High-grade gliomas in children and adolescents

INTRODUCTION — High-grade gliomas are infiltrative, malignant primary brain tumors most commonly occurring in the cerebral hemispheres and brainstem. Although uncommon in children compared with adults, high-grade gliomas account for a high percentage of childhood cancer mortality due to their dismal prognosis.

With improved molecular understanding of high-grade gliomas in children and adolescents, it is now recognized that these tumors are distinct entities with unique molecular drivers compared with their histologically similar equivalents in adults. Thus, the World Health Organization (WHO) classification of central nervous system (CNS) tumors recognizes pediatric-type diffuse high-grade gliomas as a unique category driven by unique molecular alterations and neoplastic drivers.

This topic will review the epidemiology, clinical features, diagnosis, and management of pediatric-type diffuse high-grade gliomas including histone 3 (H3) G34-mutant diffuse hemispheric gliomas and isocitrate dehydrogenase (IDH)-wildtype high-grade gliomas. H3 K27-altered diffuse midline gliomas, infant-type high-grade gliomas, and IDH-mutant high-grade gliomas also occur in the pediatric population but are discussed in separate topics:

●(See "Diffuse intrinsic pontine glioma".)

●(See "Infant-type hemispheric gliomas".)

●(See "Treatment and prognosis of IDH-mutant astrocytomas in adults".)

●(See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults".)

EPIDEMIOLOGY — Brain tumors are the second most common childhood cancer but account for the highest mortality among cancer types. High-grade gliomas in children and adolescents (age 1 to 19 years) make up 9 percent of pediatric brain tumors but account for over 40 percent of brain tumor mortality [1].

The incidence of high-grade glioma varies by age group and is further defined by molecular type and location. The highest incidence is in the 5-to-9-year age group; the majority of these are midline tumors, often in the brainstem. Incidence is equal in males and females without a strong preference in race or ethnicity [1].

Histone 3 (H3) G34-mutated diffuse astrocytomas account for 5 to 15 percent of pediatric diffuse high-grade gliomas and are enriched in the adolescent population, with a median age at diagnosis of 15 to 17 years. Such tumors are rare in adults, making up 1 to 2 percent of adult high-grade gliomas and primarily affecting young adults in the third decade of life. There appears to be a slight male predominance [2].

Histone- and isocitrate dehydrogenase (IDH)-wildtype diffuse high-grade gliomas compose the largest subgroup in children, accounting for approximately 40 percent of all pediatric high-grade gliomas. Age range is wide and encompasses pediatric patients of all ages with no clear sex predilection. (See "Epidemiology and classification of central nervous system tumors in children".)

RISK FACTORS — There are few known risk factors for high-grade gliomas in children.

●Ionizing radiation – The only environmental factor known to be associated with high-grade glioma is exposure to ionizing radiation. Prior radiation exposure is most commonly related to cranial irradiation for acute lymphoblastic leukemia or a primary brain tumor (eg, medulloblastoma) in early childhood. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Brain tumors' and "Risk factors for brain tumors", section on 'Ionizing radiation'.)

●Genetic predisposition syndromes – Several tumor or cancer predisposition syndromes are associated with increased incidence of central nervous system (CNS) tumors in the pediatric and adolescent age range. In those diagnosed with pediatric high-grade gliomas, up to 14 percent are found to have an underlying genetic syndrome, and this number increases when histone mutated high-grade gliomas are excluded [3,4]. For high-grade gliomas in children, the most important syndromes include:

•Li-Fraumeni syndrome (LFS) – LFS is an autosomal dominant disorder caused by a germline pathogenic variant in the tumor suppressor gene, tumor protein p53 (TP53). LFS is associated with a wide range of brain tumors, including choroid plexus carcinoma in infants, medulloblastoma in children, and high-grade glioma in children and adults. The overall prevalence of CNS tumors in individuals with LFS is 9 to 14 percent, with most occurring in childhood [5]. (See "Li-Fraumeni syndrome".)

Most LFS-associated high-grade gliomas in children are histone 3 (H3)- and isocitrate dehydrogenase (IDH)-wildtype [6,7]. IDH-mutant astrocytomas, in particular those associated with IDH1 R132C, occur mostly in young adults. (See "Risk factors for brain tumors", section on 'Li-Fraumeni syndrome'.)

•Neurofibromatosis type 1 (NF1) – NF1 is most often associated with low-grade gliomas (eg, pilocytic astrocytoma), but high-grade gliomas in childhood also occur. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Other central nervous system neoplasms'.)

•Mismatch repair deficiency – Mismatch repair deficiency syndromes including Lynch syndrome and constitutional mismatch repair deficiency (CMMR-D) are associated with increased risk of high-grade gliomas, which can manifest in children and adolescents. This is an important pathologic distinction to recognize as there are therapeutic implications for this small percentage of high-grade gliomas [5,8]. (See "Risk factors for brain tumors", section on 'Mismatch repair deficiency' and 'Patients with mismatch repair deficiency' below.)

PATHOLOGY — The 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System recognizes four pediatric-type diffuse high-grade gliomas, defined by their histone and isocitrate dehydrogenase (IDH) status, age, and location (table 1) [9]:

●Diffuse midline glioma, histone 3 (H3) K27-altered, discussed separately (see "Diffuse intrinsic pontine glioma")

●Diffuse hemispheric glioma, H3 G34-mutant

●Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

●Infant-type hemispheric glioma (see "Infant-type hemispheric gliomas")

The histopathologic appearance of high-grade gliomas in children is not distinct, and separate molecular entities can overlap microscopically. Molecular testing is therefore key to accurate diagnosis. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Key molecular diagnostic tests'.)

Diffuse hemispheric glioma, H3 G34-mutant — H3 G34-mutant tumors are grade 4 tumors (regardless of histology) with variable histologic characteristics [10-12]. They may resemble anaplastic astrocytoma, glioblastoma, or central nervous system (CNS) embryonal tumor [10].

Over 90 percent are associated with co-occurring TP53 and ATRX chromatin remodeler (ATRX) mutations, and O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter methylation is present in over half of the cases. A subset have additional activating mutations in platelet-derived growth factor receptor A (PDGFRA) or alterations in the cyclin-dependent kinase 4/6 (CDK4/6) pathway [12].

Missense variants in the H3F3A gene can result in G34R or G34V mutations, which can be detected by sequencing or mutant-specific immunohistochemistry. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'H3 G34 mutation'.)

Diffuse high-grade glioma, H3-wildtype and IDH-wildtype — Diffuse pediatric-type high-grade gliomas without IDH or histone mutations are WHO grade 4 tumors that are distinct from IDH-wildtype glioblastomas in adults. With tumor DNA methylation and integrated molecular testing, these tumors are further subclassified into three high-grade glioma (HGG) groups defined by either methylome profiling or key molecular alterations including MYCN, PDGFRA, and epidermal growth factor receptor (EGFR) [9,13].

●HGG-MYCN – HGG-MYCN subgroup tumors are enriched with MYCN amplification as well as TP53 mutations. A majority of HGG-MYCN tumors with somatic TP53 mutations appear to be associated with a germline TP53 pathogenic variant, indicative of Li-Fraumeni syndrome (LFS) [13,14].

●HGG-RTK1 – HGG-RTK1 subgroup tumors often have PDGFRA alterations. HGG-RTK1 is the most common subgroup associated with radiation-induced gliomas as well as those associated with underlying genetic conditions [15].

●HGG-RTK2 – HGG-RTK2 is the least common of the three and is often enriched with EGFR mutations. These tumors tend to have a better prognosis compared with other subgroups. (See 'Prognosis' below.)

Molecular heterogeneity — Pediatric high-grade gliomas are molecularly diverse, and an understanding of molecular heterogeneity among existing WHO-defined tumors continues to evolve. Further work is needed to guide treatment and prognosis. Whenever possible, tumor specimens should undergo broad molecular characterization at the time of diagnosis. While most pediatric high-grade gliomas do not have known targetable mutations, a small number have alterations for which targeted therapy is available or clinical trials are in progress. (See 'Recurrence/progression' below.)

CLINICAL FEATURES

Signs and symptoms — Presenting signs and symptoms of high-grade gliomas in children and adolescents are similar to those of other pediatric brain tumors and depend on location of the tumor and age of the patient. In a meta-analysis of presenting symptoms in pediatric brain tumors, tumor location was the most relevant factor in predicting presenting signs [16]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Common presenting signs and symptoms'.)

High-grade gliomas are aggressive tumors, and initial symptoms typically evolve acutely or subacutely over days to weeks. Headaches, vomiting, fatigue, and seizures are common presentations of all brain tumors in children. For supratentorial hemispheric high-grade tumors, patients may present with nonspecific symptoms of increased intracranial pressure (ICP; eg, headache, nausea, vomiting, blurred vision) or with focal symptoms such as seizures and focal neurologic signs. Brainstem high-grade tumors usually present with coordination/balance issues, cranial nerve palsies, weakness, and headaches [16]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

Tumor location — Most histone 3 (H3) G34-mutant high-grade gliomas occur in the cerebral hemispheres and are localized at presentation. Approximately 10 percent of patients present with metastatic disease, and the most common pattern is leptomeningeal spread [2].

H3- and isocitrate dehydrogenase (IDH)-wildtype high-grade gliomas can be located throughout the central nervous system (CNS), with up to 15 percent occurring infratentorially in the cerebellum or brainstem. Similar to H3 G34-mutant tumors, 90 percent occur locally as a single lesion, but leptomeningeal spread can be seen [13].

Neuroimaging — While head computed tomography (CT) is often obtained first for practical reasons, brain magnetic resonance imaging (MRI) with and without contrast is the preferred imaging modality for all brain tumors.

On MRI, supratentorial high-grade gliomas are typically large, infiltrative tumors with T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity, surrounding vasogenic edema and mass effect, and heterogenous contrast enhancement (image 1). T2/FLAIR sequences demonstrate indistinct tumor borders and an infiltrative growth pattern, which may involve spread through the corpus callosum. Due to high cellularity and high nuclear-to-cytoplasm ratio, diffusion-weighted images (DWI) often show restricted diffusion within the tumor. H3 G34-mutant and H3/IDH-wildtype high-grade gliomas have a similar appearance on MRI (image 2) and do not have defining radiographic features that allow them to be distinguished from one another [17].

Perfusion-weighted imaging can aid in differentiating infiltrative tumor from surrounding edema due to the increased microvascular proliferation seen in high-grade gliomas. Magnetic resonance spectroscopy (MRS) in high-grade gliomas typically shows some combination of increased choline-to-creatine ratio, increased N-acetylaspartate (NAA), decreased choline, and a lactate peak. MRS can also be useful in the recurrent and follow-up setting to help differentiate between residual/recurrent tumor and radiation-induced changes [17,18]. (See 'Response assessment' below.)

DIAGNOSIS — High-grade glioma is suspected based on an enhancing mass lesion on MRI and must be confirmed histopathologically with biopsy, typically obtained at the time of attempted resection.

Differential diagnosis — The radiographic differential diagnosis of an enhancing mass lesion on MRI in children and adolescents includes both neoplastic and nonneoplastic etiologies.

Among enhancing infiltrative brain tumors in the cerebral hemispheres in children, high-grade glioma is the most common etiology; other less common neoplastic etiologies with overlapping imaging features, location, and age group include high-grade glioneuronal tumors, circumscribed astrocytic gliomas such as pleomorphic xanthoastrocytoma or astroblastoma, choroid plexus carcinoma and supratentorial ependymoma, and embryonal tumors such as atypical teratoid/rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and high-grade neuroepithelial tumors (HGNET). Biopsy is ultimately required to distinguish among these. (See "Uncommon brain tumors".)

In the brainstem, histone 3 (H3)/isocitrate dehydrogenase (IDH)-wildtype high-grade gliomas and diffuse midline glioma/diffuse intrinsic pontine glioma have a similar appearance and are distinguished by the presence or absence of an H3 K27 molecular alteration on biopsy. (See "Diffuse intrinsic pontine glioma".)

Nonneoplastic mimics of high-grade glioma in children and adolescents are similar to those seen in adults, including intraparenchymal hemorrhage, venous or arterial ischemic infarction, vascular malformation, abscess, and inflammatory processes such as tumefactive multiple sclerosis and other demyelinating disorders. Differentiating features are discussed in more detail separately. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis'.)

Extent of disease evaluation — Brain MRI with and without contrast should be obtained in all patients with suspected high-grade glioma. We obtain advanced sequences, including perfusion-weighted imaging, whenever possible, and we obtain magnetic resonance spectroscopy (MRS) selectively when there is diagnostic uncertainty. (See 'Neuroimaging' above.)

Patients with suspected high-grade glioma should also undergo spine MRI with and without contrast to evaluate the full craniospinal axis, even those who do not have signs or symptoms suggesting spinal disease [19]. Although disseminated disease at the time of diagnosis is uncommon in pediatric high-grade glioma, it does occur in high-grade glioma and, more commonly, with other neoplasms on the differential diagnosis. If spine MRI is not obtained preoperatively, postoperative spine MRI for staging is typically delayed for two to three weeks to allow for postoperative changes to resolve.

Lumbar puncture for cerebrospinal fluid (CSF) cytology is generally not recommended for high-grade gliomas for staging unless there is clinical or radiographic concern for dissemination or an alternative diagnosis. If lumbar puncture is performed, it should be delayed at least 10 to 14 days after definitive surgery to allow for resolution of postoperative changes.

Systemic imaging and staging is not necessary, as metastases outside of the central nervous system (CNS) are exceedingly rare at diagnosis.

Surgery — Surgery is essential in nearly all childhood and adolescent brain tumors for tissue diagnosis and molecular classification, relief of increased intracranial pressure, and cytoreduction. The type of surgery (biopsy versus resection) is dependent on the location of the tumor, structures involved, and infiltrative and invasive nature of the tumor.

For all supratentorial, hemispheric, and non-brainstem infratentorial tumors with imaging features concerning for high-grade glioma, we recommend maximal safe resection, with the goal of gross total resection. Midline tumors are not meaningfully resectable in most cases, but a biopsy is usually feasible and provides important diagnostic confirmation.

Extent of resection is guided by tumor location and may be limited by eloquent cortex to avoid severe neurologic disability (motor and speech in particular). Advanced neurosurgical techniques, including intraoperative MRI and pre-operative planning with diffusion tensor imaging (DTI), are available to improve the extent of resection while maintaining neurologic outcomes and function [20,21]. Children should be referred to a tertiary care center with pediatric oncologic neurosurgical expertise whenever possible. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Intraoperative techniques'.)

While overall prognosis for high-grade glioma is poor, extent of resection is one of the few variables consistently associated with improved progression-free and overall survival [22,23]. In a meta-analysis of 37 observational studies including 1387 patients with pediatric high-grade glioma, gross total resection was associated with improved survival compared with subtotal resection at one year (hazard ratio [HR] 0.69, 95% CI 0.56-0.83) and two years (HR 0.74, 95% CI 0.67-0.83) [23]. Within the same study, an individual patient data meta-analysis of 427 patients that allowed for multivariable regression and subgroup analysis by tumor location found that gross total resection was associated with prolonged survival for both hemispheric high-grade gliomas (HR 0.29, 95% CI 0.15-0.54) and infratentorial high-grade gliomas (HR 0.44, 95% CI 0.24-0.83).

More extensive data supporting maximal safe resection in adults with high-grade glioma are reviewed separately. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Extent of resection'.)

MANAGEMENT

Initial treatment — Treatment of pediatric high-grade gliomas other than diffuse midline glioma has historically been modeled after adult high-grade gliomas and typically includes both focal radiation therapy and chemotherapy, with selection of a specific agent or agents guided by a small number of randomized trials in children with high-grade glioma and indirect evidence from randomized trials in adults with high-grade glioma. Radiation therapy is typically withheld for patients three years of age or younger due to concerns of toxicity on the developing brain, although it can be considered with a focal field in those older than one year.

With increasing recognition of the molecular heterogeneity of pediatric high-grade gliomas and their unique alterations compared with adult diffuse gliomas, clinical trials are focused on molecular diagnosis and stratification to identify effective therapies in molecularly homogeneous patient populations. In the meantime, outside of clinical trials, focal radiation therapy with or without chemotherapy remains the standard of care for all but the youngest patients.

Patients >3 years old — For most patients >3 years of age with a newly diagnosed high-grade glioma (either hemispheric histone 3 [H3] G34-mutant or H3/isocitrate dehydrogenase [IDH]-wildtype), we suggest involved field radiation plus chemotherapy rather than radiation alone. Outside of a clinical trial, temozolomide (concurrent and adjuvant) plus lomustine (adjuvant) is the most used regimen based on the trials reviewed below.

●Radiation – Radiation therapy for high-grade glioma should begin within four to eight weeks of surgery [19]. Involved field radiation therapy to a dose of 54 to 60 Gy in daily fractions of 1.8 to 2 Gy is the standard approach for high-grade gliomas in both children and adults, targeting the postoperative tumor volume plus a margin of radiographically appearing normal tissue [24,25]. In uncommon patients with leptomeningeal spread of disease at diagnosis, we typically use craniospinal irradiation (23 to 36 Gy) with a targeted tumor boost to 59 to 60 Gy.

Three-dimensional conformal radiation and intensity-modulated radiation therapy (IMRT) are the most common methods of planning and delivery for high-grade gliomas. Proton radiation and IMRT are prioritized for craniospinal irradiation. (See "Radiation therapy for high-grade gliomas", section on 'Planning and delivery methods'.)

Trials of hyperfractionated radiation therapy to higher doses (eg, 78 Gy), mostly in the diffuse midline glioma group, have shown increased radiation-related complications without evidence of a benefit on overall survival [26,27]. Hypofractionated courses, particularly in diffuse midline gliomas (eg, 39 Gy in 13 fractions), can be considered given the palliative nature of radiation in these cases to limit time in treatment and improve quality of life. The role of hypofractionated radiation in hemispheric tumors is less clear, however.

●Chemotherapy – For most patients, we suggest use of concurrent temozolomide during radiation therapy followed by adjuvant temozolomide and lomustine. Use of this regimen is supported by the phase II Children's Oncology Group (COG) ACNS0423 trial, in which 108 patients age 3 to 21 years (median 12 years) with high-grade glioma were treated with focal radiation therapy with concurrent daily temozolomide (90 mg/m²/day) followed by up to six cycles of adjuvant chemotherapy (lomustine 90 mg/m² on day 1 and temozolomide 160 mg/m² on days 1 to 5, repeated every 42 days or when counts recovered) [24]. One-year event-free and overall survival were 49 and 72 percent, respectively; at three years, event-free and overall survival were 22 and 28 percent. These results were improved compared with the historical reference cohort of patients treated with radiation plus concurrent daily and adjuvant temozolomide, without lomustine, on the ACNS0126 trial [28]. The most common grade 3/4 toxicities during concurrent radiation and temozolomide were lymphopenia (19 percent) and thrombocytopenia (14 percent) [24]. Hematologic toxicity was common during adjuvant chemotherapy, with grade 3/4 neutropenia in 63 percent and thrombocytopenia in 52 percent.

Although these results are supportive of this regimen, overall benefit remains modest, and cross-trial comparisons are difficult due to changes in tumor classification over the decades as well as improvements in neurosurgical and supportive care. An early cooperative group randomized trial (CCG-943) did show an improvement in overall survival with focal radiation plus multiagent chemotherapy compared with radiation alone, but these data have been challenged by central pathology review showing that many patients had low-grade gliomas, rather than high-grade gliomas [29].

Several other regimens have been studied in cooperative group, mostly single-arm studies but do not have clear advantages over temozolomide with or without lomustine; these include prednisone-lomustine-vincristine [30], cisplatin-based regimens [31,32], high-dose methotrexate [33], and temozolomide plus bevacizumab [34].

Ongoing and completed trials are examining targeted agents and/or incorporating molecular diagnosis into stratification and targeted therapy options to improve outcomes. In some cases, data in the recurrent setting provide rationale for use in the upfront setting, as an alternative to traditional chemotherapy. (See 'Recurrence/progression' below.)

Patients 1 to 3 years old — Pediatric-type diffuse high-grade gliomas are rare in the under-three-year-old age group and pose treatment challenges. Complete molecular, ribonucleic acid (RNA) sequencing, and DNA methylation profiling should be prioritized, as a high percentage of high-grade gliomas in this age group will have targetable fusions (eg, NTRK, ALK, ROS1) and/or classify as infant-type hemispheric gliomas or low-grade gliomas. Treatment approach and prognosis of these tumors significantly differ from those of pediatric-type high-grade glioma, highlighting the importance of integrated diagnosis [35]. (See "Infant-type hemispheric gliomas".)

In those with confirmed pediatric-type H3/IDH-wildtype high-grade glioma, no standard-of-care treatment plan exists. Multimodal chemotherapy including platinum and alkylating agents with or without high-dose methotrexate has been used to delay radiation [35,36]. Focal radiation should be considered in consultation with a pediatric radiation oncologist in patients over the age of one year before or after multiagent chemotherapy.

Similar to older children, if a targetable mutation is found, small molecular inhibitors and targeted therapy should be considered along with clinical trial enrollment.

BRAF V600E-mutant tumors — In the small percentage of pediatric high-grade gliomas with a BRAF V600E mutation, we suggest targeted therapy with BRAF/mitogen-activated protein kinase kinase (MEK) inhibition (eg, dabrafenib plus trametinib) as adjuvant therapy after radiation, rather than chemotherapy. Although the two have not been compared directly, BRAF/MEK inhibitors are active in recurrent BRAF V600E-mutant high-grade gliomas in children, and their use in the adjuvant setting is a rational strategy based on experience in other cancer types. However, upfront data are not yet available, and reserving use of BRAF/MEK inhibition until recurrence is a reasonable alternative. Clinical trial participation is encouraged.

The optimal duration of targeted therapy in the adjuvant setting is not known; we typically treat for up to two years, depending on tumor response and tolerability.

This approach is supported by results of a phase II trial of dabrafenib plus trametinib in 41 pediatric patients with previously treated BRAF V600E-mutated high-grade glioma [37]. With a median follow-up of 25 months, the overall objective response rate was 56 percent (median duration of response, 22 months), and median overall survival was 32.8 months (95% CI, 19.2 months to not reached). The most common adverse effects were pyrexia (51 percent), headache (34 percent), and dry skin (32 percent). The rate of treatment discontinuation due to adverse effects was low (5 percent, in both cases due to rash).

Patients with mismatch repair deficiency — A small percentage of pediatric high-grade gliomas, typically associated with underlying germline mismatch repair deficiency, have a unique molecular profile with high mutational burden and/or a mutation in a mismatch repair enzyme. Such patients may have increased levels of chemoresistance because alkylating agents require a functional mismatch repair system to achieve cancer cell damage [38]. In addition, there are case reports of impressive and durable responses to checkpoint inhibitors in these patients [8,39-41].

Additional studies are needed, and optimal upfront treatment is uncertain. As in other patients, maximal safe resection and focal radiation are considered standard therapies, but the benefit of temozolomide and/or lomustine is less certain. When mismatch repair deficiency is known at the time of initial diagnosis, we generally withhold alkylating agent chemotherapy and instead use anti-programmed cell death 1 (PD1) therapy (eg, pembrolizumab, nivolumab) as adjuvant therapy after completion of radiation therapy [19].

If anti-PD1 therapy is not available or preferred as upfront therapy, use of pembrolizumab in the recurrent/progressive setting falls under tissue-agnostic approval from the US Food and Drug Administration (FDA) for children and adults with mismatch repair deficient solid tumors that have progressed following standard therapy [42]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Response assessment — Brain MRI should be obtained approximately 4 to 6 weeks after completion of radiation and then every 8 to 12 weeks for the first two years. Similar to adults with diffuse high-grade gliomas, children are at risk for pseudoprogression and radiation necrosis that can mimic early progression in the months following completion of radiation therapy. If there is concern for early progression versus pseudoprogression, we obtain more frequent imaging and/or advanced imaging such as perfusion and magnetic resonance spectroscopy (MRS) to help differentiate. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)

Recurrence/progression — Event-free survival is often less than one year despite initial multimodality therapy, and more effective therapies are needed. In a meta-analysis of 17 nonrandomized studies in 129 pediatric patients with high-grade glioma treated between 1996 and 2016, median overall survival from the time of first recurrence or progression was only 5.6 months [43]. Survival was shortest in the subgroup of patients who received traditional chemotherapy (4.0 months) and was somewhat longer with immunotherapy (6.9 months), targeted therapy (9.3 months), and repeat radiotherapy (14 months). Bevacizumab, while not shown to affect overall survival in the recurrent setting [34], is beneficial for symptom control and radiation necrosis [44].

Given these data, all therapies at recurrence are considered palliative, and treatment decisions are individualized. Where possible and when patients and families/caregivers are interested, clinical trial participation is encouraged. Ongoing trials in pediatric high-grade glioma are examining immunotherapy, including programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) monoclonal antibodies and chimeric antigen receptor T (CAR-T) cells targeting the central nervous system (CNS), targeted agents such as small molecule inhibitors, and tumor treating fields (TTFields).

Molecular alterations with targeted agents can help drive treatment decisions. As examples:

●BRAF V600E-mutant tumors – Patients with BRAF V600E-mutant tumors who did not receive targeted therapy at the time of initial diagnosis may be treated with BRAF/MEK inhibition (eg, dabrafenib plus trametinib) at recurrence. (See 'BRAF V600E-mutant tumors' above.)

●High tumor mutational burden – For tumors with high mutational burden, use of a checkpoint inhibitor is a reasonable strategy. (See 'Patients with mismatch repair deficiency' above.)

●Fusion-positive tumors – Although less common than in infant-type hemispheric glioma, fusion-positive (eg, NTRK, ALK, ROS1) high-grade gliomas in children are good candidates for targeted therapy including entrectinib and lorlatinib, which are being explored in clinical trials [35,45]. Both have regulatory approval in the United States for use in NTRK fusion-positive solid tumors. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Use in patients with central nervous system tumors'.)

●Other alterations – There are ongoing pediatric studies examining the role of epidermal growth factor receptor (EGFR) inhibitors, platelet-derived growth factor receptor A (PDGFRA) inhibitors, and immunotherapy in patients with high-grade gliomas with specific molecular profiles. A searchable database of clinical trials is available through the United States National Library of Medicine.

Absent a targetable molecular alteration or clinical trial option, reirradiation can be used in selected patients, depending on the timing and location of recurrence and original field of radiation [46-48]. In our practice, we consider reirradiation to be an option when it has been at least 9 to 12 months after the initial course of radiation and the recurrence is local, within the original field of radiation. For distant recurrences, reirradiation can be considered earlier in discussion with the treating radiation oncologist.

We use bevacizumab selectively in patients who are steroid-dependent and/or have ongoing symptoms from tumor progression, edema, or radiation necrosis. The goal of bevacizumab in these settings is to improve quality of life through reduction in cerebral edema and weaning of steroids [34,44].

Role of germline genetic testing — Germline genetic testing should be considered for all pediatric patients with high-grade glioma. Patients with a strong family history of cancer should be referred for genetic counseling and evaluation for specific germline testing depending on tumor classification and pedigree. We also refer patients with somatic (tumor) molecular alterations associated with known genetic syndromes, including TP53 mutation, mismatch repair deficiency, and neurofibromin 1 (NF1) mutations. (See 'Risk factors' above.)

PROGNOSIS — Unfortunately, despite ongoing efforts to improve outcomes with new and targeted treatment modalities, long-term survival in patients with childhood high-grade glioma remains dismal. Median overall survival is approximately 18 months, and five-year overall survival ranges from 15 to 35 percent across multiple cohorts and historical studies [24,28,30-34,49,50]. Median survival from the time of first recurrence is less than six months [43].

Certain molecular markers have prognostic significance. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, mostly studied in adult high-grade gliomas, has shown a trend towards improved survival and response to alkylating chemotherapy in small pediatric high-grade glioma cohorts [51]. Histone 3 (H3) 34R-mutated hemispheric gliomas tend to show improved survival compared with wildtype high-grade gliomas in children, although this is at least partially confounded by high levels of MGMT methylation in H3 G34R-mutated tumors [2].

Among wildtype diffuse high-grade gliomas, the RTK2 subgroup has the best prognosis (median overall survival approximately 44 months), followed by RTK1 tumors (approximately 21 months) and MYCN tumors (approximately 14 months) [9].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Brain cancer (The Basics)" and "Patient education: What are clinical trials? (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors – Approximately 15 percent of high-grade gliomas in children are associated with a genetic cancer predisposition syndrome, such as Li-Fraumeni syndrome, neurofibromatosis type 1, or Lynch syndrome/constitutional mismatch repair deficiency. Ionizing radiation is the only known risk factor for sporadic tumors. (See 'Risk factors' above.)

●Pathology – The 2021 World Health Organization (WHO) classification recognizes four pediatric-type diffuse high-grade gliomas, defined by their histone 3 (H3) and isocitrate dehydrogenase (IDH) status, age, and location (table 1). (See 'Pathology' above.)

The histopathologic appearance of high-grade gliomas in children is not distinct, and separate molecular entities can overlap microscopically. Molecular testing is therefore key to accurate diagnosis. (See 'Diffuse hemispheric glioma, H3 G34-mutant' above and 'Diffuse high-grade glioma, H3-wildtype and IDH-wildtype' above.)

●Clinical manifestations – High-grade gliomas are aggressive tumors, and initial symptoms typically evolve acutely or subacutely over days to weeks. Headaches, vomiting, fatigue, and seizures are common presentations of all brain tumors in children. (See 'Clinical features' above.)

●Diagnosis – High-grade glioma is suspected based on an enhancing mass lesion on MRI (image 1 and image 2) and must be confirmed histopathologically with biopsy, typically obtained at the time of attempted resection. (See 'Diagnosis' above.)

Patients with suspected high-grade glioma on brain MRI should also undergo spine MRI with and without contrast to evaluate the full craniospinal axis. (See 'Extent of disease evaluation' above.)

●Management

•Surgery – For all supratentorial, hemispheric, and non-brainstem infratentorial tumors with imaging features concerning for high-grade glioma, we recommend maximal safe resection rather than biopsy (Grade 1B). Gross total resection, when feasible, is a strong prognostic factor for improved survival in both children and adults. Children should be referred to a tertiary care center with pediatric oncologic neurosurgical expertise whenever possible. (See 'Surgery' above.)

•Postoperative therapy – For most patients >3 years of age with a newly diagnosed high-grade glioma (either hemispheric H3 G34-mutant or H3/IDH-wildtype), we suggest involved field radiation plus chemotherapy rather than radiation alone (Grade 2C). Outside of a clinical trial, temozolomide (concurrent and adjuvant) plus lomustine (adjuvant) is the most used regimen (see 'Patients >3 years old' above). Exceptions include the following:

-For patients with a BRAF V600E-mutant high-grade glioma, we suggest dabrafenib plus trametinib after completion of radiation therapy, rather than chemotherapy (Grade 2C). (See 'BRAF V600E-mutant tumors' above.)

-For patients with known germline mismatch repair deficiency, we suggest anti-programmed cell death 1 (PD1) therapy (eg, pembrolizumab, nivolumab) after completion of radiation therapy, rather than chemotherapy (Grade 2C). (See 'Patients with mismatch repair deficiency' above.)

-For most younger children (1 to 3 years), we suggest multiagent chemotherapy that includes a platinum and an alkylating agent (Grade 2C). Focal radiation should be considered in consultation with a pediatric radiation oncologist in patients over the age of one year before or after multiagent chemotherapy. (See 'Patients 1 to 3 years old' above.)

•Recurrence/progression – Rational targeted therapies are available for a small subset of patients whose tumors harbor certain molecular alterations (eg, BRAF V600E). Where possible and when patients and families/caregivers are interested, clinical trial participation is encouraged. (See 'Recurrence/progression' above.)

●Prognosis – Long-term survival in patients with childhood high-grade glioma remains dismal. Median overall survival is approximately 18 months, and five-year overall survival ranges from 15 to 35 percent. (See 'Prognosis' above.)