Characterising tumour progression and pseudoprogression on preoperative multimodal MRI imaging
Jiun-Lin Yan1,2,3, Anouk van der Hoorn4, Timothy J Larkin5, Natalie Rosella Boonzaier5, Tomasz Matys6, and Stephen J Price5

1Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom, 2Department of neurosurgery, Chang Gung Memorial Hospital, Keelung, Taiwan, 3Department of neurosurgery, Chang Gung University College of Medicine, Taoyuan, Taiwan, 4Department of radiology (EB44), University of Groningen, Groningen, Netherlands, 5Brain tumour imaging laboratory, University of Cambridge, Cambridge, United Kingdom, 6Department of radiology, University of Cambridge, Cambridge, United Kingdom

Synopsis

Glioblastoma is a highly malignant tumor which recur mostly within 2 cm around the resected contrast enhancement. However, it is difficult to identify tumor invasiveness pre-surgically especially in non-enhanced area. Thus, we aimed to identify possible imaging characteristics preoperatively using multimodal MR techniques in the peritumoral regions that eventually leads to tumor recurrence or progression. Our study showed lower isotorpic p, anisotopic q and ADC for progression compared to non-progression regions. In addition, MRS showed a not statistically significant trend of higher choline/NAA, higher choline and lower NAA in these progression area.

Purpose

To characterise MR imaging biomarker in the peri-tumoral area with recurrence, progression or pseudo-progression on preoperative multi-model MRI.

Methods

We retrospectively included 26 newly diagnosed cerebral glioblastoma patients, of which five showed also pseudoprogression earlier. All patients were treated with 5-aminolevulinic acid (5-ALA) fluorescence guidance with the aim of maximal tumour resection and standard postoperative concomitant chemoradiotherapy. Preoperative MRI data acquisition was performed using a 3.0 Tesla Siemens MR Magnetron system (Siemens Healthcare, Munich, Germany). Imaging included an anatomical 3D contrast T1-weighted sequence with fat suppression, perfusion, DTI, spectroscopy. We further decomposed the diffusion tensor into isotropic (p) component and anisotropic (q) component after eigenvalues were calculated in the DTI data.1 Follow up MRI at time point of progression or pseudoprogression were co-registered to the preoperative T1 with contrast by using a previously described two stage semi-automatic non-linear coregistration methods (Figure 1-A, B, C). The site of tumour progression and pseudoprogression (Figure 1-D, E) were selected based on T1 post contrast. As tumour progression and pseudoprogression both occur mainly in the periresectional area, a periresectional area of 5mm, 10mm, 15 mm and 20mm excluding the progression area was used as non-progression regions (Figure 1-F) for comparison. In addition, a contralateral area of normal appearing with matter of 5mm in diameter was used as control representing normal peritumoural brain and normal brain tissue, respectively.

Results

Patients’ clinical characteristics were shown on table 1. Patients with pseudoprogression demonstrated a better progression free survival than patients with tumour recurrence (287 ± 190 and 773 ± 272 days, respectively; p < 0.001). A similar result was seen for overall survival (534 ± 293 and 864 ± 298 days; p = 0.047). Multimodal MRI characterisation FLAIR In areas of later progression, there was significant increase in the FLAIR signal compare to all non-progression area (p = 0.0003 – 0.0024) and control (p < 0.0001). No difference between area of progression, lesion and pseudo-progression. In area of pseudo-progression, there was increased signal in FLAIR than non-progression area and control, but this achieve only marginal significance. Diffusion MR Characterising isotropic p component (Figure 3A) showed a significant decrease in progression area than contrast enhanced area (p=0.0004), non-progression 5-15mm peritumoral area (p=0.0001 – 0.0067) and control (p<0.0001). No significant decrease in area of pseudo-progression was shown. Anisotropic q component (Figure 3D) was lower in contrast enhanced area than progression, non-progression and control (p<0.0001). In area of progression, q was lower than non-progression peritumoral 5 mm area (p=0.0204) and control (p=0.0088). Q was also lower in pseudo-progression area than the 5mm peritumoral non-progression area (p=0.0309). ADC (Figure 3B) was significant lower within the contrast enhanced area than all peritumoral area (p<0.0001). The ADC value in the progression area are lower than in the 5 mm peritumoral non-progression area (p=0.0038), but did not have difference when comparing to a more distant non-progression area. In area of pseudo-progression, the ADC value had no difference from others. Fractional anisotropy (FA) (Figure 3E) was significant lower in contrast enhanced area (p<0.0001) and was also lower in progression and pseudo-progression area when comparing to contralateral control (p=<0.0001, p=0.0129 respectively). However, FA showed no difference between progression area and non-progression area (p=0.7041-0.8390). DSC-MRI Relative cerebral blood volume was increased in lesion, progression area and pseudo-progression area comparing to control (Figure 3C, p=0.002, <0.0001 and 0.041 respectively). However, there was no difference between non-progression area and progression area or pseudo-progression area. MRS MR spectroscopy data included regions of interests those occupied more than 1/2 of MRS voxel. Only 9 patients with valid MRS data were analysed (Figure 3F). Although no statistics significance were noted between progression, non-progression and control area, a trend of higher Cho/Naa, higher Choline and lower NAA+NAAG can been observed in progression area.

Disucssion

Diffusion tensor image has been used to evaluate tumor infiltration and showed optimal results. We have previously shown that specific DTI pattern can predict this microscopic tumor invasion.5 In particular, regions with >12% decrease in q (anisotropic) component showed white matter disruption by cancer. Therefore, in our result, compare to non-progression area, a decrease in q can lead to more malignant sequel of progression. Other study using DTI showed that by calculating the relationship of axial-diffusivity and radial diffusivity, tumor infiltrated edema can be distinguished from pure vasogenic edema.2 Therefore, a change in anisotropic diffusion can be seen in tumor infiltration.

Conclusion

Multimodal MR imaging, especially diffusion tensor imaging can demonstrate distinct characteristics in areas of potential later progression on preoperative MRI. This provides a direction for future study and treatment target.

Acknowledgements

This research was funded by National Institute of Health Clinician Scientist Fellowship [SJP], the Remmert Adriaan Laan Fund [AH], the René Vogels Fund [AH] and grant from Chang Gung Medical Foundation and Chang Gung Memorial Hospital [JLY]. None of the authors have financial of other conflict of interest related to the work presented in this paper.

References

1. Kono K, Inoue Y, Nakayama K, Shakudo M, Morino M, Ohata K, et al: The role of diffusion-weighted imaging in patients with brain tumors. AJNR Am J Neuroradiol 22:1081-1088, 2001

2. Min ZG, Niu C, Rana N, Ji HM, Zhang M: Differentiation of pure vasogenic edema and tumor-infiltrated edema in patients with peritumoral edema by analyzing the relationship of axial and radial diffusivities on 3.0T MRI. Clin Neurol Neurosurg 115:1366-1370, 2013

3. Pena A, Green HA, Carpenter TA, Price SJ, Pickard JD, Gillard JH: Enhanced visualization and quantification of magnetic resonance diffusion tensor imaging using the p:q tensor decomposition. Br J Radiol 79:101-109, 2006

4. Petrecca K, Guiot MC, Panet-Raymond V, Souhami L: Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J Neurooncol 111:19-23, 2013

5. Price SJ: Improved delineation of glioma margins and regions of infiltration with use of DTI...image-guided biopsy study.pdf. American journal of neuroradiology 27:1969-1974, 2006

Figures

An example of tumor progression (B) was coregistered to presurgical image (A). The coregistered image (C, D blue) can further create progression area (E, red) and non-progression area (F, green). Figure G-I showed an example of preoperative (G), pseudo-progression 6 months after operation (H), and follow up resolved MRI (I).

Multimodel MRI characteristics of the progression (outlined with red) or pseudo-progression were obtained on FLAIR (A), p map (B), ADC (C), rCBV (D), q map (E) and FA (F).

Figure 3 showed MRI characteristics (A-E) of contrast enhanced, progression, non-progression (NP) area in 5-20 mm peritumoral area and contralateral normal appearing white matter (NAWM, control). F showed MRS of Cho/NAA, Choline, NAA+NAAG and Glu+Gln of progression (P), non-progression (NP) and NAWM. *: p<0.05; **: p<0.01; ***: p<0.001

Numbers or mean values and standards deviation are presented for the main patient characteristics. Abbreviations: GTR = gross total resection; FLAIR = fluid attenuation inversion recovery; IDH = isocitrate dehydrogenase; MGMT = O6-methylguanin-DNA-methyltransferase; ml = millilitre; mm = millimetre; STR = subtotal resection.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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