Understanding Childhood Brain Tumors: New Classifications and Treatments

Table of Contents

• Introduction: Why This Research Matters
• New Classification System for Brain Tumors
• Pediatric Low-Grade Gliomas
• Pilocytic Astrocytomas
• Pediatric High-Grade Gliomas
• Ependymal Tumors
• Embryonal Tumors and Medulloblastomas
• What This Means for Patients and Families
• Study Limitations
• Recommendations for Families
• Source Information

Introduction: Why This Research Matters

Brain tumors represent a significant health challenge for children, being the most common solid tumors and the leading cause of death from cancer in this age group. Tumors of the central nervous system (CNS) account for 20% of all childhood cancers, second only to leukemia in frequency. The average annual incidence in the United States is 5.65 cases per 100,000 children (newborn to 14 years old), with 0.72 deaths per 100,000 children.

Recent advances in diagnosis and treatment have led to improvements in survival and quality of life for many young patients. However, the prognosis remains poor for many children with brain tumors, and treatments often have long-term side effects. This article explains the major changes in how doctors classify and manage childhood brain tumors, focusing on the most common types that families are likely to encounter.

New Classification System for Brain Tumors

The World Health Organization's fifth edition of the Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduced major changes in how brain tumors are categorized. The new system emphasizes molecular diagnostic features alongside traditional classifications based on how tumors look under a microscope.

This hybrid approach combines molecular biomarkers with conventional histologic (microscopic tissue), ultrastructural, and immunohistochemical features. While these changes may seem like simple renaming to non-specialists, they reflect an important trend toward assigning diagnostic categories based on genetic features that often drive prognosis and offer potential targets for treatment.

The new system introduces 22 unique tumor types, many with specific molecular alterations. Some names are quite complex, such as "diffuse pediatric-type high-grade glioma, H3 wild type and IDH wild type" and "desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant."

It's important to note that molecular profiling isn't widely available in developing countries, and even in the United States, comprehensive genetic testing (exome and genome sequencing) can take weeks. Treatment may need to begin before molecular diagnosis is complete, creating a gap between understanding tumor biology and applying these insights to clinical practice.

Pediatric Low-Grade Gliomas

Low-grade gliomas are the most frequent brain tumors of childhood, accounting for approximately one-third of all cases when mixed glioneuronal and neuronal tumors are included. Unlike low-grade gliomas in adults, which often transform into higher-grade tumors, pediatric low-grade gliomas rarely undergo this transformation.

The initial treatment for most low-grade gliomas in children is surgery to establish a tissue diagnosis and achieve maximal safe removal. In a large international study, the 5-year progression-free survival for children with low-grade gliomas was 69%, and overall survival was an encouraging 95%.

Risk factors for tumor progression include:

• Young age at diagnosis
• Incomplete surgical removal
• Fibrillary histologic features (specific microscopic appearance)
• Location in the hypothalamus or optic chiasm

Complete surgical removal is often not possible, particularly for tumors located deep in the brain's midline. Many of these tumors grow slowly, and careful observation with regular brain imaging is sometimes an option. Radiation therapy is effective for recurrent or residual low-grade gliomas, with 5-year progression-free survival of 71% and overall survival of 93%.

Children at risk for tumor progression based on age, location, and genetic features are often treated with chemotherapy due to concerns about radiation's neurotoxic effects on the developing brain. Effective chemotherapeutic agents include:

1. Vincristine
2. Carboplatin
3. Vinblastine
4. 6-thioguanine
5. Procarbazine
6. Lomustine
7. Cisplatin
8. Etoposide
9. Irino

Research has identified important molecular alterations in the MAPK pathway (a cellular signaling system that regulates growth). Most low-grade gliomas have one or more alterations in this pathway, including:

• Mutation or fusion of the BRAF oncogene
• NF1 mutation (associated with neurofibromatosis type 1)
• Fibroblast growth factor receptor 1 mutation
• NTRK family fusions

Two common BRAF alterations are particularly important:

• BRAF V600E point mutation (found in 15-20% of low-grade gliomas)
• KIAA1549-BRAF fusion (found in 80% of pilocytic astrocytomas)

New targeted therapies called BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib and selumetinib) are showing promise. Children with BRAF-mutated low-grade gliomas, particularly those with homozygous deletion of the tumor-suppressor gene CDKN2A, have a poor response to conventional chemoradiation therapy. However, BRAF inhibition has led to initial and durable responses in clinical trials.

Pilocytic Astrocytomas

Pilocytic astrocytomas are the most common astrocytomas of childhood, accounting for about 20% of brain tumors in children, adolescents, and young adults under 20 years old. These tumors are generally slow-growing and well-defined, with 10-year survival exceeding 90%.

Most pilocytic astrocytomas are located in the cerebellum and suprasellar region, though they can appear elsewhere in the brain. Although they rarely undergo malignant transformation and generally have a favorable prognosis, approximately 20% have a poor outcome with local recurrence or dissemination.

The KIAA1549-BRAF fusion occurs in 80-90% of pilocytic astrocytomas, particularly those in the posterior fossa (back of the brain), and may be associated with increased overall survival.

Pediatric High-Grade Gliomas

Pediatric-type high-grade gliomas account for 10% of brain tumors in children and have a poor prognosis. Despite surgery and adjuvant therapy, 70-90% of affected children die within 2 years after diagnosis. The term "glioblastoma" has been removed from the classification of childhood tumors in the new WHO system, reflecting better understanding of these tumors' unique biology in children.

Researchers have identified four main subtypes of high-grade gliomas in children:

1. Diffuse midline gliomas - Particularly aggressive tumors affecting young children, often in the brainstem
2. Diffuse hemispheric gliomas, H3G34-mutant - Occur in the cerebral hemispheres of older children and young adults
3. Diffuse pediatric-type high-grade glioma, H3 wild type and IDH wild type - Aggressive tumors usually found in the cerebral hemispheres
4. Infant-type hemispheric glioma - Distinct tumors in newborns and infants often with targetable gene fusions

The identification of driver mutations in the histone H3 gene family represents a major advance. In patients with diffuse midline or hemispheric gliomas, somatic mutations decrease methylation and block normal cell differentiation, promoting tumor formation.

Standard treatment is focal palliative irradiation, but long-term survival remains poor with no significant improvement in outcomes over the past 50 years. The 3-year event-free survival and overall survival rates for children with high-grade gliomas are just 10% and 20%, respectively.

The outcome for diffuse midline gliomas of the pons is particularly devastating, with a median survival of just 4 months without radiotherapy and only 8-11 months with radiotherapy. New targeted therapies, including histone deacetylase (HDAC) inhibitors like panobinostat and fimepinostat, are being investigated in clinical trials along with immunotherapy approaches.

Ependymal Tumors

Ependymomas are the third most common brain tumors of childhood, after gliomas and medulloblastomas, accounting for 5-10% of CNS neoplasms in children. Approximately 90% are intracranial, with most arising in the posterior fossa, and the remainder are spinal.

These tumors are classified based on histologic characteristics, molecular features, and location, with at least nine molecular subtypes identified. The classification system has been modified because the previous histologic classification didn't correlate well with prognosis.

Ependymomas are now classified as grade 1, 2, or 3 according to the degree of anaplasia (abnormal cell appearance). The rare subependymoma is grade 1, while myxopapillary ependymoma is now classified as grade 2 due to similar recurrence rates as conventional spinal ependymomas.

Supratentorial ependymomas (above the tentorium) are categorized based on two oncogenic molecular fusions:

• ZFTA fusion (previously called C11orf95-RELA fusion) - occurs in 70% of cases
• YAP1 fusion - occurs in 30% of cases

Posterior fossa ependymomas are divided into two main subtypes:

• PFA tumors - occur predominantly in infants, located laterally, with worse prognosis
• PFB tumors - occur in older children, generally with better prognosis

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

Embryonal Tumors and Medulloblastomas

Embryonal tumors are a heterogeneous group of malignant CNS neoplasms that primarily affect young children, accounting for approximately 20% of childhood brain tumors. These tumors were previously categorized as primitive neuroepithelial tumors (PNETs), but molecular profiling has led to reclassification based on genetic drivers.

The umbrella term "PNET" has been replaced by "CNS embryonal tumor," emphasizing molecular differentiation. The two main types are medulloblastomas and other CNS embryonal tumors, distinguished by integrated histomolecular criteria.

Medulloblastomas are now classified into four molecularly defined groups:

• WNT-activated medulloblastoma (10% of cases)
• SHH-activated medulloblastoma, TP53 wild type or mutation (30% of cases)
• Non-WNT, non-SHH medulloblastoma (60% of cases)

Each subtype has distinct age distributions, tumor locations, metastatic patterns, and genomic profiles that influence treatment approach and prognosis.

What This Means for Patients and Families

The molecular revolution in childhood brain tumor classification has significant implications for patients and families. The new classification system means that diagnosis is becoming more precise, which can lead to more targeted treatments and better understanding of prognosis.

For low-grade gliomas, the excellent overall survival rate of 95% at 5 years is encouraging news. The identification of specific genetic alterations means that targeted therapies are becoming available that may be more effective and less toxic than conventional chemotherapy.

For high-grade gliomas, while outcomes remain poor, the identification of specific molecular subtypes provides opportunities for developing targeted therapies. Clinical trials investigating HDAC inhibitors, immunotherapy, and other novel approaches offer hope for future improvements.

The reclassification of tumors means that families may hear new terminology when discussing their child's diagnosis. It's important to ask healthcare providers to explain what these terms mean in practical terms for treatment and prognosis.

Study Limitations

This review article acknowledges several important limitations in the current understanding and treatment of childhood brain tumors. Molecular profiling is not widely available in developing countries, creating disparities in access to precision diagnosis.

Even in developed countries like the United States, comprehensive genetic testing can take weeks, and treatment often needs to begin before molecular results are available. This creates a gap between scientific understanding and clinical application.

The new classification system with 22 tumor types and complex molecular terminology can be challenging for both specialists and non-specialists to navigate. Some of the targeted therapies discussed are still in clinical trials and not yet widely available.

Additionally, while molecular classification provides more precise prognostic information, treatment protocols based on these new classifications are still evolving, and long-term outcomes for many of the newly defined subtypes are not yet fully established.

Recommendations for Families

For families facing a childhood brain tumor diagnosis, we recommend:

1. Seek care at a specialized pediatric neuro-oncology center with experience in the latest classification systems and treatment approaches
2. Ask about molecular testing for your child's tumor to guide treatment decisions
3. Inquire about clinical trials that may offer access to targeted therapies
4. Request clear explanations of any new terminology used in your child's diagnosis
5. Discuss both short-term and long-term implications of treatment options, including potential side effects
6. Seek support services including psychological support, educational resources, and connections with other families
7. Maintain hope - advances in understanding are happening rapidly, leading to continuously improving outcomes

Source Information

Original Article Title: Brain Tumors in Children
Authors: Alan R. Cohen, M.D. (Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore)
Editor: Allan H. Ropper, M.D.
Publication: The New England Journal of Medicine 2022;386:1922-31
DOI: 10.1056/NEJMra2116344

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine and aims to make complex medical information accessible to patients and families while preserving all scientific accuracy and detail from the original publication.