Tumor-related Perfusion Changes in White Matter Adjacent to Brain Tumors: Pharmacodynamic Analysis of Dynamic 3T Magnetic Resonance Imaging

Discussion

Brain metastases usually have very well-defined and clearly circumscribed margins, regardless of the large heterogeneity of their primary solid tumors. The maximum depth of brain tissue infiltration with malignant metastatic cells is observed in small-cell lung cancer and melanoma, however, the distances do not exceed approximately 1 mm from the anatomically defined margins of metastases (7, 8). Usually, there is also vasogenic edema present in the area surrounding metastases and this leads to restriction of blood perfusion according to the level of edema (9). For GBM on the other hand, very aggressive infiltrative growth is typical (10). Malignant cells invade mostly individually or in small groups alongside tracks of myelinated fibers in white matter, in perivascular, perineuronal and subpial spaces, and these malignant cells can histopathologically be found even several centimeters from the anatomically defined tumor (11, 12). Very often in GBM, there is also high expression of vascular endothelial growth factor, which is the main cause of vasodilatation, neovascularization and high microvascular permeability of tumor (13, 14). The extent of neovascularization determines the biological aggressiveness of the tumor.

In brain tumors, conventional non-dynamic MRI with administration of contrast agent uses the effect of blood–brain barrier disruption, and that is why contrast enhancement is not present in the whole tumor mass, but only in areas with preserved vascular circulation together with those with blood–brain barrier disruption. In GBM, this phenomenon is usually in the form of an irregular ring-like rim around central necrosis. Diffuse infiltration with tumor cells near the rim, not yet causing blood–brain barrier disruption and contrast leakage into the cerebral interstitial tissue, combined with vasogenic edema, is not visible in conventional MRI. However, the presence of tumor cell infiltration in this phase leads to vascular changes that are apparent as increased vessel caliber and neovascularization, with increased perfusion in surrounding areas (15, 16). The changes of perfusion parameters in areas surrounding GBM, and thus the indirect detection of its infiltrative growth, can be distinguished by dynamic post-contrast imaging. Results of our analysis correlate well with GBM-related circulatory and vascularization characteristics and parameters. The white matter peritumoral changes were better represented by iAUC values, which reflect the inflow of contrast agent into the region of interest within 60 seconds of its i.v. administration, and represent vascular perfusion. In contrast, K^trans is a calculated parameter obtained from a two-compartment exchange model, and reflects the combined characteristics of blood flow, vascular space volume and permeability (blood–brain barrier disruption) (17, 18). Increased blood perfusion in the area of GBM has also been described in several smaller groups of patients who were examined by dynamic susceptibility-weighted contrast-enhanced (DSC) MRI (19, 20). Mathematic models used in DSC methods presume full integrity of the blood–brain barrier, and cannot be used to investigate capillary leakage, which is why permeability (blood–brain barrier disruption) is not taken into consideration in this situation. In comparison, DCE MRI has an advantage in its capability to quantify microvascular permeability and characterize the tumor tissue. Quantitative measurement of microvascular permeability in human brain tumors achieved using DCE MRI correlates with histological grade (21) and helps find the most suitable location for targeted biopsy.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1.

Imaging of glioblastoma (upper panel) and breast cancer metastasis (lower panel). T1 Volumetric interpolated breath-hold examination (VIBE) image with contrast-enhanced ring lesions (left hand images), T1 VIBE fusion with maps of initial area under the contrast-uptake curve with region of interest located in peritumoral (middle images) and contralateral healthy white matter area (right hand images).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2.

Distribution of relative values of initial area under the contrast-uptake curve and transfer constant measured in the peritumoral area of brain metastases (MT) and glioblastoma multiforme (GBM).

In the case of treated brain tumors, DCE MRI differentiates pseudoprogression from recurrent GBM (22). DCE MRI allows better quantification of perfusion parameters using less volume of contrast agent (17, 23).

In order to minimize the influence of artefacts and to standardize measurement methods in our study, a rather large ROI was used to assess perfusion parameters. In some cases, it was rather difficult to find a standardized ROI fulfilling all the demands defined by the study protocol (i.e. diameter, distance, white matter not containing grey matter nor vessels). The low negative predictive value of the test was probably influenced by highly heterogeneous GBM growth, whereby various parts of the tumor may present various and different biological characteristics ranging between infiltrative and non-infiltrative tumor growth (12) and with variable changes in circulatory and vascularization. We can postulate that in daily practice, the finding of even a small peritumor area with a high iAUC value may lead to significant suspicion of GM.