Medulloblastoma: Symptoms, Types, Causes and Treatment

Medulloblastoma is the most common malignant brain tumor in children, representing a major challenge in pediatric oncology. Over the past decade, advances in molecular biology have revolutionized our understanding of this disease, leading to more tailored and effective treatment approaches. This article provides a comprehensive overview of medulloblastoma, including its symptoms, the latest classification of its types, known causes, and state-of-the-art treatment options.

Symptoms of Medulloblastoma

Recognizing the symptoms of medulloblastoma early is critical for timely diagnosis and effective treatment. However, symptoms can be subtle and nonspecific, especially in young children, which can lead to delays in diagnosis. The presenting signs are largely due to the tumor's location in the cerebellum and its effect on intracranial pressure.

Symptom	Description	Frequency / Details	Source(s)
Vomiting	Typically early morning, persistent	Most common symptom (88%)	2
Headaches	Often worse in the morning	79% of cases	2
Psychomotor Regression	Loss of developmental milestones	60% of children under 3 years	2
Psychological Symptoms	Behavioral changes, irritability	27% of cases	2
Strabismus	Crossed or misaligned eyes	26% of cases	2
Asthenia	Generalized weakness	25% of cases	2
Intracranial Hypertension	Lethargy, decreased consciousness	Often a late, life-threatening sign	2

Table 1: Key Symptoms

Common Presenting Symptoms

Medulloblastoma typically arises in the cerebellum, the part of the brain that controls balance and coordination. As the tumor grows, it can block the flow of cerebrospinal fluid, leading to increased intracranial pressure. This results in classic symptoms such as persistent vomiting (especially in the morning) and headaches. These are the most frequent findings and should always prompt further investigation when they are persistent or worsening in a child 2.

Age-Dependent Manifestations

In children under three years, psychomotor regression—the loss of previously acquired skills like walking or talking—is particularly common. Young children may also be less able to articulate headaches, so behavioral changes or irritability may be more prominent. In about a third of these younger children, diagnosis is only made after severe, life-threatening signs of intracranial hypertension develop, underscoring the importance of early recognition 2.

Neurological and Behavioral Changes

Strabismus (crossed eyes) and asthenia (general weakness) are also reported. Additionally, a significant number of patients present with psychological symptoms such as mood changes, apathy, or irritability. These non-specific features can lead to longer delays in diagnosis, particularly if neurological examination is initially normal or symptoms remit temporarily 2.

Diagnostic Challenges

The time from symptom onset to diagnosis remains lengthy, with a median of around 65 days. Factors associated with longer diagnostic intervals include subtle or inconsistent symptoms, periods of symptom remission, late appearance of neurological signs, and the presence of psychological rather than physical symptoms 2.

Types of Medulloblastoma

Not all medulloblastomas are the same. Recent advances in genomics have shown that medulloblastoma is actually a group of distinct diseases, each with its own biology, prognosis, and optimal treatment strategy.

Subtype	Key Features	Prognosis / Age	Source(s)
WNT	WNT pathway mutations, dorsal brainstem origin	Best prognosis, older children/teens	3 4 5 6 11
SHH	SHH pathway mutations, cerebellar hemisphere origin	Infants/children, variable prognosis	3 4 5 6 11
Group 3	MYC amplification common, frequent metastasis	Poor prognosis, infants/children	3 4 6 7 11
Group 4	Most common, neuronal-like, isochromosome 17q	Intermediate prognosis, older children/adolescents	3 4 6 7 11

Table 2: Medulloblastoma Types

The Four Core Molecular Subgroups

Medulloblastoma is now classified into four main molecular subgroups:

• WNT Subtype: Tumors with activated WNT signaling pathway, often arising from the dorsal brainstem. These have the best prognosis, with survival rates exceeding 90% 3 4 5 6 11.

• SHH Subtype: Characterized by aberrant Sonic Hedgehog pathway activation, these tumors arise from the cerebellar hemispheres and affect infants, children, and young adults. Prognosis is variable and depends on age and other features 3 4 5 6 11.

• Group 3: Known for frequent MYC gene amplification and high rates of metastasis at diagnosis, this group has the worst prognosis. It predominantly affects infants and young children 3 4 6 7 11.

• Group 4: The most common subtype, Group 4 tumors often show isochromosome 17q. They have an intermediate prognosis and mainly affect older children and adolescents 3 4 6 7 11.

Subgroups Within Subtypes

Deeper genomic and epigenomic profiling has revealed additional layers of complexity. Some studies suggest up to twelve subtypes, especially within SHH and Group 3/4, each with unique molecular and clinical characteristics 7 17. This fine-grained classification helps guide risk stratification and individualized therapy.

Distinct Developmental Origins

Each subtype is believed to originate from different precursor cell populations within the developing brain:

• WNT tumors: Arise from cells in the dorsal brainstem.
• SHH tumors: Originate from granule neuron precursor cells in the cerebellum.
• Group 3/4: Likely originate from other progenitor populations with distinct neuronal differentiation patterns 5 6.

Implications for Prognosis and Treatment

The type of medulloblastoma influences not only the patient's prognosis but also their response to therapy. For example, WNT tumors are highly sensitive to current treatments, while Group 3 tumors require more aggressive and novel approaches due to their poor outcomes 3 4 7 11 16 17.

Causes of Medulloblastoma

Understanding what causes medulloblastoma is crucial for developing better prevention and treatment strategies. While most cases are sporadic and not linked to inherited syndromes, major advances have been made in unraveling the genetic and molecular mechanisms that drive tumor development.

Factor	Mechanism/Role	Example(s) / Notes	Source(s)
Genetic Mutations	Affect developmental signaling pathways	SHH, WNT, MYC, TP53, PTCH1, PARP-1	8 9 10 12 17
Developmental Disruption	Failure of normal cell differentiation	Persistence of progenitor cells	5 8 12
DNA Repair Deficiency	Increased genomic instability	PARP-1, p53 mutations	9
Pathway Deregulation	Overactive signaling in cerebellar development	SHH, WNT, Notch	10 11 16

Table 3: Causes and Mechanisms

Genetic and Molecular Pathways

Medulloblastoma arises from the dysregulation of key developmental pathways—especially Sonic Hedgehog (SHH) and WNT signaling. Mutations in genes such as PTCH1 (a negative regulator of SHH), CTNNB1 (involved in WNT pathway), and MYC (an oncogene amplified in Group 3) are commonly implicated 3 5 8 9 10 12 17.

• SHH Pathway: Mutations drive abnormal proliferation of granule neuron precursor cells in the cerebellum 8 12.
• WNT Pathway: Mutations cause tumors to develop from dorsal brainstem cells 5 10.
• MYC: High-level amplification is associated with Group 3 medulloblastoma and poor outcomes 3 4 7 17.

Developmental Disruption

A hallmark of medulloblastoma is the failure of normal differentiation among neuronal precursor cells. Persistence or expansion of these progenitor populations, such as Sox2+ or Atoh1+ cells in the cerebellar external germinal layer, can provide a basis for tumor formation, especially when combined with pathway-activating mutations 8 12.

DNA Repair Deficiency and Genome Instability

Alterations in genes responsible for DNA repair—like p53 and PARP-1—can also predispose to medulloblastoma by allowing accumulation of mutations and chromosomal aberrations 9. Mouse models have shown that combined loss of DNA repair genes and pathway activation leads to rapid tumor development 9.

Other Contributory Factors

• Notch signaling: Emerging evidence suggests roles for additional pathways such as Notch in tumorigenesis 10.
• Epigenetic changes: Modifications affecting gene expression without altering DNA sequence are increasingly recognized as important, especially in subtype specification 17.

Treatment of Medulloblastoma

Medulloblastoma treatment has evolved from a one-size-fits-all approach to a more nuanced, risk-adapted strategy based on tumor subtype and patient characteristics. The goal is to maximize cure rates while minimizing long-term side effects, particularly in young children.

Modality	Description	Role / Notes	Source(s)
Surgery	Maximal safe resection	First-line, crucial for outcome	11 13 16 17
Radiotherapy	Craniospinal irradiation	Standard in older children, risks for young children	11 13 14 16 17
Chemotherapy	Multi-agent regimens	Used post-op, may be primary in infants	11 13 16 17
Targeted Therapy	Pathway-specific (e.g., SHH inhibitors)	Under investigation, personalized	14 16 17
Immunotherapy	Cancer vaccines, CAR T, NK cells, etc.	Promising, investigational	15

Table 4: Treatment Approaches

Multimodal Standard Therapy

The mainstay of medulloblastoma treatment is a combination of:

• Surgical resection: Removing as much of the tumor as safely possible is the critical first step and is a strong predictor of prognosis 11 13 16 17.
• Radiotherapy: Craniospinal irradiation targets both the primary site and potential metastatic spread. It is standard in children over the age of three, but carries risks of cognitive and endocrine side effects, especially in younger patients 11 13 14 16 17.
• Chemotherapy: Multi-agent regimens (e.g., cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide) are used after surgery and, in some protocols, can delay or reduce the need for radiation in very young children 11 13 16 17.

Risk-Adapted and Subtype-Specific Strategies

Recent molecular insights have led to more refined risk stratification:

• WNT tumors: Given their excellent prognosis, clinical trials are exploring reduced-intensity therapies to minimize long-term toxicity 3 4 11 16 17.
• SHH tumors: Targeted SHH pathway inhibitors are under study, especially for patients with specific activating mutations 14 16 17.
• Group 3/4 tumors: Due to higher risk of recurrence and metastasis, these subtypes may require more aggressive or novel therapies, including high-dose chemotherapy and investigational agents 3 4 11 16 17.

Chemotherapy-Only Protocols for Infants

For children under three, radiotherapy can cause severe neurocognitive impairment. In selected cases, intensive postoperative chemotherapy alone has been shown to be effective, particularly in non-metastatic disease 13.

Emerging Therapies and Clinical Trials

• Targeted therapies: Inhibitors of SHH and other pathways are being developed and tested in clinical trials, aiming for more personalized treatments 14 16 17.
• Immunotherapy: Approaches such as cancer vaccines, oncolytic viral therapy, CAR T cells, and natural killer cell therapies are under investigation. Early results are promising, especially for high-risk and relapsed cases, but more research is needed 15.

Multidisciplinary Care

Optimal management of medulloblastoma requires coordination between neurosurgeons, oncologists, radiologists, pathologists, and rehabilitation specialists to balance cure and quality of life 16.

Conclusion

Medulloblastoma is a complex and heterogeneous disease, but advances in molecular biology and treatment are rapidly improving outlooks for affected children. Early recognition of symptoms, precise tumor classification, and risk-adapted therapies are key to optimizing survival and minimizing long-term side effects.

Key Takeaways:

• Medulloblastoma symptoms are often subtle and non-specific, especially in young children, leading to diagnostic delays 2.
• There are four main molecular subtypes (WNT, SHH, Group 3, Group 4), each with distinct biology and prognosis 3 4 5 6 7 11.
• Tumorigenesis is driven by genetic mutations and developmental pathway disruptions, particularly affecting SHH and WNT signaling 5 8 9 10 12 17.
• Treatment involves surgery, radiotherapy, and chemotherapy, with emerging targeted and immunotherapies aiming for personalized care 11 13 14 15 16 17.
• Multidisciplinary and risk-adapted approaches are crucial for maximizing survival and quality of life in medulloblastoma patients 16.

Ongoing research and clinical trials hold promise for even more effective and less toxic therapies in the future, offering new hope to children and families impacted by this challenging disease.