Brain Tumors in Children: New England Journal of Medicine Review

Brain tumors are the most common solid tumor in children and the leading cause of death from malignant tumo.
Central nervous system (CNS) tumors account for 20% of childhood malignancies and are second only to leukemia in inciden.
According to data, there are at least 50,000 new cases of brain tumors/central nervous system tumors among people aged 0-19 years in China, and there is a rapid growth tre.
On May 19, 2022, the New England Journal of Medicine (NEJM) published a review "Children's Brain Tumors", focusing on the latest classification of childhood brain tumors based on molecular biological evidence, and the most representative gliomas and C.
embryonal tum.
We introduce its main content he.
To read the full text translation, please visit the official website of NEJM Medical Frontiers, APP or click on the WeChat applet pictu.
Classification of Brain Tumors in Children The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS5), released in 2021, makes major changes to the classification of brain tumors, emphasizing molecular diagnostic featur.
This has resulted in a hybrid nomenclature encompassing molecular biomarkers and traditional classifications (histological, ultrastructural, and immunohistochemical features), and these changes reflect the trend toward determining diagnostic categories based on genetic features, which in many cases will Drive prognosis and suggest potential therapeutic targe.
Gliomas Pediatric diffuse low-grade gliomas Low-grade gliomas are the most common brain tumors in children, and if mixed glial neuronal and neuronal tumors are also included, low-grade gliomas will account for all 1/3 of the cases (F.
1.
This group of tumors is heterogeneous; unlike adult low-grade gliomas, childhood low-grade gliomas rarely transform into higher-grade tumo.
IDH1 or IDH2 mutants commonly found in adult low-grade gliomas (which can transform into higher-grade tumors) are much less common in childhood tumo.
FigureT1-weighted contrast-enhanced magnetic resonance imaging (MRI) scans of typical brain tumors in children MRI scans demonstrate the heterogeneity of childhood brain tumors in terms of location, size, enhancement, and internal structu.
The initial treatment for most childhood low-grade gliomas is surgery to establish a tissue diagnosis and maximize safe resecti.
In a large international study, children with low-grade glioma had a 5-year progression-free survival rate of 69% and an overall survival rate of 9
Risk factors for progression are younger age, incomplete resection, fibrous histology, and location of the hypothalamus or optic chia.
Gross resection of low-grade gliomas in children is often impossible, especially for gliomas located deep in the midli.
Many of these tumors are indolent, and observation and surveillance with brain imaging are sometimes an opti.
Radiation therapy is effective for recurrent or residual low-grade gliomas, with a 5-year progression-free survival rate of 71% and an overall survival rate of 9
Adjuvant chemotherapy is often used in children at risk for tumor progression based on age, anatomical location, and genetic characteristics because of concerns about radiation-induced neurotoxicity in the developing bra.
Chemotherapy drugs that have been shown to be effective (alone or in combination) include vincristine, carboplatin, vinblastine, 6-thioguanine, procarbazine, lomustine, cisplatin, etoposide, and irinotec.
Molecular alterations have been targeted with drugs that may be more effective and less toxic than conventional chemothera.
Alterations in signaling pathways downstream of the rat sarcoma virus-mitogen-activated protein kinase (MAPK) pathway have attracted considerable attenti.
This pathway sends messages from the cell surface and in this way regulates gene expression for several cellular functions, including grow.
Most low-grade gliomas have one or more alterations in the MAPK pathway, including mutations or fusions in the BRAF oncogene (Table 1), NF1 mutations, fibroblast growth factor receptor 1 gene mutations, and neurotrophic tyrosine Acid receptor kinase gene (NTRK) family fusio.
TableBRAF oncogene alterations in childhood low-grade gliomas* Poor response, especially when BRAF mutations are combined with homozygous deletion of the tumor suppressor gene CDKN
Studies have found that somatic alterations in BRAF or germline alterations in NF1 may play a role in tumorigenes.
Some low-grade gliomas have altered BRAF, which encodes a downstream regulator of the MAPK pathway, serine-threonine kinase protein (BRA.
Two common BRAF alterations are point mutations in the BRAF V600E oncogene and fusion of BRAF with another large gene of unknown function, KIAA1549 (Table
BRAF inhibitors (dabrafenib) and downstream MEK inhibitors (trametinib and selumetinib) are under investigati.
Children with BRAF-mutated low-grade gliomas, especially those associated with homozygous deletion of the tumor suppressor gene CDKN2A, respond poorly to conventional chemoradiati.
However, BRAF inhibitors allowed children to achieve initial and durable responses, and in a phase 2 trial involving children with abnormal BRAF or NF1-related low-grade, relapsed, progressive, or refractory gliomas, selumetinib Ni wor.

These results drive a phase 3 trial comparing selumetinib to standard chemotherapy in newly diagnosed low-grade gliomas
Pilocytic Astrocytoma The most common childhood astrocytoma is pilocytic astrocytoma, which accounts for approximately 20% of brain tumors in children, adolescents, and young adults (<20 years) (Figure 1.

They are usually slow growing and limited in scope, with a 10-year survival rate of over 9
Most of these tumors are located in the cerebellum and suprasellar region, but they can also occur in other sit.

Although pilocytic astrocytomas rarely undergo malignant transformation and generally have a favorable prognosis, 20% have a poor outcome with local recurrence or disseminati.

KIAA1549–BRAF fusion occurs in 80% to 90% of pilocytic astrocytomas, especially in the posterior fossa, and may be associated with prolonged overall surviv.

Pediatric Diffuse High-Grade Glioma Pediatric high-grade glioma accounts for 10% of childhood brain tumors and has a poor prognosis (Table
Even after surgery and adjuvant therapy, 70% to 90% of children still die within 2 years of diagnos.

TablePediatric Diffuse High-Grade Glioma** ACVR1 for activin A receptor type 1, ATRX for alpha-thalassemia X-linked, EGFR for epidermal growth factor receptor, TP53 for tumor protein 53, and MGMT for O6 - Methylguanine-DNA methyltransferase, MYCN denotes v-myc avian myeloma virus oncogene neuroblastoma-derived homolog, PDGFRA denotes platelet-derived growth factor receptor alp.

† H3 and IDH wild-type gliomas have three prognostic subgrou.

One of our advances in understanding high-grade gliomas has been the identification of driver mutations in the histone gene H3, a family of chromatin-remodeling gen.
In patients with diffuse midline or hemispheric gliomas, somatic mutations in the H3 tail reduce methylation and block glial differentiation, thereby promoting gliomagenes.

Four subtypes of gliomas have been identifi.

The first subtype is diffuse midline glioma, an extremely lethal tumor that affects young children and is unresectab.

The new term "H3K27-altered" replaces the previous term "H3K27 mutation" as other molecular alterations have been discover.

Methylation studies in diffuse midline gliomas have identified oncogenic histone missense point mutations in histone HPatients with these tumors had worse survival than those with wild-type tumors (F.

1.

H3K27 alterations can predict prognosis better than histological gra.

H3K27 alterations appear to be specific to childhood diffuse midline high-grade gliom.

The second subtype is diffuse hemispheric glioma, H3G34-mutant, which originates in the cerebral hemispheres of older children and young adul.

The tumor was also associated with other genetic alterations, including alpha-thalassemia X-linked (ATRX) and TP53 tumor protein 53 (TP53) mutations, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylati.

Histone mutations are found in more than 80% of midline high-grade gliomas and in more than 40% of cerebral hemispheric gliomas, mainly in childr.

The third subtype is diffuse childhood-type high-grade glioma, H3 wild-type and IDH wild-type (F.

1.

This is an aggressive tumor, usually found in the cerebral hemispheres, with a poor prognosis
The fourth subtype is a clinically distinct tumor in neonates and infants called infantile hemispheric glioma, which often carries gene fusions of receptor tyrosine kinases including ALK, NTRK1/2/3 , ROS1 and METThese kinase alterations have the potential to be therapeutic targets, and preliminary studies suggest improved outcomes in patients with kinase fusion-positive tumo.

The standard adjuvant treatment for childhood-onset diffuse high-grade glioma is local palliative radiotherapy, but long-term survival is poor, and outcomes have not improved significantly over the past 50 yea.

The 3-year event-free survival and overall survival rates for children with high-grade glioma were 10% and 20%, respective.

Diffuse midline gliomas in the pons have an extremely poor outcome, with median survival of 4 months without radiation and only 8 to 11 months with radiati.

Mutation-driven targeted therapies have so far not produced substantial effects, but such therapies have only recently entered clinical practi.

In general, chemotherapy has limited efficacy in children with high-grade gliom.

Investigators have targeted H3K27 mutants with histone deacetylase (HDAC) inhibito.

Panobinostat, a pan-HDAC and PI3K inhibitor for the treatment of multiple myeloma, is currently in Phase 1 trials enrolling patients with high-grade gliomas and patients with relapsed medulloblasto.

Other therapies currently under development include immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, malignancy vaccines, and oncolytic virus thera.

Ependymoma is the third most common childhood brain tumor after glioma and medulloblastoma, accounting for 5% to 10% of childhood CNS tumors; 90% occur intracranially, and most originate from Posterior cranial fossa, the rest occurs in the spinal cord
Ependymomas are a heterogeneous group of tumors classified according to histological features, molecular features, and location, with at least nine molecular subtyp.

Ependymomas are classified as grade 1, 2 or 3 according to the degree of anaplast.

Rare subependymomas are grade Grade 2 and 3 ependymomas were located either supratentorial or infratentorial (Table
Supratentorial ependymomas are classified according to the fusion of two oncogenic molecul.

The C11orf95-RELA fusion occurred in 70% of cases and resulted in constitutive activation of the NF-κB signaling pathway (F.

1.

The new designation of the C11orf95 gene is ZFTA; ZFTA can be fused to more ligands than just RE.

Another fusion involves YAPCompared with YAP1 fusions, the newly named ZFTA fusions have been reported to predict the clinical course better than histological classifications and lead to worse prognos.

However, not all patients with ZFTA fusions who received conformal radiotherapy (beams matched to tumor shape) had poor outcomes, suggesting that the clinical significance of these fusions remains uncle.

TablePediatric ependymoma * The ZFTA gene was formerly known as C11orf9Chromosomal fragmentation refers to large-scale chromosomal breaks and rearrangements of chromosome 1Posterior fossa ependymomas are subdivided into the two most common subtypes based on methylomic features: PFA and PFB ependymom.

The former occurs mainly in infants, is laterally located, and has a worse prognosis than PFB ependymoma
Compared with PFB tumors, PFA tumors have a relative absence of epigenetic markers of H3K27 trimethylati.

The PFB subtype occurs in older children and generally has a better prognosis (F.

1.

However, no prognostic value was found when children in the PFA and PFB groups received conformal radiothera.

Children with nonmetastatic ependymoma were first treated with maximally safe resection followed by local conformal radiotherapy, except for infan.

The role of chemotherapy has not been established, but is being studi.

Despite advances in surgery and radiotherapy, the long-term outcome of childhood ependymomas remains poor, with 10-year overall and progression-free survival rates of 50% and 30%, respective.

CNS Embryonic Tumors Embryonic tumors are also a group of heterogeneous CNS malignancies that mainly occur in young children and account for about 20% of childhood brain tumo.

These tumors, with dense small round blue cells with sparse cytoplasm and varying degrees of differentiation, were initially classified as primitive neuroepithelial tumors (PNET.

Embryonic tumors originating in the posterior cranial fossa are called medulloblastomas, and embryonal tumors originating in the pineal region are called pineoblastomas (these names are still in use despite the new classification), originating from Embryonic tumors of the tentorium are called supratentorial PNE.

Medulloblastoma Low-grade glioma is the most common childhood brain tumor, and medulloblastoma is the most common childhood malignant brain tum.

Medulloblastoma usually originates in the cerebellum, and patients present with increased intracranial pressure or cerebellar dysfuncti.

Medulloblastoma accounts for more than 60% of childhood embryonal tumors, 70% occur in children under 10 years of age, and affects more boys than girls, although age and sex differences vary by tumor subty.
One-third of cases occur in children under 3 years of a.

Factors associated with poor outcomes in children with medulloblastoma include large size, disseminated disease at presentation, young age (<3 years), and postoperative imaging with residual tumor greater than 5 .

Previous morphological classifications included 4 subtypes: classic medulloblastoma, large cell/anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and extensive nodular medulloblasto.

The latter two histological variants have a better prognosis than the first t.

The CNS5 system now includes two types of medulloblastoma: molecularly defined medulloblastoma and histologically defined medulloblasto.

Molecularly defined medulloblastomas comprise 4 subtypes, each with distinct methylomic and transcriptomic features, as well as distinct clinical behaviors (Table
Genetic analysis has identified subtypes of subtypes and suggested new treatment strategi.

TableMolecularly defined medulloblastomas** DNMB indicates desmoplastic/nodular medulloblastoma, LCA indicates large cell/anaplastic medulloblastoma, and MBEN indicates extensive nodular medulloblasto.

† In wingless/integrated signaling (WNT)-activated medulloblastoma, TP53 mutations have no prognostic significan.

‡ In sonic hedgehog (SHH)-activated medulloblastoma, TP53 mutations result in a significantly worse prognos.

WNT-activated medulloblastoma The wingless/integrated signaling pathway (WNT) activated subtype accounts for 10% of all medulloblastomas, affects boys and girls in equal proportions, and occurs in older children or adolescents (F.

1.

Tumors are located in the midline of the cerebellum and sometimes involve the cerebellar peduncle and brainst.
WNT-type medulloblastoma has typical histological features and is often associated with accumulation of CTNNB1-encoded β-caten.

CTNNB1 mutations are found in 90% of cases and lead to the accumulation of nuclear β-catenin, which promotes tumorigenes.

The prognosis for these tumors is excellent, with a 10-year event-free survival rate of over 9
They have abnormally permeable vasculature driven by excess mutated beta-catenin, which compromises the blood-brain barrier, potentially enabling chemothera.

This feature of WNT-type tumors may explain why some patients ble.

Because of the good survival of patients with WNT-type tumors, treatment strategies to reduce radiation and chemotherapy are currently being investigat.

SHH-activated medulloblastoma Sonic hedgehog (SHH)-activated medulloblastoma accounts for 30% of medulloblastomas, is evenly distributed in both genders, and occurs in young children and young adults (Figure 1.

Usually located in the cerebellar hemisphere, it is currently thought to originate from precursor cells of the outer granular cell layer of the cerebell.

Unlike WNT medulloblastoma, SHH medulloblastoma has greater biological and clinically relevant heterogenei.

They are usually caused by germline or somatic alterations in the SHH-PTCH-SMO-GLI signaling pathway, including deletion or inactivating mutations in the tumor suppressor gene PTCH1 (43% of cases), activating mutations in the proto-oncogene SMO (9%) ) and amplification of the oncogenes GLI1 and GLI2 (9.

SHH-type medulloblastoma can be stratified by the presence or absence of the TP53 tumor suppressor ge.
TP53 mutation (occurring in 9% of cases) is a driver of tumorigenesis and predicts poor prognosis, whereas TP53 mutation in WNT-type tumors does not affect outco.

TERT promoter mutations affecting maintenance of telomere structure occur in 40% of SHH-type medulloblastomas and are present in nearly all adult cas.

Molecular stratification of SHH-type medulloblastoma helps us conduct clinical trials of targeted therapi.

An example is the use of novel SMO inhibitors vismodegib and sonidegib in the treatment of refractory or relapsed SHH-type medulloblasto.

Non-WNT/non-SHH medulloblastoma In current nomenclature, the non-WNT/non-SHH subtype includes subtype 3 and subtype 4 medulloblasto.

Unlike WNT and SHH medulloblastomas, these tumors affect more boys than girls and are more likely to have metastasized at presentati.

They are located in the midline of the cerebellum and usually have classic or large cell/anaplastic histolo.

Potential driver mutations have not been identified (Figure 1.

Subtype 3 tumors account for 25% of medulloblastomas, occur in infants and children, and have the worst prognosis, with a 5-year overall survival rate of 5
Cytogenetic abnormalities are common, including the isoarm (mirror) chromosome 17q seen in nearly half of cas.

In young children (<3 years of age), surgical resection may be followed by novel therapies, including high-dose chemotherapy combined with autologous stem cell salvage therapy and other risk-based regimens to delay radiotherapy and avoid myeloablati.

Subtype 4 tumors are the most common, accounting for 35% of all medulloblastom.
They occur in older children and adolescents and have a moderate prognosis with a 5-year overall survival rate of 7
Genetic alterations include amplification of the MYCN oncogene (6% of cases) and CDK6 (5% to 10% of case.

Similar to type 3 medulloblastoma, these tumors have several chromosomal aberrations, with isoarm chromosome 17q present in 80% of cas.

They were divided into a high-risk group enriched in isochrosome 17q (10-year overall survival rate of 36%) and a low-risk group with chromosome 11 deletion and MYCN amplification (10-year overall survival rate of 72%, this survival rate 2 times that of the high-risk grou.

Treatment of medulloblastoma consists of maximum safe resection followed by whole brain and whole spinal cord radiotherapy and chemothera.

Current research focuses on de-escalation of treatment regimens for WNT medulloblastoma (with the aim of reducing the toxicity of whole brain and whole spinal cord radiotherapy and chemotherapy), therapies targeting SHH medulloblastoma SMO and its downstream pathways, and targeting third Risk-adjusted therapy for subtype and subtype 4 non-WNT/non-SHH medulloblasto.

Other CNS embryonal tumors The category of other CNS embryonal tumors is divided into several subtypes, including atypical teratoid/rhabdoid tumors; embryonal tumors with multilayer rosettes; CNS neuroblastoma, FOXR2-activated ; and CNS tumors with BCOR internal tandem repea.

SUMMARY Genome sequencing and DNA methylome analysis have dramatically changed the classification of childhood brain tumo.

While the prognosis of some tumors has improved due to advances in surgery and adjuvant therapy, knowledge of molecular diagnostics has so far brought only limited therapeutic advanc.

Today, we look to targeted therapy to improve outcomes in refractory tumors and reduce adverse effects of treatme.
References Cohen .

Brain tumors in childr.

N Engl J Med 2022; 386:1922-193 Copyright information This article is translated, written or requested by the editorial department of "NEJM Frontiers in Medicin.

For translations and articles written from English products of NEJM Group, please refer to the original English versi.

The full text of the Chinese translation and the included diagrams, e.

, are exclusively authorized by the Massachusetts Medical Association NEJM Gro.

For reprinting, please contact nejmqianyan@nejmqiany.

.

Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal responsibili.