Early Detection of Malignant Transformation in Resected WHO II Low-Grade Glioma Using Diffusion Tensor-Derived Quantitative Measures.

Here, we retrospectively investigate the value of voxel-wisely plotted diffusion tensor-derived (DTI) axial, radial and mean diffusivity for the early detection of malignant transformation (MT) in WHO II glioma compared to contrast-enhanced images.Forty-seven patients underwent brain magnetic resonance imaging follow-up between 2006-2014 after gross-tumor resection of intra-axial WHO II glioma. Axial/Mean/Radial diffusivity maps (AD/MD/RD) were generated from DTI data. ADmin/MDmin/RDmin values were quantified within tumor regions-of-interest generated by two independent readers including tumor contrast-to-noise (CNR). Sensitivity/specificity and area-under-the-curve (AUC) were calculated using receiver-operating-characteristic analysis. Inter-reader agreement was assessed (Cohen's kappa).Eighteen patients demonstrated malignant transformation (MT) confirmed in 8/18 by histopathology and in 10/18 through imaging follow-up. Twelve of 18 patients (66.6%) with MT showed diffusion restriction timely coincidental with contrast-enhancement (CE). In the remaining six patients (33.3%), the diffusion restriction preceded the CE. The mean gain in detection time using DTI was (0.8±0.5 years, p = 0.028). Compared to MDmin and RDmin, ROC-analysis showed best diagnostic value for ADmin (sensitivity/specificity 94.94%/89.7%, AUC 0.96; p<0.0001) to detect MT. CNR was highest for AD (1.83±0.14), compared to MD (1.31±0.19; p<0.003) and RD (0.90±0.23; p<0.0001). Cohen's Kappa was 0.77 for ADmin, 0.71 for MDmin and 0.65 for RDmin (p<0.0001, respectively).MT is detectable at the same time point or earlier compared to T1w-CE by diffusion restriction in diffusion-tensor-derived maps. AD demonstrated highest sensitivity/specificity/tumor-contrast compared to radial or mean diffusivity (= apparent diffusion coefficient) to detect MT

Reciever operating characteristic analysis of minimum values (averaged between the two readers).

<p>The test was positive for recurrence if the variable results were less than or equal to the cut-off value. Axial diffusivity was found to have superior diagnostic value (sensitivity, specificity, area under the curve and positive predictive values) to detect the recurrence compared to mean and radial diffusivity. Positive predictive values of AD_min/MD_min/RD_min for the given cut-offs were 81.0%/60.7%/73.9%.</p

Segmentation of the T2w-hyperintensity zone to derive AD_min/MD_min/RD_min.

<p>Because DTI-maps are intrinsically co-registered the ROI may easily be transferred to each of the employed parameter maps. The colored crosshair in the images indicates the localization of the automatically determined minimum value. In the given example, the patient was diagnosed with anaplastic transformation.</p

MRI protocol between 2006–2014.

<p>For T1w-CE, patients were injected with 0.1mmol/kg of Gadobutrol (Gadovist, Bayer Healthcare, Germany). b-values for DTI were 0, 1000 s/mm² for 12 diffusion directions.</p

Female patient (24y) with a malignant transformation (anaplastic astrocytoma WHO III) of a primary fibrillary Astrocytoma WHO II.

<p>The transformation according to currently accepted radiologic definition was visible as a new punctual CE at the last column. However, changes in cellularity (red triangles) were preceding CE (white triangle) more than one year. The area of the most focal diffusion restriction corresponds to the focal uptake. Upper row: Axial diffusivity maps; Middle row: T1w-CE; Bottom row: T2w-FLAIR. Dates are given in day/month/year.</p

Quantitative analysis of group-wise data distribution regarding AD_min/MD_min/RD_min as visualized in Fig 8, given for 18 patients with MT versus 29 stable patients at the same time point of follow-up.

<p>In 6 patients of the MT group mean AD_min/MD_min/RD_min values were 0.82±0.09/0.73±0.05/0.62±0.07 mm²/s with a signal drop of 64.1%/73.0%/63.9% compared to the stable group in the examination prior to first CE appearance thus indicating early MT.</p

Reciever operating characteristic analysis of minimum diffusion tensor parameters.

<p>Quantitative results are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164679#pone.0164679.t004" target="_blank">Table 4</a>.</p

Boxplot analysis of obtained ROI-averaged diffusivity parameters to visualize group differences (stable versus progress).

<p>Plotted values were obtained at the first appearance of CE (progress) or at the last acquired timepoint available (stable). Quantitative results including p-values are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164679#pone.0164679.t003" target="_blank">Table 3</a>.</p

Female patient (44y) with malignant transformation of a primary resected oligoastrocytoma WHO II into anaplastic oligoastrocytoma III in the left frontal lobe demonstrating heterogeneity within the patchy contrast-enhancing region.

<p>Increased diffusion restriction (red triangles) is noted at the same timepoint as new CE. Within the patchy area of CE, the spatial position of hypercellularity is visualized as red cluster (last image). Comparing T2w-FLAIR and axial diffusivity, the hypercellularity is found to be located in a T2w-hypointense region with a punctual CE focus. However, large proportions of patchy CE do not match with the diffusion restriction. Such information is important to consider for guidance of stereotactic biopsy and focal treatment planning.</p

Tumor histology of finally included patients determined after surgical resection according to the WHO 2007 criteria[2].

<p>Tumor histology of finally included patients determined after surgical resection according to the WHO 2007 criteria[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164679#pone.0164679.ref002" target="_blank">2</a>].</p