Ependymoma: Symptoms, Types, Causes and Treatment

Ependymoma is a rare tumor that arises from the ependymal cells lining the brain's ventricles and the central canal of the spinal cord. Although these tumors can develop at any age, they are most commonly diagnosed in children and young adults, and their symptoms, classification, underlying causes, and treatment approaches have become increasingly nuanced thanks to advances in molecular biology and clinical research. This article dives deep into the key features of ependymoma, synthesizing the latest research to provide a comprehensive overview for patients, families, and healthcare professionals.

Symptoms of Ependymoma

Ependymomas can present with a wide array of symptoms, which often depend on the tumor's location within the central nervous system (CNS), its size, and whether it is causing obstruction of cerebrospinal fluid or compressing adjacent structures. Recognizing these symptoms early is crucial for diagnosis and management.

Symptom	Location	Severity/Impact	Source(s)
Headache	Brain	Common, may be severe	2
Nausea/Vomiting	Brain	Frequently observed	2
Weakness	Spine > Brain	More severe in spine	2 3
Pain	Spine	Often neck/back pain	2 3
Numbness	Spine	More severe in spine	2
Fatigue	Both	Higher in spinal cases	2
Bowel/Bladder Changes	Spine	Noted in spinal cases	2
Cognitive Issues	Brain	More in low-income pts	2
Appetite Loss	Brain	Mild, less frequent	2

Table 1: Key Symptoms of Ependymoma

Symptom Variation by Tumor Location

Brain (Intracranial) Ependymomas:

• Symptoms often relate to increased intracranial pressure, such as headaches, nausea, and vomiting.
• Cognitive difficulties and changes in appetite may also occur, but are generally less severe in comparison to spinal cases.
• Subependymomas in the brain can sometimes be asymptomatic unless they reach a large size, but when symptomatic, they may cause headaches and neurological deficits depending on their precise location 1 2.

Spinal Ependymomas:

• Tend to produce more pronounced symptoms, including severe pain (often neck or back pain), numbness, weakness, and changes in bowel or bladder function.
• Sensory symptoms usually precede motor symptoms, and fatigue is frequently reported 2 3.

Socio-Economic and Demographic Factors

• Patients with lower income report more significant cognitive symptoms, independent of tumor location, underscoring the broader impact of disease and care disparities 2.
• In some cases, especially with subependymomas, symptoms may not appear until the tumor is large or in a critical location, such as the fourth ventricle, which can lead to dangerous complications 1.

Less Common or Early Symptoms

• Isolated neck pain may be the only presenting symptom in early spinal ependymoma, highlighting the importance of considering ependymoma in the differential diagnosis for unexplained persistent neck or back pain in young adults 3.
• Seizures, balance problems, and visual changes are less frequently reported but may occur depending on tumor location.

Types of Ependymoma

Ependymomas are a diverse group of tumors that differ by location, histological appearance, and—crucially—molecular characteristics. Recent advances have led to a refined classification that guides prognosis and, increasingly, treatment.

Type	Key Features	Typical Location	Source(s)
Classic Ependymoma	WHO Grade II, moderate growth	Brain/Spine	8 7
Anaplastic Ependymoma	WHO Grade III, aggressive	Brain/Spine	8
Subependymoma	Slow-growing, often benign	Brain (ventricles)	1 7 8 15
Myxopapillary Ependymoma	Distinct, grade II	Spine (lower)	7 8
ST-EPN-RELA	RELA fusion, aggressive	Supratentorial	6 8 9 15
ST-EPN-YAP1	YAP1 fusion, better prognosis	Supratentorial	6 8 9 15
PF-EPN-A	Epigenetically driven, poor outcome	Posterior Fossa	4 6 8 12 15
PF-EPN-B	Genomic instability, better outcome	Posterior Fossa	4 6 8 12 15
SP-MPE	Myxopapillary molecular class	Spine	7 8

Table 2: Main Types and Molecular Subgroups of Ependymoma

Histological Subtypes

• Classic Ependymoma (WHO Grade II):
  The traditional form, with moderate cellularity and typical perivascular pseudorosettes 8.
• Anaplastic Ependymoma (WHO Grade III):
  More aggressive, with higher cellularity, increased mitotic activity, and poorer prognosis. The distinction between classic and anaplastic ependymoma is becoming less central due to new molecular classification systems 8 17.
• Subependymoma:
  A slow-growing, often benign tumor, usually found incidentally in the brain's ventricular system and only rarely symptomatic unless large 1 7 8 15.
• Myxopapillary Ependymoma:
  Occurs almost exclusively in the lower spinal cord (filum terminale), has a distinct gelatinous appearance, and is now considered WHO Grade II 7 8.

Molecular Subgroups

Recent research has shown that ependymomas are best understood through their molecular profiles, which reflect differences in genetics, prognosis, and response to therapy.

• Supratentorial Ependymomas:
  • ST-EPN-RELA: Defined by the C11orf95-RELA gene fusion, this group is aggressive and mainly affects children 6 8 9 15.
  • ST-EPN-YAP1: Characterized by YAP1 gene fusion, usually has a better prognosis and may occur in younger children 6 8 9 15.
• Posterior Fossa Ependymomas:
  • PF-EPN-A (PFA): Most common in young children, characterized by epigenetic dysregulation (loss of H3K27me3), and has a poor clinical outcome 4 6 8 12 15.
  • PF-EPN-B (PFB): More frequent in older children and adults, marked by genomic instability, and typically has a more favorable prognosis 4 6 8 12 15.
• Spinal Ependymomas:
  • SP-MPE: The molecularly defined class of myxopapillary ependymoma, predominantly in the lower spinal cord 7 8.
  • A rare, highly aggressive variant with MYCN amplification has also been described 8.

Diagnostic and Prognostic Implications

• Molecular classification now offers more precise diagnostic and prognostic information than histology alone, guiding both clinical trial design and individualized treatment 7 8 17 18.
• Some tumors previously diagnosed by histology as ependymomas are being reclassified based on molecular findings, highlighting the importance of integrated diagnostics 6 7.

Causes of Ependymoma

The causes of ependymoma are complex and multifaceted, involving both genetic and environmental factors. However, much remains to be discovered about the precise mechanisms that drive these tumors.

Cause/Factor	Details/Genetics	Prevalence/Impact	Source(s)
Somatic Mutations	Gene fusions (RELA, YAP1, etc.)	Frequent in subtypes	6 8 9 12 15
Epigenetic Changes	H3K27me3 loss, EZHIP expression	Key in PFA	12 15
Germline Mutations	NF2, NF1, LZTR1, POLR2A (rare)	<4% pediatric cases	10 13
Radiation Exposure	No strong link established	Unknown	11
Environmental Factors	Largely unknown	Unknown	11

Table 3: Key Causes and Risk Factors for Ependymoma

Genetic and Molecular Drivers

• Somatic Mutations and Gene Fusions:

  • Most supratentorial ependymomas are driven by fusion genes such as C11orf95-RELA or YAP1 fusions 6 8 9 15.
  • Posterior fossa group A ependymomas (PFA) lack recurrent mutations but are characterized by epigenetic changes, particularly the global loss of H3K27me3 due to aberrant EZHIP expression 12 15.
  • Spinal ependymomas may show MYCN amplification in rare, aggressive cases 8.

• Epigenetic Dysregulation:

  • Particularly important in PFA ependymomas, where the tumor’s behavior is driven by abnormal regulation of gene expression rather than classic cancer mutations 12 15.

Hereditary Factors

• Familial Syndromes:
  • A small percentage (<4%) of pediatric ependymoma cases are linked to inherited mutations, mainly in the NF2 and NF1 genes, with LZTR1 and rare variants in POLR2A being possible contributors 10 13.
  • Most patients with ependymoma do not have a family history or identifiable genetic risk factors 10.

Environmental Factors

• Radiation/Exposures:
  • To date, there is no strong evidence linking environmental or radiation exposure to the development of ependymoma 11.
  • Unlike some other brain tumors, established environmental risk factors are lacking.

Tumor Cell of Origin

• Ependymomas are thought to arise from ependymal cells, which line the ventricles and central canal of the spinal cord. Some subtypes may arise from more primitive progenitor cells, as suggested by molecular and electron microscopic studies 5.
• This cell of origin may help explain the tumor's diversity and varying locations within the CNS 5 8 15.

Treatment of Ependymoma

Treatment for ependymoma is tailored to the tumor’s location, molecular subtype, and patient age. The mainstay of therapy remains surgical removal, but advances in radiation and emerging molecular therapies are reshaping the standard of care.

Modality	Indication/Use	Key Considerations	Source(s)
Surgery	First-line for all resectable tumors	Gross total resection best	14 18
Radiotherapy	Post-op, especially in grade III/incomplete resection	Local vs. craniospinal field	14 18
Chemotherapy	Young children, recurrent or unresectable	Limited efficacy	18 11
Molecular/Targeted	Clinical trials, certain subtypes	Ongoing research	11 15 16
CAR-T Therapy	Experimental, relapsed PFA, others	Promising in trials	16

Table 4: Overview of Ependymoma Treatments

Surgery

• Primary Approach:
  Surgery is the cornerstone of treatment for both children and adults, with maximal safe resection (removal of as much tumor as possible) being the primary goal 14 18.
• Spinal vs. Brain Tumors:
  Spinal ependymomas often have better outcomes due to the higher likelihood of achieving gross total resection 14.

Radiotherapy

• Adjuvant Therapy:
  Radiotherapy is recommended after surgery for most intracranial (brain) ependymomas, particularly WHO grade III or if complete resection is not possible 14 18.
  • For spinal ependymomas, radiotherapy is reserved for incompletely resected tumors 18.
• Field Selection:
  • Localized radiotherapy is favored, but craniospinal irradiation is considered if there is evidence of tumor spread along the CNS axis 14 18.

Chemotherapy

• Limited Role:
  Chemotherapy is generally reserved for very young children (to delay radiation) or for recurrent/unresectable tumors, as most ependymomas are not highly responsive to standard chemotherapeutic agents 18 11.
• Ongoing Trials:
  New agents are under investigation, but chemotherapy remains a secondary option 11 18.

Molecular and Targeted Therapies

• Precision Medicine:
  • Next-generation therapies targeting specific molecular alterations, such as tyrosine kinase inhibitors, telomerase inhibitors, and agents targeting tumor-specific signaling pathways, are in early clinical trials 11 15.
  • For tumors with RELA fusion or NF-κB pathway activation, targeted therapies are being explored 9 15.
• Epigenetic Therapies:
  Agents targeting the epigenetic abnormalities in PFA ependymomas, such as disruption of H3K27me3, are being developed 12 15.
• CAR-T Cell Therapy:
  • Chimeric antigen receptor (CAR) T-cell therapies targeting surface markers (e.g., EPHA2, HER2, IL13Rα2) have shown promise in preclinical models and are being tested in early-phase trials, particularly for relapsed or refractory PFA ependymomas 16.

Prognosis and Follow-Up

• Outcomes:
  Prognosis depends on tumor location, molecular subtype, and extent of resection. Spinal and PFB ependymomas have more favorable outcomes, while supratentorial RELA-fusion and PFA subtypes are associated with higher risk of recurrence and worse prognosis 4 6 7 14 15.
• Recurrence:
  Local recurrence remains the main challenge, especially for brain ependymomas, highlighting the need for ongoing surveillance and potential for re-intervention 14.

Future Directions

• Molecular Stratification:
  Routine molecular profiling is increasingly recommended to guide prognosis and clinical trial eligibility 8 17 18.
• Personalized Therapy:
  Ongoing studies will clarify the best use of targeted and immunotherapies, potentially transforming the treatment landscape for ependymoma in the coming years 11 15 16 18.

Conclusion

Ependymoma is a rare CNS tumor with diverse symptoms, types, causes, and treatment strategies. Advances in molecular biology have dramatically refined our understanding and classification of these tumors, leading to more personalized care.

Key Takeaways:

• Symptoms vary by tumor location: Brain tumors often cause headaches and nausea, while spinal tumors frequently lead to pain, numbness, and weakness 2 3.
• Modern classification blends histology and molecular profiling: Subtypes such as RELA-fusion, YAP1-fusion, and PFA/PFB are increasingly important for prognosis and treatment planning 6 8 9 15.
• Causes are multifactorial: Most ependymomas are sporadic, with a small percentage linked to hereditary syndromes (NF2, NF1, LZTR1) or epigenetic dysregulation (PFA) 10 12.
• Treatment is multimodal: Surgery is the mainstay, supplemented by radiotherapy; chemotherapy has a limited role, while emerging molecular and immunotherapies are under investigation 11 14 15 16 18.
• Molecular diagnostics are the future: They are reshaping prognosis, clinical trial design, and, ultimately, patient outcomes 8 17 18.

Ongoing research and clinical trials promise to further improve the outlook for patients with ependymoma, making personalized, targeted therapy an increasingly achievable goal.