High‐grade gliomas: Babies are not small adults! (commentary on Sanders et al., pp 888)

H igh-grade gliomas (HGG) are by and large life threatening tumours in adults with a median survival of less than one year from diagnosis. Consensual favourable prognostic factors have been reached in adult cohorts: lower grade (e.g., anaplastic astrocytoma vs. glioblastoma), adequate surgical removal, primary location (e.g., hemispheric tumours vs. deeply seated tumours) and IK over 70%. MGMT methylation status, presence of 1p19q deletion and levels of telomerase activity were recently shown to provide accurate prognosis. HGG in children may be somewhat less aggressive and with ambiguous prognostic factors compared to adults. For several reasons HGG in toddlers represent an entirely different entity, our understanding lacking adequate international consensus. The report by Sanders et al. [1] adds a lot to our knowledge of this specific sub-population. The one and foremost question is whether typical glioblastoma multiforme (GBM) or anaplastic astrocytoma as observed by the pathologist truly represent the same entity in babies, children and in adults. The recent publication by Faury et al. [2] sheds some light on the specificity of paediatric HGG. There are at least two subsets of paediatric GBM: both over express Y-box protein-1 that may help drive oncogenesis. However, the first subset is closer to its adult counterpart (e.g., Ras and Akt pathway activation, increased expression of genes involved in cell proliferation including neural stem cells, and very poor prognosis) whereas the second has no known association with Akt or Ras pathways, may originate from astroglial progenitors and behaves more favourably in children despite its lack of similarity with genes and markers usually associated with long-term survival in adults with GBM. It would be fascinating to investigate these findings in babies as well. Unfortunately, the extreme rarity of this tumour (16 patients in 20 years in a major onco-paediatric institution) makes it unlikely to even fulfil the statistical considerations for a solid retrospective analysis in this cohort. Common wisdom among pathologists has that paediatric HGG are misleading entities. Many series from the US and Europe conclude that features from low-grade gliomas may mimic HGG [3]. This may somehow explain the relatively better prognosis of HGG in children compared to adults. Along those lines, undifferentiated tumours such as atypical teratoid rhabdoid tumours (ATRT) and medulloblastomas are often confused with HGG in toddlers as seen in the present series. A special mention should be made for infratentorial gliomas. This location is extremely rare in adults but represents 20% in this and other series. Here again, it would be fascinating if specific markers were to be identified in this particular site (similarly to the site specificity that was demonstrated in ependymoma, for instance [4]). One may wonder whether an altered cerebellar developmental process contributes to this disease. Standard treatment strategy in adults uses surgery whenever feasible followed by radiation therapy and chemotherapy. Twometa analysis suggest that the addition of nitrosourea-containing regimen provides a modest albeit significant advantage in terms of overall survival [5]. Temozolomide administered concomitantly with radiation therapy and monthly for 6 months thereafter was recently shown to significantly improve survival mostly in adults with an IK over 70% and in whom large surgical tumour excision had been possible [6]. This benefit is still lacking demonstration in children. Pioneering work by Duffner et al. [7] indicating that postponing or avoiding radiation therapy is safe in toddlers has now been widely accepted—a fact to share with parents during the initial diagnostic talk. The major long-term neuro-psychological sequelae and the devastating quality of life reported in the current retrospective series provide further evidence in favour of refraining from front line radiation therapy. Recent reports suggest however that very young children with ependymoma or medullobastoma can sustain irradiation to the posterior fossa with minimal side effects [8]. Whether this approach can be applied to HGG of the posterior fossa remains to be seen. Most current prospective series use systemic therapies with or without intrathecal chemotherapy. Whether or not tyrosine kinase inhibitors or anti-angiogenic compounds will provide a major breakthrough in the field warrants further investigation in both adults and children. Unfortunately, recent published work report that alterations in PTEN and amplification of EGFR are uncommon in paediatric malignant gliomas contrary to those of adults [9]. This should not alleviate the controversy aswhethermolecularly defined, targeted drugs validated in adults with HGG should be proposed in children without a proven biological substratum. Time is due for international cooperation for the treatment of toddlers with HGG—an orphan disease in its own rights. A key preliminary step would be to compare biological features on tumour samples from children and adults. As importantly, we should retrospectively analyse our national treatment guidelines in order to fuel our discussions on a future prospective international trial.