MR Angiography of Tumor-related Vasculature: From the Clinic to the Micro-environment

doi:10.1148/rg.25si055512

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MR Angiography of Tumor-related Vasculature: From the Clinic to the Micro-environment¹

Marion van Vliet, MD, Cornelis F. van Dijke, MD, PhD, Piotr A. Wielopolski, PhD, Timo L. M. ten Hagen, PhD, Jifke F. Veenland, PhD, Anda Preda, MD, Antonius J. Loeve, BSc, Alexander M. M. Eggermont, MD, PhD and Gabriel P. Krestin, MD, PhD

¹ From the Departments of Radiology (M.v.V., C.F.v.D., P.A.W., J.F.V., A.P., A.J.L., G.P.K.), Surgical Oncology (T.L.M.t.H., A.M.M.E.), and Medical Informatics (J.F.V.), Erasmus MC–University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Presented as an education exhibit at the 2004 RSNA Annual Meeting. Received February 28, 2005; revision requested April 11 and received May 25; accepted May 31. All authors have no financial relationships to disclose.

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Figure 1. Diagrams show the stages of tumor-induced angiogenesis. When the tumor reaches a diameter of 1–2 mm, its growth no longer can be sustained by the diffusion of nutrients from external vessels (top left). Growth factors (GF) are then produced by the tumor (top right) that induce external vessels to bud and form new branches (bottom left), which grow toward and into the tumor (bottom right).

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Figure 2a. Digital photographs, obtained through a dorsal skin-fold window approximately 3 mm thick, show highly vascularized high-grade nonimmunogenic BN-175 soft-tissue sarcoma. (a) Dotted line indicates tumor circumference after 2 weeks of growth. (b) Magnified gray-scale view shows chaotic intratumoral vasculature and feeding vessels.

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Figure 2b. Digital photographs, obtained through a dorsal skin-fold window approximately 3 mm thick, show highly vascularized high-grade nonimmunogenic BN-175 soft-tissue sarcoma. (a) Dotted line indicates tumor circumference after 2 weeks of growth. (b) Magnified gray-scale view shows chaotic intratumoral vasculature and feeding vessels.

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Figure 3a. Contrast-enhanced MR angiograms obtained for monitoring of treatment response in experimental (a, b) and clinical (c, d) settings. (a, b) Volumetric reconstructions of MR image data obtained with a T1-weighted 3D sequence after the administration of a blood pool contrast agent show sarcoma in a rat limb before (a) and after (b) administration of tumor necrosis factor ${alpha}$ combined with melphalan in a closed-loop system to destroy the vascular bed. Note the considerably decreased enhancement in the tumor in b. (c, d) Arterial phase MR angiograms show tumor vessels in the ankle of a patient before (c) and after (d) systemic treatment similar to that administered in the rat tumor model. Note the enhancement of the tumor vessels in c (arrowhead), and the absence of enhancement in d despite heating of the foot in a warm bath before imaging. The treatment was considered successful.

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Figure 3b. Contrast-enhanced MR angiograms obtained for monitoring of treatment response in experimental (a, b) and clinical (c, d) settings. (a, b) Volumetric reconstructions of MR image data obtained with a T1-weighted 3D sequence after the administration of a blood pool contrast agent show sarcoma in a rat limb before (a) and after (b) administration of tumor necrosis factor ${alpha}$ combined with melphalan in a closed-loop system to destroy the vascular bed. Note the considerably decreased enhancement in the tumor in b. (c, d) Arterial phase MR angiograms show tumor vessels in the ankle of a patient before (c) and after (d) systemic treatment similar to that administered in the rat tumor model. Note the enhancement of the tumor vessels in c (arrowhead), and the absence of enhancement in d despite heating of the foot in a warm bath before imaging. The treatment was considered successful.

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Figure 3c. Contrast-enhanced MR angiograms obtained for monitoring of treatment response in experimental (a, b) and clinical (c, d) settings. (a, b) Volumetric reconstructions of MR image data obtained with a T1-weighted 3D sequence after the administration of a blood pool contrast agent show sarcoma in a rat limb before (a) and after (b) administration of tumor necrosis factor ${alpha}$ combined with melphalan in a closed-loop system to destroy the vascular bed. Note the considerably decreased enhancement in the tumor in b. (c, d) Arterial phase MR angiograms show tumor vessels in the ankle of a patient before (c) and after (d) systemic treatment similar to that administered in the rat tumor model. Note the enhancement of the tumor vessels in c (arrowhead), and the absence of enhancement in d despite heating of the foot in a warm bath before imaging. The treatment was considered successful.

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Figure 3d. Contrast-enhanced MR angiograms obtained for monitoring of treatment response in experimental (a, b) and clinical (c, d) settings. (a, b) Volumetric reconstructions of MR image data obtained with a T1-weighted 3D sequence after the administration of a blood pool contrast agent show sarcoma in a rat limb before (a) and after (b) administration of tumor necrosis factor ${alpha}$ combined with melphalan in a closed-loop system to destroy the vascular bed. Note the considerably decreased enhancement in the tumor in b. (c, d) Arterial phase MR angiograms show tumor vessels in the ankle of a patient before (c) and after (d) systemic treatment similar to that administered in the rat tumor model. Note the enhancement of the tumor vessels in c (arrowhead), and the absence of enhancement in d despite heating of the foot in a warm bath before imaging. The treatment was considered successful.

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Figure 4. Diagrams show the difference in permeability between normal vessels (left) and tumor vessels (right). Extracellular contrast agents (top row, small dots) leak into the interstitium from both normal vessels and tumor vessels because of the small size of the molecules in these agents, and this leakage causes contrast enhancement in the vessels and surrounding tissues. Blood pool contrast agents (bottom row, large dots), with a larger molecular size, remain inside normal vessels. Tumor vessel walls, which contain larger gaps than do normal vessel walls, allow blood pool contrast agents to leak into the interstitium.

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Figure 5a. Comparison of tumor delineation and vessel enhancement between an MR image obtained with a macromolecular contrast agent, albumin-(Gd-DTPA)₄₅ (a), and an MR image obtained with a combination of albumin-(Gd-DTPA)₄₅ and a small-molecular agent, gadopentetate dimeglumine (Magnevist; Schering) (b). In b, massive extravasation of gadopentetate dimeglumine is visible, and the depiction of the internally fragmented tumor is improved.

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Figure 5b. Comparison of tumor delineation and vessel enhancement between an MR image obtained with a macromolecular contrast agent, albumin-(Gd-DTPA)₄₅ (a), and an MR image obtained with a combination of albumin-(Gd-DTPA)₄₅ and a small-molecular agent, gadopentetate dimeglumine (Magnevist; Schering) (b). In b, massive extravasation of gadopentetate dimeglumine is visible, and the depiction of the internally fragmented tumor is improved.

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Figure 6a. Tumor at 2 weeks after implantation in a rat limb. (a) High-resolution T2-weighted fat-suppressed MR image depicts only the mass. (b) Three-dimensional volume-rendered MR image, obtained with a T1-weighted sequence (field of view, 4 cm) after administration of the blood pool contrast agent albumin-(Gd-DTPA)₄₅, shows high-signal-intensity vessels surrounding the tumor (arrow), which was artificially enhanced with postprocessing to better show its position with regard to the vasculature.

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Figure 6b. Tumor at 2 weeks after implantation in a rat limb. (a) High-resolution T2-weighted fat-suppressed MR image depicts only the mass. (b) Three-dimensional volume-rendered MR image, obtained with a T1-weighted sequence (field of view, 4 cm) after administration of the blood pool contrast agent albumin-(Gd-DTPA)₄₅, shows high-signal-intensity vessels surrounding the tumor (arrow), which was artificially enhanced with postprocessing to better show its position with regard to the vasculature.

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Figure 7a. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 7b. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 7c. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 7d. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 7e. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 7f. Increased vascularity associated with soft-tissue sarcoma in the left leg of a patient. (a–e) Sequential 3D MR angiograms obtained with gadopentetate dimeglumine show enhancement of the vasculature and the tumor at five time points from the peak arterial phase to the venous phase. Greater vessel density around the tumor borders in the affected leg is attributable to vessel recruitment by the tumor. (f) Subtraction image (unenhanced image minus late-phase contrast-enhanced image) from T1-weighted turbo spin-echo MR imaging shows marked enhancement of the tumor border and minimal enhancement of the tumor center.

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Figure 8a. Increased vascularity related to soft-tissue sarcoma. (a) Arterial phase MR angiogram obtained with gadopentetate dimeglumine shows enhanced vessels that surround a large unenhanced tumor in the neck of a patient. (b) T1-weighted image, obtained after MR angiography, shows the enhanced tumor.

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Figure 8b. Increased vascularity related to soft-tissue sarcoma. (a) Arterial phase MR angiogram obtained with gadopentetate dimeglumine shows enhanced vessels that surround a large unenhanced tumor in the neck of a patient. (b) T1-weighted image, obtained after MR angiography, shows the enhanced tumor.

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Figure 9a. MR angiograms obtained after the administration of albumin-(Gd-DTPA)₄₅ show sarcomas in the thigh in two different rats 2 weeks after implantation. The tumor size and contrast enhancement pattern in a differs markedly from that in b, although the same tumor model was used.

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Figure 9b. MR angiograms obtained after the administration of albumin-(Gd-DTPA)₄₅ show sarcomas in the thigh in two different rats 2 weeks after implantation. The tumor size and contrast enhancement pattern in a differs markedly from that in b, although the same tumor model was used.

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Figure 10a. (a) Arterial phase MR angiogram, obtained after administration of gadopentetate dimeglumine, shows a soft-tissue sarcoma and related vasculature. Partial blockage of a venous segment (arrow) just below the enhancing tumor may be due to clotting. An arterial blockage proximal to the tumor (obscured in this projection) also was observed. (b) Axial T2-weighted MR image provides better delineation of the tumor.

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Figure 10b. (a) Arterial phase MR angiogram, obtained after administration of gadopentetate dimeglumine, shows a soft-tissue sarcoma and related vasculature. Partial blockage of a venous segment (arrow) just below the enhancing tumor may be due to clotting. An arterial blockage proximal to the tumor (obscured in this projection) also was observed. (b) Axial T2-weighted MR image provides better delineation of the tumor.

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Figure 11a. MR angiograms obtained in the arm of a patient during the arterial phase (a) and the venous phase (b) illustrate the advantages of performing MR angiography at different time points after contrast material administration. Whereas a shows no tumor, b clearly depicts a tumor (arrow) in the forearm.

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Figure 11b. MR angiograms obtained in the arm of a patient during the arterial phase (a) and the venous phase (b) illustrate the advantages of performing MR angiography at different time points after contrast material administration. Whereas a shows no tumor, b clearly depicts a tumor (arrow) in the forearm.

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Figure 12a. Diagrams show the position (a) and use (b) of the skin-fold window model in a rat. In b, the processes of tumor implantation (left), tumor growth (middle), and coil positioning for MR imaging (right) are shown. A flap of skin was removed and sandwiched between two frames, and the skin and frames were fixed in place with sutures. Before the surgical site was closed, a small piece of tumor (0.1 mm³) was implanted. The window was then closed with the insertion of an 18-mm-diameter layer of microscopic cover glass on both sides of the implantation site, and the tumor was allowed to grow. For high-resolution MR imaging (MR angiography), a 1- or 2-cm loop receiver antenna was placed on the window to obtain resolution of 60 x 60 x 100-µm and 40 x 40 x 100-µm interpolated voxels, respectively, with examination times of less than 20 minutes on a clinical 3.0-T MR imager. In this way, high-resolution MR angiography with use of a blood pool contrast agent can be performed over the course of several days to monitor tumor growth and angiogenesis.

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Figure 12b. Diagrams show the position (a) and use (b) of the skin-fold window model in a rat. In b, the processes of tumor implantation (left), tumor growth (middle), and coil positioning for MR imaging (right) are shown. A flap of skin was removed and sandwiched between two frames, and the skin and frames were fixed in place with sutures. Before the surgical site was closed, a small piece of tumor (0.1 mm³) was implanted. The window was then closed with the insertion of an 18-mm-diameter layer of microscopic cover glass on both sides of the implantation site, and the tumor was allowed to grow. For high-resolution MR imaging (MR angiography), a 1- or 2-cm loop receiver antenna was placed on the window to obtain resolution of 60 x 60 x 100-µm and 40 x 40 x 100-µm interpolated voxels, respectively, with examination times of less than 20 minutes on a clinical 3.0-T MR imager. In this way, high-resolution MR angiography with use of a blood pool contrast agent can be performed over the course of several days to monitor tumor growth and angiogenesis.

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Figure 13a. MR and optical images of a tumor in a skin-fold window model in a rat. Digital photograph (a) and comparable high-resolution MR angiogram obtained with the blood pool contrast agent albumin-(Gd-DTPA)₄₅ (b) show tumor vasculature 2 weeks after implantation. Often, as in b, the tumor is not optimally depicted against the background on MR angiograms obtained with a blood pool agent, and gadopentetate dimeglumine is added to improve tumor delineation, as in c.

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Figure 13b. MR and optical images of a tumor in a skin-fold window model in a rat. Digital photograph (a) and comparable high-resolution MR angiogram obtained with the blood pool contrast agent albumin-(Gd-DTPA)₄₅ (b) show tumor vasculature 2 weeks after implantation. Often, as in b, the tumor is not optimally depicted against the background on MR angiograms obtained with a blood pool agent, and gadopentetate dimeglumine is added to improve tumor delineation, as in c.

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Figure 13c. MR and optical images of a tumor in a skin-fold window model in a rat. Digital photograph (a) and comparable high-resolution MR angiogram obtained with the blood pool contrast agent albumin-(Gd-DTPA)₄₅ (b) show tumor vasculature 2 weeks after implantation. Often, as in b, the tumor is not optimally depicted against the background on MR angiograms obtained with a blood pool agent, and gadopentetate dimeglumine is added to improve tumor delineation, as in c.

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Figure 14a. Image series obtained with high-resolution MR angiography and the blood pool agent albumin-(Gd-DTPA)₄₅ over the course of 2 weeks in the skin-fold window model in a rat. Maximum intensity projections show development of the tumor and tumor feeding vessels at day 1 (tumor diameter, approximately 3 mm) (a), day 3 (tumor diameter, approximately 7 mm) (b), and day 7 (tumor diameter, approximately 11 mm) (c).

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Figure 14b. Image series obtained with high-resolution MR angiography and the blood pool agent albumin-(Gd-DTPA)₄₅ over the course of 2 weeks in the skin-fold window model in a rat. Maximum intensity projections show development of the tumor and tumor feeding vessels at day 1 (tumor diameter, approximately 3 mm) (a), day 3 (tumor diameter, approximately 7 mm) (b), and day 7 (tumor diameter, approximately 11 mm) (c).

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Figure 14c. Image series obtained with high-resolution MR angiography and the blood pool agent albumin-(Gd-DTPA)₄₅ over the course of 2 weeks in the skin-fold window model in a rat. Maximum intensity projections show development of the tumor and tumor feeding vessels at day 1 (tumor diameter, approximately 3 mm) (a), day 3 (tumor diameter, approximately 7 mm) (b), and day 7 (tumor diameter, approximately 11 mm) (c).

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Figure 15a. (a) High-resolution MR angiogram (maximum intensity projection) obtained with the blood pool agent albumin-(Gd-DTPA)₄₅ and with a 1-cm loop receiver coil on a 3.0-T clinical MR imager shows a tumor 1 $1/2$ weeks after implantation in a skin-fold window model in a mouse. (b–d) Magnification of the maximum intensity projection image enables a comparison of vessels depicted on the MR angiogram (b) with those depicted on an optical photomicrograph (c) and fluorescence photomicrograph (d).

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Figure 15b. (a) High-resolution MR angiogram (maximum intensity projection) obtained with the blood pool agent albumin-(Gd-DTPA)₄₅ and with a 1-cm loop receiver coil on a 3.0-T clinical MR imager shows a tumor 1 $1/2$ weeks after implantation in a skin-fold window model in a mouse. (b–d) Magnification of the maximum intensity projection image enables a comparison of vessels depicted on the MR angiogram (b) with those depicted on an optical photomicrograph (c) and fluorescence photomicrograph (d).

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Figure 15c. (a) High-resolution MR angiogram (maximum intensity projection) obtained with the blood pool agent albumin-(Gd-DTPA)₄₅ and with a 1-cm loop receiver coil on a 3.0-T clinical MR imager shows a tumor 1 $1/2$ weeks after implantation in a skin-fold window model in a mouse. (b–d) Magnification of the maximum intensity projection image enables a comparison of vessels depicted on the MR angiogram (b) with those depicted on an optical photomicrograph (c) and fluorescence photomicrograph (d).

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Figure 15d. (a) High-resolution MR angiogram (maximum intensity projection) obtained with the blood pool agent albumin-(Gd-DTPA)₄₅ and with a 1-cm loop receiver coil on a 3.0-T clinical MR imager shows a tumor 1 $1/2$ weeks after implantation in a skin-fold window model in a mouse. (b–d) Magnification of the maximum intensity projection image enables a comparison of vessels depicted on the MR angiogram (b) with those depicted on an optical photomicrograph (c) and fluorescence photomicrograph (d).

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Figure 16a. Digital photograph (a), confocal fluorescence photomicrograph (b), and volume-rendered MR angiogram (c) show similar morphologic features of tumor-related vasculature at the center (solid arrow) and periphery (open arrow) of a skin-fold window model. The close correlation between images from the different modalities indicates that noninvasive quantification of angiogenesis may be possible in the future with MR imaging.

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Figure 16b. Digital photograph (a), confocal fluorescence photomicrograph (b), and volume-rendered MR angiogram (c) show similar morphologic features of tumor-related vasculature at the center (solid arrow) and periphery (open arrow) of a skin-fold window model. The close correlation between images from the different modalities indicates that noninvasive quantification of angiogenesis may be possible in the future with MR imaging.