Brain tumors are the most common solid neoplasms and the main cause of death from cancer in children.1-3 Tumors of the central nervous system (CNS) represent 20% of childhood cancers and are second only to leukemia in frequency.4
The age-adjusted average annual incidence of brain tumors in children in the United States is 5.65 cases per 100,000 population, with 0.72 deaths per 100,000 (neonates to age 14).3
Recent diagnostic and therapeutic advances have led to improved survival and quality of life for many children with CNS cancers. However, the prognosis for many children with brain tumors remains poor, and treatments leave long-term consequences.2,5
This review highlights recent changes in the classification and management of brain tumors in children. Given the large number of such tumors and the complexity of new classification schemes, only the most common and representative types are discussed here.
| Classification of brain tumors in children |
The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS5), published in 2021, introduced important changes to the taxonomy of brain tumors, emphasizing molecular diagnostic features.6
This has created a hybrid nomenclature of conventional classifications with molecular biomarkers based on histological, ultrastructural and immunohistochemical features. These changes are extensive and to non-specialists (and specialists) may seem like a simple name change, but they reflect the trend of assigning diagnostic categories based on genetic characteristics that in many cases drive prognosis and offer potential targets for treatment.
The new system has introduced 22 unique tumor types , many of which include specific molecular alterations. Some names are difficult to handle, such as “pediatric diffuse high-grade glioma, H3 wild type AND IDH wild type” and “desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant.”
Molecular profiling is not widely available in developing countries, and even in the United States, exome and genome sequencing can take weeks and treatment may need to be initiated before a molecular diagnosis is established.7 There is also a gap between the perspective of understanding the genesis and behavior of brain tumors in children and the application of this new knowledge in clinical practice.
| Gliomas |
> Pediatric diffuse low-grade gliomas
Low-grade gliomas are the most common brain tumors in childhood and represent a third of all cases if mixed glioneuronal and neuronal tumors are included.8
This group of tumors is heterogeneous; Unlike low-grade gliomas in adults, low-grade gliomas in children rarely transform into higher-grade tumors.9 IDH1 or IDH2 mutations common in low-grade gliomas in adults, which develop into higher-grade tumors grade, are much less frequent in children.10
The initial treatment for most low-grade gliomas in children is surgery to establish a tissue diagnosis and achieve maximum safe resection. In a large international study, the 5-year progression-free survival of children with low-grade gliomas was 69%, and overall survival was 95%.11 Risk factors for progression were younger age, incomplete resection, fibrillar histological characteristics and hypothalamic or chiasmatic location.
Macroscopic total resection of low-grade gliomas in children is often not possible, particularly those located deep in the midline. Many of these tumors are indolent, and observation with follow-up brain imaging is sometimes an option.
Radiotherapy is effective for the treatment of recurrent or residual low-grade gliomas, with 5-year progression-free survival of 71% and overall survival of 93%.12 Children at risk of tumor progression based on age, location Anatomical and genetic characteristics are often treated with adjuvant chemotherapy because of concerns about the neurotoxic effects of radiation on the developing brain.10 Chemotherapeutic agents that have been shown to be effective, either alone or in combination, include vincristine, carboplatin , vinblastine, 6-thioguanine, procarbazine, lomustine, cisplatin, etoposide and irinotecan.8,13,14
Multiagent chemotherapy has been evaluated in a trial that compared carboplatin and vincristine with 6-thioguanine, procarbazine, lomustine, and vincristine. Event-free survival was similar in the two chemotherapy groups and was similar to or superior to event-free survival with radiotherapy.15 Tumors in both chemotherapy groups progressed within 5 years, but the four-agent regimen was associated with greater toxic effects.
The role of the alkylating agent temozolomide is less clear in childhood low-grade gliomas than in adult gliomas, for which it is widely used.8 The drug stabilized the disease in children with recurrent low-grade gliomas in a phase-in trial. 2, although progression-free survival was only 17% at 4 years, and 70% of patients required other treatments after temozolomide.16 In another phase 2 trial involving children with recurrent low-grade gliomas , temozolomide was ineffective.17
Molecular alterations have been targeted by drugs that may be more effective and less toxic than conventional chemotherapy.18 Alterations in the downstream signaling pathway of the rat sarcoma virus mitogen-activated protein kinase (MAPK) pathway ) have generated considerable attention. This pathway sends information from the cell surface to modulate gene expression for various cellular functions, including
growth. Most low-grade gliomas have one or more alterations in the MAPK pathway, including BRAF oncogene mutation or fusion, NF1 mutation , fibroblast growth factor receptor 1 mutation, and neurotrophic tyrosine receptor family fusions. kinase ( NTRK ).19,20
Somatic alterations of BRAF or germline alterations of NF1 may play a role in tumorigenesis.9 Some low-grade gliomas have alterations in BRAF , which encodes a protein serine-threonine kinase (BRAF), a downstream regulator of the MAPK pathway. . Two common BRAF alterations are a point mutation in the BRAF V600E oncogene and the fusion of BRAF and another large gene of unknown function, KIAA1549.21,22
BRAF inhibitors (dabrafenib) and MEK downstream inhibitors (trametinib and selumetinib) are under investigation.2,7 Children with BRAF- mutated low-grade gliomas , particularly those associated with homozygous deletion of the tumor suppressor gene CDKN2A , have a poor response to conventional chemoradiotherapy.22,23 BRAF inhibition , however, has led to initial and durable responses,22 and selumetinib was effective in a phase 2 trial involving children with low-grade gliomas associated with NF1 or aberrant BRAF recurrent, progressive, or refractory to treatment.24 These findings have prompted phase 3 trials comparing selumetinib with standard chemotherapy for newly diagnosed low-grade gliomas.
> Pilocytic astrocytomas
The most common astrocytomas of childhood are pilocytic astrocytomas, which represent around 20% of brain tumors in children, adolescents, and young adults (<20 years of age).8,25-27 They are generally slow growing and circumscribed. , with a 10-year survival rate of over 90%.26,28
Most of these tumors are located in the cerebellum and suprasellar region, but they can appear elsewhere.
Although pilocytic astrocytomas rarely undergo malignant transformation and generally have a favorable prognosis, 20% have a poor outcome, with local recurrence or dissemination.18,25 KIAA1549-BRAF fusion occurs in 80 to 90% of pilocytic astrocytomas, particularly in those in the posterior fossa, and may be associated with greater overall survival.19,25,29
> Pediatric high-grade diffuse gliomas
Pediatric high-grade gliomas account for 10% of brain tumors in children and have a poor prognosis.30 Despite surgery and adjuvant therapy, 70 to 90% of affected children die within 2 years. at diagnosis.31 The term “glioblastoma multiforme”, the most common primary malignant brain tumor in adults, has been reclassified in the WHO CNS5, with emphasis on molecular markers. The new classification defines glioblastoma strictly as a diffuse IDH wild-type astrocytic glioma in adults with specific histological or molecular alterations. As a result, the term “glioblastoma” has been removed from the lexicon of neoplasms in children.6
A breakthrough in the understanding of gliomas has been the identification of driver mutations in the chromatin remodeling gene family, histone H3.32,33 In patients with diffuse midline or hemispheric gliomas, somatic mutations in the tail of H3 decrease methylation and block glial differentiation, promoting gliomagenesis.34
Four subtypes of gliomas have been identified. Diffuse midline glioma is a particularly lethal tumor that affects young children and is unresectable. A new term, "H3K27-altered," has replaced the previous term, "H3K27 mutant," as additional molecular changes have been identified.6 H3K27-altered tumors include the formerly called diffuse intrinsic pontine glioma, along with aggressive gliomas that involve the thalamus and other midline structures. Methylation studies of diffuse midline gliomas have identified an oncogenic histone missense point mutation in histone H3.35,36 These tumors are associated with worse survival than their wild-type counterparts.37 The H3K27 alteration is more predictive of prognosis. than histological classification.35
The H3K27 alteration appears to be specific to diffuse high-grade midline gliomas in children.38 A second subtype, diffuse hemispheric glioma, H3G34 mutation, arises in the cerebral hemispheres in older children and young adults.35,39,40 This tumor is associated with other genetic alterations, including X-linked α-thalassemia ( ATRX ) and tumor protein 53 (TP53) mutations and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation.8 Mutations have been identified of histones in more than 80% of high-grade midline gliomas and in more than 40% of hemispheric ones, predominantly in children.32,41
A third subtype is pediatric diffuse-type, H3 wild-type, and IDH wild-type high-grade glioma. This is an aggressive tumor, usually found in the cerebral hemispheres, with a poor prognosis.42 The fourth subtype, a clinically distinctive neoplasm in newborns and infants, is infantile-type hemispheric glioma, which often harbors fusions of receptor tyrosine kinase genes, including ALK , NTRK1/2/3 , ROS1 and MET4 . These kinase alterations are potentially targetable, and preliminary studies suggest a better outcome in patients with kinase fusion-positive tumors.41,43,44
The standard adjuvant treatment is focal palliative irradiation, but long-term survival is poor, with no appreciable improvement in outcome over the past 50 years. The 3-year event-free survival and overall survival rates for children with high-grade gliomas are 10% and 20%, respectively.45 The outcome for diffuse pontine midline gliomas is abysmal, with a median survival of 4 months in the absence of radiotherapy and only 8 to 11 months with radiotherapy.46
Mutation-driven targeted therapy has so far not had a substantial effect, but has recently been introduced into clinical practice. In general, chemotherapy has had only limited effectiveness in treating high-grade gliomas in children. In adults with high-grade gliomas, temozolomide has improved event-free and overall survival compared with radiotherapy alone.45 This has not been the case in children.
In a phase 2 study, temozolomide failed to improve outcome for children with newly diagnosed high-grade gliomas. However, MGMT overexpression negatively affected survival, which may have caused lack of response to temozolomide.47 In an effort to overcome presumed MGMT-mediated resistance, a phase 2 study added lomustine to temozolomide in a regimen of dual alkylator to deplete MGMT and resulted in better event-free and overall survival compared to temozolomide alone.48
The H3K27 mutant has been attacked with the use of histone deacetylase (HDAC) inhibitors. For example, panobinostat, used to treat multiple myeloma, has demonstrated efficacy in vitro and in murine orthotopic xenograft models of infiltrative gliomas and is being evaluated in clinical trials.2,49 Fimepinostat, a pan-HDAC and PI3K inhibitor, is under investigation in a phase 1 trial in patients with high-grade gliomas and recurrent medulloblastomas. Other treatments under investigation include immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, cancer vaccines, and oncolytic virotherapy.
> Ependymal tumors
Ependymomas are the third most common brain tumor of childhood, after gliomas and medulloblastomas, representing 5 to 10% of CNS neoplasms in children; 90% are intracranial, with the majority arising in the posterior fossa, and the remainder are spinal.50,51
Ependymal tumors are a heterogeneous group, classified based on histological characteristics, molecular characteristics and location, with at least nine molecular subtypes.6,52 The old WHO histological classification does not correlate well with prognosis and has been modified.
Ependymomas are still classified as grade 1, 2, or 3 depending on the degree of anaplasia. The rare subependymoma is grade 1. Myxopapillary ependymoma, once considered grade 1, is now classified as grade 2, as the likelihood of recurrence is thought to be similar to that of conventional spinal ependymomas.6 Emphasis has been placed on molecular aberrations, and the term “anaplastic ependymoma” is no longer listed.
Grade 2 and 3 ependymomas are supratentorial or infratentorial in location. Supratentorial ependymomas are classified based on two oncogenic molecular fusions. The C11orf95-RELA fusion occurs in 70% of cases, causing constitutive activation of the nuclear factor κB signaling pathway.52
The new designation of the C11orf95 gene is ZFTA ; ZFTA can fuse with more ligands than just RELA.6 The other fusion involves YAP1 . Compared with YAP1 fusion , the newly named ZFTA fusion has been reported to outperform histological classification in predicting clinical course, conferring a worse prognosis.53 However, patients with ZFTA fusion who received conformal radiotherapy (with beams tailored to tumor shape) did not have a uniformly poor outcome, suggesting that the clinical significance of this fusion remains unclear.52,54
Posterior fossa ependymomas are subdivided based on methylomic profile into two most common subtypes: PFA and PFB ependymomas. The former occur predominantly in infants, are located laterally, and have a worse prognosis than PFB ependymomas. PFA tumors have a relative loss of the H3K27 trimethylation epigenetic marker compared to PFB tumors.52,55 The PFB subtype occurs in older children and generally has a better prognosis.56 However, no prognostic value was found when children in the PFA and PFB groups received conformal radiotherapy.54
Children with nonmetastatic ependymomas are initially treated with maximal safe resection, followed by focal conformal irradiation, except for infants.2,50,53 The role of chemotherapy has not been established but is under investigation. Despite advances in surgery and radiotherapy, the long-term outcome for childhood ependymomas remains poor, with 10-year overall and progression-free survival rates of 50% and 30%, respectively.50
> CNS embryonal tumors
Embryonal tumors are also a heterogeneous group of CNS malignancies, primarily affecting young children and accounting for approximately 20% of childhood brain tumors.57 These tumors have small, round, densely packed blue cells with scant cytoplasm and variable grades. differentiation and were initially classified as primitive neuroepithelial tumors (PNET).1,58
Those originating in the posterior fossa were called medulloblastomas, those in the pineal region were called pineoblastomas, names still in common use despite the new classification, and those above the tentorium were called supratentorial PNETs.58,59
Molecular profiling has led to the reclassification of these tumors based on genetic drivers combined with histological characteristics.29,60 The general term “PNET” has been replaced by the term “CNS embryonal tumor”, underlining the molecular differentiation.61 According to the WHO CNS5, the two types of embryonal tumors are medulloblastomas and other embryonal tumors of the CNS. The distinction is based on an integrated taxonomy with strong emphasis on molecular profiling.
> Medulloblastomas
Although low-grade gliomas are the most common brain tumors of childhood, medulloblastomas are the most common malignant brain tumors of childhood.62
They usually arise in the cerebellum, and patients present with signs of increased intracranial pressure or cerebellar dysfunction.
Medulloblastomas represent more than 60% of childhood embryonal tumors, and 70% occur in children under 10 years of age, affecting boys more than girls, although age and sex differences vary depending on the tumor subtype.3 ,63,64 One third of cases arise in children under 3 years of age.65
Factors associated with a poor outcome for children with medulloblastoma include large size, disseminated disease at presentation, younger age (<3 years), and residual tumor greater than 1.5 cm2 on postoperative imaging.62
Previous morphological classifications identified four subtypes: classic medulloblastoma, anaplastic large cell medulloblastoma, desmoplastic-nodular medulloblastoma, and medulloblastoma with extensive nodularity.61 The last two histological variants have a more favorable prognosis than the first two.65
The CNS5 system now recognizes two types of medulloblastoma: molecularly defined medulloblastoma and histologically defined medulloblastoma. The molecularly defined medulloblastoma category contains four subtypes, each with unique methylomic and transcriptomic profiles and distinctive clinical behavior. Genetic analyzes have identified subcategories of subtypes and suggest new treatment strategies.49
• Medulloblastomas with WNT activation
The subtype with WNT activation represents 10% of all medulloblastomas, affecting boys and girls equally and occurring in older children or adolescents. The tumors are located in the midline of the cerebellum and sometimes involve the peduncles and brain stem.
WNT medulloblastomas have classic histological features and are frequently associated with the accumulation of β-catenin, encoded by CTNNB1 . The CTNNB1 mutation is present in 90% of cases and causes the accumulation of nuclear β-catenin, which drives oncogenesis.5,61,63,66,67
These tumors have a very good prognosis, with a 10-year event-free survival rate of over 95%.68
They present an aberrant fenestrated vasculature driven by excessive levels of β-catenin mutants, which disrupts the blood-brain barrier and allows access for chemotherapy. This characteristic of WNT tumors may explain why some patients present with hemorrhage.69,70 Because WNT tumors are associated with good survival, treatment strategies for reducing radiotherapy and chemotherapy are being investigated.2,49,66 .71
• Medulloblastomas with SHH activation
Medulloblastomas with SHH activation represent 30% of medulloblastomas and have an equal sex distribution, affecting young children and young adults. They are normally located in the cerebellar hemispheres and are thought to arise from precursors in the outer granule cell layer of the cerebellum.
In contrast to WNT medulloblastomas, SHH medulloblastomas have more biologically and clinically relevant heterogeneity. They commonly arise from somatic or germline alterations in the SHH–PTCH–SMO–GLI signaling pathway, including deletions or loss-of-function mutations in the tumor suppressor gene PTCH1 (43% of cases), activating mutations in the SMO proto-oncogene (9%) and amplifications in the GLI1 and GLI2 oncogenes (9%).66,68,69
SHH medulloblastomas have been stratified according to the presence or absence of the tumor suppressor gene TP53 . TP53 mutations (occurring in 9% of cases) act as drivers of tumorigenesis and portend a poor prognosis, while TP53 mutations in WNT tumors do not affect outcome.66,72
TERT promoter mutations, which affect the structural maintenance of telomeres, occur in 40% of SHH medulloblastomas and are present in almost all cases in adults.67 Molecular stratification of SHH medulloblastomas has led to clinical trials of targeted therapies . An example is the use of the new SMO inhibitors, vismodegib and sonidegib, for refractory or recurrent SHH medulloblastomas.1,2,5,68,69,73
• Non-WNT, non-SHH medulloblastomas
In current nomenclature, the non-WNT, non-SHH subtype includes group 3 and group 4 medulloblastomas. Unlike WNT and SHH medulloblastomas, these tumors affect boys more than girls and are more likely to occur. have metastases at the time of presentation. They are located in the midline of the cerebellum and usually have classical or anaplastic large cell histologic features.5 No underlying driver mutations have been identified.63
Group 3 tumors represent 25% of medulloblastomas, occur in infants and children, and have the worst prognosis, with an overall survival rate of 50% at 5 years.68 Cytogenetic abnormalities are common, including isochromosome ( mirror image) 17q in almost half of the cases.1,66,67
For young children (<3 years), new treatments have been administered after surgical resection, including high-dose chemotherapy with autologous stem cell rescue and other risk-adaptive regimens to delay irradiation and avoid myeloablation.5
Group 4 tumors are the most common, representing 35% of all medulloblastomas.2 They occur in older children and adolescents and have an intermediate prognosis, with a 5-year overall survival rate of 70%.5
Genetic alterations include amplifications in the MYCN oncogene (in 6% of cases) and in CDK6 (in 5 to 10% of cases).1,24 Like group 3 medulloblastomas, these tumors have several chromosomal aberrations, with isochromosome 17q present in 80% of cases.68
They have been divided into a high-risk group enriched for isochromosome 17q, with an overall 10-year survival rate of 36%, and a low-risk group with chromosome 11 loss and MYCN amplification , with an overall survival rate at 10 years of 72%, double that of the high-risk group.66,72
Management of medulloblastomas consists of maximal safe resection followed by craniospinal radiation and chemotherapy.5 Current research focuses on de-escalation of treatment for WNT medulloblastomas to reduce the toxic effects of craniospinal radiation and chemotherapy, therapy targeting SMO and its descending pathway for SHH medulloblastomas, and risk-adjusted treatments for non-WNT, non-SHH medulloblastoma subtypes of groups 3 and 4.5,66
> Other embryonal tumors of the CNS
The category of other CNS embryonal tumors is divided into subtypes. These include atypical teratoid-rhabdoid tumors; embryonal tumors with multilayered rosettes; CNS neuroblastomas, activated by FOXR2 ; and CNS tumors with internal tandem duplication of BCOR .
| Summary |
Genome sequencing and DNA methylome profiling have greatly altered the categorization of brain tumors in children. Although the prognosis for selected tumors has improved as a result of refinements in surgical and adjuvant treatment, molecular diagnostic prospects have so far provided only limited therapeutic advances. However, there is reason to expect that targeted therapy will improve outcome in intractable tumors and mitigate the adverse effects of treatment.
