Elevated citrate in pediatric astrocytomas with malignant progression

Abstract

In vivo magnetic resonance spectroscopy (MRS) provides information about metabolite concentrations in tissue. Recently citrate was detected by MRS in subgroups of pediatric brain tumors. Citrate is an intermediate in the tricarboxylic acid (TCA) cycle and accumulates in tissue when the glycolytic rate exceeds the TCA cycle activity, a feature of malignant tumors. Currently, no practical indicators allow clinicians to predict risk for malignant progression of pediatric astrocytomas (World Health Organization [WHO] grade II). Medical records and citrate concentrations measured with in vivo MRS of 29 pediatric astrocytomas were reviewed. This included 6 patients with astrocytomas (WHO II) who had stable disease (indolent LGA) for >2 years, 7 with aggressive grade II astrocytomas (aggressive LGA), 13 with anaplastic astrocytomas (WHO III), and 3 with glioblastoma (WHO IV) with disease progression within 2 years. Citrate was observed in all patients with aggressive LGA, and the mean citrate concentration was significantly higher in this group than among those with indolent LGA (mean ± standard deviation, 4.1 ± 1.1 vs 0.6 ± 0.8 mmol/kg; P < .0001). There was no consistent pattern for citrate in anaplastic astrocytoma and glioblastoma, with citrate prominent in some lesions whereas undetectable in others. It is unclear whether citrate accumulation occurred because of fundamental defects of citrate regulation or was secondary to altered physiological conditions. Nonetheless, prominent citrate identified a subgroup of pediatric grade II astrocytomas destined for aggressive behavior. Citrate was not specific for poor outcome because it was not detectable in all high-grade astrocytomas. In high-grade astrocytoma, tumors with prominent citrate may constitute a metabolic subclass.

Fig. 1.

Shown are averaged spectra computed from all grade II astrocytoma and of all grade III astrocytoma. Overall, the patterns were comparable (A). When grade II astrocytomas were subdivided into 2 groups according to clinical outcome, citrate (Cit) at ∼2.6 ppm was significantly more prominent in aggressive astrocytoma (B). Other chemicals that can be quantified with in vivo MR spectroscopy include N-acetyl-aspartate (NAA), creatine (Cr), lactate (Lac), choline (Cho), and myo-inositol (mI). Note that NAA levels in aggressive astrocytoma were significantly lower than in stable astrocytoma but to a much lesser extent than citrate. Despite the more prominent appearance of lactate in grade II astrocytomas with malignant progression, significance was not reached due to considerable scatter of measured concentrations. All spectra are scaled to the measured concentrations to allow direct comparison.

Fig. 2.

Transverse fluid-attenuated inversion recovery (FLAIR) and T2-weighted magnetic resonance image (MRI) for a patient with an infiltrating nonenhancing bithalamic lesion extending into parts of the brainstem with enlarged ventricles and periventricular edema at diagnosis (A). A magnetic resonance spectrum was not obtained at diagnosis. The patient subsequently underwent shunt surgery, and a biopsy of the lesion was performed (grade II diffuse astrocytoma). MRI at three months demonstrated reduced size of the ventricles and resolved edema (B). In the spectrum obtained at that time of the tumor, N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) were readily detectable. There was no evidence for citrate. Shown are the unfiltered raw data (thin grey line) and the fit to the data used for quantitation (black line). The box on the FLAIR MR image (B) indicates the region of interest from where the spectrum was acquired. This patient is alive and doing well 5 years after initial diagnosis.

Fig. 3.

Magnetic resonance spectra and T2-weighted magnetic resonance image (MRI) indicating the region of interest from which spectra were obtained of a grade II bithalamic astrocytoma with aggressive behavior. A spectrum acquired from a nonenhancing diffuse astrocytoma at initial presentation (A) shows no evidence of elevated lipids or lactate (Lac) and choline (Cho) levels are moderate. On the other hand, citrate (Cit) is readily detectable at baseline (cf. Fig. 2). Progressive disease was apparent on MRI within 1 year after initial diagnosis (B and C), and the patient died within 2 years after diagnosis. Only the spectrum obtained at baseline was used for the analysis of differences between aggressive and indolent grade II astrocytomas. Note that Cho, Lac, and lipid (Lip) levels increased as the disease progressed, whereas the citrate level did not increase but may have decreased slightly in this patient. A similar trend of decreasing citrate levels was reported earlier for progressing diffuse pontine gliomas.

Fig. 4.

No consistent pattern was observed for citrate (Cit) in grade III anaplastic astrocytoma. For example, there was no evidence of Cit in a patient with an anaplastic astrocytoma and gliomatosis cerebri (A). In contrast, in another patient with a hypocellular left thalamic anaplastic astrocytoma with intraventricular extension, Cit was readily detectable (B). Both spectra were acquired at initial presentation. Shown are also the apparent diffusion coefficient (ADC) maps for each patient. For the correlation with Cit concentrations, the mean ADC values were obtained from the area of the tumor that was also selected for the magnetic resonance spectroscopy (MRS) study. Cho indicates choline; Cr indicates creatine; mI indicates myo-inositol.

Fig. 5.

Shown is a representative spectrum of biopsy-confirmed pediatric glioblastoma (average of three studies). Unlike for aggressive LGA and some anaplastic astrocytoma, there is no apparent citrate peak detectable at 2.6 ppm. Cho indicates choline; Cr indicates creatine; Lac indicates lactate; Lip indicates lipids; mI indicates myo-inositol.