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. 2014 Mar;16(3):449-56.
doi: 10.1093/neuonc/not197. Epub 2013 Dec 4.

Challenges for the Functional Diffusion Map in Pediatric Brain Tumors

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Free PMC article

Challenges for the Functional Diffusion Map in Pediatric Brain Tumors

Matthew Grech-Sollars et al. Neuro Oncol. .
Free PMC article

Abstract

Background: The functional diffusion map (fDM) has been suggested as a tool for early detection of tumor treatment efficacy. We aim to study 3 factors that could act as potential confounders in the fDM: areas of necrosis, tumor grade, and change in tumor size.

Methods: Thirty-four pediatric patients with brain tumors were enrolled in a retrospective study, approved by the local ethics committee, to examine the fDM. Tumors were selected to encompass a range of types and grades. A qualitative analysis was carried out to compare how fDM findings may be affected by each of the 3 confounders by comparing fDM findings to clinical image reports.

Results: Results show that the fDM in areas of necrosis do not discriminate between treatment response and tumor progression. Furthermore, tumor grade alters the behavior of the fDM: a decrease in apparent diffusion coefficient (ADC) is a sign of tumor progression in high-grade tumors and treatment response in low-grade tumors. Our results also suggest using only tumor area overlap between the 2 time points analyzed for the fDM in tumors of varying size.

Conclusions: Interpretation of fDM results needs to take into account the underlying biology of both tumor and healthy tissue. Careful interpretation of the results is required with due consideration to areas of necrosis, tumor grade, and change in tumor size.

Keywords: apparent diffusion coefficient; childhood tumors; diffusion-weighted magnetic resonance imaging; functional diffusion map; parametric response map.

Figures

Fig. 1.
Fig. 1.
Construction of the fDM. The fDM is built by using tumor images at 2 time points. After registration of the 2 images, a difference image is calculated. A decrease in ADC is labeled in blue, an increase in ADC is labeled in red, and no change in ADC is labeled in green.
Fig. 2.
Fig. 2.
Theoretical change in areas of necrosis by treatment. Necrotic areas of a tumor can increase in size as a result of (A) tumor growth (causing increased hypoxic regions and hence necrosis) and (B) successful treatment (as cells are killed, tumor regions are replaced by areas of necrosis). Conversely, a reduction in size of necrotic regions can be due to (C) tumor growth through angiogenesis (making the tumor more vascular and hence more cellular in areas that would otherwise have been necrotic), and (D) tumor size reduction due to successful treatment (as the tumor shrinks in size, areas of necrosis may be replaced by glial cells).
Fig. 3.
Fig. 3.
Theoretical changes in the fDM in tumors of varying grade. (Red represents an increase, blue a decrease, and green no change in ADC). The upper half of the image shows the theoretical change in ADC in high-grade tumors, which appear dark with low ADC values. (A) Progressive high-grade tumors will increase in cellularity and result in a lower and darker ADC value (blue in fDM). (B) Conversely, a high-grade tumor responding well to therapy will decrease in cellularity and increase in ADC to values more similar to those of healthy tissue (red in fDM). The lower half of the image shows the theoretical change in ADC in low-grade tumors, which appear bright with high ADC values. (C) In progressive disease, it is expected that the tumor will either grow or become necrotic. Hence, excluding areas of necrosis, it is not expected to change in ADC (green in fDM), which is also indicative of stable disease. (D) Low-grade tumors that respond to therapy are likely to be replaced by lower ADC healthy tissue, and hence, responsive low-grade tumors would decrease in ADC (blue in fDM).
Fig. 4.
Fig. 4.
The fDM in areas of necrosis. The DIPG patient was treated with radiotherapy and chemotherapy, and the fDM was constructed from 1 post treatment image and a 3-month follow-up image. (A and B) The fDM in DIPG shows areas of increased ADC (red) (A) that are eliminated when excluding areas of necrosis (B). The GC patient was treated via surgery followed by chemotherapy, and the fDM was constructed from 1 image taken 3 months after start of chemotherapy and a 1-year follow-up image. (C and D) The fDM in GC showed areas of increased ADC in necrotic regions (C) , which were again eliminated when necrotic regions were excluded (D). Removal of the necrotic regions is concordant with no tumor response in 2 patients with no change in tumor size.
Fig. 5.
Fig. 5.
The fDM in tumors of varying grade. A comparison is shown of the fDM in GBM (A and D), DIPG (B and E), and OPG (C and F) in areas of progression (top row) and treatment response (bottom row). (A) In high-grade tumors, a decrease in ADC (blue) was indicative of an increase in cellularity and progression. (E and F) In mid- and low-grade tumors, a decrease in ADC was indicative of positive treatment response as high ADC tumor was replaced by healthy tissue. (D) Similarly, an increase in ADC (red) was indicative of positive treatment response in high-grade tumors, and in the above cases (B and C), progression in mid- and low-grade tumors (B and C). Tumor progression and treatment response were defined by a radiologist at the time of second imaging.
Fig. 6.
Fig. 6.
Change in tumor size. (A and C) A comparison of the fDM when using a pretreatment mask and (B and D) only the overlap between pre- and posttreatment images is shown in a SEGA patient. The top row shows T1-weighted postcontrast imaging. The bottom row shows the fDM in 1 case, showing (C) a mixture of areas of increased ADC (red) and decreased ADC (blue) when considering the pretreatment mask, and (D) mostly areas of increased ADC when considering the tumor overlap area.
Fig. 7.
Fig. 7.
Histological comparison of low- and high-grade tumors. A comparison of a low-grade OPG (B), with a histological diagnosis of pilocytic astrocytoma (WHO grade I) and a high-grade GBM (C) are shown together with a comparative image from normal-appearing white matter (WM) (A). The low-grade tumor showed some areas with high cellularity (as compared with WM) as well as myxoid areas shown in B. The microcystic changes observed in the low-grade tumor could explain the increased ADC observed in these tumors when compared with normal-appearing white matter. The high-grade tumor (C) showed the highest cellularity, which restricts diffusion and explains why these tumors appear dark in ADC images. (All images are hematoxylin-eosin stained and at the same magnification [x20].)

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