It is the most common malignant pediatric intracranial tumor.
Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment related morbidities.
Medulloblastoma, genetically defined
Under the current consensus classification of medulloblastoma four principle subgroups are identified:
Medulloblastoma WNT activated
Sonic hedgehog Medulloblastoma and TP53 Mutant
Medulloblastoma non WNT/non SHH
Group 4 medulloblastoma
Medulloblastoma, histologically defined
The data show that medulloblastomas of Group 3/4 differ metabolically as measured using Magnetic resonance spectroscopy (MRS) when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups 1).
The evidence suggests that each of the four principle subgroups will likely have distinct ‘subsets’ that are biologically and clinically homogeneous as compared to other subsets from within the same subgroup. As the nature and number of subsets for each subgroup are currently unknown, the consensus classification suggests that each subset be named using a Greek letter (α, β, γ, etc.) until such time as they are sufficiently characterized to be named based on their molecular etiology 2).
Several lines of evidence implicate granule neuron precursors (GNP) in the external granule layer (EGL) of the developing cerebellum as likely cells of origin for certain classes of medulloblastomas.
1). For example, cells that compose a preneoplastic stage of medulloblastoma colocalize with GNPs in the EGL and they express molecular markers of immature granule neurons ( 2). Another possible medulloblastoma cell of origin has been identified: a neural progenitor located in the cerebellar white matter and expressing both nestin and prominin ( 3). Signal transduction pathways that stimulate proliferation and inhibit differentiation of GNPs and other neural progenitor cells during development have been implicated in medulloblastoma. Thus, understanding the mitogenic functions of these pathways will yield insights into medulloblastoma formation.
The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation. Two known mitogens for neural progenitors are the c-Myc oncoprotein and Sonic hedgehog (Shh), a crucial determinant of embryonic pattern formation in the central nervous system.
Several genes have been implicated in the development of medulloblastoma in children, including Patched-1 and Smoothened. The protein products of these genes function within the sonic hedgehog molecular signaling pathways, which are important in neural development and disease.
Combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis 4).
Both pathways are essential regulators of granule neuron precursors (GNP) proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3beta-dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown
Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma 5).
Cerebrospinal fluid (CSF) dissemination to the cranio-spinal axis occurs in 30% to 40% of cases 6).
It appears as a homogenously enhancing hyperdense mass on computed tomography scan and is associated with the clinical picture of posterior fossa syndrome. This unique clinic-radiological pattern in considered “typical” medulloblastoma, but medulloblastomas does not follow the typical clinic-radiological pattern in a significant number of children and adult cases and should be considered in all midline posterior fossa tumors, hemisphere and cerebellopontine angle despite having clinical and radiological features suggestive of other tumors. Definitive diagnosis requires histologic confirmation in all cases 12).
Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing 13).
Enhancing medulloblastomas exhibited strong VEGFR1/2 and CD31 expression relative to nonenhancing tumors. There was no significant difference in perioperative complications or patient survival between the 2 groups.
These results suggest that in patients with medulloblastoma the presence of enhancement on MRI may correlate with increased vascularity and angiogenesis, but does not correlate with worse patient prognosis in the short or long term 14).
Apparent diffusion coefficient
Using only apparent diffusion coefficient (ADC) values measured on ADC maps. One hundred and three pediatric patients with pre-operative magnetic resonance imaging scans showing a posterior fossa tumor with histological verification were retrospectively identified from a ten-year period at a tertiary care medical center. A single observer measured the lowest ADC values in all tumors to determine the mean minimum ADC (ADCmin) value that provided greatest accuracy in distinguishing medulloblastomas from other tumors, which was determined to be 0.66×10(-3) mm(2)/s. Imaging studies, including ADC maps, from 90 patients were provided to two neuroradiologists, who provided a diagnosis, which was later dichotomized as medulloblastoma or other. Two medical students measured ADCmin within tumors and those with ADCmin < 0.66×10(-3) mm(2)/s were recorded as medulloblastoma; any other value was recorded as other. Diagnostic accuracy was measured. ADCmin values allowed a correct identification of lesions as either medulloblastoma or other in 91% of cases. After diagnoses by the two neuroradiologists were categorized as either medulloblastoma or other, their diagnoses were correct in 90% and 84% of cases, respectively. In 19 cases, at least one neuroradiologist was incorrect; the addition of ADC values to clinical interpretation would have allowed a correct diagnosis in 63% of such cases. Diagnostic accuracy based on ADC values by medical students was comparable to that of subspecialty-trained neuroradiologists. This findings suggest that the addition of ADC values to standard film interpretation may improve the diagnostic rate for these tumors 15).
Both ADCmin and nADC could serve as the basis for a CAD program to distinguish medulloblastoma from other posterior fossa tumors with a high degree of accuracy 16).
Usually arises from the floor of the 4th ventricle
Typically squeezes out the foramen of Luschka
Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.
Surgical resection is undertaken with the goal of gross total resection. Postoperative neuroimaging studies are compared with preoperative studies to determine the amount of residual disease.
The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection 17).
Cerebrospinal fluid is obtained from a lumbar puncture done at the conclusion of the surgical resection or 2 weeks after surgery in order to determine microscopic leptomeningeal spread. Children are enrolled, when possible, in open clinical trials.
Chemotherapy and radiation
Chemotherapy and radiation are given as per protocol. The goal of current treatment approaches is to tailor therapy based on clinical risk factors, with intensification of treatment for children with high-risk disease and reduction of radiation therapy for those with standard-risk disease.
Chemotherapeutic trials have been developed to assess the safety and efficacy of various multi-agent therapies to improve the poor results of high-risk patients and to allow reduction in the dose of radiation needed to cure standard-risk patients, which may allow a decrease in late cognitive sequelae. Currently, it is policy to evaluate all children with posterior fossa tumors characteristic of medulloblastoma with preoperative, staging neuroimaging studies of the craniospinal axis.
Although surgery, radiation and high-dose chemotherapy have led to increased survival, one-third of patients succumb to their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment.
Through analysis of several well-designed multi-institutional trials, much has been learned about the clinical factors that influence outcome in children with medulloblastomas. Age younger than 3 years, bulky residual disease postoperatively, and metastasis constitute adverse prognostic features and indicate patients who are considered “high risk” for recurrence with standard therapy using 3600 cGy craniospinal radiation in conjunction with a posterior fossa dose of 5400 cGy. Patients lacking these features are considered “standard risk.”
Evaluation of biologic predictors of outcome, which may further refine treatment stratification, is in progress.
Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), Cerebrospinal fluid cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined.
Warren et al. recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other RANO recommendations, these need to now be prospectively validated in clinical trials 18).
A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in a study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients’ median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months).
At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p < 0.001), older age (≥ 3 years) at diagnosis (p = 0.010), gross-total resection (p = 0.012), annual family income higher than $3000 (p = 0.033), and living in urban areas (p = 0.008) were favorable prognostic factors. Multivariate analysis revealed that postoperative RT combined with chemotherapy was an independent prognostic factor (p < 0.001). The treatment abandonment rate in this cohort was 31% (21 of 67 cases).
There was a large gap between the outcome of medulloblastoma in Chinese children and the outcome in Western children. Based on this data, treatment abandonment was the major cause of therapeutic failure. Parents’ misunderstanding of medulloblastoma played a major role in abandonment, followed by financial and transportation difficulties. Establishment of multidisciplinary treatment teams could improve the prognosis of medulloblastoma in Chinese children 19).
Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases.
The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups 20).
Sure et al describe the incidence of secondary tumour manifestations in 66 patients of a single centre who underwent surgery for medulloblastoma between 1975 and 1990. No patient was excluded due to a poor postoperative course. Thirty-five patients showed evidence of secondary tumour growth. Of these, 17 suffered from local recurrence, and 27 developed metastastatic disease. The median latencies for secondary manifestations were 25 months for local recurrence (n = 17), 11 months for spinal metastases (n = 10), 15 months for supratentorial metastases (n = 8), 8 months for subleptomeningeal dissemination (n = 6), and 23 months for systemic metastases (n = 8). Two patients developed primary metastatic spread to the posterior fossa. Of 8 patients with supratentorial metastases, 6 developed fronto-basal lesions. In our patients, 89% of secondary lesions occurred within less than 3 years after primary diagnosis. 85% of patients with extra-axial tumour spread had been treated with a permanent shunt. Radical tumour resection and radiotherapy with 30 Gy to the neuraxis and 20 Gy boost to the posterior fossa was an important prognostic factor in this series. Patients with additional chemotherapy did not benefit significantly from this treatment. We conclude that optimal management of the primary lesions should aim at (i) total resection, (ii) avoid permanent shunting, and (iii) completion of the radiotherapy with inclusion of the medial frontobasal cisterns in the radiotherapeutic regimen. Our analysis suggests that adequate postoperative screening programmes should consist of 3-monthly scans of the neuraxis in the first three postoperative years and 6-monthly scans thereafter 21).