. Intravenous reovirus as well as Newcastle disease virus are being evaluated. Other immunotherapies that are being studied for pediatric high-grade glioma include immunomodulatory agents such as thalidomide and pomalidomide. Chimeric antigen receptor T cells, which are T lymphocytes genetically engineered to target specific proteins with greater affinity, are currently in phase 1 trials, including children with recurrent high-grade glioma (34).

Finally, inhibitors against key survival pathways such as Akt and Notch signaling are also being investigated as potential therapeutic targets.

Tumor tumor fields. Tumor tumor fields are intermediate-frequency alternating current electric fields delivered to the tumor site via an array of electrodes applied directly to the scalp, acting as cytotoxic modalities by interfering with key components of cell division, specifically disrupting the spatial orientation of highly polarized molecules required for mitosis (04). The EF-14 trial showed that the addition of tumor tumor fields to standard of care adjuvant temozolomide following concurrent radiation and chemotherapy improved the 5-year overall survival in newly diagnosed glioblastoma patients (13% vs. 5%, p=.004) (92). In a feasibility study applying tumor tumor fields to 5 pediatric patients with high-grade glioma, all 5 patients tolerated tumor tumor fields well without treatment-limiting toxicities; hence a pediatric clinical trial is under way (30).

Special considerations

Pregnancy

It is advisable that women of childbearing age take measures to avoid pregnancy during treatment for supratentorial malignant gliomas, due to the known teratogenic effects of chemotherapy and radiotherapy. It is not known what the effects are on children conceived by men undergoing therapy for malignant glioma. There is a risk of sterility for both men and women following treatment for malignant glioma.

Anesthesia

In general, all types of anesthesia are safe and medication does not need to be changed or discontinued in anticipation of planned surgical procedure. However, it should be kept in mind that mental status and seizure threshold may be compromised by any anesthesia and or sedation medication administered to patients with supratentorial malignant gliomas.