Neuropathology and Applied Neurobiology (2015), 41, 106–108
doi: 10.1111/nan.12193
Editorial
Medulloblastoma: selecting children for
reduced treatment
A major challenge in paediatric neuro-oncology is to
accurately predict the outcome for an individual patient.
Particularly, so those patients with a good prognosis can
avoid life-long complications of intensive treatment. In a
paper in this issue of the journal, Goschzik and colleagues investigate the best way to do this in medulloblastoma, the commonest malignant brain tumour in
children [1].
Survival rates for children with medulloblastoma are
impressive compared with many malignant brain tumours
but complications of treatment are frequent and the children carry the burden of this disability, potentially for the
many years of their adult life [2–5]. For example, one study
found significant impairment on neuropsychological
testing in more than 50% of medulloblastoma survivors
[5]. Therefore, there is a pressing need to be able to identify
children for whom treatment might be reduced without
increasing the risk of tumour relapse.
David Ellison, Steve Clifford and colleagues first showed
in a trial cohort that activation of the WNT signalling
pathway could be used to identify a subgroup of paediatric
medulloblastoma with an excellent prognosis [6]. They
found that patients with WNT activation had a 5-year
overall survival of 92.3%, compared with 65.2% in
patients without WNT activation. This result has subsequently been replicated in several studies [7–11].
However, the data available suggest that adults with WNTgroup medulloblastoma may not benefit from the same
survival advantage as children [12].
The almost universally good prognosis in WNT-group
medulloblastoma in children has led to the suggestion that
these patients could be offered less intensive treatment.
This hypothesis is being tested in the next set of clinical
trials both in Europe and the USA and it is likely that some
patients will seek reduced treatment off trial.
A significant problem is how to identify this low-risk
group with confidence. This is critical so that no child risks
relapse due to insufficient treatment and none suffer as a
Conflict of interest: The authors declare no conflict of interest.
106
consequence of unnecessarily aggressive treatment. Interestingly, in one focus group study, most parents of medulloblastoma patients stated a preference for ‘survival at all
costs’ with aggressive treatment regardless of subsequent
quality of life [13]. Finally, the success of trials to test the
effectiveness of reduced treatment depends on the accurate ascertainment of WNT-group cases.
WNT-group medulloblastoma can be identified by a
variety of techniques: nuclear accumulation of
β-catenin on immunohistochemistry, a mutation in the
β-catenin gene (CTNNB1), monosomy for chromosome
6, or by gene expression or methylation signatures [14–
19]. However, at present, it is unclear which of these, if
any, represent the best way to identify a WNT-group
tumour for clinical diagnosis or for trial design. For
example, WNT-tumours have been reported without
monosomy 6 or CTNNB1 mutations [6,16]. A particular
problem with staining for nuclear β-catenin is determining the percentage threshold of positive cells at which a
diagnosis of WNT subtype is made, an issue confounded
by variability in staining protocols and the subjective
nature of interpretation.
In this issue, Goschzik et al. have addressed these uncertainties by comparing three standard approaches:
immunohistochemistry for nuclear β-catenin, sequencing
of CTNNB1 and chromosome 6 copy number analysis.
In addition, they undertook tumour subtyping on
methylation arrays. In a large cohort of 186 cases, they
found that immunohistochemistry for nuclear β-catenin
(at a threshold of 5% of the cells) identified all the WNTgroup tumours (when compared with the other tests), suggesting that this a very sensitive screening test for
WNT-group tumours. However, their data suggest that
immunohistochemistry cannot be used definitively in isolation. In particular, they found that 3 out of the 21
tumours that were positive for nuclear β-catenin belonged
to non-WNT subgroups as judged by methylation profiling.
Interestingly, all three of these cases had β-catenin staining
that was close to the 5% threshold. The authors found that
all of the remaining 18 cases with >5% nuclear β-catenin
positivity had mutations in CTNNB1 but in contrast,
monosomy 6 was only present in 15 of the cases. On the
basis of this data, the authors recommend that patients are
© 2015 British Neuropathological Society
Editorial
Figure 1. Proposed strategy for risk stratification in paediatric
medulloblastoma. Patients with nuclear β-catenin positivity in >5%
of cells and mutant CTNNB1 are classed as low risk. Those with
MYC/MYCN amplification or anaplastic/large cell change are
considered high risk. Cases not matching criteria for either
category and without high-risk clinical features (e.g. metastatic
disease) are considered standard risk.
screened using β-catenin immunohistochemistry but that
positive cases are confirmed by a second technique, probably CTNNB1 sequencing.
While not seen in this study, previous investigations
suggest that some true WNT-group medulloblastomas
would be excluded by this approach because they are negative for a CTNNB1 mutation [19]. However, the approach
taken by Goschzik et al. avoids the danger of undertreating
children with non-WNT-group tumours and therefore
risking relapse. The techniques employed are conducive to
large cohorts and can be undertaken in real time in diagnostic practice in many labs. Therefore, the suggested protocol provides a practical way to introduce stratification
into trials and clinical practice (Figure 1).
T. J. Stone*†
T. S. Jacques*†
*Developmental Biology of Birth Defects Section, Developmental
Biology & Cancer Programme, UCL Institute of Child Health,
and †Department of Histopathology, Great Ormond Street
Hospital for Children NHS Foundation Trust, London, UK
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