Rationale and Objectives
The enhancement pattern of malignant tumors has been studied in short-term animal models (7–14 days), but the reported results have been variable and inconsistent. The purpose of this study was to investigate the changing blood flow characteristics of VX2 tumors implanted in rabbit livers with contrast-enhanced multidetector computed tomography (MDCT) to establish a predictable pattern of vascular evolution over an extended 28-day growth period.
Materials and Methods
VX2 carcinoma was implanted in livers of 10 male New Zealand White rabbits. Dynamic CT (2/seconds × 60 seconds) was conducted on days 7, 14, 21, and 28 after tumor implantation. Enhancement parameters of time-density curve (TDC), time to start (T0), time to peak (TP), maximum enhancement (ΔH), slope of enhancement (SLe), and washout (SLw) in tumor center, tumor rim, and normal liver were analyzed. Tumor samples corresponding to CT images of one tumor on days 14 and 21 and seven tumors on day 28 were stained with hematoxylin and eosin and anti-CD31 monoclonal antibody. The relationship between enhancement parameters and histology parameters (thickness of tumor border, extent of blood stasis, and luminar vessel density) was analyzed.
Results
Consistent growth, appearance, and vascular changes occurred in 7 of 10 animals over the 4-week observation period. Peripheral rim-like enhancement was noted in CT images. TDC analysis showed that tumor rim enhancement was pronounced and more rapid than normal liver initially but this difference diminished with tumor progression. The SLe, SLw, and ΔH decreased from 10.03 ± 3.25 Hu/second, 0.42 ± 0.25 Hu/sec, and 58.00 ± 25.27 Hu on day 7 to 5.86 ± 2.73 Hu/second, 0.10 ± 0.13 Hu/second, and 37.78 ± 8.89 Hu/second on day 28, respectively. TP increased from 12.71 ± 4.85 seconds on day 7 to 25.57 ± 7.75 seconds on day 28. No significant changes were noted on the TDC parameters in normal liver. The maximum density difference between tumor rim and normal liver (D rim-liver ) appeared 10.5 ± 2.1 seconds after contrast injection. The maximum D rim-liver decreased from 54.33 ± 37.86 Hu on day 7 to 11.16 ± 13.03 Hu on day 28. On histological analysis, viable tumor cells were found in tumor rim with few luminar vessels. The tumor border showed desmoplastic reaction, vascular dilation and proliferation, inflammatory cell infiltration, and blood stasis. These findings were more obvious on day 28 than those on day 14. TP showed significant positive correlations with the extent of blood stasis in tumor border and adjacent liver and the maximum thickness of the tumor border ( r = 0.945 and 0.893 respectively, P < .05).
Conclusion
The rabbit VX2 liver tumor is a hypovascular tumor with perilesional enhancement over its lifespan as imaged by MDCT. Consistent changes in the measured vascular parameters correlated with the size/age of the tumor implants. These findings suggest that the accuracy of CT enhancement imaging for VX2 liver tumor detection might be decreased with tumor development.
With the increasing speed of imaging technology, dynamic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) have been widely used in the characterization of solid tumors, particularly for tumors of the liver, kidney, and breast . Among these studies, analyzing the enhancement pattern of the liver tumor was used as a vital approach to differentiate malignant from benign lesions , evaluate tumor vascularity , and response to treatment . However, the degree of the tumor enhancement was varied. This variation was reported to be due to the differences of tumor vasculature and permeability , the extent of peritumoral inflammatory reactions , the existence of arterioportal shunts , and the circulation time of contrast in the systemic and portal systems .
Numerous studies have shown that tumor growth and angiogenesis are complex processes that involve the expression of many growth factors, nutrient and oxygen delivery, metabolic waste drainage, and immunoreactions of the host . With tumor development, the effect of these factors likely changes. Previous studies reported that serum VEGF levels were positively correlated with the stage of ovarian cancer . Au et al found that the mRNA levels of glucose transporter 1 and glucose transporter 3 of ascites tumor cells increased progressively in the tumor during development. Stewart et al explored the relationship between glucose metabolism and growth of VX2 liver tumors using fluorine 18 fluorodeoxyglucose positron emission tomography/CT scan and found that the glucose utilization of tumors increased with tumor growth. We hypothesize that tumor perfusion will change with the stage or development of the liver tumor.
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Materials and methods
Overall Experiment Design
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VX2 Tumor Model
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Dynamic CT
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TDC Analysis
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Tumor Growth Monitoring and Tumor Size Determination
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Histology and Immunohistochemistry
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Data Analysis
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Results
Progression of Tumor Growth
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Table 1
Change in VX2 Tumor Size as Determined by Computed Tomography
Tumor Age (Days) 7 14 21 28 Tumor diameter (cm) 0.83 ± 0.27 1.41 ± 0.41 1.77 ± 0.53 2.05 ± 0.75 Tumor area (cm 2 ) 0.55 ± 0.31 1.50 ± 0.72 2.55 ± 1.70 3.11 ± 1.99 Necrosis area (cm 2 ) 0.13 ± 0.11 0.63 ± 0.39 1.56 ± 1.32 2.02 ± 1.63 Tumor rim area (cm 2 ) 0.42 ± 0.22 0.88 ± 0.36 0.98 ± 0.39 1.09 ± 0.42
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TDC Analysis
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Table 2
Time-density Curve Parameters Changes in Different ROIs of VX2 Liver Tumor
Tumor Age (Days) 7 14 21 28 Tumor center T0 (seconds) 1.50 ± 0.76 2.54 ± 2.64 9.43 ± 10.80 8.93 ± 6.11 TP1 (seconds) 4.93 ± 1.95 16.18 ± 13.90 10.3 ± 5.56 14.71 ± 6.48 TP2 (seconds) 4.93 ± 1.95 16.18 ± 13.90 13.80 ± 8.33 14.71 ± 6.48 ΔH1 (Hu) 43.63 ± 20.82 9.43 ± 7.60 5.28 ± 3.17 1.68 ± 1.90 ΔH2 (Hu) 43.63 ± 20.82 9.43 ± 7.60 5.33 ± 3.24 1.68 ± 1.90 SLe (Hu/second) 11.09 ± 5.81 1.47 ± 1.91 0.71 ± 0.77 0.19 ± 0.23 SLw (Hu/second) -0.11 ± 0.21 -0.09 ± 0.15 0.04 ± 0.06 0.01 ± 0.02 Tumor rim T0 (seconds) 1.57 ± 0.61 1.14 ± 0.85 1.46 ± 0.82 1.79 ± 0.70 TP1 (seconds) 5.21 ± 1.65 5.79 ± 1.32 5.61 ± 1.64 6.21 ± 3.01 TP2 (seconds) 12.71 ± 4.85 13.79 ± 6.94 17.39 ± 6.14 25.57 ± 7.75 ∗ ΔH1 (Hu) 50.18 ± 18.99 48.62 ± 14.09 32.83 ± 13.29 29.45 ± 12.69 ∗ ΔH2 (Hu) 58.00 ± 25.27 56.92 ± 12.24 41.50 ± 13.56 37.78 ± 8.89 SLe (Hu/second) 10.03 ± 3.25 10.25 ± 3.93 7.21 ± 2.86 5.86 ± 2.73 ∗ SLw (Hu/second) -0.42 ± 0.25 -0.41 ± 0.25 -0.10 ± 0.11 -0.10 ± 0.13 ∗ Normal liver T0 (seconds) 3.71 ± 1.55 3.86 ± 2.90 4.36 ± 2.82 4.50 ± 2.69 TP1 (seconds) 16.79 ± 6.51 21.86 ± 10.42 26.64 ± 11.76 19.71 ± 10.37 TP2 (seconds) 16.79 ± 6.51 24.79 ± 7.76 26.64 ± 11.76 23.50 ± 7.75 ΔH1 (Hu) 49.65 ± 14.80 45.52 ± 11.41 49.67 ± 13.28 48.67 ± 25.15 ΔH2 (Hu) 49.65 ± 14.80 48.26 ± 10.81 49.67 ± 13.28 56.29 ± 19.58 SLe (Hu/second) 2.94 ± 1.26 3.67 ± 2.38 2.42 ± 1.17 3.88 ± 3.06 SLw (Hu/second) -0.44 ± 0.25 -0.49 ± 0.19 -0.51 ± 0.32 -0.44 ± 0.11 Rim-liver Baseline (Hu) -9.12 ± 1.70 -14.9 ± 4.62 -11.82 ± 6.03 -13.66 ± 4.72 TP (seconds) 10.79 ± 1.75 11.36 ± 2.27 9.64 ± 1.80 10.29 ± 2.40 Max. (Hu) 54.33 ± 37.86 37.06 ± 11.98 16.45 ± 12.45 11.16 ± 13.03 ∗
SLe: slope of enhancement; SLw: slope of washout.
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Table 3
The Distribution of Enhancement Patterns in VX2 Liver Tumor Rim
Type Day I II III IV 7 0 0 6 1 14 0 1 5 1 21 1 4 2 0 28 2 2 3 0
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Histology Findings
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Correlation between Enhancement Parameters and Histology
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Discussion
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Acknowledgment
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