Rationale and Objectives
The treatment of glioma with bevacizumab results in decreased enhancement, making it challenging to diagnose tumor recurrence. Therefore, the primary aim of this retrospective study was to determine if the underlying biological processes occurring within regions of recurrent glioblastoma in patients undergoing bevacizumab therapy influence morphologic and diffusion-weighted magnetic resonance (MR) imaging characteristics.
Materials and Methods
In this Health Insurance Portability and Accountability Act–compliant and institutional review board–approved study, 26 patients treated with bevacizumab for high-grade glioma underwent lesion-wide apparent diffusion coefficient analysis before therapy and at the time of clinical/radiological progression, allowing for stratification by the presence or absence of reduced diffusion. Lesions with reduced diffusion were classified into “block” or “salt & pepper” phenotypes. Eight of the 26 patients underwent image-guided tissue sampling at the time of suspected disease recurrence allowing for direct biological correlation. Clinical, histologic, and MR imaging differences between diffusion groups were assessed using a two-sample Welch t test.
Results
All patients had histologic evidence of recurrent disease with or without a background of treatment effect. Sixty-two percent of the cohort had developed reduced diffusion at clinical progression following bevacizumab. Image-guided tissue sampling demonstrated that treatment effect was not observed within regions of reduced diffusion. Recurrent tumor intermixed with treatment effect was more likely to be observed within the “salt & pepper” phenotype when compared to “block” phenotype.
Conclusions
Following bevacizumab therapy, recurrent glioblastoma can manifest as nonenhancing regions characterized by reduced diffusion. Histologically, these MR imaging characteristics correlate with aggressive biological features of disease recurrence.
Introduction
High-grade glioma is the malignant form of primary glial neoplasms; the presence of which forebodes poor prognosis. Vascular endothelial growth factor, a hypoxia-regulated gene, is a powerful mediator of tumor progression via its role in tumor angiogenesis and vascular hyperplasia. Bevacizumab, a nonselective monoclonal antibody (mAb) for vascular endothelial growth factor, is clinically used for its antiangiogenic properties in patients with recurrent high-grade glioma.
Currently, the post-therapeutic radiological diagnosis of high-grade glioma recurrence is, in part, characterized by progressive contrast enhancement on serial magnetic resonance (MR) imaging. The presence of contrast enhancement is predicated on the expression of leaky microvasculature. The antiangiogenic effects of bevacizumab histologically causes pseudonormalization of the tumor microvasculature that is biologically manifested as reduced vascular permeability, reduced interstitial pressure, and diminished contrast-enhancing volume on MR imaging. As a result, it can be clinically challenging, in the setting of concurrent bevacizumab administration, to determine whether increasing T2 hyperintensity within a region of diminishing contrast enhancement is a hallmark of tumor response to therapy or the development of nonenhancing recurrent tumor.
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Materials and Methods
Patient Population
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Table 1
Clinical and Qualitative MR Imaging Measurements
Patient Number Initial Dx Age Image-guided Tissue Sample KPS Pathology Group Concurrent Therapies Location SVZ Post Tx T2 Pattern DWI Phenotype 1 GBM 53 N 90 Recurrent Rd CPT, Carbo F 3 I S 2 GBM 50 N 80 Recurrent Rd CPT F 3 I S 3 GBM 50 N 90 Mixed Rd Carbo F 3 E S 4 GBM 64 N 80 Mixed Rd None O 3 I S 5 GBM 50 N 90 Recurrent Rd TMZ T 1 I B 6 GBM 63 N 90 Mixed Rd CPT P 3 E S 7 GBM 42 N 70 Recurrent Rd CPT T 4 I B 8 GBM 62 N 70 Recurrent Rd CPT P 1 I S 9 GBM 64 Y 70 Recurrent Rd None P 1 I B 10 AO 54 Y 90 Mixed Rd CPT F 3 I B 11 AOA 47 Y 90 Mixed Rd CPT P 2 I S 12 GBM 38 Y 90 Recurrent Rd TMZ F 3 I S 13 AO 56 Y 70 Recurrent Rd None P 3 I B 14 GBM 57 Y 80 Mixed Rd TMZ F 3 I S 15 GBM 62 Y 80 Recurrent Rd None P 1 I S 16 GBM 51 Y 90 Recurrent Rd None P 1 I B 17 GBM 52 N 90 Recurrent NRd Carbo T 3 E None 18 GBM 58 N 80 Recurrent NRd CPT P 2 E None 19 GBM 64 N 80 Recurrent NRd CPT T 3 E None 20 GBM 27 N 90 Recurrent NRd TMZ P 4 E None 21 GBM 35 N 90 Recurrent NRd TMZ T 4 I None 22 GBM 47 N 90 Recurrent NRd CPT P 4 I None 23 GBM 68 N 90 Mixed NRd None P 4 E None 24 GBM 58 N 90 Recurrent NRd None F 1 E None 25 GBM 56 N 80 Recurrent NRd None P 4 E None 26 GBM 47 N 90 Recurrent NRd CPT F 4 E None
AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; B, block; CPT, irinotecan, carbo, Paraplatin; DWI phenotype, reduced diffusion-weighted imaging phenotype; E, edematous; F, frontal; GBM, glioblastoma; I, infiltrative; Initial Dx, initial histologic diagnosis; KPS, Karnofsky Performance Scale Index (obtained before initiation of bevacizumab); Mixed, recurrent glioblastoma within background of treatment change/effect; NRd, nonreduced diffusion; O, occipital; P, parietal; Pathology, pathologic diagnosis at time of recurrence following Avastin; Post Tx T2 Pattern, post-bevacizumab therapy T2 pattern; Rd, reduced diffusion; Recurrent, recurrent glioblastoma; S, salt & pepper; SVZ, subventricular zone; T, temporal; Tissue Sample, underwent image-guided tissue sampling, Yes or No; TMZ, temozolomide; Type 1, enhancement contacting cortex and subventricular zone; Type 2, enhancement contacting subventricular zone alone; Type 3, enhancement contacting cortex alone; Type 4, no enhancement of the cortex or subventricular zone.
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MR Imaging Protocol
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Morphologic MR Imaging Characterization
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Diffusion-weighted MR Imaging Analysis
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![Figure 1, Development of block phenotype reduced diffusion in a 50-year-old man following 3 months of bevacizumab therapy. (a) Pre-therapeutic T1-weighted contrast-enhanced ( left ), axial fluid-attenuated inversion recovery (FLAIR) ( center left ), diffusion-weighted image ( center right ), and apparent diffusion coefficient (ADC) map ( right ) show no indication of reduced diffusion. (b) Post-therapeutic magnetic resonance (MR) imaging demonstrates interval development of mass like infiltrative minimally enhancing T2 hyperintensity and block phenotype reduced diffusion involving the right temporal lobe (lesion average T2 ADCmin = 350, ADCmean = 967, rADC min = 0.49, and rADCmean = 1.1). Pre-contrast T1-weighted images ( not shown ) did not demonstrate T1-shortening/blood products that would account for artificially reduced diffusion. Robust contrast enhancement predominately involving the anterior temporal lobe is not associated with reduced diffusion. (c) Image-guided tissue sampling of reduced diffusion lesion ( left ; T1 postcontrast sampling site, center ; ADC map, right ; hematoxylin and eosin [H&E]) showed heterogeneous highly cellular recurrent tumor with some samples demonstrating increased cellular necrosis (H&E stain, 10× Mmagnification; top and bottom samples; greater than 50%) when compared to regions demonstrating densely cellular tumor recurrence without necrosis ( middle sample ). Markedly elevated measures of cellular proliferation, vascular hyperplasia, and necrosis were also observed within regions of reduced diffusion when compared to regions without reduced diffusion ( not shown ).](https://storage.googleapis.com/dl.dentistrykey.com/clinical/TheDevelopmentofReducedDiffusionFollowingBevacizumabTherapyIdentifiesRegionsofRecurrentDiseaseinPatientswithHighgradeGlioma/0_1s20S1076633216300721.jpg)
![Figure 2, Development of salt & pepper phenotype reduced diffusion in a 57-year-old woman following 2 months of bevacizumab therapy. (a) Pre-therapeutic T1-weighted contrast-enhanced ( left ), axial fluid-attenuated inversion recovery (FLAIR) ( center left ), diffusion-weighted image ( center right ), and apparent diffusion coefficient (ADC) map ( right ) show no indication of reduced diffusion. Note the region of artificially reduced diffusion along the medial aspect of the resection cavity due to blood products that subsequently resolved. (b) Post-bevacizumab magnetic resonance (MR) imaging demonstrates interval development of mass like infiltrative T2 hyperintensity involving the frontal lobe with extension into the cingulate gyrus and genu of the corpus callosum associated with salt & pepper phenotype reduced diffusion (lesion average T2 ADCmin = 665, ADCmean = 1082, rADC min = 0.95, and rADCmean = 1.3). Minimal contrast enhancement involves the region of reduced diffusion. (c) Image-guided tissue sampling of the lesion ( left ; T1 post contrast sampling site, center ; ADC map, right ; hematoxylin and eosin [H&E]) showed heterogeneous regions of recurrent tumor and treatment-related changes (H&E stain; 200× magnification). Tissue sample #3 ( bottom ), corresponding to a region of reduced diffusion, demonstrated infiltrating recurrent tumor with minimal necrosis. Tissue samples #1 and #2 ( top and middle ) corresponded to regions without reduced diffusion. Tissue sample #1 demonstrated infiltrating recurrent tumor margin with minimal necrosis. Tissue sample #2 demonstrated extensive necrosis without evidence of recurrent tumor most consistent with treatment effect.](https://storage.googleapis.com/dl.dentistrykey.com/clinical/TheDevelopmentofReducedDiffusionFollowingBevacizumabTherapyIdentifiesRegionsofRecurrentDiseaseinPatientswithHighgradeGlioma/1_1s20S1076633216300721.jpg)
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MR Image-guided Biopsy Collection and Processing
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Statistical Analysis
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Results
Patient Population
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Distinct Patterns of Disease Recurrence Following Bevacizumab Therapy Are Stratified by Morphologic and Diffusion-weighted MR Imaging Characteristics
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Table 2
Comparison of Pre- and Post-therapeutic Diffusion-weighted Imaging for All Patients
T2 Area T2 T2 T2 CE Area CE CE CE (cm 2 ) rADC min rADC mean rADC max (cm 2 ) rADC min rADC mean rADC max PreTx 13.4(12.2) 0.99(0.15) 1.66(0.34) 2.12(0.40) 2.36(2.94) 1.12(0.33) 1.51(0.23) 1.88(0.43) PostTx 17.7(9.8) 0.71(0.21) 1.30(0.18) 2.02(0.54) 3.82(7.08) 0.82(0.23) 1.20(0.33) 1.61(0.55)P value 0.16 0.01 0.01 0.41 0.34 0.01 0.01 0.05
CE, contrast enhancing region of interest; Mean (standard deviation), T2, T2 FLAIR hyperintensity region of interest; PostTx, following bevacizumab administration; PreTx, before bevacizumab administration.
Table 3
Comparison Diffusion-weighted Imaging Values for Reduced Diffusion Group
T2 Area T2 T2 T2R CE Area CE CE CE (cm 2 ) rADC min rADC mean rADC max (cm 2 ) rADC min rADC mean rADC max PreTx 17.3(13.0) 0.95(0.15) 1.71(0.41) 2.06(0.35) 3.25(3.43) 1.01(0.18) 1.46(0.23) 1.81(0.35) PostTx 20.5(9.91) 0.58(0.13) 1.21 0.13) 1.88(0.59) 4.49(8.69) 0.69(0.17) 1.05(0.13) 1.35(0.59)P value 0.44 0.01 0.01 0.30 0.60 0.01 0.01 0.01
CE, contrast enhancing region of interest; Max, maximum value; Mean, average value; Mean (standard deviation), T2, T2 FLAIR hyperintensity region of interest; Min, minimum value; PostTx, following bevacizumab administration; PreTx, before bevacizumab administration.
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ADC Metrics and Lesion Biological Characteristics Within Regions of Treatment Effect Are Significantly Different From Those Composed of Recurrent Glioblastoma
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Table 4
Comparison of Diffusion-weighted Imaging and Cellular Proliferation Metrics Between Regions with Recurrent Tumor and Treatment Effect
ADC min ADC mean ADC max rADC min rADC mean rADC max Ki-67 RT 541(179) 711(206) 892(260) 0.96(0.21) 0.93(0.23) 0.94(0.31) 16.3(13.5) TE 838(78) 1154(110) 1455(257) 1.36(0.36) 1.62(0.35) 1.76(0.31) 1.7(1.63)P value <0.01 <0.01 <0.01 0.04 <0.01 <0.01 <0.01
ADC, apparent diffusion coefficient; Ki-67, expressed in percentage; rADC, relative apparent diffusion coefficient; RT, recurrent tumor; TE, treatment effect.
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Regions of Recurrent Glioblastoma Following Bevacizumab Therapy Characterized by Reduced Diffusion Demonstrate Markedly Different Biological Properties Compared to Regions of Recurrent Tumor without Reduced Diffusion
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![Figure 3, Histopathologic correlation of recurrent glioblastoma tissue samples obtained from regions with and without reduced diffusion using image-guided stereotactic neurosurgical techniques in a patient demonstrating salt & pepper phenotype following bevacizumab therapy. (a) Intraoperative tissue sampling site superimposed on a post-therapeutic T1-weighted contrast-enhanced image, diffusion-weighted image, and apparent diffusion coefficient (ADC) map demonstrates mass like infiltrative T2 hyperintensity involving the left frontal lobe associated with salt & pepper phenotype reduced diffusion and minimal contrast enhancement. Tissue sampling site from region without reduced diffusion ( left ) demonstrated ADC min of 842 and ADC mean of 951. Tissue sampling site from region with reduced diffusion demonstrated ADC min of 485 and ADC mean of 646 ( right ). (b) Tissue samples obtained from region of recurrent tumor without reduced diffusion ( blue region of interest [ROI] ) demonstrated infiltrating cellular tumor ( left ; H&E stain 200× magnification), cellular proliferation of 1% ( middle ; Ki-67), with minimal vascular hyperplasia ( right ; factor VIII = delicate vascular appearance). (c) Tissue samples obtained from region of recurrent tumor with reduced diffusion ( red ROI ) demonstrated infiltrating cellular tumor ( left ; H&E stain 10× magnification) with elevated cellular proliferation ( middle ; Ki-67 = 11%), and predominantly simple vascular hyperplasia ( right ; factor VIII). No significant necrosis was observed within either tissue specimens. (Color version of figure is available online.)](https://storage.googleapis.com/dl.dentistrykey.com/clinical/TheDevelopmentofReducedDiffusionFollowingBevacizumabTherapyIdentifiesRegionsofRecurrentDiseaseinPatientswithHighgradeGlioma/2_1s20S1076633216300721.jpg)
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![Figure 4, Recurrent glioblastoma following bevacizumab therapy with block phenotype reduced diffusion demonstrates elevated cellular proliferation. (a–c) Post-therapeutic T1-weighted contrast enhanced ( left ), axial fluid-attenuated inversion recovery (FLAIR) ( center left ), diffusion-weighted image ( center right ), and apparent diffusion coefficient (ADC) map ( right ) demonstrate mass like infiltrative T2 hyperintensity involving the frontal operculum associated with block phenotype reduced diffusion and minimal contrast enhancement. All tissue sampling sites were obtained within regions of reduced diffusion (ADC min A–C = 315, 336, and 246; ADC mean A–C = 365, 406, and 287; color circle region of interest [ROI]). Immunohistochemical analysis demonstrated markedly elevated cellular proliferation (Ki-67 A–C = 32%, 26%, and 29%, brown-stained cells; right column) irrespective of the presence (biopsy site C) or absence (biopsy sites A and B) of contrast enhancement. Additionally, elevated necrosis (H&E, less than 50%; not shown) was observed. (Color version of figure is available online.)](https://storage.googleapis.com/dl.dentistrykey.com/clinical/TheDevelopmentofReducedDiffusionFollowingBevacizumabTherapyIdentifiesRegionsofRecurrentDiseaseinPatientswithHighgradeGlioma/3_1s20S1076633216300721.jpg)
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Phenotypic Patterns of Reduced Diffusion Are Associated with Histopathologic Characteristics of Recurrent Disease
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Pre-bevacizumab MR Imaging Characteristics Are Predictive of Reduced Diffusion Development Following Bevacizumab Therapy
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Discussion
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Conclusion
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Acknowledgements
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Appendix
Supplementary material
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Table S1
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