Medulloblastoma became a curable disease during the 1970s with the combined use of maximal surgery and craniospinal radiotherapy. The standard use of chemotherapy has altered treatment paradigms, and recently new molecular stratifications have set the framework for the implementation of more tailored therapies. All these efforts have been justified by the need to improve the outcome of the most aggressive forms of the disease and the need to improve the neurocognitive outcome of the children, especially the younger ones. Our increased understanding of the molecular aspects and response to treatments makes it evident that medulloblastoma does not represent a single disease.
Medulloblastomas are the most common form of brain tumor seen in children, comprising almost 25% of all central nervous system (CNS) cancers before the age of 15 years of age. This tumor may present at any age (from birth until adulthood), but the majority are diagnosed between 5 and 10 years of age. Most series report a male predominance of 2:1. Most cases are sporadic, although familial cases have been described, most notably in the context of Gorlin syndrome.
Posterior fossa primitive neuroectodermal tumors (PNETs) are most commonly detected (in 75%) due to the presence of signs of raised intracranial pressure (RICP): headaches, vomiting, and, more rarely, convulsions. RICP in these cases develops due to an obstructive hydrocephalus, caused by a blockage of the fourth ventricle. Papilledema is not always present. Difficulty walking in the context of a cerebellar syndrome is often noted (60% of cases). Cranial nerve deficits or motor impairment indicate brainstem involvement. A general clinical deterioration may be present, with dehydration due to recurrent vomiting and anorexia. In up to one third of cases, the diagnosis is delayed due to the erroneous assumption that the signs are due to a psychological problem.1
In infants, medulloblastomas generally present with psycho-motor regression, which can be present several months before other signs of a posterior fossa tumor are noted. Asking the parents about the maximum level of development attained by the child often reveals premorbid developmental retardation.2 Clinical observations and animal models of medulloblastomas suggest that this type of tumor develops due to an anomaly in cerebellar embryogenesis.
Diagnostic delay is highly variable and not linked to the patient′s age. In a recent population-based study in the region of Paris, we found a median delay between first signs and diagnosis of 65 days (interquartile range 31 to 121 days), significantly longer in children presenting with psychological symptoms1 ( Table 35.1 ). A prolonged prediagnostic history is not associated with more aggressive disease presentation or outcome.3
Initial imaging features that indicate a medulloblastoma should lead to a complete imaging workup to rule out a metastatic disease preoperatively with a spinal magnetic resonance imaging (MRI) ( Fig. 35.1 ). A medulloblastoma is generally a median homogeneous mass filling the fourth ventricle, with peritumoral edema. Fewer than 20% are hemispheric. The tumor is spontaneously hyperdense on computed tomography (CT), that is, as cellular as the cerebellar cortex. Cysts and necrosis can be seen, but rarely calcifications ( Table 35.2 ). The tumor can show extension in the foramen of Luschka but rarely to the cerebellopontine angle. On MRI, due to its high cellularity, diffusion is restricted and signal on T1 and T2 resembles the signal of the cerebellar cortex. Contrast enhancement is frequently intense but less than in pilocytic astrocytoma. A macronodular aspect can be observed, especially in very young children, corresponding to the entity called medulloblastoma with extensive nodularity. Metastases can be either nodular or linear due to leptomeningeal dissemination, but they always show contrast enhancement. Disease extension and dissemination are categorized according to Chang′s classification. We have recently challenged the prognostic impact of this classification and suggested the need for its revision, to take into account the nodular or laminar appearance of the metastases.4 Multimodal magnetic resonance (MR) can offer further the arguments for the diagnosis of medulloblastoma by showing high choline, taurine, and glutamate on spectroscopy5 as well as increased relative cerebral blood volume (rCBV).
Raised intracranial pressure (ICP) (headache/vomiting), often due to hydrocephalus
Cranial nerve deficits
Psychomotor regression (infants)
Homogeneous mass in fourth ventricle with peritumoral edema
Hyperdense on computed tomography (CT)
Cysts/necrosis not uncommon
Variable contrast enhancement
Elevated choline, taurine, glutamate on magnetic resonance spectroscopy
Cerebrospinal fluid (CSF) analysis should be performed at least 10 days after surgery to detect clumps of tumors cells after cytocentrifugation.6 However, tumor cells in the CSF taken from the ventricles before surgery at the time of shunting can also detect the presence of disseminated disease.
Pathology and Biology
In 1925, Bailey and Cushing gave these tumors the name medulloblastoma because the tumoral cells resembled developing neural tube cells. Eighty years later this hypothesis was confirmed with identification and characterization of tumor stem cells in medulloblastomas.7–10 In 1985, Lucy Rorke included these tumors in the PNET category, although it is now recognized that their biology is completely different depending on their site of origin. Medulloblastoma presents as a highly cellular and proliferative neoplasm with a blastema appearance and express neuronal markers such as synaptophysin and neuronal nuclei antigen (NeuN). Myoblastic (as in medullomyoblastoma) or astrocytic differentiation (with glial fibrillary acidic protein [GFAP]-positive tumor cells) may be also present. In the last World Health Organization (WHO) classification of 2007, three subtypes of medulloblastoma were identified: (1) The desmoplastic subtype, which has the best prognosis, is associated with neuronal differentiation nodules separated by undifferentiated zones with a raised index of proliferation and an intense reticulin network around the nodules ( Table 35.3 ). This latter characteristic is a mandatory criterion for this subtype of medulloblastoma. Extensive nodularity can be seen in the very young.11 This subtype is seen in 15 to 20% of cases, and generally in children younger than 3 years of age. (2) The anaplastic/large cell subtype has the worst prognosis, but only represents a small proportion of medulloblastomas, around 10%. It can present at any age. (3) The standard (classical) form is the most common subtype, found in 70% of cases.
Using the genomic profile of medulloblastomas, it is possible to identify four biologically distinct subtypes, each of which is characterized by a specific signaling pathway that plays a role in cerebellar development12 ( Table 35.4 ). It has been recently emphasized that subtypes of medulloblastomas have distinct cellular origins within the cerebellum.13 The first group is characterized by a mutation in the β-catenin oncogene, a monosomy 6, and an activation of the Wnt signaling pathway. The histological aspect of this group is of the standard subtype, although there is also a nuclear accumulation of the mutated β-catenin protein, which can be detected by immunohistochemistry. The prognosis of this subgroup is excellent.14,15 The second group is characterized by alterations in the PTCH1 or SUFU genes, a loss of the long arm of chromosome 9 or 10, and an activation of the Sonic Hedgehog (SHh) pathway. This group corresponds with the desmoplastic form.16 The other groups are less well defined biologically. They overexpress genes involved in neuronal differentiation or photoreceptor genes, and they are associated with anomalies of chromosome 17, such as an isochromosome 17q. They are more frequently metastatic at presentation. The amplification of the oncogene c-myc is strongly associated with the anaplastic/large cell subtype and carries a poor prognosis. The proposed classification into four biological subtypes may be complicated by the introduction of some variants.17 It should be noted that the biological significance of the most frequent chromosomal alteration found in medulloblastoma, isochromosome 17, is still debated, although it is now accepted that chromosome 17p loss has an adverse outcome.18 Immunohistochemical markers have been proposed to classify the different subtypes of medulloblastomas and they will need to be validated prospectively.19 Accurate biological risk prediction will require the integration of complex parameters acquired by genome-wide analysis, including mutations. In this study, in addition to known mutations of p53 and of members of the SHh and Wnt pathways, a few new mutations were discovered, namely on histone-lysine N-methyltransferase genes MLL2 and MLL3 in 16% of cases.20
Well-differentiated neuronal nodules mixed in with undifferentiated zones
Intense reticulin network
Nodularity seen in very young children
The initial management consists of treating the hydrocephalus either by performing a ventriculocisternostomy several days before the definitive surgery,21 or by inserting an external ventricular drain directly prior to resection of the tumor. The benefits of the former are that it allows the posterior fossa to decompress, thereby limiting the peri- and postoperative complications.22 Apart from certain particular cases (such as large, infiltrating tumors with metastatic disease) or when chemotherapy is indicated to reduce tumor size preoperatively,23 surgery of the tumor is the first component of the treatment. It is extremely important to perform as extensive a resection as possible, particularly in the younger children, as a complete resection in their case may avoid the need to use radiotherapy.24,25 In older children, a subtotal resection is not clearly associated with outcome, although in some series, especially those not employing adjuvant chemotherapy, the presence of significant residual disease (arbitrarily greater than 1.5 cm) was associated with poorer outcome and treatment with high-risk therapeutic approaches. It is essential to evaluate the extent of resection with imaging within 72 hours of the operation to avoid difficulties in interpreting a potential residue due to postoperative inflammation.
Mutated β-catenin oncogene
Activated Wnt pathway
Altered PTCH1/SUFU genes
Activated Sonic Hedgehog
Amplification of c-myc oncogene
Altered photoreceptor gene
Loss of neuronal differentiation
Extent of dissemination
Extent of resection
Diffuse anaplastic; large cell
*Any one factor.
**Not found in all series.
For decades, the decision concerning the type of postsurgical adjuvant therapy was based on the completeness of resection and the presence or not of metastases. Metastasis is determined by pre- or postoperative total neuraxis imaging and CSF (lumbar) cytological examination. For children older than 3 years of age, two major risk groups were identified ( Table 35.5 ). Biological risk factors are increasingly used to stratify the treatment options ( Table 35.6 ). It is therefore of paramount importance to obtain adequate material for the biological workout, that is, frozen material in addition to sufficient formalin-fixed tumor.
Craniospinal radiotherapy has been the mainstay for the adjuvant treatment of medulloblastoma in the past 30 years. It is classically performed with single daily fractions totaling 36 Gy, together with a boost on the posterior fossa totaling 55 Gy.
Reduced Craniospinal Radiotherapy
In average-risk patients (i.e., completely or subtotally resected, without metastasis, and age over 3 years), the adjunction of 1 year of chemotherapy after radiotherapy has enabled the safe reduction of the CSI dose from 36 to 23.4 Gy,26 whereas there was an increased risk of early relapse in patients who did not have chemotherapy.27 The benefit in terms of neuropsychological outcome has been largely demonstrated, although there often is still some degree of cognitive loss, especially in children younger than 8 or 9 years of age. Refinement of this strategy using conformal radiotherapy of the tumor bed to deliver the boost has been recently tested by the Children′s Oncology Group (COG) after the excellent results obtained by the St. Jude Children′s Research Hospital, albeit at the expense of a very intense chemotherapy.28