Some of the primary brain tumors mainly gliomas are characterized by high morbidity and mortality with low cure and high recurrence rates; this depends to a great degree on the angiogenesis of the tumor beside the location of the lesion and its accessibility to surgery [8].
Conventional MRI sequences are not very sensitive for the detection of tumor angiogenesis and thus grading of lesions. In conventional MRI, there is overlap in findings between low- and high-grade gliomas, with some high-grade tumors showing no enhancement and some low-grade lesions showing avid post contrast enhancement, as contrast enhancement depends on disturbance of blood-brain barrier, not on tumor vascularization or angiogenesis [9].
This finding was confirmed in the current study as out of 35 cases studied, six out of the 14 low-grade gliomas (42.8%) showed variable degrees of post contrast enhancement and five out of the 21 high-grade gliomas (23.8%) did not show post contrast enhancement. Such results confirm that enhancement is not a reliable factor for determining the tumoral grade, similarly with previous results.
In order to answer the question of the title of the study and understand the role of ASL-perfusion in the grading of gliomas, the current study tried to find an answer to the following questions: Is post contrast DSC-perfusion accurate in estimating the grade of gliomas? and Are ASL-perfusion results comparable to the more established post contrast DSC-perfusion in accurate prediction of glioma grading?
Perfusion MRI techniques non-invasively estimate the functional hemodynamic parameters of the brain including tumors angiogenesis. Many different MRI techniques are available including dynamic susceptibility contrast (DSC) as well as dynamic contrast-enhanced (DCE) T1-weighted perfusion imaging along with non-contrast arterial spin-labeling (ASL) perfusion [3].
Is post contrast DSC-perfusion accurate in estimating the grade of gliomas?
DSC perfusion imaging is the most commonly used modality for perfusion assessment in clinical practice. Previous studies reported that DSC-PI provided useful information about glioma grading [3, 10]. Our findings confirm those of previous studies showing the best positive correlation between the degree of DSC-perfusion parameters and pathologically proven tumor grade.
The rCBV calculated out of DSC-PI is commonly used in evaluating perfusion in brain tumors, but some studies also used rCBF for grading gliomas [10]. According to our results, both rCBV and rCBF were significantly different between low- and high-grade gliomas. Our study showed that rCBF higher than 0.9 and rCBV higher than 1.1 showed the highest sensitivity, specificity, and predictive values in the estimation of high-grade gliomas. Such values were less than those produced in the study of Cebeci et al. [11], who found that a cutoff value of 1.80 for rCBV had a higher specificity than the cutoff value of 1.36 for rCBF for the prediction of high-grade gliomas.
Are ASL-perfusion results comparable to the more established post contrast DSC-perfusion in the prediction of glioma grading?
No need for intravenous contrast agent injection is the major advantage of ASL, which makes ASL easy repeatable. ASL may thus be useful in patients with renal failure, because they may be at risk for contrast-related nephrogenic systemic fibrosis, and in children for whom the intravenous rapid bolus injection of contrast agents may be difficult [12].
According to our results, ASL perfusion parameters, including both absolute and relative cerebral blood flow, could differentiate low- and high-grade tumors. Absolute CBF values obtained with ASL were capable of differentiating tumoral grade, but we think relative values were more reliable.
Because there are individual differences in CBF values, in order to ensure accuracy of the quantitative measurement of CBF, the present study used a ratio of CBF values of white matter from the contralateral side as quantitative indicators to attain the relative CBF.
Some studies stated that using white matter as a reference region is still questionable due to the long transit time and high water content of the normally appearing white matter in brain tumors, and this may result in underestimation of white matter CBF by ASL [13]. However, in our study as well as Jiang et al. study [14], the white matter was used as a reference region and revealed a highly strong correlation between ASL and DSC.
The vascular pathology of low-grade glioma states that tumor vessels are mainly formed of normal endothelial cells, with cell-to-cell tight junction and relatively intact blood-brain barrier resulting in decreased blood flow and blood volume parameters in perfusion MRI techniques [3]. Most of the previous studies differentiating high-grade glioma from low-grade glioma by perfusion MRI techniques revealed low perfusion parameters in low-grade glioma patients [15, 16].
In our study, 9 out of 14 low-grade glioma patients showed hypoperfusion in ASL-CBF comparable to DSC-PI, while four cases showed hyperperfusion on ASL, three of which were hypoperfused on DSC-PI. The last case was isoperfused on ASL and interpreted as an indeterminate grade.
An explanation for such false hyperperfusion in some low-grade gliomas on ASL could be attributed to the nature of these lesions; as three out of the four lesions were proved to be grade II oligodendrogliomas on pathology. Lev et al. [17] investigated glial tumor grade by DSC-PI and found that there were confounding effects of oligodendrogliomas so that two low-grade oligodendrogliomas showed rCBV value higher than the threshold for low-grade lesions. Such finding was confirmed in the current study but only in ASL where rCBF was higher than the threshold for low-grade oligodendroglioma. Lev et al. [17] found that given the fine capillary network that is typical of even low-grade oligodendrogliomas, it is not surprising that their perfusion pattern should differ from that of low-grade astrocytomas and therefore can confound the reliability of perfusion values in distinguishing high-grade from low-grade untreated glial cell tumors [17].
On the other hand, 19 out of 21 cases with high-grade gliomas in the current study showed hyperperfusion in ASL while all 21 cases showed hyperperfusion in DSC. These results agreed with the previous studies of Cebeci et al. [11], Soni et al. [13], and Jiang et al. [14] who stated that high-grade gliomas consistently show hyperperfusion on ASL perfusion; explained by the vascular histopathological features of such gliomas that have copious neovascularization characterized by disorganized, irregular, and tortuous vessels with arteriovenous shunting resulting in increased perfusion.
Comparing ASL perfusion to DSC-PI has shown ASL-derived rCBF > 2.08 to have 80.95% sensitivity, 85.71% specificity, and overall accuracy of 82.86% compared to 100% sensitivity, specificity, and accuracy of DSC-PI-derived rCBV and rCBF of > 1.1 and > 0.9, respectively.
Some discrepancy was noted with the latest study of Hong et al. [18] in which ASL-rCBF had the largest area under the ROC curve (0.836). When the cutoffs for ASL-rCBF, DSC-rCBF, and DSC-rCBV were taken (2.24, 1.85, and 1.68), the sensitivities of HGG diagnosis were 83.2, 91.3, and 91.3%, and the specificities were 77.7, 63.9, and 66.7%, respectively.
Such discrepancy in results is likely attributed to the difference in taking the reference values as in their study, the contralateral normal ROI was selected by using the mirror image of the tumor ROI in contrast to our study where the contralateral normal-appearing white matter was taken as reference.
Spearman correlation analysis between the two perfusion techniques demonstrated a strong positive correlation between ASL-derived rCBF and DSC-rCBF (r reaching 0.8 with p < 0.001) and less yet still fair correlation with rCBV (r reaching 0.68 with p < 0.001).
A strong positive correlation between ASL and DSC has been reported for grading of gliomas in a few recent studies. A nearly similar study by Cebeci et al. [11] on 33 patients (20 high-grade and 13 low-grade gliomas) revealed a significant positive correlation between DSC-rCBV and rCBF-ASL (r = 0.81, p < 0.001). However, the correlation between DSC-rCBF and rCBF-ASL was weaker (r = 0.64, p < 0.001).
Soni et al. [13] studied 30 cases of brain tumors, eight of which were gliomas and found a high correlation reaching 0.9 between ASL-rCBF and DSC-rCBF when compared to gray matter.
A less but still significant correlation was noted in Hong et al. study [18] on 50 glioma patients, as they found that Spearman correlation analysis demonstrated that ASL-rCBF had a significantly positive correlation with DSC-rCBF (r = 0.580, P < 0.01) and significantly moderate positive correlation with DSC-rCBV (r = 0.431, P < 0.01).
In general, most of the studies support the opinion that ASL could be a noninvasive alternative to DSC.
However, 3D ASL has a number of deficiencies compared with DSC-PWI. Firstly, 3D ASL has a relatively poor signal-to-noise ratio when compared to DSC. Secondly, 3D ASL cannot measure as many parameters as DSC-PWI and has only one CBF parameter, which limits its application. Thirdly, aging and carotid atherosclerosis affect cerebral perfusion [12] and lastly, the longer acquisition time of ASL reaching 4 min compared to 1 min and 30 s of DSC-PI.
Points of strength
All lesions in the current study had histologically proven diagnoses, and all MR imaging examinations were done at a high magnetic field of 3T with a higher signal to noise ratio (SNR), thus leading to decreased motion artifacts compared to 1.5T. Both perfusion techniques (DSC-PI and ASL) were done in all patients to facilitate comparison data.
Limitations of the study
The main limitation of the current study was doing single-phase ASL which we think may have resulted in the relatively lower sensitivity and specificity data as compared to the DSC-PI. Still, the ASL technique with multiple repetitions usually causes longer imaging times which should be taken into consideration versus the main advantage of this technique being a non-contrast study.