This study has shown that the metabolite and lipid levels of tumours, detected non-invasively by short echo time MRS at diagnosis, predict survival in a cohort of children with brain tumours. Our results confirm that tumour lipids, previously reported as a prognostic biomarker,28
are robust in this larger cohort. Furthermore, due to the shorter echo time (30 ms) used in this study, we were able to identify glutamine and scyllo-inositol as useful prognostic markers.
Our study found that the combination of lipids, glutamine and scyllo-inositol were able to predict survival with a similar accuracy to histologic grade (). Most paediatric brain tumours undergo surgery; therefore a histologic grading is often available. However, MRS provides additional prognostic information on the tumour, which may strengthen, or challenge that obtained from histopathology and other tests. Where a tumour associated with a favourable prognosis has an MRS profile implying a more aggressive course, treatment intensification may be considered. For tumours that are not biopsied, approximately a quarter of all cases, prognostic information is still available from MRS since it is a non-invasive technique. Where this information contradicts that available from other methods, such as conventional imaging, an argument could be made for biopsying the tumour or altering the treatment plan. In addition, tissue biopsy may present a risk of morbidity for tumours in certain locations and MRS can provide important non-invasive information for these cases.
Many children with brain tumours are treated on sophisticated protocols which stratify patients on an increasingly complex set of prognostic markers combining clinical information, conventional imaging, histological markers and more recently tumour biology. The role of MRS within this process needs to be determined by its inclusion in large multi-centre clinical trials and this study demonstrates the importance of including MRS in such trials.
A strong association between MRS detectable lipids and tumour grade has been reported in adult gliomas19–21
and childhood brain tumours22
suggesting that high intracellular lipid levels are a non-invasive marker of brain tumour malignancy. Work on cultured cells, tumour tissue ex-vivo
and animal models have shown that an increase in MRS detectable lipids is associated with cell stress,29
and hypoxia as a result of compromised vascularity.31
MRS detectable lipids are therefore associated with several factors known to be present in aggressive tumours that have a poor prognosis.
The link between lipids and malignancy is expected since one of the key requirements for rapidly proliferating cells is a boost in lipid synthesis, providing constituent molecules for cellular membranes. The recent work of Metallo et al.32
has shown that glutamine, rather than glucose, is the major carbon source for lipid synthesis in A549 adenocarcinoma cells under hypoxic conditions through a previously underappreciated pathway. In our work, intra-cellular glutamine has been shown to be a prognostic marker of survival in paediatric brain tumours, supporting evidence of its importance to tumour proliferation. Furthermore, an inverse correlation between intra-cellular glutamine and mobile lipids has been shown () supporting recent studies linking glutamine and lipogenesis.33
illustrates the variance of glutamine and lipids present in medulloblastoma, and further work is warranted to investigate therapeutic targeting of these pathways.
The MRS measurement of glutamate and glutamine is difficult at 1.5 T, due to their overlap with other signals. However, two recent studies comparing high-resolution in-vitro
have shown a good correlation between the techniques for these metabolites, suggesting that their prognostic strength is high enough to outweigh the inaccuracy in their measurement. Further in-vivo
MRS studies using higher field strengths, such as 3 T which are now commonly available in clinics,36
optimised acquisition parameters37
and advanced analysis methods8
will improve the detection accuracy of these and other metabolites in clinical practice.
In addition to lipids and glutamine, N-acetyl aspartate and scyllo-inositol were found to be significant prognostic markers. N-acetyl aspartate is commonly used as a marker of neuronal density and viability and has been noted in a previous study as a potential prognostic marker when combined with choline.28
The exact function of N-acetyl aspartate in tumours is unknown. In diffuse tumours it may indicate the level of entrapped neurones, however it is thought to play an important role in osmoregulation and this could be relevant to its presence in tumour cells.38
Scyllo-inositol is a novel prognostic marker, however its role in tumour metabolism is poorly understood and warrants further study.
In conclusion, the study has demonstrated that short echo time single voxel MRS can be used to predict patient survival in paediatric brain tumours with a similar accuracy to histologic grading. A novel link between intracellular glutamine and mobile lipids has been identified, a pertinent finding given recent evidence that glutamine is crucial to lipogenesis in hypoxic tumour cells. These findings provide information that may improve both the clinical management and molecular understanding of paediatric brain tumours.