Brain Tumors in Childhood

Key Points:

• Brain tumors are the most common solid tumors in children
• They account for about 20-25% of all pediatric cancers
• Peak incidence occurs between ages 3-9 years
• Etiology is largely unknown, with few established risk factors
• Prognosis and treatment vary widely depending on tumor type, location, and extent

Brain tumors in childhood represent a diverse group of neoplasms that can arise in various locations within the central nervous system (CNS). They are the most common solid tumors in children and the second most frequent childhood malignancy after leukemia. These tumors can be benign or malignant, and their behavior, treatment, and prognosis vary significantly based on histological type, molecular features, and location within the CNS.

Unlike adult brain tumors, which are predominantly supratentorial, pediatric brain tumors are more commonly found in the infratentorial region. This difference in location affects both the clinical presentation and the surgical approach to these tumors. The etiology of most pediatric brain tumors remains unknown, although certain genetic syndromes (e.g., neurofibromatosis, tuberous sclerosis) and prior exposure to ionizing radiation are recognized risk factors.

Classification

Brain tumors in children are classified based on their histological appearance, molecular features, and location. The World Health Organization (WHO) classification system is widely used and incorporates both histological and molecular parameters. Some of the most common types of pediatric brain tumors include:

1. Astrocytomas:
   • Low-grade astrocytomas (e.g., pilocytic astrocytoma)
   • High-grade astrocytomas (e.g., glioblastoma multiforme)
2. Embryonal Tumors:
   • Medulloblastoma
   • Atypical Teratoid/Rhabdoid Tumor (AT/RT)
3. Ependymomas
4. Craniopharyngiomas
5. Brain Stem Gliomas
6. Germ Cell Tumors
7. Choroid Plexus Tumors

Each tumor type has distinct characteristics, treatment approaches, and prognostic implications. Recent advances in molecular profiling have led to further subclassification of these tumors, allowing for more tailored treatment strategies and improved prognostic accuracy.

Clinical Presentation

The clinical presentation of brain tumors in children can be variable and often depends on the tumor's location, size, and rate of growth. Symptoms may develop gradually or appear suddenly. Common signs and symptoms include:

• Increased Intracranial Pressure (ICP):
  • Headaches, especially in the morning or worsening with recumbency
  • Nausea and vomiting, often projectile
  • Altered mental status or behavior changes
  • In infants: increased head circumference, bulging fontanelle
• Focal Neurological Deficits:
  • Weakness or paralysis
  • Visual disturbances (e.g., diplopia, visual field defects)
  • Hearing loss
  • Speech difficulties
• Seizures: May be focal or generalized
• Endocrine Dysfunction: Especially with tumors near the pituitary gland or hypothalamus
• Cerebellar Signs: Ataxia, dysmetria, nystagmus (common in posterior fossa tumors)
• Developmental Regression or Delay: Particularly in younger children

It's important to note that symptoms can be nonspecific, especially in younger children, leading to potential delays in diagnosis. A high index of suspicion is necessary, particularly when symptoms persist or progress over time.

Diagnosis

The diagnosis of brain tumors in children involves a combination of clinical evaluation, neuroimaging, and often, histopathological analysis. The diagnostic process typically includes:

1. Clinical History and Physical Examination:
   • Detailed neurological examination
   • Assessment of developmental milestones
   • Evaluation of vision, hearing, and endocrine function
2. Neuroimaging:
   • Magnetic Resonance Imaging (MRI): Gold standard for diagnosis and surgical planning
   • Computed Tomography (CT): May be used in emergency situations
   • Advanced imaging techniques: MR spectroscopy, diffusion tensor imaging, perfusion studies
3. Biopsy or Surgical Resection:
   • Provides tissue for histological diagnosis and molecular profiling
   • May be deferred in some cases where imaging is diagnostic (e.g., typical diffuse intrinsic pontine glioma)
4. Molecular and Genetic Testing:
   • Immunohistochemistry
   • Cytogenetic analysis
   • Next-generation sequencing for specific genetic alterations
5. Cerebrospinal Fluid (CSF) Analysis:
   • Cytology to detect tumor cells
   • Measurement of tumor markers (e.g., alpha-fetoprotein, beta-HCG in germ cell tumors)
6. Endocrine Evaluation: Particularly for tumors near the pituitary or hypothalamus
7. Ophthalmological Examination: To assess visual acuity and fields

The combination of these diagnostic modalities allows for accurate classification of the tumor, which is crucial for determining the appropriate treatment strategy and prognosis.

Treatment

The treatment of brain tumors in children is complex and multidisciplinary, often involving a combination of surgery, radiation therapy, and chemotherapy. The specific treatment plan depends on the tumor type, location, extent of disease, and the child's age. Key components of treatment include:

1. Surgery:
   • Primary goal is maximal safe resection
   • May be curative for some benign tumors
   • Provides tissue for diagnosis and reduces tumor burden
   • Techniques include microsurgery, endoscopic surgery, and intraoperative mapping
2. Radiation Therapy:
   • Often used for malignant tumors or residual disease after surgery
   • Types include focal radiation, craniospinal irradiation, and proton beam therapy
   • Use is limited in very young children due to long-term neurocognitive effects
3. Chemotherapy:
   • Used in most malignant tumors and some benign tumors
   • May be given before or after surgery, or concurrently with radiation
   • High-dose chemotherapy with stem cell rescue used in some protocols
4. Targeted Therapies:
   • Molecular targeted agents (e.g., BRAF inhibitors for BRAF-mutated gliomas)
   • Immunotherapies, including checkpoint inhibitors
5. Supportive Care:
   • Management of increased intracranial pressure
   • Anticonvulsants for seizure control
   • Hormone replacement for endocrine dysfunction
   • Rehabilitation services (physical, occupational, and speech therapy)

Treatment strategies are often risk-adapted, with more intensive therapy for high-risk tumors. Clinical trials investigating novel therapies, including immunotherapies and molecularly targeted agents, are ongoing and may offer additional options for some patients.

Prognosis

The prognosis for children with brain tumors varies widely depending on several factors:

• Tumor Type and Grade: Generally, low-grade tumors have a better prognosis than high-grade tumors
• Tumor Location: Affects resectability and potential for neurological deficits
• Extent of Surgical Resection: Complete resection often associated with better outcomes
• Age at Diagnosis: Very young children may have poorer outcomes due to limitations in treatment options
• Molecular Features: Certain genetic alterations are associated with better or worse prognosis
• Response to Initial Therapy: Early response often predictive of long-term outcome

Overall survival rates have improved significantly over the past few decades, with 5-year survival rates now exceeding 70% for all pediatric brain tumors combined. However, outcomes can vary dramatically based on specific tumor types:

• Low-grade gliomas: >90% 5-year survival
• Medulloblastoma: 60-80% 5-year survival, depending on risk group
• Ependymoma: 50-75% 5-year survival
• High-grade gliomas: Generally poor prognosis, with 5-year survival <25% for glioblastoma

Long-term follow-up is essential due to the risk of late effects from tumor and treatment, including neurocognitive deficits, endocrine dysfunction, and secondary malignancies. Quality of life considerations are increasingly important in treatment planning and long-term care.

Future Directions:

Ongoing research focuses on improving outcomes while minimizing toxicity. Areas of active investigation include:

• Molecular profiling for more precise diagnosis and treatment selection
• Development of targeted therapies based on tumor genetics
• Immunotherapy approaches
• Optimization of radiation techniques to minimize long-term side effects
• Strategies to improve quality of life and neurocognitive outcomes for survivors