**1.2. Clinical presentation and diagnosis**

with drug resistance remain significant concerns. For the clinician, one of the challenges to treating medulloblastoma is its complexity as it may be grouped either histologically or molecularly. Currently, there are four molecular subgroups of medulloblastoma, each of which

Medulloblastoma is classified as a primitive neuroectodermal tumor, typically occurring in the cerebellar vermis which is located in the posterior fossa of the skull (**Figure 1**) [1]. This tumor accounts for 40% of those arising from the posterior fossa [4]. Medulloblastoma is the most common malignant central nervous system (CNS) tumor of childhood, comprising 15– 30% of pediatric CNS tumors and 1–3% of adult CNS tumors [5]. Medulloblastomas can affect any age group, although the majority (85%) occurs in childhood, and of those half occur between the ages of 4–9 [6]. Tumors most often arise sporadically, although they may arise as part of inherited disorders such as Li-Fraumeni, Turcot, or Gorlin syndrome [7]. The cellular origins of medulloblastoma differ by the tumor subgroup (described below). For example, medulloblastomas of the sonic hedgehog (SHH) subgroup arise from granule neuron progenitors (GNPs) that reside in the outermost layer of the cerebellum [8]. Wnt-subgroup medulloblastomas, on the other hand, arise from lower rhombic lip precursors in the brain‐

**Figure 1.** Medulloblastoma is a primitive neuroectodermal tumor commonly arising in the cerebellar vermis. The left image is a sagittal view of an MRI for a pediatric patient. The right image is a horizontal view of an MRI showing tumor growth towards the right cerebellar hemisphere, with displacement of the vermis. Copyright © 2014 from *Ped‐ iatric medulloblastoma—update on molecular classification driving targeted therapies* (DeSouza, Jones, Lowis and Kurian,

contains specific genetic or cytological backgrounds which may impact prognosis [3].

**1.1. Origin and epidemiology of medulloblastoma**

382 Neurooncology - Newer Developments

stem [9].

Front. Oncol. 2014).

Given that the cerebellum is located against the fourth ventricle, tumors arising from it result in mass effect and hydrocephalus. Consequently, patients initially diagnosed with medullo‐ blastoma present most commonly with symptoms of elevated intracranial pressure—chronic progressive nausea, vomiting, and headache [10]. These symptoms can progress to altered mental status, sensorimotor symptoms, and cerebellar symptoms if left untreated [10]. Children and infants may present instead with nonspecific lethargy and weakness. Neuro‐ logical signs, often subtle, may be present for 3 or more months before diagnosis [11].

Medulloblastoma metastasizes most commonly to the spinal cord. In an international metaanalysis of medulloblastoma, metastatic disease was identified in 103 of 432 patients (24%) on initial diagnosis [6], although the incidence was much lower in adults (2%). Metastatic disease was most common in Group 3 and Group 4 medulloblastomas (30 and 31%, respectively), while much lower in the Wnt group (9% of children) [6].

Although a biopsy specimen is required for definitive diagnosis of medulloblastoma, brain magnetic resonance imaging (MRI) with gadolinium is the preferred imaging modality to best characterize lesions suspected to be medulloblastoma. Brain MRIs allow for greater resolu‐ tion of soft tissue with less interference from bone compared to computed tomography [12]. MRI findings associated with medulloblastoma can have varying enhancement patterns and intensities. Imaging can also identify areas of hemorrhage, calcification, or findings that suggest leptomeningeal metastasis [12]. It has been suggested that certain MRI findings may be more associated with certain histopathological subtypes [12].

#### **1.3. Current conventional treatments and treatment considerations**

Once identification of suspected medulloblastoma has been made on imaging, a decision needs to be as to how tissue sample should be accessed. The current standard of care is to resect as much of the lesion as possible if able to do so in a safe manner [13]. If it is deemed unsafe to do so, a stereotactic biopsy of the suspected lesion would allow for a confirmatory patholog‐ ic diagnosis. Once tissue has been obtained, the patient must be reassessed and assigned to the standard-risk group or high-risk group which informs subsequent patient treatment regi‐ men. The goal of this treatment regimen, which includes chemotherapy with or without chemoradiation, is to treat disease that may not have been fully resected by surgery.

In order to place patients into one of these groups, additional imaging is required postopera‐ tively, as well as cerebrospinal fluid (CSF) analysis and adequate pathologic specimen. Specifically, these two risk classifications are defined by size of residual tumor following resection and status of metastasis [14]. Standard-risk groups are less likely to have tumor recurrence following resection, while high-risk groups are more likely to have tumor recur‐ rence.

Standard-risk medulloblastoma occurs in 70% of patients [15]. Although prospective random‐ ized trials comparing radiotherapy alone to combined chemoradiation for treatment of standard-risk medulloblastoma have not been performed, combined therapy is currently the standard of care of standard risk medulloblastoma [16]. Patients in this risk group are typically treated with a combination of chemotherapy followed by radiation, although radiation therapy alone has been used [15, 17, 18]. Multiple protocols exist for the chemotherapeutic treatment of medulloblastoma. One chemotherapeutic regimen includes treatment with a combination of vincristine, cisplastin, lomustine, and cyclophosphamide alongside radiation therapy over about a 1-year period [15]. High-risk or unresectable tumors are also treated with chemora‐ diation. Infants (<3 years old) are typically not treated with radiation owing to intolerability of side effects.

Risk stratification of medulloblastoma patients has improved cure rates for high-risk cases and limited radiation therapy exposure in treatment regimen for standard-risk patients, thereby reducing side effects. Nevertheless, even with improved cure rates for patients, long-term sequelae of treatment remain a concern. Radiation therapy has been associated with long-term neurocognitive deficits, cytopenias, opportunistic infections, and secondary malignancies [15, 19]. Children are especially sensitive to the adverse effects of radiation therapy, and as such radiation doses for treatment are lower for pediatric than for adult patients [15].

Long-term chemotherapy too has known side effects that have been described extensively elsewhere and include neurocognitive impairment, hearing loss, endocrine perturbations, cardiac and respiratory conditions, and secondary malignancies [15, 20]. Moving forward, further studies need to be performed to optimize current treatment or to identify new therapeutics to minimize side effect profile. Classification of medulloblastoma subgroups, for instance, focuses research toward drug targets within molecular pathways driving these subgroups. These subgroups are described in detail below.

#### **1.4. Prognosis**

In one trial of pediatric medulloblastoma, 10-year event free survival (EFS) and overall survival (OS) rates were 75 and 80%, respectively, for kids with standard-risk medulloblasto‐ ma treated with radiation followed by chemotherapy [21]. In another trial, 5-year EFS ranged from 65 to 70% in patients who received both chemotherapy and radiation following tumor resection [13]. Treatment with radiation therapy alone had survival rates 50–65% even with higher dose radiation [21, 22].

In comparison to pediatric medulloblastoma literature, studies assessing the treatment of adult medulloblastoma are rare. One retrospective study of adult medulloblastoma treated with chemotherapy and craniospinal radiation identified a 4-year EFS of 68% [18]. Other studies have identified survival rates of 40–80% [23].

Relapses most likely occur within the first 2 years of diagnosis, with one-third occurring within the first 3–5 years [21]. Earlier relapses are more likely to be associated with metastatic disease [21], while later relapses (>5 years after diagnosis) were more likely to be related to local disease. The posterior fossa is the most common site of relapse. Relapses must be distinguished from secondary tumors. Secondary tumors can occur following radiation, either at sites of prior irradiation or at extracranial sites near sites of primary radiation (thyroid, bone, etc.). One study identified a 4.2% 10-year cumulative incidence of secondary tumors follow‐ ing treatment with chemoradiation [21]. Increased use of mutagenic chemotherapy has also been suggested to play a role in the increasing incidence of secondary tumors following treatment of medulloblastoma.

Molecular subgrouping of medulloblastoma plays an important role in prognosis. In brief, the Wnt subgroup demonstrates the most favorable prognosis, whereas Group 3 medulloblasto‐ mas present the worst. Other factors that may affect prognosis include stage and complete or incomplete resection of tumors [18].
