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(Radiology. 2001;219:166-170.)
© RSNA, 2001

Experimental Studies

Quantified Power Doppler US of Tumor Blood Flow Correlates with Microscopic Quantification of Tumor Blood Vessels1

Edwin F. Donnelly, MD, Ling Geng, MD, Walter E. Wojcicki, MD, PhD, Arthur C. Fleischer, MD and Dennis E. Hallahan, MD

1 From the Departments of Radiology (E.F.D., W.E.W., A.C.F.), Radiation Oncology (L.G., D.H.), and Biomedical Engineering (D.H.), Vanderbilt University Medical Center, 1301 22nd Ave S, B-902 The Vanderbilt Clinic, Nashville, TN 37232-5671. Received March 21, 2000; revision requested May 2; revision received July 20; accepted August 29. Supported by National Cancer Institute grants CA58508, CA89674, and CA70937 and a grant from ATL/Phillips. Address correspondence to D.E.H.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the ability of a quantified power Doppler ultrasonography (US) system to help quantitate differences in tumor vascularity after radiation therapy and administration of tumor necrosis factor (TNF).

MATERIALS AND METHODS: Murine glioblastoma tumors were grown in the thighs of two sets of 25 mice each. Each mouse was assigned to one of four treatment groups: control (no treatment), radiation therapy, TNF therapy, or combination therapy (both radiation and TNF therapies). Mice were then evaluated with quantified power Doppler US, and a vascularity index (color area) was calculated for different tumor regions in each group. The tumors were then excised, and histologic evaluation was performed by using an immunofluorescence-tagged monoclonal antibody against blood vessel endothelium. The number of stained blood vessels per high-power field was correlated with the sonographically determined vascularity index.

RESULTS: The color area of the total tumor decreased to 37% of that in the control group in mice treated with radiation therapy alone (P = .02), 26% of that in the control group in mice treated with TNF alone (P = .05), and 8% of that in the control group in those treated with both TNF and radiation (P = .006). These results correlated well with the quantified results from immunofluorescent staining (r = 0.98).

CONCLUSION: Quantified power Doppler US is a noninvasive method for the evaluation of tumor vascularity and blood flow.

Index terms: Animals • Blood vessels, abnormalities, 9*.922 • Blood vessels, US, 9*.12984 • Therapeutic radiology, experimental studies • Ultrasound (US), experimental studies, 9*.12984 • Ultrasound (US), power Doppler studies, 9*.12984


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The development of blood vessels, a process termed angiogenesis, is essential for the growth of tumors (1,2). Tumor angiogenesis is a complex process involving both the incorporation of existing host blood vessels into the tumor and the creation of tumor microvessels. This process is moderated by tumor angiogenesis factors (3). Blood flow through these tumor vessels is heterogeneous. Some areas have high flow, others have slower flow and develop necrosis (3).

Ionizing radiation has been shown to promote platelet aggregation (4). Ionizing radiation induces von Willebrand factor expression (5). Ionizing radiation enhances platelet adhesion to the extracellular matrix by increasing the release of von Willebrand factor by endothelial cells (6). Platelet aggregation can result in obliteration of tumor vasculature (7). Radiation therapy alone, however, is often unsuccessful in treating tumors because of tumor cell resistance to radiation. Tumor necrosis factor (TNF) is a biologic response modifier with antiangiogenic properties (8). The combination of TNF and radiation therapy produces occlusion of tumor microvessels without any damage to normal tissues (9).

Power Doppler ultrasonography (US) displays the amplitude of the Doppler signal but lacks the velocity and directional information present in frequency-based color Doppler US. This technique is more sensitive than frequency-based color Doppler US in the depiction of tumor vascularity (10,11). Power Doppler US depicts intratumoral vascularity and flow (12) and small tumor vessels (down to 100 µm) better than frequency-based color Doppler US (13,14).

Techniques have been developed to quantitate the power Doppler signal. Various indices are used to create a vascularity index for a region of tumor. The vascularity index gives an objective measure of tumor angiogenesis (15) and allows monitoring of tumor response to treatment (16). The purpose of our study was to evaluate whether changes in the vascularity index (color area) at power Doppler US correlated with changes in the number of blood vessels visible histologically in tumors treated with radiation therapy, TNF, or both.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Subject Preparation
Approval was obtained from the institution animal care and use committee. Two sets of 25 tumors were produced in C57 BL/6 mice (Jackson Lake, Bar Harbor, Mass) injected subcutaneously in the right thigh with 1,000,000 viable cells of a murine glioblastoma (GL 261) suspended in 0.2 mL of a 0.6% solution of agarose.

Each set of 25 mice was divided randomly into four groups. The first group contained four mice and received no treatment (control group). Each of the other three groups (treatment groups) contained seven mice. Treatment began 14 days after the tumor cells had been injected, when the tumors were approximately 10 mm in diameter. The second group received radiation therapy. Irradiated mice were immobilized in polymerized methyl methacrylate chambers, and the entire body was shielded with lead except for the tumor-bearing hind limb. A total dose of 10 Gy was administered in two fractionated doses on consecutive days. The third group received TNF vector administered through a single injection of 108 plaque-forming units of an adenovirus vector (AdGvEGR.TNF; GenVec, Rockville, Md) (7). The fourth group received both radiation therapy and TNF. The radiation therapy was administered in the same manner as in the radiation-only group. The adenovirus vector was injected on the 1st day of irradiation.

One set of 25 mice was randomly chosen to be followed up for 7 weeks for tumor volume calculation. The second set of 25 mice underwent US imaging, sacrifice, and immunofluorescent staining.

Tumor Volumes
The first set of 25 mice was followed up for 7 weeks. Tumors were measured twice weekly by one author (L.G.), and tumor volumes were calculated by using skin calipers to measure (a) length, (b) width, and (c) depth of tumor as previously described (7). Tumor volumes were calculated from a formula (a x b x c/2) that was derived from the formula for an ellipsoid ({pi}d3/6). Data were calculated as the percentage of original (day 0) tumor volume and graphed as fractional tumor volume plus SD.

Imaging
The second set of 25 murine tumors were imaged 3 days after the completion of therapy. Tumors were imaged by one author (E.F.D.) with a 10-5-MHz linear probe (Entos; ATL/Phillips, Bothell, Wash) attached to a US scanner (HDI 5000; ATL/Phillips). Power Doppler US images were obtained with the power gain set to 82%. Ten evenly spaced images were acquired for each tumor. Care was taken to minimize motion artifact. Images were stored on an optic disk in data exchange file format, or DEFF.

The color area was quantified by using commercially available software (Insight version 5.9; GT Software, Everett, Wash). This software allows direct evaluation of power Doppler US images stored in DEFF format. Regions of interest were drawn by hand by one author (E.F.D.) around the entire tumor. A second region of interest was drawn 2–3 mm within the first region to allow estimation of differences between estimated "peripheral" and "central" regions of the tumor. The color area was recorded for peripheral and central regions, as well as for the entire tumor. Values for the color area were averaged for each treatment group, and treated groups were compared with the control group by performing the unpaired Student t test for total tumor, peripheral region, and central region. In addition, the values for the color area of the group that received both treatments were compared with those of the two single-treatment groups by performing the unpaired Student t test for total tumor, peripheral region, and central region.

Immunofluorescence
The second set of 25 mice (those imaged with power Doppler US) were sacrificed after the power Doppler US imaging session. Tumor samples were fixed in buffered 10% formalin and embedded in paraffin blocks. A total of 10 sections per tumor, evenly spaced throughout the tumor, were cut 5 µm thick, placed onto glass slides, and allowed to air dry overnight. Sections were then cleared in xylene and rehydrated through descending alcohol concentration to distilled water. After brief washing with phosphate-buffered saline solution, the sections were blocked with 5% goat serum in phosphate-buffered saline solution at 37°C for 30 minutes to prevent nonspecific binding. The slides were then washed in antibody buffer solution and subsequently in phosphate-buffered saline solution.

The tumor vasculature was depicted by using rabbit monoclonal antibody against human von Willebrand factor antigen (DAKO, Carpenteria, Calif). This antibody cross-reacts with the murine antigen that is expressed on the endothelial cell membrane. Tissue sections were incubated in von Willebrand factor antibody overnight at 4°C at 1:200 dilution in antibody buffer. The sections were again washed in both antibody buffer and phosphate-buffered saline solution.

A second antibody (Biotin-SP-conjugated AffiniPure Goat Anti-Rabbit IgG [H+L]; Jackson ImmunoResearch Laboratories, West Grove, Pa) was prepared at 1:200 dilution in antibody buffer. To this was added avidin (NeutrAvidin, Oregon Green 514 Conjugate; Molecular Probes, Eugene, Ore) at 10 µg/mL, and the mixture was allowed to sit for 30 minutes at room temperature. Finally, the tissue sections were incubated with the conjugated antibody for 40 minutes at 37°C. After washing with phosphate-buffered saline solution twice, one drop of phenylenediamine dihydrochloride was added to each slide, and coverslips were placed over the sections. To view fluorescent tissue sections, a color filter (NB Blue; Olympus Camera, Melville, NY) was used in ultraviolet light (x20 objective, x10 eyepiece, x200 total magnification).

Tumor vessels were counted in each section by hand and recorded as the number of vessels per high-power field identified in 10 random locations throughout each slide by one author (D.H.). No attempt was made to distinguish between the central and peripheral regions of the tumor. These values were correlated to the color area for the total tumor, and the correlation coefficient (r) was determined by performing the linear regression test. Treated groups were compared with the control group by performing the unpaired Student t test. In addition, the group receiving combination therapy was compared with the groups receiving individual therapy by performing the unpaired Student t test. Photomicrographs were obtained with color slide film (T160; Eastman Kodak, Rochester, NY), with 5-minute exposure time for each picture.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Tumor Volumes
The tumors in the control group appeared to continue to grow over time. Tumors treated with TNF alone appeared to plateau 3 days after treatment. Tumors treated with radiation therapy alone appeared to decrease in size after 9 days. Tumors treated with both radiation therapy and TNF appeared to decrease in size to less than baseline after 9 days. These tumor growth results are summarized in Figure 1.



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  		Figure 1. Graph shows the logarithm of relative tumor volume as a function of days after treatment. Growth of tumors treated with adenovirus vector ({blacksquare}) or with radiation therapy ({blacktriangleup}) is diminished relative to that in the control group ({circ}). Tumors receiving combined treatment ({blacklozenge}) decreased in size over time. Error bars = SD.

 
Tumor Blood Flow Measured with Power Doppler US
All tumors demonstrated neovascularity at power Doppler US. In all cases, the majority of the color area was in the periphery of the tumor. The central portions of the tumor appeared relatively anechoic as illustrated by the representative images from each treatment group in Figure 2. The color area of the total tumor decreased to 37% (0.550/1.48) ± 9.5 (SD) of that in the control group in mice treated with radiation therapy alone (P = .02), 26% (0.391/1.48) ± 12 of that in the control group in mice treated with TNF alone (P = .05), and 8% (0.116/1.48) ± 3.2 of that in the control group in those treated with both TNF and radiation (P = .006). In the combined treatment group, the color area decreased to 25% (0.116/0.470) ± 10 of the mean of the single treatment groups (P = .003). These results are summarized in Figure 3.



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  		Figure 2a. Representative power Doppler US images from (a) tumors in the control group, (b) tumors treated with TNF, (c) tumors treated with radiation therapy, and (d) tumors receiving combined TNF and radiation therapy. Depicted blood vessels are greatest in the periphery of the tumors (arrowheads in a). Treatment with radiation alone or TNF alone results in a decrease in depicted blood vessels. Combined therapy results in a greater decrease in depicted blood vessels.

 


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  		Figure 2b. Representative power Doppler US images from (a) tumors in the control group, (b) tumors treated with TNF, (c) tumors treated with radiation therapy, and (d) tumors receiving combined TNF and radiation therapy. Depicted blood vessels are greatest in the periphery of the tumors (arrowheads in a). Treatment with radiation alone or TNF alone results in a decrease in depicted blood vessels. Combined therapy results in a greater decrease in depicted blood vessels.

 


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  		Figure 2c. Representative power Doppler US images from (a) tumors in the control group, (b) tumors treated with TNF, (c) tumors treated with radiation therapy, and (d) tumors receiving combined TNF and radiation therapy. Depicted blood vessels are greatest in the periphery of the tumors (arrowheads in a). Treatment with radiation alone or TNF alone results in a decrease in depicted blood vessels. Combined therapy results in a greater decrease in depicted blood vessels.

 


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  		Figure 2d. Representative power Doppler US images from (a) tumors in the control group, (b) tumors treated with TNF, (c) tumors treated with radiation therapy, and (d) tumors receiving combined TNF and radiation therapy. Depicted blood vessels are greatest in the periphery of the tumors (arrowheads in a). Treatment with radiation alone or TNF alone results in a decrease in depicted blood vessels. Combined therapy results in a greater decrease in depicted blood vessels.

 


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  		Figure 3. Bar graph shows quantification of power Doppler signal displayed as color area of tumor. Treatment with radiation alone (XRT) or TNF alone results in a decrease in depicted blood vessels. Combined therapy (XRT + TNF) results in a greater decrease in depicted blood vessels. Error bars = SD.

 
Because of the visible differences between the central and peripheral zones, similar analyses were performed on these areas. Similar trends were found in both the central and peripheral regions. In the peripheral region, color area decreased to 40% (0.479/1.21) ± 3.4 of that in the control group after radiation therapy (P = .02), 28% (0.342/1.21) ± 11 of that in the control group after TNF (P = .05), and 8% (0.097/1.21) ± 5.0 of that in the control group after combination therapy (P = .006). In the combined treatment group, the color area decreased to 24% (0.097/0.410) ± 15 of the mean of the single treatment groups (P = .003). In the central region, the color area decreased to 26% (0.070/0.275) ± 19 of that in the control group after radiation therapy (P = .006), 18% (0.050/0.275) ± 17 of that in the control group after TNF (P = .02), and 7% (0.019/0.275) ± 4.7 of that in the control group after combination therapy (P = .005). The color area in the combined treatment group decreased to 32% (0.019/0.060) ± 21 of the mean of the single treatment groups (P = .17), which was not statistically significant.

Histologic Studies of Tumor Blood Vessels
Immunofluorescent staining for tumor blood vessels on histologic sections fixed at 3 days after treatment showed a reduction to 21% (10.4/50.4) ± 3.6 of that in the control group in mice treated with radiation alone (P < .001). Likewise, tumors treated with TNF gene therapy alone showed a reduction of staining of blood vessels to 19% (9.6/50.4) ± 1.0 of that in the control group tumors (P < .001).

When TNF gene therapy and radiation were combined, endothelial staining was reduced to 5% (2.6/50.4) ± 1.7 of that in the control group (P < .001). In the combined treatment group, endothelial staining decreased to 26% (2.6/10.0) ± 8.6 of the mean of the single treatment groups (P < .001). These results are summarized in Figure 4. Figure 5 shows representative photomicrographs of immunofluorescence histologic findings.



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  		Figure 4. Bar graph shows the number of vessels per high-power field that are visible with immunofluorescence antibody labeling. A decrease in antibody staining is seen after treatment with either TNF or radiation (XRT) therapy alone. A greater decrease in antibody staining is seen after combination therapy (TNF + XRT). Error bars = SD.

 


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  		Figure 5a. Representative photomicrographs of immunofluorescent stained sections of tumors from (a) the control group, (b) the TNF treatment group, (c) the radiation treatment group, and (d) the combination therapy group. A decrease in antibody staining (yellow) is seen after treatment with either TNF or radiation therapy alone. A greater decrease in antibody staining is seen after combination therapy. (Original magnification, x200.)

 


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  		Figure 5b. Representative photomicrographs of immunofluorescent stained sections of tumors from (a) the control group, (b) the TNF treatment group, (c) the radiation treatment group, and (d) the combination therapy group. A decrease in antibody staining (yellow) is seen after treatment with either TNF or radiation therapy alone. A greater decrease in antibody staining is seen after combination therapy. (Original magnification, x200.)

 


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  		Figure 5c. Representative photomicrographs of immunofluorescent stained sections of tumors from (a) the control group, (b) the TNF treatment group, (c) the radiation treatment group, and (d) the combination therapy group. A decrease in antibody staining (yellow) is seen after treatment with either TNF or radiation therapy alone. A greater decrease in antibody staining is seen after combination therapy. (Original magnification, x200.)

 


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  		Figure 5d. Representative photomicrographs of immunofluorescent stained sections of tumors from (a) the control group, (b) the TNF treatment group, (c) the radiation treatment group, and (d) the combination therapy group. A decrease in antibody staining (yellow) is seen after treatment with either TNF or radiation therapy alone. A greater decrease in antibody staining is seen after combination therapy. (Original magnification, x200.)

 
Correlation between Histology and Doppler US
To determine the predictive value of power Doppler US in the measurement of tumor vascularity, we correlated power Doppler US with microscopic quantification of microvessels by using immunofluorescence histology. Results of linear regression analysis of the correlation between reduction in tumor blood flow as measured with power Doppler US, as compared with reduction in tumor blood vessels as determined by means of histologic evaluation, were statistically significant (r = 0.98, P = .012).

The histologic data from immunofluorescent staining for endothelial cell von Willebrand factor demonstrates a similar pattern to that of the quantified power Doppler US study. A decrease in the number of blood vessels was observed after either TNF or radiation therapy alone. The combination of the two resulted in even fewer vessels. Figures 3 and 4 summarize these results. Representative images from each treatment group are shown in Figures 2 and 5.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Quantified power Doppler US is a technique for the evaluation of tumor vascularity. This technique can be performed easily and noninvasively. This technique also offers the advantages of allowing serial measurements of tumor vascularity during a treatment regimen and easy adaptability to humans. The use of immunofluorescent staining in this study allows validation of the results of quantified power Doppler US in a treated tumor model. The results of the tumor volume study show that these results visible at 3 days after the end of treatment seem to predict the pattern of the tumor volume data that occurs later.

The technique is not without limitations. As with any US technique, results may vary depending on the operator. Power Doppler US is also subject to motion artifact from the transducer, which can simulate blood flow. In the case of superficial implanted tumors, this problem can easily be solved with careful and slow motion of the transducer through the tumor volume. In humans, the study of deeper organs may be more limited by motion artifact from adjacent respiratory or heart motion. Moreover, the analysis of the images is subject to variability in the way the regions of interest are drawn and the tumor is framed within the analysis software. Attempts were made to center the image of the tumor in the power Doppler US box, and regions of interest were drawn to include only tumor.

Radiation therapy alone was shown to decrease the color area in this study. This effect was potentiated by the addition of TNF. A previous study (9) in which radiation therapy was used with an adenoviral vector coded TNF showed an enhanced result when the two were administered together.

These results suggest many possible routes for further investigation. The technique of quantified power Doppler US may be improved by the additional use of US contrast agents that enhance the Doppler signal. The contrast agent consists of gas-filled microspheres and is administered intravascularly. Contrast agent–enhanced power Doppler US has been shown to be superior to nonenhanced power Doppler US in the demonstration and characterization of tumor vascularity (17) and allows the depiction of a greater number of intratumoral vessels (18). Work with animal models has shown that administration of contrast agent allows earlier detection of tumor neovascularity (19) and demonstrated areas of vascularity better than without contrast agent (14).

Practical application: These results suggest that quantified power Doppler US may play a role in the future evaluation of antiangiogenic agents. The technique is applicable to animal and human studies. It has been shown that antiangiogenesis agents can potentiate the effects of radiation therapy (20). The power Doppler US study may offer advantages over the traditional longitudinal tumor volume studies such as the one performed in this study, since it may help detect a response of the tumor to treatment sooner than can be measured by using tumor volumes, as happened in our study. Although similar results can now be obtained histologically, as was also done in this study, those studies require sacrifice of the animal and preclude longitudinal studies.


   ACKNOWLEDGMENTS
 
The authors thank Graham Thirsk, BS, of ATL/Phillips for providing the software needed to quantify vascularity and David Pickens, PhD, for his assistance with the data analysis. George Holburn, MS, is thanked for his assistance with the handling of the animals.


   FOOTNOTES
 
2 9* Vascular system, location unspecified Back

Abbreviation: TNF = tumor necrosis factor

Author contributions: Guarantor of integrity of entire study, E.F.D.; study concepts, E.F.D., D.E.H., A.C.F.; study design, all authors; definition of intellectual content, E.F.D., D.E.H., A.C.F.; literature research, E.F.D., D.E.H., L.G.; experimental studies, E.F.D., W.E.W., L.G., D.E.H.; data acquisition, E.F.D., W.E.W., L.G., D.E.H.; data analysis, E.F.D., D.E.H., L.G.; statistical analysis, E.F.D., D.E.H.; manuscript preparation, E.F.D., D.E.H.; manuscript editing, E.F.D., D.E.H., A.C.F.; manuscript review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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  5. Jahroudi N, Ardekani AM, Greenberger JS. Ionizing irradiation increases transcription of the von Willebrand factor gene in endothelial cells. Blood 1996; 88:3801-3814.[Abstract/Free Full Text]
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  7. Hallahan DE, Mauceri HJ, Seung LP, et al. Spatial and temporal control of gene therapy by ionizing radiation. Nat Med 1995; 1:786-791.[Medline]
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  15. Cheng WF, Lee CN, Chu JS, et al. Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma. Cancer 1999; 85:651-657.[Medline]
  16. Meyerowitz CB, Fleischer AC, Pickens DR, et al. Quantification of tumor vascularity and flow with amplitude color Doppler sonography in an experimental model: preliminary results. J Ultrasound Med 1996; 15:827-833[Erratum: J Ultrasound Med 1997; 16:218.].[Abstract]
  17. Kim AY, Choi BI, Kim TK, et al. Hepatocellular carcinoma: power Doppler US with a contrast agent—preliminary results. Radiology 1998; 209:135-140.[Abstract/Free Full Text]
  18. Hosten N, Puls R, Lemke AJ, et al. Contrast-enhanced power Doppler sonography: improved detection of characteristic flow patterns in focal liver lesions. J Clin Ultrasound 1999; 27:107-115.[Medline]
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