Medulloblastoma in Children

Patients present most commonly with symptoms associated with increased intracranial pressure and cerebellar dysfunction, which may include vomiting, headache, nausea, visual changes (eg, double vision), and unsteady walking or clumsiness.

• MRI

• Histologic evaluation of biopsy specimen or entire resected tumor

• Tumor molecular profiling (especially DNA methylation profiling)

MRI with gadolinium contrast is the test of choice for initial evaluation of possible medulloblastoma (1). Definitive diagnosis is made using tumor tissue obtained by biopsy or ideally by gross total resection of the tumor at initial presentation.

Medulloblastoma

Image

This contrast-enhanced MRI scan shows a medulloblastoma that grows in the roof of and obstructs the fourth ventricle.

Image courtesy of William R. Shapiro, MD

Once the initial diagnosis is established, staging and risk stratification are critical in medulloblastoma (1). Staging tests include:

• MRI of the entire spine

• Lumbar puncture for cerebrospinal fluid cytology

• Postoperative brain MRI to assess for any residual tumor

Risk stratification is based on tumor molecular group, the amount of residual tumor remaining after initial resection, evidence of metastasis, and tumor histology (1–3). Tumors are classified as standard (average)or high risk. Risk stratification is critical because it determines the intensity of treatment.

The 4 major molecular groups are:

• WNT-activated

• SHH-activated (further subdivided into TP53 wild-type  and TP53 mutant)

• Group 3

• Group 4

New subgroups with prognostic significance have emerged at a more granular level beyond the 4 major molecular groups. Second-generation subgrouping of non-WNT/non-SHH medulloblastoma has been validated in a large international meta-analysis of 1501 medulloblastomas (4). This analysis defines 8 Group 3/Group 4 subtypes (I–VIII) with disparate survival outcomes and molecular genetic profiles.

• Surgery, radiation, and chemotherapy

Treatment of medulloblastoma includes surgery, radiation, and chemotherapy. Contemporary treatment approaches increasingly incorporate molecular subgrouping and risk stratification to tailor therapy intensity, reduce long-term toxicity, and improve outcomes in pediatric medulloblastoma. Combination therapy typically provides the best long-term survival.

Initial surgical resection, when possible, is also part of the diagnostic, staging, and risk-assessment process (1).

For children ≥ 3 years with standard-risk disease, treatment typically consists of maximal safe surgical resection followed by craniospinal irradiation (CSI) with concurrent vincristine and then multi-agent maintenance chemotherapy (1). Two major treatment frameworks are commonly used: the Children’s Oncology Group (COG) protocol and the St. Jude protocol.

In standard-risk disease, reduced-dose CSI is combined with a posterior fossa or tumor-bed boost. The COG protocol is prolonged maintenance therapy with alternating cycles of cisplatin, lomustine (CCNU), vincristine, and cyclophosphamide, whereas the St. Jude protocol is cisplatin, cyclophosphamide, and vincristine for 4 cycles. Importantly, once treatment begins, these protocols are usually not interchanged.

Children ≥ 3 years with high-risk disease receive intensified CSI therapy with concurrent vincristine and focal boost radiation followed by maintenance chemotherapy. Group 3 tumors that have MYC amplification are a particularly aggressive subgroup, and carboplatin may be administered to patients before each radiation fraction to enhance radiosensitization. Maintenance therapy for the COG and St. Jude protocols typically includes cisplatin, cyclophosphamide, and vincristine.

Infants and children < 3 years are generally treated with radiation-sparing or radiation-delaying strategies because CSI at this age is associated with profound, long-term neurocognitive toxicity (1). Multiple protocols have explored using intensive chemotherapy combinations, intraventricular methotrexate, and high-dose chemotherapy with autologous stem cell rescue to avoid or postpone radiation while preserving survival outcomes and neurodevelopment (2–7).

Management of recurrent or progressive medulloblastoma remains challenging, and enrollment in clinical trials is strongly encouraged whenever feasible. Several salvage regimens are recommended, including temozolomide/irinotecan plus bevacizumab, which has shown improved survival compared with chemotherapy alone; temozolomide/topotecan; carboplatin/etoposide; and the celecoxib, cyclophosphamide, etoposide, thalidomide, and bevacizumab combination regimen (1).

Prognosis depends on age, stage, histology, cytogenetics, and molecular parameters of the tumor (1):

• Age > 3 years: Five-year disease-free survival rates are 60 to 70% for a high-risk tumor and approximately 80 to 85% for a standard-risk tumor (1).

• Age ≤ 3 years: Prognosis is more problematic, in part because up to 40% of children have disseminated disease at diagnosis (2, 3) and radiation therapy is typically avoided or delayed in this age group. Children who survive are at risk of severe long-term neurocognitive deficits (eg, in memory, verbal learning, and executive function).

Specific molecular features are also directly associated with prognosis. Molecular group WNT-activated has the best prognosis with approximately 95% overall survival (4). Ongoing pediatric clinical trials are being done to determine whether therapy can be reduced in patients with WNT-activated medulloblastoma (5). Molecular features associated with higher risk disease and poorer prognosis include MYC/MYCN amplification and TP53 mutation (6).