Our study showed that it is possible distinguishing a GB from a solitary BM using a multiparametric analysis and a VOI-based method, with a sensitivity of 95% and a specificity of 86%.
The differentiation of metastasis from other malignant tumors on conventional MRI is usually straightforward due to the clinical history of the patient or the existence of multiple lesions [13] . We know that the differentiation of glioma from single brain metastasis is clinically crucial, because it affects the clinical outcome of patients and changes patient management. As GB and BM have similar conventional MRI characteristics, advanced MRI techniques can be useful to evaluate some features of the tumor, such as cellularity, ultrastructure of tumor capillaries and permeability, that differ greatly between GB and BM [3, 4, 14]. Furthermore, it has been found that glioma tends to infiltrate the peritumoral edema region as well, while this condition is not typical of brain metastases [14].
Previously, some studies tried to evaluate the role of MRI with a single or multimodal approach for differentiating glioma from brain metastasis [3, 4, 6-21]. More frequently, Diffusion MRI and DSC perfusion techniques were applied, alone or in association with MR Spectroscopy and Diffusion Tensor Imaging. Usually, a ROI-based analysis was utilized; only Qin et al. [6] used a VOI-based method for a histogram analysis concerning the perfusion DSC technique. We use a VOI-based method to verify diffusion and perfusion differences between GB and solitary BM in both, solid tumor portion and peritumoral oedema.
By using the VOIs to include only the solid component of the tumor tissue, avoiding cyst and necrotic degeneration, the results are more reliable and allow a better and more objective evaluation of images than using a ROI-based method. Indeed, results of the VOI method, as well as the ones of the histogram method, showed greater interobserver agreement and diagnostic accuracy than the localized hotspot ROI method [6].
In contrast with almost all previous studies, we found a statistically significant difference (p<0.001) between the mean ADC VOI-values in the solid portion of the tumors, lower in GB than in BM. Reviewing the literature, there is not agreement in distinguishing these lesions by using ADC values. Lee et al. and Tsougos et al., imputed the absence of significant differences among the ADC values of these lesions to the heterogeneous signal intensity due to necrosis and susceptibility artifacts [9, 12]. Only Chiang et al. reported similar results to ours, assessing that the higher ADC in metastasis suggests higher intracellular and extracellular water fractions than in high-grade gliomas [21]. More recently, Poulon et al [22] compared specimens of twenty-five patients with brain tumors including GB and BM. They reported that brain metastasis were characterized by hypercellularity and disorganized stroma with numerous blood vessels and dense collagen network. On the other hand, in GB samples the solid tumor component was associated with a highly disorganized tumor cell architecture with microvascular proliferation. Since it is well known that that brain neoplasm with higher cellularity showed a significant reduction in ADC values, the structural pattern showed by Poulon et al. could explain ours and Chiang et al. results [21, 22] characterized by higher ADC values in BM as an expression of the vascular and collagen components than in GB characterized by higher cellularity.
We believe that in our study the substantial results about ADC values are also related to the use of VOIs that include only the solid component of tumoral tissue, avoiding cyst or necrotic degeneration, instead of using the ROI-based method.
According to the literature, we confirm that it is not possible to distinguish solitary BM and GB using the rCBV values of perfusion MRI in the solid portion of the tumor, also using the VOI-based method. rCBV as a biomarker of increased angiogenesis should therefore be interpreted with caution in differentiating BM and GB, particularly within enhancing tumor [3]. Only Qin et al in a recent study, using a histogram analysis, reported different results with GBMs characterized by higher perfusion and more heterogeneous status in the distribution of blood perfusion due to a lower different expression level of vascular epidermal growth factor, than to metastasis [6].
Nevertheless, the evaluation of the percent value of signal recovery (PSR) derived from the DR2* curve of DSC perfusion MR imaging is a method that can distinguish these lesions. We obtained a significant difference (p=0,003) between GB and BM with lower recovery of signal intensity inside the lesion for metastasis group. Cha et al [4] assessed that the significant difference in the percentage of signal intensity recovery between GB and BM, reduced in metastasis, is probably due to the difference in capillary permeability. Capillaries of metastatic brain tumor in fact resemble those of systemic origin and are associated with a defective endothelium, devoid of any rudimentary BBB architecture. The same results were obtained from Neska-Matuszewska et al [7]. The lower sensitivity and specificity results, despite the significant difference found between the two groups, are likely due to the greater number of patients with brain metastasis from lung cancer, lesions with less vascularization compared to others (for example metastasis from kidney or melanoma) [14]. We suppose that the lower representation of pathological capillaries could justify the reduced permeability of these lesions and the partial signal recovery compared to GB.
The highly aggressive nature of GB is associated with their infiltrative growth in the peritumoral area exceeding the limits of the enhancing tumor core, while metastases usually grow by expansion, displacing the surrounding brain tissue, which shows pure vasogenic edema [7]. In GB, the peritumoral brain zone has already been evaluated in the literature using DWI or PWI, showing increased values of rCBV accepted by all, and controversial results in the ADC values [3, 7, 9-12, 16]
Indeed, the peritumoral rCBV derived from DSC represents a valid parameter to distinguish metastasis and GB with higher values of rCBV in GB peritumoral edema due to an infiltrative process, which is not found in solitary BM [7, 9, 11, 13, 14]. In brain metastases vasogenic edema associated with the leakage through abnormal capillary walls allows compression of the microcirculation close to the lesion and reduction of rCBV values [10].
In our study, this result is evident only in VOIs drawn within 5mm around the enhancing tumor; on the other hand in regions located far from this spatial limit, only a trend of significant results were appreciable suggesting that in GB peritumoral zone there is a decreasing gradient of rCBV values from the area close to the enhancing solid lesion to the normal white matter, while in BM the rCBV values in these regions were similar without any gradient appearance. This interesting result is in accord with the study of She et al, reflecting the gradient of infiltrative pattern of GB [11].
Concerning the peritumoral zone, ADC represents a parameter with debated results in the literature. Some authors assessed the role of ADC in recognizing the presence of tumoral infiltration in GB [3, 7, 12, 14]. The significantly increased ADC value in edema surrounding metastases suggests that they cause more fluid production than high-grade gliomas [14]. Lee et all found a significantly lower minimum ADC value in the peritumoral oedema of GB than of BM, identifying infiltrative peritumoral edema in GB [12]
Some authors [9] did not find any difference comparing ADC values in GB and BM peritumoral edema, as well as us. Indeed, we reported that mean and minimum ADC VOI values neither in peritumoral edema nor in distant edema are useful to differentiate infiltrative oedema in GB from vasogenic oedema in metastasis.
We cannot exclude that a ROI-based analysis used in previous studies is associated with lower accuracy than a VOI-based method.
Our study has several limitations: the retrospective nature of the analysis limits the generalizability of the results. Moreover, we focused on MRI parameters, but there is a lack of histopathologic correlation between imaging parameters and surgical specimens, its results should be validated in prospective studies with strict histopathologic, although such point-to-point correlations are very difficult to obtain.