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Original Research |
1 Department of Neuroradiology, Hospital General Universitario Gregorio
Marañón, Madrid, Spain 28007.
2 Unidad de Medicina y Cirgugía Experimental, Hospital General
Universitario Gregorio Marañón, C/Dr. Esquerdo 46, Madrid, Spain
28007.
3 Department of Radiology, Hospital General Universitario Gregorio
Marañón, Madrid, Spain 28007.
Received January 12, 2006;
accepted after revision June 7, 2006.
Address correspondence to M. Desco
(desco{at}mce.hggm.es).
Abstract
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SUBJECTS AND METHODS. We performed MRI and 1H MR spectroscopic studies on seven treatment-naive patients with gliomatosis cerebri and on 16 healthy volunteers. We then analyzed the association between survival time and levels of choline (Cho) and N-acetyl aspartate (NAA) normalized to creatine (Cr).
RESULTS. The results showed a statistically significant (p = 0.05) inverse relation between Cho/Cr ratio and survival time. In addition, NAA/Cr ratio was significantly lower in the patient group than in the control group (p = 0.001).
CONCLUSION. Cho/Cr ratio measured with MR spectroscopy seems to be related to survival time, possibly explaining the inconsistent findings previously reported for this parameter.
Keywords: brain • gliomatosis cerebri • MRI technique • MR spectroscopy
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Gliomatosis cerebri is essentially diagnosed when MRI studies show diffuse and contiguous infiltration of the white matter that is isointense on T1-weighted sequences and hyperintense on T2- and proton density-weighted sequences. Brain structure is preserved, frequently with bihemispheric extension through commissural pathways, such as the corpus callosum, to the basal ganglia and brainstem [4-6]. In most cases, brain biopsy is performed for antemortem diagnosis [7], although it is possible to diagnose this tumor with imaging criteria because the MRI appearance is quite distinctive. Biopsy specimens are often difficult to evaluate [8] often making it impossible to assess the degree of aggressivity of this tumor. In addition, areas of the lesion have varying degrees of cellular proliferation and differentiation, as autopsy studies have shown [9]. Stereotactic brain biopsy does not yield information useful for prognosis in cases of gliomatosis cerebri [8]. Furthermore, the surgical procedure involved in brain biopsy, however minimal, is not exempt from mortality and morbidity [7].
MR spectroscopy (MRS) is a noninvasive diagnostic method that can be used for metabolic characterization of brain tumors. Use of MRS in gliomatosis cerebri has been reported only fairly recently [10], and the largest published series to date is nine cases [8]. The most common finding in gliomatosis cerebri is a decreased level of N-acetyl aspartate (NAA). The existence of a peak in myoinositol-to-glycine ratio has also been described as characteristic of gliomatosis cerebri, especially in the absence of elevated choline (Cho) level [11-13]. In the case of choline, however, there are discrepancies in the literature. Although some authors have reported a moderate increase in this metabolite in patients with gliomatosis cerebri [10-13], others have described normal values [1, 8]. To the best of our knowledge, this discrepancy has not been explained. The purpose of our study was to study the differences, taking into account survival time as an additional possible explanatory variable for the discrepancy in choline levels.
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The following sequences were used in the imaging study: sagittal T1-weighted spin echo (TR/TE, 409/15), axial FLAIR (8,000/120), axial T2-weighted turbo spin echo (3,500/120), and axial T1-weighted spin echo (600/15) with magnetization transfer contrast enhancement after IV injection of gadopentetate dimeglumine, 0.1 mmol/kg (Magnevist, Schering).
Radiologic inclusion criteria were strict, including not only the WHO criteria (contiguous infiltration of at least two brain lobes) but also those postulated by Galanaud et al. [8]. The latter criteria are no history of focal glioma, no significant mass effect, lesion primarily affecting the white matter and basal ganglia, and no significant enhancement (< 1 cm3) on the MR image after IV contrast injection at the time of diagnosis.
Tumor biopsy was performed on all patients. In one case, biopsy was an open procedure, and in the others, stereotactic technique was used. The results were compatible with the tentative imaging diagnosis. In another case, the histologic specimen was not evaluable because of poor quality; however, the diagnosis of gliomatosis cerebri was confirmed on the basis of imaging and clinical progression criteria.
We collected data on age, sex, initial symptoms, time between initial symptoms and MRS, stereotactic biopsy results, treatment received (radiation therapy and dosage), and survival time from onset of the initial symptom through the date of death. Five patients were treated with whole-brain radiation therapy, receiving total doses of 40-55 Gy. Two patients received no treatment, one because of rapidly progressive deterioration and the other because of refusal by the patient's family. In all cases, the cause of death was secondary to progression of the primary disease with progressive worsening of neurologic symptoms and no contribution by other intercurrent diseases.
The spectroscopic study consisted of single-voxel acquisition localized in the bulk of the gliomatosis infiltration and avoiding unaffected areas. The acquisition protocol entailed a single-voxel point-resolved spectroscopic sequence (1,500/136; number of excitations, 128) [14] with a sample volume of 10.32 ± 7.7 cm3 (mean ± SD). This protocol was selected in an attempt to achieve accurate quantification of the NAA, creatine, and choline peaks.
The control group consisted of 16 recruited healthy volunteers. These subjects underwent MRI with T1-weighted (gradient echo; 15/4.5) and T2-weighted (5,809/120) sequences. The spectroscopic study was performed with a point-resolved spectroscopic sequence with the same parameters as for the patients, localized in the frontal lobe (because this lobe is considered the one with the largest proportion of white matter) with a mean sample volume of 6.59 ± 1.9 cm3.
Processing of the spectroscopic images consisted of decreasing exponential weighting of the data in the time domain with a decay constant of 2 Hz. Before the signal was quantified, the residual water peak was removed by use of a Hankel total least squares algorithm [15]. The spectra were quantified with a nonlinear time-domain analysis and an advanced method for accurate, robust, and efficient spectral fitting algorithm [16]. The NAA (2.01 ppm), creatine (3.02 ppm), and choline (3.22 ppm) peaks were analyzed. These resonances were adjusted to a Lorentzian (decreasing complex exponential) model through acquisition of the signal amplitude for each peak in relation to the T2* relaxation effects. The NAA and choline amplitude values were normalized to the creatine values.
We can accept that if they correspond to a relatively short period of survival time, the data can be modeled as a linear regression. In this linear model, the age and sex of each patient can be included as independent variables. Unless otherwise stated, all the values are mean ± SD. All subjects or their legal representatives (for two patients, one because of incapacity and one because of minor age) signed an informed consent form before MRI was performed. The entire study had received previous approval by the independent ethics committee of our hospital.
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Fitting the data to a linear model with survival time, sex, and age as independent variables (r = -0.92) showed that survival time was statistically significant (t = -3.187, p =0.05) but that age and sex were not (t = -0.841, -0.395; p = 0.462, 0.206, respectively). Although no association was observed between NAA-to-creatine (NAA/Cr) ratio and survival time, comparison between the mean NAA/Cr ratios of control subjects (1.93 ± 0.4) and of patients (1.07 ± 0.7) showed that the average NAA/Cr ratio was significantly lower (t = 3.763, p = 0.001) in patients than in control subjects. In the patient with the shortest survival time, the spectrum showed a characteristic lactate signal doublet at 1.33 ppm (Fig. 1A), presumably associated with anaerobic glycolysis.
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In our series, even though all of the evaluable histologic specimens were classified as low-grade tumors, the survival time ranged from 3 to 25 months with a clear lack of association with histologic diagnosis. In our work, we found a negative correlation between survival time and choline level. Because this linear relation was obtained for a relatively short range of survival times, extrapolation of results may not be straightforward. This result suggests that choline value may influence survival time, perhaps explaining the discrepancies in the scientific literature regarding gliomatosis cerebri. Some authors have found a significant increase in choline level compared with the value among control subjects [10-13], whereas others have reported normal choline levels [1, 8]. Because it is well established that the aggressiveness of a tumor is directly related to higher choline level [19], we hypothesize that the histologic malignancy of gliomatosis cerebri may be indirectly reflected as reduction in survival time. Previous reports [1] have described the relation between grade of gliomatosis cerebri and spectroscopic findings. Thus high-grade lesions (WHO grades III and IV) have markedly higher maximum Cho/Cr and Cho/NAA ratios and lower NAA/Cr ratios, and the differences are most pronounced for the Cho/NAA relation. In addition, the presence of lipids or lactate indicates the presence of high-grade gliomatosis cerebri. One of our patients had a spectrum with lactate doublet at 1.33 ppm, and the disease was the most aggressive from the clinical perspective, the survival time being 3 months.
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One of the limitations of our study was the use of single-voxel MRS, in which only a volume element is analyzed and spatial diversity is not shown [1]. Areas in which images showed maximum tumoral involvement were selected for the spectroscopic study because they presumably corresponded to the areas of highest histologic aggressivity. Two patients in our series did not undergo radiation therapy. It is not likely, however, that this lack of treatment would have been a confounding factor because it is unclear whether radiation therapy improves outcome among patients with gliomatosis cerebri [23].
To conclude, we suggest that in patients with gliomatosis cerebri, choline level may be associated with survival time. This relation may explain discrepancies in quantification of this metabolite in the absence of other variables, such as histologic grade determined with biopsy, that may clarify the discrepancies.
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