¹⁸ F-FDG PET standard uptake values of the normal pons in children: establishing a reference value for diffuse intrinsic pontine glioma

Positron emission tomography (PET) scanning with [¹⁸ F]fluorodeoxyglucose (¹⁸ F-FDG) provides information on glucose metabolism. ¹⁸ F-FDG PET positively correlates with an increasing WHO grade in astrocytomas [1]. In high-grade glioma (HGG), ¹⁸ F-FDG PET is an indicator of response to therapy and is used for PET-guided planning of stereotactic brain biopsy [2‐5]. In the past few years, ¹⁸ F-FDG PET studies have been introduced in diffuse intrinsic pontine glioma (DIPG) [6‐10], a fatal disease that almost exclusively occurs in children [11]. Interestingly, ¹⁸ F-FDG metabolism in the majority of the DIPG was lower than that in the non-affected occipital lobe, but increased ¹⁸ F-FDG uptake correlated with decreased overall survival [10]. However, reference values of ¹⁸ F-FDG uptake in the normal pons of children of increasing age are mandatory to know what increased uptake is in the pons, and these data are lacking. Therefore, the aim of this study was to calculate the standard uptake value ratios (SUVr) for the pons/cerebellum (SUVr_p/c) and for the pons/occipital lobe (SUVr_p/o) in subjects with a normal pons and to investigate the influence of age, pontine size, and post-injection interval on the SUVr. The SUVr of the normal pons were then compared to the SUVr and SUVrmax of DIPG.

In an era where numerous drug trials in DIPG are ongoing or will be initiated shortly, it is essential to develop tools to predict disease evolution and to monitor response to therapy [14]. ¹⁸ F-FDG PET has the potential to be such a tool. However, the interpretation of ¹⁸ F-FDG PET results in DIPG is hampered by a lack of data on normal pontine glucose metabolism in children. We show in this study that ¹⁸ F-FDG SUV ratios of the normal pons versus those of the cerebellum and occipital lobe are very consistent in between controls, independent of sex, age, and pontine volume, and are therefore suitable as a reference value for ¹⁸ F-FDG PET studies in DIPG. Not only the pons of controls but also the pons infiltrated by tumor often showed lower ¹⁸ F-FDG uptake than the cerebellum and occipital lobe, a phenomenon that has been reported before [10]. Moreover, the mean SUVr of DIPG were not significantly higher than those of the normal pons, but this is probably due to the small DIPG sample size as the standard deviations were high. One may therefore question the role of ¹⁸ F-FDG PET in DIPG; however, the mean SUVrmax clearly increased in DIPG compared to the normal pons. Indeed, a recent study showed a significant correlation between increased ¹⁸ F-FDG tumor uptake and decreased survival in patients with this disease [10]. This correlation might be even stronger when considering that a SUVr_p/o in DIPG between 0.5 and 1.0 already reflects increased ¹⁸ F-FDG uptake in comparison with the normal pons. This consideration is not taken into account in studies using semi-quantitative measurements that lead to classification as ‘hypo/iso/hypermetabolic’ compared to other brain areas [6‐10].

An explanation for the limited ¹⁸ F-FDG uptake in DIPG compared to supratentorial HGG is that DIPGs are heterogeneous tumors with a mixed histologic tumor grade, as local uptake of the tracer is related to the presence of anaplastic features [11, 15, 16]. Calculating the SUVrmax, reflecting the highest local uptake in the tumor, is helpful in those tumors with heterogeneous ¹⁸ F-FDG uptake. Other explanations of the limited uptake are the frequently observed integrity of the blood–brain barrier in DIPG and the presence of white matter in the pontine region, which has low glucose metabolism [17].

We further investigated whether the time between injection and PET scanning had an influence on the ¹⁸ F-FDG uptake in the pons of controls compared to other brain areas. Indeed, SUVr_p/c and SUVr_p/o were positively correlated with increasing post-injection time. This suggests a delayed uptake of this tracer in the pons compared to the cerebellum and occipital lobe. However, the SUVr regression coefficients were small, and therefore, the influence of the uptake interval in clinical practice is negligible.

The main advantage of SUV ratios is that the possible errors in the measurement of weight or transcription and dose administered are minimized by the ratio between the two SUV measurements [18]. This applies especially for pediatric cancer, with low patient numbers and therefore often multi-national multi-center trials. In this study, we showed that SUV ratios of the normal pons are independent of sex, pontine volume, and age, although we had an under-representation of the youngest children (<5 years) in the control group. Although SUV ratios may give useful information in serial measurements, they have their limitations. In situations in which the ¹⁸ F-FDG uptake of the reference tissue varies, changes in SUV ratios can be misleading. For example, this may be the case when patients use steroids, which influence the glucose metabolism of the brain [19]. A methodological issue in this study was the use of epilepsy patients as controls, as ¹⁸ F-FDG PET data of healthy children could not be obtained due to ethical reasons regarding radiation exposure. We, however, do not expect significant changes in glucose metabolism of the pons due to epilepsy as all our subjects were in an inter-ictal state, which is not associated with changed glucose metabolism [20]. Furthermore, several anti-epileptic drugs including phenobarbital, phenytoin, benzodiazepines, and valproic acid have been associated with hypometabolism of the brain and especially the cerebellum and may therefore overestimate the SUVr_p/c. Of these drugs, only valproic acid and clobazam were used in this study by, respectively, 3 and 4 out of 37 controls [21, 22]. The lack of variance in between controls of both SUVr_p/c and SUVr_p/o presumes that the use of anti-epileptic drugs has not influenced our results significantly. In addition, the use of the cerebellum as a reference in epileptic patients in ¹⁸ F-FDG PET studies is not uncommon [23, 24].

Future ¹⁸ F-FDG PET studies in DIPG may now compare SUVr and SUVrmax in DIPG to the here reported mean SUV ratios of the normal pons. By comparing SUV ratios to the normal pons, smaller increases in glucose metabolism can be detected in comparison with semi-quantitative measurements, as DIPGs often show lower glucose metabolism than the reference brain tissue (occipital lobe). In this way, the sensitivity and applicability of ¹⁸ F-FDG PET as a predictive and response monitoring tool for patients with DIPG can be increased.

We established a reference SUVr for ¹⁸ F-FDG uptake in the normal pons. SUV ratios are very consistent in between controls and independent of pontine volume, sex, or age. Not only was the ¹⁸ F-FDG uptake in the normal pons low compared to that in the reference brain areas, but also the uptake in DIPG was often lower than that in the occipital and cerebellar tissues. We encourage a study in controls to validate our results and propose that future ¹⁸ F-FDG PET trials in DIPG calculate SUV and SUV(max) ratios in order to relate these to the here reported mean SUV ratios of the normal pons. Smaller changes in the tumor’s glucose metabolism can be detected in this way, which may have prognostic relevance for the patient.