The added value of apparent diffusion coefficient to cerebral blood volume in the preoperative grading of diffuse gliomas

BACKGROUND AND PURPOSE:In cerebral gliomas, rCBV correlates with tumor grade and histologic findings of vascular proliferation. Moreover, ADC assesses water diffusivity and is inversely correlated with tumor grade. In the present work, we have studied whether combined rCBV and ADC values improve the diagnostic accuracy of MR imaging in the preoperative grading of gliomas.MATERIALS AND METHODS:One hundred sixty-two patients with histopathologically confirmed diffuse gliomas underwent DWI and DSC. Mean rCBV and ADC values were compared among the tumor groups with the Student t test or ANOVA. ROC analysis was used to determine rCBV and ADC threshold values for glioma grading.RESULTS:rCBV had significantly different values between grade II and IV gliomas and between grade III and IV tumors, but there were no significant differences between grade II and III gliomas (P > .05). Grade II and III tumors also did not differ when astrocytomas, oligodendrogliomas, and oligoastrocytomas were considered separately. ADC values were significantly different for all 3 grades. The ADC threshold value of 1.185 × 10⁻³ mm²/s and the rCBV cutoff value of 1.74 could be used with high sensitivity in the characterization of high-grade gliomas. The area under the ROC curve for the maximum rCBV and minimum ADC was 0.72 and 0.75, respectively. The combination of rCBV and ADC values increased the area under the ROC curve to 0.83.CONCLUSIONS:ADC measurements are better than rCBV values for distinguishing the grades of gliomas. The combination of minimum ADC and maximum rCBV improves the diagnostic accuracy of glioma grading.

Gliomas are the most common primary neoplasms of the brain in adults,^1,2 ranging in grade from low to high. Glioma grading is based on the histopathologic assessment of the tumor and is critical for planning therapeutic approaches and assessing prognosis and response to therapy.² Advanced MR imaging techniques such as DSC and DWI provide physiologic information that complements the anatomic information obtained from conventional MR imaging.^3–6 DWI quantifies cellularity on the basis of the premise that water diffusivity within the extracellular compartment is inversely related to the content and attenuation of the intracellular space.⁷ The higher the tumor cellularity and grade are, the lower the ADC is because of decreased water diffusivity.^6–8 However, other factors may be complicating this relationship: ADC increases with increased edema and increased edema is seen in high-grade tumors. DSC provides noninvasive assessment of tumor vascularity and angiogenesis^3–6,9 through the examination of the degradation of signal intensity with time associated with the first pass of a bolus of paramagnetic contrast agent.⁹ Because higher vascularity corresponds to a higher tumor grade, as the grade of the astrocytoma increases, the maximum tumor CBV tends to increase.^3,6,7The aim of this study was to evaluate the diagnostic accuracy of combined ADC and CBV values in the preoperative differentiation of diffuse gliomas. Our objectives were the following: 1) to calculate CBV and ADC values for diffuse gliomas included in the study, 2) to establish whether there is any difference in rCBV and ADC values in gliomas classified by tumor grade and histology, 3) to estimate a cutoff CBV and ADC value for differentiation of high- and low-grade gliomas, and 4) to investigate whether combined CBV and ADC values improve the diagnostic accuracy of MR imaging.     

Amide proton transfer imaging to discriminate between low- and high-grade gliomas: added value to apparent diffusion coefficient and relative cerebral blood volume

Objectives

To evaluate the added value of amide proton transfer (APT) imaging to the apparent diffusion coefficient (ADC) from diffusion tensor imaging (DTI) and the relative cerebral blood volume (rCBV) from perfusion magnetic resonance imaging (MRI) for discriminating between high- and low-grade gliomas.

Methods

Forty-six consecutive adult patients with diffuse gliomas who underwent preoperative APT imaging, DTI and perfusion MRI were enrolled. APT signals were compared according to the World Health Organization grade. The diagnostic ability and added value of the APT signal to the ADC and rCBV for discriminating between low- and high-grade gliomas were evaluated using receiver operating characteristic (ROC) analyses and integrated discrimination improvement.

Results

The APT signal increased as the glioma grade increased. The discrimination abilities of the APT, ADC and rCBV values were not significantly different. Using both the APT signal and ADC significantly improved discrimination vs. the ADC alone (area under the ROC curve [AUC], 0.888?vs.?0.910; P?=?0.007), whereas using both the APT signal and rCBV did not improve discrimination vs. the rCBV alone (AUC, 0.927?vs.?0.923; P?=?0.222).

Conclusions

APT imaging may be a useful imaging biomarker that adds value to the ADC for discriminating between low- and high-grade gliomas.

Key points

? Higher APT values were correlated with higher glioma grades. ? Adding the APT signal to the ADC improved glioma grading. ? Adding the APT signal to rCBV did not improve glioma grading. ? APT is a useful adjunct to the ADC for glioma grading.

     

Apparent diffusion coefficient: a quantitative parameter for in vivo tumor characterization

PURPOSE: The purpose of the this study was to evaluate the potential of diffusion weighted imaging (DWI) to distinguish different tissue compartments in early, intermediate and advanced tumor stages. MATERIALS AND METHODS: Twenty-two male mice were induced with squamous cell tumor (SCCVII) and scanned with a clinical 1.5 T scanner. T1-SE, T2-FSE, diffusion weighted Line-Scan-MRI and contrast enhanced T1-SE were obtained from mice with early (tumor volume 10-100 mm(3)), intermediate (200-600 mm(3)), advanced tumors (600-1000 mm(3)) and tumor necrosis (>1500 mm(3)). The apparent diffusion coefficient (ADC) of different tumor compartments was calculated offline with a pixel-by-pixel method. The animals were sacrificed immediately after scanning and histopathologic correlation was performed. RESULTS: In early stages of tumor development, tumors appeared homogeneous on diffusion weighted images with an ADC of 0.64+/-0.06 x 10(-3) mm(2)/s. With tumor progression the ADC in the rim areas of tumor increased significantly (intermediate stage: 0.70+/-0.11 x 10(-3) mm(2)/s; advanced stage: 0.88+/-0.11 x 10(-3) mm(2)/s; tumor necrosis 1.03+/-0.06 x 10(-3) mm(2)/s), whereas the ADC in viable tumor remained constant. Histologically the areas with an increased ADC correlated well with areas of necrosis (reduced cell density). CONCLUSION: The ADC is a non-invasive technique to monitor changes in the biological structure of tumor tissue during tumor progression. Thus, DWI is a potential diagnostic tool for in-vivo tissue characterization.     

Apparent diffusion coefficient determination in normal fetal brain: a prenatal MR imaging study

BACKGROUND AND PURPOSE: Diffusion-weighted MR imaging studies of normal brain development have focused on premature babies who were free of focal lesions on conventional MR images. The condition of prematurity, however, is dissimilar to intrauterine life. We sought to establish normal values of fetal brain apparent diffusion coefficient (ADC) to highlight its abnormal changes in pathologic conditions and to obtain information about normal brain development. METHODS: We measured the ADC, in utero, by using an echo-planar three-axes diffusion-sensitized sequence (b factor, 0 and 600 s/mm(2)), in frontal and occipital white matter and basal ganglia gray matter of 15 fetuses. Their gestational ages ranged from 22 to 35 weeks, and the postnatal MR images or sonograms revealed normal brain. RESULTS: Mean ADC value was 1.96 +/- 0.1 micro m(2)/ms (SD) in frontal white matter, 1.95 +/- 0.1 micro m(2)/ms in occipital white matter, and 1.56 +/- 0.1 micro m(2)/ms in basal ganglia. A significant negative correlation between ADC and gestational age was found for basal ganglia, whereas only a trend was present for frontal white matter. CONCLUSION: Although moderately higher, the ADC determinations we obtained are consistent with those reported in the literature in postnatal studies performed in premature babies.     

Apparent diffusion coefficient and Magnetic resonance spectroscopy in grading of malignant brain neoplasms

Aim

This work aims to study the role of combined apparent diffusion coefficient (ADC) and Magnetic resonance spectroscopy (MRS) in grading malignant brain neoplasms.

Methods

A prospective study included 40 patients who were evaluated by standard contrast enhanced MRI, diffusion weighted imaging and multivoxel spectroscopy.

Results

Statistically significant difference was found between tumoral ADC values in low grade versus high grade tumors and metastasis and also between the peritumoral ADC values in metastasis versus low and high grade tumors. Statistically significant difference is noticed between tumoral Cho/Cr ratio values in low grade versus high grade tumors and metastasis, and also peritumoral Cho/Cr ratio values in low grade and metastasis versus high grade tumors. Statistically significant difference between tumoral Cho/NAA ratio in low grade versus high grade tumors and metastasis and lastly between peritumoral Cho/NAA ratio in low grade and metastasis versus high grade tumors was found. Lipid and lactate peaks were found frequently in high grade tumors and metastasis.

Conclusion

The combination of calculated ADC values and MR spectroscopy is useful in grading of malignant brain tumors and were more useful together than each on its own.     

Normal brain and brain tumor: multicomponent apparent diffusion coefficient line scan imaging

Magnetic resonance line scan diffusion imaging of the brain, with diffusion weighting between 5 and 5,000 sec/mm(2), was performed in healthy subjects and patients with a 1.5-T machine. For each voxel, biexponential signal decay fits produced two apparent diffusion constants and respective signal amplitudes. Images based on these parameters show potential for use in the differentiation of gray and white matter, edema, and tumor.     

Using relative cerebral blood flow and volume to evaluate the histopathologic grade of cerebral gliomas: preliminary results

OBJECTIVE: Relative cerebral blood flow has rarely been studied as part of the preoperative assessment of tumor grade, although relative cerebral blood volume is known to be useful for this assessment. The purpose of our study was to determine the usefulness of relative cerebral blood flow in assessing the histopathologic grade of cerebral gliomas. SUBJECTS AND METHODS: MR imaging was performed in 17 patients with proven cerebral gliomas (11 high-grade gliomas and six low-grade gliomas), using a first-pass gadopentetate dimeglumine-enhanced T2-weighted echoplanar perfusion sequence. The perfusion data were deconvoluted with an arterial input function, using singular value decomposition to obtain a color map of relative cerebral blood volume and flow; the relative cerebral blood volume and flow ratios were expressed relative to values measured in the contralateral white matter. The Wilcoxon's rank sum test was performed to test the difference between the mean of the relative cerebral blood volume (or flow) ratio in high-grade gliomas and that in low-grade gliomas. Receiver operating characteristic curve analysis was used to evaluate the association between the relative cerebral blood volume (or flow) ratio and the grade of the glioma, as well as to calculate the relative cerebral blood volume and flow ratio cutoff value permitting discrimination between high- and low-grade gliomas. The correlation between relative cerebral blood volume and flow ratios was evaluated using Spearman's rank correlation analysis. We also made a qualitative assessment regarding the match or mismatch of areas of maximal contrast enhancement with the areas of highest color perfusion maps. RESULTS: The mean of the relative cerebral blood volume ratio was 4.91 in the high-grade gliomas and 2.00 in the low-grade gliomas. The mean relative cerebral blood flow ratio was 4.82 in the high-grade gliomas and 1.83 in the low-grade gliomas. A significant difference in each relative cerebral blood volume and flow ratio was found between the high- and low-grade gliomas (Wilcoxon's rank sum test, p < 0.05). Both the relative cerebral blood volume and flow ratios strongly matched the grade of the glioma, but the difference between the two areas was not significant (receiver operating characteristic curve analysis, p > 0.05). The desired cutoff value was 2.93 in the relative cerebral blood volume ratio and 3.57 in the relative cerebral blood flow ratio. Additionally, there was a strong correlation between the relative cerebral blood volume and flow ratios (Spearman's rank correlation coefficient = 0.762; p < 0.05). There was frequent mismatch (33%) between the qualitative assessment of the contrast-enhanced T1-weighted MR images and the perfusion maps. CONCLUSION: First-pass gadopentetate dimeglumine-enhanced T2-weighted echoplanar perfusion MR imaging is useful for the preoperative assessment of tumor grade. A relative cerebral blood flow ratio, in addition to a relative cerebral blood volume ratio, can be a useful tool in the evaluation of the histopathologic grade of cerebral gliomas.     

Apparent diffusion coefficient in pancreatic cancer: characterization and histopathological correlations

PURPOSE: To clarify the components primarily responsible for diffusion abnormalities in pancreatic cancerous tissue. MATERIALS AND METHODS: Subjects comprised 10 patients with surgically confirmed pancreatic cancer. Diffusion-weighted (DW) echo-planar imaging (b value = 0, 500 s/mm(2)) was employed to calculate the apparent diffusion coefficient (ADC). ADC values of cancer and noncancerous tissue were calculated. Furthermore, ADC values of the cancer were compared with histopathological results. RESULTS: The mean (+/-standard deviation) ADC value was significantly lower for tumor (1.27 +/- 0.52 x 10(-3) mm(2)/s) than for noncancerous tissue (1.90 +/- 0.41 x 10(-3) mm(2)/s, P < 0.05). Histopathological examination showed similar proportions of fibrotic area, cellular component, necrosis, and mucin in each case. Regarding the density of fibrosis in cancer, three cases were classified in the loose fibrosis group and the remaining seven cases were classified in the dense fibrosis group. The mean ADC value was significantly higher in the loose fibrosis group (1.88 +/- 0.39 x 10(-3) mm(2)/s) than in the dense fibrosis group (1.01 +/- 0.29 x 10(-3) mm(2)/s, P < 0.05). In quantitative analysis, ADC correlated well with the proportion of collagenous fibers (r = -0.87, P < 0.05). CONCLUSION: Collagenous fibers may be responsible for diffusion abnormalities in pancreatic cancer.     

MR cerebral blood volume maps correlated with vascular endothelial growth factor expression and tumor grade in nonenhancing gliomas

BACKGROUND AND PURPOSE: Relative cerebral blood volume (rCBV) measurements derived from perfusion-weighted imaging (PWI) may be useful to evaluate angiogenesis and preoperatively estimate the grade of a glioma. We hypothesized that rCBV is correlated with vascular endothelial growth factor (VEGF) expression as marker of the angiogenic stimulus in presumed supratentorial low-grade gliomas (LGGs). METHODS: From February 2001 to February 2004, we examined 20 adults (16 men, four women; mean age 36 years; range, 23-60 years) with suspected (nonenhancing) supratentorial LGG on conventional MR imaging. Preoperative MR imaging used a dynamic first-pass gadolinium-enhanced, spin-echo echo-planar PWI. In heterogeneous tumors, we performed stereotactic biopsy in the high-perfusion areas before surgical resection. Semiquantitative grading of VEGF immunoreactivity was applied. RESULTS: Nine patients had diffuse astrocytomas (World Health Organization grade II), and 11 had other LGG and anaplastic gliomas. In patients with heterogeneous tumors on PWI, the high-rCBV focus had areas of oligodendroglioma or anaplastic astrocytoma on stereotactic biopsy, whereas the surgical specimens were predominantly astrocytomas. Anaplastic gliomas had high rCBV ratios and positive VEGF immunoreactivity. Diffuse astrocytomas had negative VEGF expression and mean rCBV values significantly lower than those of the other two groups. Three diffuse astrocytomas had positive VEGF immunoreactivity and high rCBV values. CONCLUSION: Our results confirmed the correlation among rCBV measurements, VEGF expression, and histopathologic grade in nonenhancing gliomas. PWI may add useful data to the preoperative assessment of nonenhancing gliomas. Its contribution in predicting tumor behavior and patient prognosis remains to be determined.     

Correlation of MR relative cerebral blood volume measurements with cellular density and proliferation in high-grade gliomas: an image-guided biopsy study

BACKGROUND AND PURPOSE:As newer MR imaging techniques are used to assist with tumor grading, biopsy planning, and therapeutic response assessment, there is a need to relate the imaging characteristics to underlying pathologic processes. The aim of this study was to see how rCBV, a known marker of tumor vascularity, relates to cellular packing attenuation and cellular proliferation.MATERIALS AND METHODS:Nine patients with histologically proved high-grade gliomas and 1 with a supratentorial PNET requiring an image-guided biopsy were recruited. Patients underwent a DSC study. The rCBV at the intended biopsy sites was determined by using a histogram measure to derive the mean, maximum, and 75th centile and 90th centile values. This measure was correlated with histologic markers of the MIB-1 labeling index (as a marker of glioma cell proliferation) and the total number of neoplastic cells in a high-power field (cellular packing attenuation).RESULTS:There was a good correlation between rCBV and MIB-1 by using all the measures of rCBV. The mean rCBV provided the best results (r = 0.66, P < .001). The only correlation with cellular packing attenuation was with the 90% centile (rCBV_90%, r = 0.36, P = .03). The increase in rCBV could be seen over 1 cm from the edge of enhancement in 4/10 cases, and at 2 cm in 1/10.CONCLUSIONS:rCBV correlated with cellular proliferation in high-grade gliomas but not with cellular packing attenuation. The increase in rCBV extended beyond the contrast-enhancing region in 50% of our patients.

The development of all tumors is dependent on having a sufficient blood supply. This is largely achieved by angiogenesis, a process that is carefully controlled by the local production of angiogenic growth factors. Studies that have quantified the extent of angiogenesis have shown that high-grade gliomas are the tumors most dependent on this process.¹During the past few years, MR imaging techniques have been devised that allow the noninvasive study of tumor vascularity. DSC, the most widespread technique in clinical practice, relies on the T2* signal-intensity change that occurs with the passage of a contrast agent through the tissues. This change allows calculation of the rCBV, a measure that has been shown to correlate with glioma vascularity^2,3 and the expression of VEGF.⁴ These techniques may also tell us more about other pathologic changes that occur in tumors. Other studies have shown that tumors that have mitotic activity have a higher rCBV,^2,5 but these studies have included patients with both high- and low-grade tumors. This difference makes it difficult to determine whether the increase in mitotic activity directly relates to the tumor grade or the high rCBV.There is an increasing interest in using these newer imaging methods as biomarkers to assist in tumor grading and biopsy guidance and to assess both progression and therapeutic response. It is, therefore, essential to understand their histologic basis. To further understand what the increase in rCBV tells us in a tumor, we have studied a more homogeneous group of high-grade gliomas undergoing image-guided brain biopsy. The aim was to assess whether rCBV values correlate with the tumor proliferation index (MIB-1 labeling index) and tumor cellular packing attenuation.     

Abnormalities in the recirculation phase of contrast agent bolus passage in cerebral gliomas: comparison with relative blood volume and tumor grade

BACKGROUND AND PURPOSE: Abnormalities in the recirculation phase of the passage of a contrast agent bolus have been identified in tumors and have been suggested to represent vascular tortuosity and hypoperfusion in areas of angiogenic neovascularization. This study was performed to examine the hypothesis that these abnormalities provide information concerning the microcirculation related to tumor grade in patients with cerebral glioma. METHODS: Contrast-enhanced dynamic susceptibility MR imaging was performed in 27 patients with glioma. Residual relaxivity effects were minimized by injection of contrast agent before dynamic imaging. Maps of relative cerebral blood volume (rCBV) and relative recirculation (rR) were calculated, and values from enhancing tumor tissue were compared with tumor grade. RESULTS: Histologic grades were grade II, astrocytoma (n = 3); grade III, anaplastic astrocytoma (n = 10); and grade IV, glioblastoma multiforme (n = 14). rCBV values varied among tumor grades, with higher mean values in higher grade tumors (P <.001). Mean rR values in grade II tumors were not significantly different from those in normal gray and white matter. Mean rR values in grades III and IV tumors were similar and were significantly higher than those in grade II tumors (P <.01). The distribution of the pixel values of rR showed significant differences between grades III and IV tumors (P <.001), with low values of skewness in keeping with a normal distribution in grade III tumors and higher values in grade IV tumors. CONCLUSION: Variation in the recirculation characteristics of a contrast agent bolus is related to tumor grade in gliomas. This supports the hypothesis that abnormalities in contrast agent recirculation provide independent information concerning the microcirculation in imaging studies of angiogenesis and may be of value as surrogate markers in trials of antiangiogenic therapy.     

Temporal and anatomical variations of brain water apparent diffusion coefficient in perinatal cerebral hypoxic-ischemic injury: Relationships to cerebral energy metabolism

Cerebral apparent diffusion coefficients {ADCs) were determined in nine newborn piglets before and for 48 h after transient hypoxia-ischemia. Phosphorus MRS revealed severely reduced cerebral energy metabolism during the insult and an apparently complete recovery 2 h after resuscitation commenced. At this time, mean ADC over the imaging slice (ADC_global) was 0.88 (0.04) × 10^{? 9} m² · s^{? 1} (mean (SD}), which was close to the baseline value of 0.92 (0.4) × 10^{? 9} m² · s^{? 1}. In seven of the animals, a “secondary” failure of energy metabolism then evolved, accompanied by a decline in ADC_global to 0.64 (0.17) × 10^{? 9} m² · s^{? 1} at 46 h postresuscitation (P < 0.001 versus baseline). For these seven animals, ADC_global correlated linearly with the concentration ratio [phosphocreatine (PCr)][inorganic phosphate (Pi)] (0.94 r < 0.99; P > 0.001). A nonlinear relationship was demonstrated between ADC_global, and the concentration ratio [nucleotide triphosphate (NTP)]/ [Pi + PCr + 3 NTP]. The ADC reduction commenced in the parasagittal cortex before spreading in a characteristic pattern throughout the brain. ADC seems to be closely related to cerebral energy status and shows considerable potential for the assessment of hypoxic-ischemic injury in the newborn brain.     

Perfusion imaging of brain gliomas using arterial spin labeling: correlation with histopathological vascular density in MRI-guided biopsies

Introduction

This study was designed to determine if cerebral blood flow (CBF) derived from arterial spin labeling (ASL) perfusion imaging could be used to quantitatively evaluate the microvascular density (MVD) of brain gliomas on a “point-to-point” basis by matching CBF areas and surgical biopsy sites as accurate as possible.

Methods

The study enrolled 47 patients with treatment-naive brain gliomas who underwent preoperative ASL, 3D T1-weighted imaging with gadolinium contrast enhancement (3D T1C+), and T2 fluid acquisition of inversion recovery (T2FLAIR) sequences before stereotactic surgery. We histologically quantified MVD from CD34-stained sections of stereotactic biopsies and co-registered biopsy locations with localized CBF measurements. The correlation between CBF and MVD was determined using Spearman’s correlation coefficient. P ≤ .05 was considered statistically significant.

Results

Of the 47 patients enrolled in the study, 6 were excluded from the analysis because of brain shift or poor co-registration and localization of the biopsy site during surgery. Finally, 84 biopsies from 41 subjects were included in the analysis. CBF showed a statistically significant positive correlation with MVD (ρ = 0.567; P = .029).

Conclusion

ASL can be a useful noninvasive perfusion MR method for quantitative evaluation of the MVD of brain gliomas.

     

Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume

Purpose

To investigate the potential value of pre‐external‐beam radiation therapy (XRT) choline‐to‐NAA (N‐acetylaspartate) index (CNI), apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) for predicting survival in newly diagnosed patients with glioblastoma multiforme (GBM).

Materials and Methods

Twenty‐eight patients with GBM were studied using in vivo proton magnetic resonance spectroscopic imaging (¹H MRSI) and diffusion‐ and perfusion‐weighted imaging after surgery but prior to XRT. Patients were categorized on the basis of their volumes of morphologic and metabolic abnormalities (volume of CNI ≥ 2 and CNI values), normalized ADC (nADC), or rCBV values within the T1 contrast‐enhancing and T2 regions. The median survival time was compared.

Results

A significantly shorter median survival time was observed for patients with a large volume of metabolic abnormality than for those with a small abnormality (12.0 and 17.1 months, respectively, P = 0.002). A similar pattern was observed for patients with a low mean nADC value compared to those with high mean nADC value within the T2 region (11.2 and 21.7 months, respectively, P = 0.004). A shorter median survival time was also observed for patients with contrast‐enhancing residual disease than for those without the presence of contrast enhancement with marginal significance.

Conclusion

The pre‐XRT volume of the metabolic abnormality and the nADC value within the T2 region may be valuable in predicting outcome for patients with GBM. J. Magn. Reson. Imaging 2004;19:546–554. © 2004 Wiley‐Liss, Inc.