Understanding Pediatric Low-Grade Gliomas: From Cellular Mechanisms to Patient Care

Table of Contents

• Introduction: What Are Pediatric Low-Grade Gliomas?
• Epidemiology and Classification
• Current Treatment Approaches
• Understanding Tumor Progression Patterns
• Molecular Mechanisms Behind Tumor Development
• Clinical Implications for Patients and Families
• Study Limitations and Future Research
• Patient Recommendations and Care Strategies
• Source Information

Introduction: What Are Pediatric Low-Grade Gliomas?

Pediatric low-grade gliomas (PLGGs) represent a diverse group of brain tumors that develop from glial and glioneuronal cells in children and adolescents. These tumors are classified as World Health Organization (WHO) central nervous system grade 1 and 2 tumors, indicating their generally slow-growing nature. Despite being the most common brain tumors in children, affecting approximately 2-3 per 100,000 children in Western populations, they present unique challenges due to their chronic nature and potential for long-term complications.

The peak incidence occurs in children between 5 and 9 years of age, though these tumors can appear at any point from infancy through adolescence. What makes PLGGs particularly challenging is their tendency to cause significant long-term disease-related and treatment-related health problems, even when survival rates remain high. Recent advances in molecular understanding have revealed that most PLGGs share common genetic pathways that drive their development and growth.

Epidemiology and Classification

According to the 2021 WHO classification system, pediatric low-grade gliomas fall into six categories under the umbrella term "glioma, glioneuronal and neuronal tumors." The most common histological types include:

• Pilocytic astrocytoma - The most frequent type, often characterized by well-defined borders
• Pleomorphic xanthoastrocytoma - Typically found in supratentorial regions
• MAPK pathway-altered diffuse low-grade glioma - A newer classification based on molecular features
• MYB-/MYBL1-altered diffuse astrocytoma - Identified through specific genetic markers
• Gangliogliomas - Contain both neuronal and glial components
• Dysembryoplastic neuroepithelial tumors (DNETs) - Often associated with seizure disorders

These tumors can develop anywhere in the central nervous system, but they most commonly appear in the cerebellum and supratentorial midline structures. The distribution varies by specific tumor type, with each entity showing preferences for particular brain regions.

A significant characteristic of PLGGs is their association with tumor predisposition syndromes. Approximately 20% of patients with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, primarily pilocytic astrocytomas, within the first decade of life. Conversely, about 40% of all patients with optic pathway gliomas have NF1. Tuberous sclerosis complex (TSC) also increases the risk of developing these tumors.

Current Treatment Approaches

Surgery remains the cornerstone of PLGG treatment, with the extent of surgical resection being the most important predictor of progression-free survival. Research shows that complete resection leads to excellent outcomes, with 5-year progression-free survival rates of approximately 94% and 10-year rates of around 85%.

Unfortunately, complete resection isn't always possible. Recent population studies show that 65-73% of patients undergo incomplete resection due to the tumor's location near critical brain areas. When tumors cannot be fully removed, the remaining tumor volume significantly impacts future progression risk. Studies indicate that residual tumor volume greater than 2.0 cm³ is associated with higher risk of radiologically detectable progression.

When surgery isn't feasible or when disease progresses after surgery, chemotherapy becomes the primary treatment option. Current regimens include:

1. Carboplatin and vincristine combination therapy
2. Vinblastine monotherapy
3. Thioguanine, procarbazine, CCNU, and vincristine combination (TPCV protocol)
4. Second-line options including irinotecan and bevacizumab

Despite these treatments, 5-year progression-free survival rates with first-line chemotherapy protocols remain around 50%, and response rates decrease significantly with subsequent treatment lines, leading to substantial long-term morbidity.

Radiation therapy has historically been used for salvage treatment but is now reserved for older non-NF1 patients due to serious long-term side effects including cognitive decline, endocrine disorders, and secondary malignancies. Newer radiation techniques like proton beam therapy and stereotactic radiation aim to improve local control while reducing side effects.

The most exciting development in PLGG treatment involves molecular therapies targeting the RAS/MAPK and mTOR pathways. Several targeted agents have shown promising results in clinical trials:

• MEK inhibitors: selumetinib, trametinib, and binimetinib
• BRAF inhibitors: vemurafenib and dabrafenib
• mTOR inhibitor: everolimus
• FGFR inhibitor: erdafitinib
• Pan-RAF inhibitor: tovorafenib

Notably, combination therapy with trametinib and dabrafenib has shown significantly higher response rates compared to carboplatin and vincristine in patients with BRAF V600E mutations, making it a potential first-line treatment for this subgroup. However, important questions about optimal treatment duration remain unanswered, and rapid rebound growth after discontinuation has been observed in a significant subset of patients.

Understanding Tumor Progression Patterns

The clinical course of pediatric low-grade gliomas is typically characterized by slow growth patterns. Nearly half of patients experience symptoms for more than six months before diagnosis, emphasizing the indolent nature of these tumors. After incomplete resection, growth deceleration and senescence (cellular aging) frequently occur, with long-term progression-free survival rates of approximately 50%.

PLGGs demonstrate versatile progression patterns, including spontaneous regression, regrowth of senescent tumors up to 12 years after initial diagnosis, and occasional malignant transformation to high-grade lesions. Research indicates that future progressiveness can be predicted by tumor growth behavior during the first two years after diagnosis.

Multiple studies have identified key risk factors that determine progression patterns:

Extent of Surgical Resection

The amount of tumor removed during surgery dramatically affects outcomes. Ten-year progression-free survival rates show stark differences based on resection completeness:

• 48% after near-total resection
• 18% after partial resection
• 16% after biopsy only

Studies show a clear linear relationship between the percentage of tumor removed and postoperative tumor growth velocity, with more complete resections leading to slower regrowth.

Tumor Location

Where the tumor develops significantly influences its progression behavior. Multiple tumor sites or extensive tumor spread at diagnosis carries higher progression risk. Supratentorial midline location is most strongly associated with progressive disease and disease-related morbidity. Other high-risk locations include:

• Brainstem tumors
• Spinal cord tumors
• Diencephalon tumors

Hypothalamic/chiasmatic tumors show the most sustained tendency to progress. However, the relationship between location and outcomes is complicated by the fact that tumors in eloquent areas are harder to resect completely.

Age at Diagnosis

Younger patients face higher risks of recurrent treatment progression, inferior treatment outcomes, treatment-related complications, and tumor-related death. The highest progression risk occurs in patients under 1 year of age. This age dependency likely reflects differences in tumor microenvironment and glial cell maturation across childhood development stages.

Histological Type

Non-pilocytic and diffuse PLGGs are associated with higher risk of progressive disease. Several studies indicate significantly higher progression rates in:

• Non-pilocytic tumors
• Diffuse fibrillary histology
• WHO grade 2 tumors (compared to grade 1)

While tumor location affects which histological types develop where, diffuse fibrillary histology has been confirmed as an independent risk factor for worse progression-free survival in multiple large studies.

Molecular Mechanisms Behind Tumor Development

Over the past two decades, research has revealed that abnormal activation of the RAS/MAPK (RAS-mitogen-activated protein kinase) pathway serves as a nearly universal feature of pediatric low-grade gliomas. This has led to PLGGs being described as a "single-pathway disease."

The RAS/MAPK pathway regulates essential cellular processes including cell cycle control, cell migration, and angiogenesis—all crucial mechanisms in tumor development and progression. The discovery of this pathway's importance began with observations in neurofibromatosis type 1 (NF1) patients, where germline mutations in the NF1 tumor suppressor gene cause loss of neurofibromin function, leading to uncontrolled RAS activity.

In non-NF1 patients, several specific genetic alterations drive RAS/MAPK activation:

• KIAA1549-BRAF fusion: Found in approximately 70% of pilocytic astrocytomas and 30% of rosette-forming glioneural tumors
• BRAF V600E mutations: Present in approximately 80% of pleomorphic xanthoastrocytomas, 45% of gangliogliomas, and 40% of pediatric-type diffuse low-grade gliomas
• FGFR1/2 alterations: Less frequent mutations that activate the pathway
• ALK fusions and KRAS mutations: Additional genetic changes that converge on RAS/MAPK activation

Less common PLGG types contain alterations in NTRK genes, MYB family transcription factors, and RAF1 fusions. Importantly, IDH1/2 mutations common in adult gliomas are rare in pediatric cases and cluster mainly among adolescent patients.

Beyond driving tumor formation, RAS/MAPK activation also triggers oncogene-induced senescence (OIS), a protective cellular mechanism that may explain the characteristically slow growth patterns of these tumors. This dual role of pathway activation—both driving growth and limiting it through senescence—creates the unique biological behavior of PLGGs.

Clinical Implications for Patients and Families

The chronic nature of pediatric low-grade gliomas means that patients and families often face years of treatment and monitoring. The need for multiple treatment lines in many cases underscores the importance of long-term planning and management strategies.

For families, understanding the specific molecular characteristics of their child's tumor can help guide treatment decisions. The presence of certain genetic markers, particularly BRAF V600E mutations, may make targeted therapies a preferable first-line option over conventional chemotherapy.

The location of the tumor significantly impacts both treatment options and quality of life. Tumors in supratentorial midline structures, while often less amenable to complete resection, may be more responsive to targeted therapies. Regular monitoring through MRI is essential, as progression patterns can be unpredictable with regrowth occurring many years after initial treatment.

Age at diagnosis plays a crucial role in treatment planning. Younger children, particularly those under one year, require specialized approaches that balance tumor control with minimizing long-term treatment effects on developing brains and bodies.

Study Limitations and Future Research

While this review synthesizes current understanding of pediatric low-grade gliomas, several limitations in our knowledge remain. The molecular mechanisms underlying age-dependent progression patterns are poorly understood, hampered by difficulties creating representative preclinical models of these tumors.

For the newer targeted therapies, crucial questions remain unanswered:

• Optimal treatment duration has not been established
• The phenomenon of rapid rebound growth after discontinuation needs further study
• Long-term toxicity data, especially in pediatric patients, is lacking
• Risk factors for treatment failure or rebound growth haven't been identified

Additionally, the impact of tumor microenvironment on PLGG formation and growth represents an emerging area of research that may yield new therapeutic approaches. The relationship between specific genetic alterations and response to targeted therapies requires more precise mapping to optimize treatment selection.

Patient Recommendations and Care Strategies

Based on the current evidence, patients and families should consider the following approach to managing pediatric low-grade gliomas:

1. Seek comprehensive molecular testing to identify specific genetic alterations that may guide treatment choices
2. Prioritize maximal safe resection when possible, as this remains the strongest predictor of positive outcomes
3. Discuss targeted therapy options with your medical team, especially for tumors with BRAF V600E mutations
4. Maintain long-term follow-up regardless of initial treatment success, as progression can occur many years later
5. Consider participation in clinical trials investigating new treatment approaches and combinations
6. Address quality of life issues throughout treatment, including neurocognitive, endocrine, and psychosocial support

For patients with neurofibromatosis type 1, special consideration should be given to avoiding radiation therapy when possible due to increased risk of secondary malignancies. These patients may benefit from earlier implementation of targeted therapies.

Families should work with multidisciplinary teams including neuro-oncologists, neurosurgeons, radiation oncologists, and supportive care specialists to develop comprehensive care plans addressing both tumor control and long-term health preservation.

Source Information

Original Article Title: Dissecting the Natural Patterns of Progression and Senescence in Pediatric Low-Grade Glioma: From Cellular Mechanisms to Clinical Implications

Authors: David Gorodezki, Martin U. Schuhmann, Martin Ebinger, Jens Schittenhelm

Publication: Cells 2024, 13(14), 1215

Note: This patient-friendly article is based on peer-reviewed research and aims to make complex scientific information accessible to patients and families while preserving all essential medical information, data, and findings from the original study.