Synopsis
Pseudoprogression is an early-delayed inflammatory response to chemoradiotherapy typically appearing up to 3 months post-treatment in brain tumors. On routine MRI, pseudoprogression closely mimics the appearance of true progression, thereby making their visual identification challenging. Early diagnosis of pseudoprogression has implications in management of treatment effects and subsequently survival. We present initial results of using a newly developed radiomic descriptor, CoLlAGE, in distinguishing the two pathologies. We report that CoLlAGe measurements when captured from the necrotic region as opposed to just the enhancing region on MRI can reliably distinguish psuedo-progression from true progression with 100% accuracy (n=17)Purpose
Following
resection and concomitant radiation treatment in brain tumors, approximately
50% of all patients present with suspicious findings on follow-up MRI
indicative of either pseudoprogression (PsP), a benign response to radiation
therapy, or “true” tumor progression. On routine MRI scans, PsP closely mimics
the appearance of tumor progression, thereby making their visual identification
challenging. Guidelines set by RANO/Macdonald’s criteria
1,2 used in clinical diagnosis are
unreliable as they are based on 2-dimensional measurements of the enhancing
tumor alone. Histopathologically,
PsP has been found to be related to necrotizing effects with complete absence
of tumor cells and characterized by vascular dilation, and endothelial damage
of normal cerebral vasculature, while true progression is characterized by the presence
of tumor cells, increased cellularity, and vascular proliferation. These
changes in heterogeneity across the two conditions are appreciable within and
around the necrotic regions of the lesion at a pathologic scale. However
radiologists are typically unable to distinguish PsP from cancer recurrence on
MRI.
In
this work, we explore the feasibility of a new computer extracted texture
(radiomic) feature called CoLlAGe
3 to distinguish PsP from tumor
progression in primary brain tumor patients. CoLlAGe aims to capture subtle differences
in heterogeneity on a per-voxel basis by measuring entropy (mathematical
construct to capture degree of disorder) of gradient orientations. We hypothesize
that the CoLlAGe measurements when captured from the necrotic region as opposed
to just the enhancing region on MRI, will be substantially different across “true”
tumor progression and PsP, potentially capturing the underlying differences in
heterogeneity as reflected on a pathologic scale.
Methods
A total of 17 MRI studies (Gd-T
1w, T
2w,
FLAIR) were obtained in an IRB approved study, for PsP (n = 5) or tumor
progression (n = 12) as established on follow-up clinical and imaging
examinations (Table 1). Our workflow first involved co-registration of Gd-T
1w,
T
2w and FLAIR sequences in order to align the anatomical
structures across different imaging sequences
4, followed by
harmonizing protocol-specific image intensities to template distributions to
account for intensity non-standardness
5. Expert delineation of
enhancing, and necrotic regions was performed on T
1w MRI and of
edema region on T
2w, and FLAIR. CoLlAGe features were then extracted
on a per-pixel basis for every region (edema, tumor necrosis, enhancing tumor),
for each of the MRI protocols. The values across all the studies were collated
for every region as a histogram, and skewness, a measure of asymmetry of
probability distributions was used as a feature to distinguish PsP from tumor
progression.
Results and
Discussion
Skewness
of the CoLlAGe distribution for every patient is shown in a linear scale in
Figure 1. The normalized mean and standard deviation values of CoLlAGe skewness
were 0.07 +/- 0.05 and 0.42 +/- 0.3 for PsP and cancer progression respectively.
As observed in Figure 1, at a threshold
of 0.08, all of the 12 tumor progression cases as well as all 5 PsP studies
were correctly identified, with 100% detection accuracy. Figures 2(a)-(c) show
the box-plots of intensity values for enhancing tumor, edema, and tumor
necrosis respectively, while Figures 2(d)-(e) show the corresponding box-plots
for CoLlAGe values extracted from each of the 3 regions on Gd-T1w
scans for all 17 patient studies. Interestingly, the intensity and CoLlAGe
values for PsP and tumor progression were fairly overlapping for the enhancing
and edema regions, while the CoLlAGe values showed near-perfect separation in
the necrotic region for Gd T1w MRI (p-value =0.0003). CoLlAGe values
for tumor progression cases were observed to be more negatively skewed as
compared to those from PsP cases. The differences in CoLlAGe values in the
necrotic region may be on account of differences in necrotizing effects observed
at a pathologic scale in patients with PsP (high hypoxia, absence of tumor
cells), as opposed to those with tumor progression.
Conclusion
We presented the initial results of employing
CoLlAGe, a new radiomic feature, to distinguish PsP from tumor progression with
a 100% detection accuracy in n=17 studies. We identified that skewness of
CoLlAGe values from within the necrotic region was markedly different between
PsP and tumor progression studies (tumor progression more negatively skewed
than PsP), as opposed to features obtained from enhancing regions, which showed
no statistical differences in values across PsP and tumor progression studies.
Clinical Implication
Reliable
distinction of PsP from true progression would allow for early identification
of patients with “true” progression who are currently subject to a
“wait-and-watch” as their tumor continues to grow. It would also help evaluate
the efficacy of treatment procedures thereby facilitating targeted treatment in
patients with early treatment failure.
Acknowledgements
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers R21CA167811-01, R21CA179327-01, R21CA195152-01, U24CA199374-01the National Institute of Diabetes and Digestive and Kidney Diseases under award number R01DK098503-02, the DOD Prostate Cancer Synergistic Idea Development Award (PC120857); the DOD Lung Cancer Idea Development New Investigator Award (LC130463),the DOD Prostate Cancer Idea Development Award; the Ohio Third Frontier Technology development Grant, the CTSC Coulter Annual Pilot Grant, the Case Comprehensive Cancer Center Pilot Grantthe VelaSano Grant from the Cleveland Clinicthe Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering at Case Western Reserve University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.References
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