Epidemiology

Medulloblastoma, the most common malignant pediatric brain tumor, is the causative pathology in 20% of these patients ( Fig. 17.1 ). In the adult population, however, medulloblastoma is exceedingly rare, causing only 1% of all primary central nervous system (CNS) tumors. ¹⁶ The median patient age at diagnosis is 8 years, and medulloblastoma is more common in males (1.5:1). ¹⁷ Medulloblastoma can also arise in the context of a familial cancer predisposition syndrome, such as neurofibromatosis 1 or Li-Fraumeni, Gorlin, or Turcot syndromes. ¹⁸

Pathophysiology

The term medulloblastoma stems from the similarity of the tumor with the embryonal medullary velum and was coined in 1925. ¹⁹ The tumor has historically been classified histologically into classic, desmoplastic or nodular, extensive nodularity, and large-cell or anaplastic types. Classic medulloblastoma accounts for two-thirds of cases and appears as a highly cellular tumor with undifferentiated, small, round, blue cells. ^{20 , 21} The desmoplastic or nodular subtype consists of dense, intercellular reticulin interspersed with reticulin-free zones. ²² Extensive nodularity medulloblastoma is rare and represents the most differentiated form. ^{23 , 24} Sheets of large round cells constitute large-cell medulloblastoma. Nuclear molding, cell-to-cell wrapping, and nuclear pleomorphism are the key features of anaplastic medulloblastoma ( Fig. 17.2 ). ²⁵

Although this histologic classification remains in use, the 2016 World Health Organization (WHO) classification of CNS tumors included molecular data to form a genetic classification of the disease. ²⁶ The genetically defined groups are the (1) wingless-type (WNT) activated, (2) sonic hedgehog (SHH) activated and tumor protein 53 (TP53) mutant, (3) SHH activated and TP53 wild type, and (4) non-WNT/non-SHH. The latter group is further subdivided into group 3 and group 4 medulloblastoma. Tumors lacking a diagnostic mutation are designated “not otherwise specified.” These groups indicate the underlying molecular pathways that are affected and result in tumorigenesis.

These genetic subtypes demonstrate different demographics, recurrence patterns, and prognoses ^{26 , 27 , 28 , 29} ( Table 17.3 ^{26 , 30} ). Thus, tumor biology is now being brought into risk-stratification classifications that previously were based on clinical and histologic findings alone. ^{26 , 29} Such stratification should inform treatment decisions.

Clinical Presentation

Patients with medulloblastoma generally present with symptoms related to increased ICP and hydrocephalus, which are typical for all posterior fossa tumors. Symptoms start several weeks to months prior to diagnosis. ^{31 , 32}

Perioperative Evaluation

On preoperative imaging, medulloblastomas in children appear as midline tumors emanating from the cerebellar vermis and extending inferiorly into the fourth ventricle from its roof. In adults, however, the tumor is more likely to be laterally placed in the cerebellar hemispheres. The tumor is heterogeneously enhancing and may possess calcification ( Fig. 17.1 ). It is classically described as having a high-density appearance on CT with a low signal on T1-weighted MRI. ³³ Hydrocephalus is present in 95% of patients. A key imaging finding of prognostic value is the presence or absence of metastases in the neuraxis secondary to CSF seeding.

Management

The classic approach to medulloblastoma management has been that of GTR followed by radiotherapy to the craniospinal axis, posterior fossa, and tumor bed. ³⁴ Because of the long-term sequelae of radiotherapy, which is more pronounced at higher doses and in younger children, combination chemotherapeutic regimens are now used postoperatively with lower-dose radiotherapy. In children younger than age 3 years, radiotherapy is generally deferred. Patients with high-risk features (metastases, significant tumor residuum, and large-cell or anaplastic histology) should receive a higher dose of radiotherapy than that administered to those deemed to have an average risk.

In recent times, the pursuit of GTR has been brought under scrutiny by evidence suggesting the equivalency in survival following near-total resection with a likelihood of reduced morbidity. ³⁵ In addition, previously reported benefits of GTR are now believed to be confounded by molecular subgrouping. Thus, current recommendations are to opt for maximal safe resection with an acceptance of near-total resection (< 1.5 cm² of tumor residuum) if such is deemed likely to reduce surgical morbidity. ²⁹

Surgery for hydrocephalus in patients with medulloblastoma takes place in approximately 22% of patients. However, Schneider et al ³² have shown that the WNT subgroup did not require any CSF diversion surgery, which they attributed to the low-hydrocephalus-risk profile of this tumor type. For example, patients with WNT tumors are older at presentation and have lower scores on the modified Canadian Preoperative Prediction Rule for Hydrocephalus scale and an absence of leptomeningeal spread.

Chemotherapy aimed at targeting the underlying subgroup-specific molecular pathways may provide new avenues of treatment for patients with medulloblastoma. The agent vismodegib is a known inhibitor of the SHH pathway that has shown efficacy in adult patients with recurrent medulloblastoma. ³⁶ However, the effect was transient, which suggests the need for multiple agents acting on different elements of the tumor pathway.

The emerging emphasis for future clinical trials in medulloblastoma is to be target directed rather than disease specific. ³⁷ There also is an emphasis on individualized therapy aimed at treating the unique molecular profile of the individual patient’s tumor.

Patient Outcomes

The main determinants of overall survival in patients with medulloblastoma are patient age, molecular subgroup, metastatic status, craniospinal irradiation, and tumor location. ³⁵ Five-year survival rates for children with average-risk disease are 70 to 80%, whereas those for children with high-risk disease are 60 to 65%. ³⁸ For infants with localized disease, 5-year survival rates are 30 to 50%.

Although survival rates in average-risk patients have improved, the burden of treatment is considerable, with patients experiencing endocrine dysfunction, hearing loss, premature aging, and poor neurocognitive function. These patients also have an increased risk of stroke and secondary malignancy. ³⁹

Epidemiology

Ependymoma is the third most common brain tumor in children, representing 8 to 12% of tumors of the CNS. It is comparatively rare in adults, accounting for only 2 to 6% of intracranial neoplasms. In children, the median age at presentation is 4 to 6 years, and boys are slightly more affected than girls. In the adult population, these tumors are observed in the third to fifth decades, with men and women affected equally. ^{40 , 41} Ten percent of ependymomas arise in the spine and are more commonly seen in adults. Of tumors arising intracranially, two-thirds occur in the posterior fossa. These tumors generally occur sporadically, but association with neurofibromatosis 2 may be seen. ⁴²

Pathophysiology

The cells of origin of ependymomas are believed to be radial glial stem cells rather than the ependymal lining of the CSF compartments. ⁴³ The tumors are classified primarily into three histologic grades. Grade I includes myxopapillary and subependymoma, which are both regarded as benign tumors. Myxopapillary tumors arise predominantly in the lower spine at the level of the conus medullaris and below. In contrast, subependymomas are found most commonly in the fourth or lateral ventricles. Grade II is classic ependymoma, subdivided into papillary, clear-cell, and tanycytic, and grade III is anaplastic ependymoma. This histologic classification is thought to be of limited clinical use as tumor genetics better inform prognosis. ⁴⁴ The latest WHO classification of tumors has included a further molecular category of RELA fusion-positive ependymoma, which is responsible for 70% of supratentorial ependymomas in children and confers a poor prognosis. ^{26 , 45}

Key histologic features in ependymoma are perivascular pseudorosettes, which are ependymal cell cytoplasmic processes radially converging onto blood vessels, and ependymal rosettes, which are tumor cells arranged as single layers to form a lumen. Pseudopalisading necrosis and microvascular proliferation are common features in anaplastic ependymoma. Ependymomas are characteristically well circumscribed, with no infiltration of surrounding brain tissue.

Molecular Biology

Recent studies suggest nine different molecular subgroups of ependymoma within the CNS and two distinct subgroups arising in the posterior fossa based on genome-wide DNA methylation patterns. ^{46 , 47} The posterior fossa tumors have been designated group A and group B. ⁴⁶ Group A tumors have an increased occurrence of chromosome 1q gain and group B tumors largely show chromosomal aberrations. Clinically, group A tumors are found in infants and young children. They are more commonly laterally placed, exhibit an infiltrative phenotype, have higher rates of recurrence, and confer poorer survival (overall survival 69%). Group B tumors mostly occur in adolescents and young adults and have a midline location. ⁴⁶ The overall survival of patients with group B tumors is 95%. Other molecular changes in ependymoma that confer a poor outcome include PI3K/Akt and epidermal growth factor receptor (EGFR) pathway activation and overexpression of hTERT and tenascin-C. ^{48 , 49 , 50 , 51} The occurrence of RELA fusion in supratentorial ependymoma refers to chromothripsis, causing fusion of the gene C11orf95 to RELA, which consequently activates the NF-κB transcription pathway. ⁴⁵

Clinical Presentation

Presenting features of patients with ependymomas depend on the size, anatomical location, and tumor grade. Posterior fossa tumors classically cause symptoms and signs of raised ICP secondary to obstructive hydrocephalus. Cerebellar and brainstem features may arise in patients with large or invasive tumors. Patients with tumors within the cervical spine present with myelopathic features, whereas those with tumors in the lower spine more commonly present with back pain. ⁴²

Perioperative Evaluation

Ependymomas are generally well-circumscribed lesions with cystic and calcified areas. MRI is the diagnostic modality of choice, and ependymomas are categorized into three variants based on MRI findings: mid-floor, lateral, and roof types. In the mid-floor type, the tumor develops from the obex, localizes only to the floor of the fourth ventricle, and is strictly exophytic. In the lateral type, the tumor develops from a lateral recess, extends into the cerebellopontine angle cistern, and involves the brainstem and CNs. In the roof type, the tumor develops from the inferior medullary velum and localizes to the roof of the fourth ventricle. ⁵² The lateral type is distinguished radiologically by the lateral displacement of the brainstem and an absence of tumor infiltrating the obex, whereas the mid-floor type displaces the brainstem anteriorly and involves the obex ⁵³ ( Fig. 17.3 ^{26 , 30} ).

Lateral tumors have been shown to confer poorer survival because of the difficulty in achieving GTR. ⁵² These tumors frequently extend into the cerebellomedullary or cerebellopontine cisterns and involve the inferior cerebellar peduncle, lower CNs, and posterior inferior cerebellar artery.

Leptomeningeal dissemination occurs most commonly in the lumbosacral region in 8 to 12% of patients. ⁵⁴ These lesions typically appear as nodular or diffuse enhancement along the surfaces.

Management

The management of ependymoma involves maximal safe surgical resection, treatment of persistent postoperative hydrocephalus, and focal radiotherapy. The extent of surgical resection is the most influential factor on tumor recurrence, overall survival, and progression-free survival. ^{54 , 55} However, GTR can be difficult to achieve in some infratentorial ependymomas because of tumor adherence to the floor of the fourth ventricle and involvement of eloquent structures, such as the brainstem, CN nuclei, and vasculature. The surgical adjuncts of neuronavigation, ultrasound, and neurophysiologic monitoring (sensory evoked potentials, motor evoked potentials, brainstem auditory evoked potentials, and electromyography) may assist in achieving GTR with reduced morbidity and mortality. ⁴⁰ The intraoperative finding of sustained CN activity on neuromonitoring or bradycardia resulting in hemodynamic instability indicates the need to limit further resection. ⁵⁶

Tumor recurrence in ependymoma patients is most commonly at the site of the primary tumor and a subsequent resection is advocated. Rates of metastatic spread have been noted to be higher on second recurrence. ⁵⁷ Radiotherapy is often delivered after a second surgery, as it has been shown to significantly increase progression-free survival. ⁵⁸

Postoperative adjuvant focal radiotherapy has been shown to improve progression-free survival in patients with ependymomas, particularly in cases of residual tumor or grade III histology. ⁴⁴ The benefit to patients with grade II histology in whom GTR is achieved is less clear. Recent evidence also suggests that the radiation effect on progression-free survival may be limited to tumors arising in the posterior fossa rather than in the supratentorial and spinal regions. ⁵⁹ Furthermore, patients with type B posterior fossa ependymomas have been shown to have a lower risk of relapse; it has therefore been suggested that a study be conducted to compare postoperative observation with irradiation in this cohort. ⁶⁰

Whole-brain or craniospinal irradiation is reserved for patients with disseminated disease, whereas conformal radiation is preferred for those with localized disease. The use of conformal radiation has helped reduce the radiation exposure to normal brain tissue, with corresponding improved neurocognitive outcomes. ⁶¹ In addition, proton-beam therapy has shown promising results in a retrospective study demonstrating comparable survival with reduced morbidity. ⁶² However, access to proton-beam therapy is limited internationally.

Postoperative combination chemotherapy is an effective treatment in up to 40% of patients with ependymomas. ^{63 , 64} However, the superiority of radiotherapy has resulted in chemotherapy being used primarily in children younger than age 3 years for whom radiation is ideally delayed.

Limited efficacy has been demonstrated in treating recurrent ependymomas with targeted therapies, including EGFR inhibitors, farnesyltransferase inhibitors, integrin antagonists, and mechanistic target of rapamycin (mTOR) inhibitors. ⁵⁰ Decitabine, a DNA-demethylating agent that affects tumor epigenetics, has shown promise in a preclinical study of patients with group A posterior fossa ependymomas. ⁶⁵