ABSTRACT: Although they represent the most common malignant brain tumor in the pediatric population, medulloblastomas are rare in adults, with an incidence of 0.5 per million. With only one exception, all of the prospective clinical trials in this disease have been done in the pediatric population, and therefore therapy for adult medulloblastoma has been either extrapolated from the pediatric literature or based on retrospective reviews. A growing body of literature underscores the genetic similarities between adult and pediatric disease, which may allow tailored therapy directed towards specific molecular pathways and may have an impact on clinical outcomes. Here we present the history, staging system, and treatment of medulloblastoma, reviewing the prognostic value and clinical application of molecular subtyping while highlighting the differences between adult and pediatric disease.
Almost 90 years ago, in June 1924, Harvey Cushing and Percival Bailey presented on the tumor “spongioblastoma cerebelli” at the American Neurological Association meeting, describing tumors they believed to arise from embryonal rests of undifferentiated cells within the roof and ependymal lining of the fourth ventricle. Although “spongioblastoma” aptly described the soft, “suckable” gross surgical qualities of the tumor, they abandoned the title in favor of “medulloblastoma” based on a paper by Shaper in 1897 that suggested the medulloblast as one of five types of stem cells populating the primitive neural tube.[2,3] Cushing reported that his medulloblastoma patients had a mean age of 11 years, and while those with midcerebellar and vermis region tumors averaged 8.3 years of age, he noted that patients with lateral cerebellar hemispheric involvement had a much higher average age of 31 years.[1,4] This description was one of the first of several differences between pediatric and adult disease to be reported, although it was not consistently confirmed in other studies. Medulloblastomas are rare in adults, with an incidence of 0.5 per million, and comprise 2% of primary brain tumors in young adults between the ages of 20 and 34 years. Children born prematurely have been noted to have a higher incidence of medulloblastoma (ratio 3.1); however, no environmental risk factors have been reliably identified. Medulloblastoma is associated with several familial genetic syndromes, including Li-Fraumeni syndrome, Gorlin syndrome (nevoid basal cell carcinoma syndrome), Turcot syndrome, and Rubinstein-Taybi syndrome. Clinical features include truncal ataxia, gait disturbances, and symptoms reflective of increased intracranial pressure caused by obstruction of cerebrospinal fluid (CSF): headaches, vomiting, and lethargy.
Unlike the majority of primary brain tumors in adults, medulloblastomas require staging, as they often disseminate along the neuroaxis. Medulloblastomas are “small round blue cell” tumors and have the capacity to behave in a highly invasive/metastatic manner. The majority of medulloblastomas originate within the posterior fossa, where they can infiltrate across the ependymal lining into the brainstem or “drop” into and disseminate within the CSF. Thus, staging requires complete imaging of the neuroaxis with magnetic resonance imaging (MRI) to exclude subarachnoid metastases, and a lumbar puncture for CSF cytology done either prior to surgery or at least 10 to 14 days afterwards, so that cells dislodged during surgery are not misinterpreted as truly disseminated disease. Postoperative MRI of the brain within 24 to 48 hours should also be done to determine the extent of resection and the amount of residual disease.
The Chang staging system (Table 1) was published in 1969 and denoted T stage, the size and invasiveness of the tumor at resection, as well as M stage, the extent of spread outside of the posterior fossa. Patients with M0-1 and T1-2 disease fared best, and only 1 patient of 30 was denoted to have M2 or M3 disease. In the present day, T staging does retain a prognostic role in adult medulloblastoma, as suggested in a prospective trial and in a large retrospective series.[10,11] M staging has shown prognostic importance in many studies, although some studies have not found a significant difference between M0 and M1 disease.[8,12,13] “Modified” Chang staging is the current standard and refers to the addition of imaging to stage these tumors, which were originally staged only surgically.Medulloblastoma is denoted as having greater or lesser risk, according to the likelihood of disease recurrence, although the terms associated with risk vary in the literature. Those in the better prognostic group have interchangeably been called “low risk,” “standard risk,” or “average risk,” and those in the poorer prognostic group are usually referred to as “high risk” or “poor risk.” To add further confusion, studies have varied in the parameters by which patients are assigned to risk groups. It is generally agreed that patients without metastases have a lower risk of recurrence, although the presence of postoperative residual disease as a prognostic factor is a matter of debate. In the pediatric literature, this appears to be true particularly for patients over 3 years of age with M0 disease, however, the most recent studies in adults have not shown a difference in survival for those with residual disease[11,12,14-21] (Table 2).
The most recent World Health Organization (WHO) classification was amended in 2007 and now recognizes five variants of medulloblastoma: classical, desmoplastic/nodular, medulloblastoma with extensive nodularity, anaplastic, and large-cell. Medullomyoblastoma describes any variant with rhabdomyoblastic elements. The likelihood of hemispheric involvement increases with age, and some series showed a prevalence of desmoplastic/nodular histology. Desmoplastic histology generally is associated with a better outcome, while large cell/anaplastic histology is associated with a poor prognosis, although this has been demonstrated primarily in pediatric disease. Since the prognostic role of histology is controversial, in recent years specific molecular subtypes and key survival and growth pathways for these tumors (ie, sonic hedgehog [SHH] pathway–activated tumors) have been researched. Given their prognostic significance and potential to influence treatment in the era of molecularly targeted therapies, subtype analysis provides complementary information and may be more clinically relevant than histologic diagnosis alone.
Recent advances in molecular genomics in the last decade have allowed for the comprehensive molecular profiling of medulloblastoma and other brain tumors. Two recent studies developed distinct molecular classifications of medulloblastoma seen in both children and adults, with implications for future molecularly targeted therapeutic clinical trials. Northcott and colleagues used integrative genomics to identify four specific molecular variants of medulloblastoma: WNT (wingless), SHH, Group 3, and Group 4. These four types have subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations (see Table 3; adapted from references 21–24). SHH tumors were seen in infants and adults, whereas WNT and Group 4 tumors were seen among patients of all ages. In a separate analysis of adult medulloblastoma, Remke et al used gene expression profiling to reveal three distinct molecular variants, with distinct demographics, genetics, transcriptome, and prognostic implications: SHH, WNT, and subtype D. Both overall survival (OS) and progression-free survival (PFS) were superior for WNT-driven tumors and intermediate for SHH-driven tumors, while patients with subtype D tumors trended toward shorter survival times. In the Northcott study, Group 3 tumors peaked in childhood, were not seen in adults, and conferred the poorest prognosis, independent of metastatic status.
At a recent meeting, a consensus was reached to refer to the four subgroups as SHH, WNT, Group 3 (also known as subtype C), and Group 4 (also known as subtype D), in order to avoid confusion. While some studies have not found Group 3 tumors among adult cases, others have identified a very small percentage of Group 3 tumors representing less than 2% of all adult medulloblastoma cases. The most common medulloblastoma subtype in adults is the SHH subtype, which accounts for 58% of all adult medulloblastoma cases—although interestingly, these tumors are genetically and transcriptionally distinct from childhood tumors with SHH pathway activation. MYCN gene amplifications and 10q deletions are rare in this group compared with their incidence in pediatric SHH tumors. Group 4 represents 28% of adult medulloblastomas. WNT tumors occur less commonly, in approximately 13% of cases. Because of the inherent difficulty and expense of molecular profiling in real time, efforts are underway to translate tumor subtype identification using gene expression data into a more readily accessible technology such as immunohistochemistry (IHC). IHC for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group 3), and KCNA1 (Group 4) could appropriately classify formalin-fixed medulloblastomas in about 98% of patients. It is important that these subtype classifications have not been prospectively validated. Notably, subtype analysis may not be confidently determined using a single IHC marker per subtype. Given the molecular heterogeneity of tumors, multigene predictors using real-time polymerase chain reaction (PCR) on RNA isolated from formalin-fixed, paraffin(Drug information on paraffin)-embedded (FFPE) samples may more reliably identify subtypes, and this procedure is routinely performed by the Radiation Therapy Oncology Group (RTOG) Brain Tumor group.