# Pediatric CNS Tumors: Medulloblastoma and Ependymoma

## Overview

Central nervous system (CNS) tumors represent the most common solid tumors in children and are the leading cause of cancer-related mortality in the pediatric population. Among these, medulloblastoma and ependymoma are two of the most frequent CNS malignancies that require radiation therapy. Treatment strategies must carefully balance the goal of cure with the need to minimize long-term developmental and neurocognitive consequences. Proton therapy has become increasingly important in this context due to its ability to reduce late effects. Additionally, advances in molecular classification have revolutionized risk stratification and treatment planning, allowing for more tailored therapeutic approaches.

## Medulloblastoma

### Epidemiology

Medulloblastoma is the most common malignant brain tumor in children, with a peak incidence between the ages of 3 and 8 years. It typically arises in the posterior fossa, specifically in the cerebellum, with approximately 75% of cases in children occurring in the midline vermis. This tumor has a notable propensity for leptomeningeal and cerebrospinal fluid (CSF) dissemination, with 30-40% of patients showing positive CSF cytology or spinal MRI evidence of spread at diagnosis.

### Molecular Classification (WHO 2021)

The World Health Organization (WHO) 2021 classification divides medulloblastoma into four molecular subgroups, each with distinct clinical and prognostic features. The WNT-activated subgroup accounts for about 10% of cases and is associated with an excellent prognosis, with over 95% five-year overall survival. These tumors often arise in the lateral cerebellar hemisphere in older children and are characterized by nuclear accumulation of beta-catenin. The SHH-activated subgroup comprises roughly 30% of cases and has a variable prognosis depending on TP53 mutation status; TP53-mutant tumors are considered high-risk. This subgroup is more common in infants and adolescents and frequently exhibits desmoplastic/nodular histology. Group 3 medulloblastomas represent about 25% of cases and carry the worst prognosis, with a five-year overall survival of 50-60%. MYC amplification within this group is a marker of high risk. Group 3 tumors are most common in young males and have the highest rate of metastatic disease at presentation. Group 4 is the largest subgroup, comprising approximately 35% of cases, and has an intermediate prognosis. It is characterized by isochromosome 17q and whole chromosome 11 loss.

| Subgroup | Frequency | Age | Location | Key Marker | 5-yr OS | Prognosis |
|---|---|---|---|---|---|---|
| WNT-activated | ~10% | Older children | Lateral cerebellum | Beta-catenin nuclear accumulation | > 95% | Excellent |
| SHH-activated | ~30% | Infants/adolescents | Cerebellar hemisphere | PTCH1, TP53 status | 60–80% (TP53-dependent) | Variable |
| Group 3 | ~25% | Young males | Midline (4th ventricle) | MYC amplification | 50–60% | Poor |
| Group 4 | ~35% | All ages | Midline | Isochromosome 17q | 70–80% | Intermediate |

### Risk Stratification

Risk stratification in medulloblastoma considers clinical and molecular factors. Standard-risk patients are typically older than 3 years, have undergone near-total or gross total resection (with residual tumor less than 1.5 cm²), show no metastatic disease (M0), and lack MYC or MYCN amplification. High-risk patients include those with large postoperative residual disease (greater than 1.5 cm²), metastatic disease (M1-M4), MYC or MYCN amplification, or large cell/anaplastic histology. The WNT subgroup is currently being investigated for treatment de-escalation regardless of traditional risk factors due to its excellent prognosis.

### Treatment: Standard-Risk

Surgical management aims for maximum safe resection of the primary tumor. Preoperative spinal MRI is essential for staging and should be performed before surgery to avoid artifacts caused by postoperative blood products. Lumbar CSF cytology is typically obtained more than 14 days after surgery for accurate assessment.

Following surgery, craniospinal irradiation (CSI) with a posterior fossa boost is standard. For standard-risk patients, the CSI dose is 23.4 Gy delivered in 13 fractions. The posterior fossa boost brings the total dose to approximately 54-55.8 Gy, combining the CSI dose with an additional 30.6-32.4 Gy boost. Recent clinical trials have explored involved-field boosts targeting the tumor bed plus a margin rather than the entire posterior fossa to reduce radiation exposure to the developing cerebellum. The ACNS 0331 trial demonstrated that tumor bed boost is an acceptable alternative to whole posterior fossa boost in standard-risk patients. The entire treatment course typically spans about six weeks.

Adjuvant chemotherapy follows radiation and usually consists of cisplatin, vincristine, and cyclophosphamide or lomustine, known as the Packer regimen. Eight cycles are administered post-radiation, with vincristine given weekly during CSI.

### Treatment: High-Risk

High-risk patients receive a higher CSI dose of 36 Gy in 20 fractions, with a posterior fossa or tumor bed boost to 54-55.8 Gy. Metastatic deposits are boosted to 45-50.4 Gy. These patients also undergo more intensive adjuvant chemotherapy regimens.

| Risk Group | CSI Dose | Boost Target | Total Boost Dose | Metastatic Boost |
|---|---|---|---|---|
| Standard-risk | 23.4 Gy / 13 fx | Tumor bed (or posterior fossa) | 54–55.8 Gy | N/A |
| High-risk | 36 Gy / 20 fx | Tumor bed / posterior fossa | 54–55.8 Gy | 45–50.4 Gy |

### CSI Technique

During CSI, patients may be positioned supine or prone, with the supine position preferred for proton therapy and intensity-modulated radiation therapy (IMRT) approaches. The cranial field encompasses the entire cranial contents, including the cribriform plate and temporal fossa, while the spinal field covers the entire thecal sac down to approximately the S2-S3 vertebral level. Managing the junction between cranial and spinal fields is technically challenging and involves techniques such as feathering junctions or gradient matching to avoid hot or cold spots in the spinal cord. Daily image-guided radiation therapy (IGRT) is employed to verify patient alignment. Proton CSI offers a significant advantage by dramatically reducing radiation dose to critical anterior structures such as the heart, lungs, kidneys, bowel, thyroid, and gonads compared to photon CSI.

### Infant Medulloblastoma (Age <3 Years)

In infants under 3 years of age, radiation therapy is typically deferred or avoided due to its severe neurocognitive effects. Instead, chemotherapy-only approaches, including high-dose chemotherapy with autologous stem cell rescue, are utilized. Radiation is reserved for residual or recurrent disease after chemotherapy. The SHH-desmoplastic/nodular subtype in infants has an excellent prognosis with chemotherapy alone.

## Ependymoma

### Epidemiology

Ependymoma is the second most common posterior fossa tumor in children after medulloblastoma. Its peak incidence occurs between 0 and 5 years for infratentorial tumors and between 30 and 40 years for supratentorial tumors in adults. In children, approximately 60% of ependymomas are located in the posterior fossa, 30% supratentorially, and 10% in the spinal cord. Unlike medulloblastoma, ependymoma rarely disseminates through the CSF, with less than 5% showing dissemination at diagnosis.

### Molecular Classification

Ependymomas are classified molecularly into several groups. Posterior fossa group A (PFA) tumors typically occur in younger children with a median age of 3 years. They are characterized by loss of H3K27me3, aggressive biology, higher recurrence rates, and overexpression of EZHIP. Posterior fossa group B (PFB) tumors occur in older children and adults and retain H3K27me3, correlating with a better prognosis. Supratentorial ependymomas include RELA-fused (ST-RELA) tumors, which activate the NF-kB pathway and are more aggressive, and YAP1-fused (ST-YAP1) tumors, which have a better prognosis. Spinal ependymomas include a high-risk MYCN-amplified subgroup.

### Treatment

Surgical resection aiming for maximum safe removal is the most important prognostic factor in ependymoma. Gross total resection (GTR) achieves a five-year progression-free survival (PFS) of 60-75%, compared to 30-40% for subtotal resection (STR). Re-resection should be considered for residual disease if it can be accomplished without significant morbidity.

Radiation therapy is indicated for all intracranial ependymomas (grades 2 and 3) following surgery. The typical dose ranges from 54 to 59.4 Gy delivered in 30-33 fractions, targeting the postoperative tumor bed with a 1-1.5 cm clinical target volume (CTV) margin. This approach is conformal and does not include craniospinal irradiation, reflecting the low rate of CSF dissemination in ependymoma. Craniospinal irradiation is reserved only for cases with documented CSF dissemination. The ACNS 0831 trial is investigating the addition of chemotherapy to radiation for incompletely resected posterior fossa ependymomas.

The role of chemotherapy in ependymoma remains limited and controversial. No chemotherapy regimen has demonstrated improved survival when added to surgery and radiation for completely resected tumors. Chemotherapy is primarily used in infants to delay radiation and for recurrent or incompletely resected disease. The ACNS 0121 trial showed that gross total resection followed by conformal radiation therapy (59.4 Gy) without chemotherapy achieved a five-year progression-free survival of approximately 77% in completely resected ependymoma.

### Infant Ependymoma

Treating ependymoma in infants is particularly challenging because radiation to the posterior fossa causes significant developmental harm. Chemotherapy is employed to delay radiation until the child reaches 1 to 3 years of age. Second-look surgery after chemotherapy may improve resectability and reduce the volume or need for radiation. Unfortunately, the PFA subtype in infants carries a poor prognosis despite aggressive therapy.

## Late Effects of Pediatric CNS Radiation

Radiation therapy in pediatric CNS tumors is associated with several late effects. Neurocognitively, children often experience a decline in IQ, estimated at approximately 2-4 points per year following craniospinal irradiation, especially in younger patients and those receiving higher doses. Executive function, processing speed, and working memory are the most affected cognitive domains. Proton therapy may reduce, but does not eliminate, cognitive decline by sparing critical structures such as the hippocampi, temporal lobes, and supratentorial white matter.

Endocrine complications are common, with growth hormone deficiency being the most frequent, occurring in over 90% of patients after CSI and requiring hormone replacement. Hypothyroidism may be primary, due to radiation exposure to the thyroid gland, or central, resulting from hypothalamic-pituitary axis involvement. Precocious puberty can arise from hypothalamic irradiation, and some patients develop adrenal insufficiency or gonadal failure.

Secondary malignancies represent a significant long-term risk, with a cumulative incidence of 5-10% at 20-30 years post-treatment. The most common secondary tumors include meningiomas, gliomas, thyroid cancer, and soft tissue sarcomas. This risk is dose- and field-dependent, and proton therapy may reduce but not eliminate it.

Other late effects include hearing loss, often related to cisplatin chemotherapy combined with cochlear irradiation; posterior fossa syndrome or cerebellar mutism as a surgical complication; vasculopathy such as moyamoya syndrome and stroke; and spinal growth impairment due to vertebral body irradiation.

<image>A composite image showing proton versus photon craniospinal irradiation treatment plans in a 5-year-old child. Sagittal and coronal dose color wash views compare the two modalities. The photon plan shows significant dose to the heart, lungs, kidneys, bowel, thyroid, and gonads (exit dose from posterior spinal fields). The proton plan shows dose confined to the CSF space with dramatic sparing of all anterior structures. A dose-volume histogram compares heart, lung, kidney, and thyroid doses between the two techniques.</image>

<image>A four-panel figure showing MRI appearances of the four molecular subgroups of medulloblastoma. WNT: lateral cerebellar hemisphere mass with moderate enhancement. SHH: cerebellar hemisphere nodular mass. Group 3: midline fourth ventricle filling mass with enhancement and possible spinal metastases on sagittal spine MRI. Group 4: midline posterior fossa mass with minimal enhancement. Each panel is labeled with the subgroup name, frequency, prognosis, and key molecular markers.</image>

<image>A posterior fossa ependymoma treatment plan showing an axial and sagittal CT/MRI fusion with conformal radiation fields. The GTV (postoperative tumor bed on MRI, red) and CTV (1 cm expansion respecting anatomic barriers including the brainstem surface and tentorium, blue) are shown. The 95% isodose line (54 Gy prescription) tightly conforms to the PTV. The uninvolved spine is not treated, distinguishing the ependymoma approach from medulloblastoma CSI.</image>

## Key Clinical Pearls

Preoperative spinal MRI is mandatory before posterior fossa surgery for medulloblastoma because postoperative blood products in the CSF can produce false-positive findings on MRI, complicating accurate staging. Molecular subtyping of medulloblastoma is now essential for risk stratification and is likely to guide future treatment strategies, including de-escalation in the WNT subgroup and intensification in Group 3 MYC-amplified tumors. Managing the craniospinal irradiation junction is one of the most technically demanding aspects of pediatric radiation therapy; techniques such as feathering junctions and daily image guidance are critical to avoid over- or under-dosage of the spinal cord at the cranial-spinal junction. Unlike medulloblastoma, ependymoma is treated with local radiation only, not craniospinal irradiation, which is a common source of confusion but a critical distinction. Proton therapy is strongly preferred for pediatric craniospinal and posterior fossa radiation when available, as the reduction in integral dose translates directly into fewer late effects in growing children. Every pediatric CNS radiation plan should include a detailed discussion with the family about potential late effects and establish a long-term follow-up plan addressing neurocognitive, endocrine, growth, hearing, and secondary malignancy surveillance.

## References
- Packer RJ et al. "Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma." *J Clin Oncol*. 2006;24(25):4202-4208.
- Merchant TE et al. "Conformal radiation therapy for pediatric ependymoma, chemotherapy for incompletely resected ependymoma, and observation for completely resected, supratentorial ependymoma." *J Clin Oncol*. 2019;37(12):974-983.
- Taylor MD et al. "Molecular subgroups of medulloblastoma: the current consensus." *Acta Neuropathol*. 2012;123(4):465-472.
- Yock TI et al. "Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study." *Lancet Oncol*. 2016;17(3):287-298.
- Pajtler KW et al. "Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups." *Cancer Cell*. 2015;27(5):728-743.