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Expression of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma and the Surrounding Liver and Correlation with MRI Findings

¹ Department of Radiology Services, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501–1193, Japan.
² Department of Radiology Services, Gifu University Hospital, Gifu 501-1193, Japan.
³ Department of Surgical Oncology, Gifu University School of Medicine, Gifu 501-1193, Japan.
⁴ Department of Diagnostic Radiology, National Cancer Center Hospital, Tsukiji, Japan.

View larger version (23K): [in a new window]   Fig. 1. —Schematic shows electrophoretic bands in Western blot technique and corresponding electrophoretic band histograms with different concentrations of vascular endothelial growth factor (VEGF) solution in control study. VEGF solution concentrations and areas of electrophoretic band histogram were well correlated (r = 0.97, p < 0.0001).

View larger version (23K): [in a new window]   Fig. 2A. —Correlations among contrast-to-noise ratios (CNRs), SD ratios, and vascular endothelial growth factor expression indexes (VEGFIND) and tumor-to-liver VEGFIND differences (VGEFIND). Scattergram shows inverse correlation (r = –0.46, p = 0.038) between tumor-to-liver contrast-to-noise ratios (CNRs) on opposed-phase T1-weighted gradient-recalled echo (GRE) images and VEGFIND of hepatocellular carcinomas. Straight line and two curves in graph indicate regression line and 95% confidence interval, respectively.

View larger version (25K): [in a new window]   Fig. 2B. —Correlations among contrast-to-noise ratios (CNRs), SD ratios, and vascular endothelial growth factor expression indexes (VEGFIND) and tumor-to-liver VEGFIND differences (VGEFIND). Scattergram shows direct correlation (r = 0.49, p = 0.025) between tumor-to-liver CNRs on T2-weighted fast spin-echo images and VEGFIND of hepatocellular carcinomas.

View larger version (26K): [in a new window]   Fig. 2C. —Correlations among contrast-to-noise ratios (CNRs), SD ratios, and vascular endothelial growth factor expression indexes (VEGFIND) and tumor-to-liver VEGFIND differences (VGEFIND). Scattergram shows inverse correlation (r = –0.49, p = 0.024) between tumor-to-liver CNRs on gadolinium-enhanced hepatic arterial phase GRE images and VEGFIND difference.

View larger version (18K): [in a new window]   Fig. 2D. —Correlations among contrast-to-noise ratios (CNRs), SD ratios, and vascular endothelial growth factor expression indexes (VEGFIND) and tumor-to-liver VEGFIND differences (VGEFIND). Scattergram shows direct correlation (r = 0.44, p = 0.044) between SD ratios (SDR) of hepatocellular carcinomas on T2-weighted fast spin-echo images and VEGFIND of hepatocellular carcinomas.

View larger version (56K): [in a new window]   Fig. 3A. —57-year-old man with chronic type C viral hepatitis and poorly differentiated 5.8-cm hepatocellular carcinoma showing high vascular endothelial growth factor (VEGF) expression, discrete hypointensity on in-phase T1-weighted, heterogeneous discrete hyperintensity on T2-weighted, and weak enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Schematic shows electrophoretic bands and corresponding histograms in this patient. VEGF solution (1.25 mg/mL) was used for calibration. Area of histogram was 376 pixels for calibration band, 3,485 pixels for hepatocellular carcinoma band (HCC), and 1,395 pixels for surrounding liver band. VEGF expression index (VEGFIND) was 9.27 in hepatocellular carcinoma and 3.71 in surrounding liver, giving VEGFIND difference of 5.56. Note that electrophoretic peaks adjacent to those of hepatocellular carcinoma and liver are caused by expression of irregular protein.

View larger version (131K): [in a new window]   Fig. 3B. —57-year-old man with chronic type C viral hepatitis and poorly differentiated 5.8-cm hepatocellular carcinoma showing high vascular endothelial growth factor (VEGF) expression, discrete hypointensity on in-phase T1-weighted, heterogeneous discrete hyperintensity on T2-weighted, and weak enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. In-phase T1-weighted spoiled gradient-recalled echo (GRE) (TR/TE, 150/4.2) axial image shows hepatocellular carcinoma (arrow) as discrete hypointense lesion with internal areas of lower signal intensity (arrowhead). Likewise, opposed-phase T1-weighted spoiled GRE (150/1.6) axial image (not shown here) shows hepatocellular carcinoma as discrete hypointense lesion with internal areas of lower signal intensity.

View larger version (123K): [in a new window]   Fig. 3C. —57-year-old man with chronic type C viral hepatitis and poorly differentiated 5.8-cm hepatocellular carcinoma showing high vascular endothelial growth factor (VEGF) expression, discrete hypointensity on in-phase T1-weighted, heterogeneous discrete hyperintensity on T2-weighted, and weak enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Fat-suppressed T2-weighted fast spin-echo (4,286/80) axial image shows hepatocellular carcinoma (arrow) as moderately hyperintense lesion with internal areas of higher signal intensity (arrowheads) presumably due to internal necrosis.

View larger version (143K): [in a new window]   Fig. 3D. —57-year-old man with chronic type C viral hepatitis and poorly differentiated 5.8-cm hepatocellular carcinoma showing high vascular endothelial growth factor (VEGF) expression, discrete hypointensity on in-phase T1-weighted, heterogeneous discrete hyperintensity on T2-weighted, and weak enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. On gadolinium-enhanced hepatic arterial phase T1-weighted spoiled GRE (150/1.6) axial image, hepatocellular carcinoma is slightly enhanced peripherally (arrows). Central areas corresponding to hyperintense internal areas on C remain unenhanced (arrowheads).

View larger version (55K): [in a new window]   Fig. 4A. —77-year-old woman with chronic type C viral hepatitis and moderately differentiated 6.8-cm hepatocellular carcinoma showing moderate vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, homogeneous moderate hyperintensity on T2-weighted, and heterogeneous, moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Schematic shows electrophoretic bands and corresponding histograms in this patient. VEGF solution (1.25 mg/mL) was used for calibration. Area of histogram was 312 pixels for calibration band, 1,654 pixels for hepatocellular carcinoma band (HCC), and 738 pixels for surrounding liver band. VEGF expression index (VEGFIND) was 5.30 in hepatocellular carcinoma and 2.37 in surrounding liver, giving VEGFIND difference of 2.93.

View larger version (136K): [in a new window]   Fig. 4B. —77-year-old woman with chronic type C viral hepatitis and moderately differentiated 6.8-cm hepatocellular carcinoma showing moderate vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, homogeneous moderate hyperintensity on T2-weighted, and heterogeneous, moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. In-phase T1-weighted spoiled gradient-recalled echo (GRE) (TR/TE, 150/4.2) axial image shows hepatocellular carcinoma as virtually isointense lesion (arrow) without internal heterogeneity. Opposed-phase T1-weighted spoiled GRE (150/1.6) axial image (not shown here) shows hepatocellular carcinoma as homogeneous, moderately hypointense lesion. Signal intensity reduction was seen between in-phase and opposed-phase GRE images, indicative of presence of intratumoral fat deposition.

View larger version (137K): [in a new window]   Fig. 4C. —77-year-old woman with chronic type C viral hepatitis and moderately differentiated 6.8-cm hepatocellular carcinoma showing moderate vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, homogeneous moderate hyperintensity on T2-weighted, and heterogeneous, moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Fat-suppressed T2-weighted fast spin-echo (3,750/80) axial image shows hepatocellular carcinoma as slightly heterogeneous, moderately hyperintense lesion (arrow).

View larger version (154K): [in a new window]   Fig. 4D. —77-year-old woman with chronic type C viral hepatitis and moderately differentiated 6.8-cm hepatocellular carcinoma showing moderate vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, homogeneous moderate hyperintensity on T2-weighted, and heterogeneous, moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. On gadolinium-enhanced hepatic arterial phase T1-weighted spoiled GRE (150/1.6) axial image, hepatocellular carcinoma exhibits heterogeneous, moderate enhancement (arrow).

View larger version (53K): [in a new window]   Fig. 5A. —70-year-old man with cirrhosis due to chronic type C viral hepatitis and moderately differentiated 7.4-cm hepatocellular carcinoma showing mild vascular endothelial growth factor (VEGF) expression, moderate hypointensity on in-phase T1-weighted, heterogeneous mild hyperintensity on T2-weighted, and heterogeneous mild enhancement on hepatic arterial dominant phase images. Child-Pugh grade was B. Schematic shows electrophoretic bands and corresponding histograms in this patient. VEGF solution (1.25 mg/mL) was used for calibration. Area of histogram was 723 pixels for calibration band, 1,559 pixels for hepatocellular carcinoma band (HCC), and 1,455 pixels for surrounding liver band. VEGF expression index (VEGFIND) was 2.16 in hepatocellular carcinoma and 2.01 in surrounding liver, giving VEGFIND difference of 0.15.

View larger version (113K): [in a new window]   Fig. 5B. —70-year-old man with cirrhosis due to chronic type C viral hepatitis and moderately differentiated 7.4-cm hepatocellular carcinoma showing mild vascular endothelial growth factor (VEGF) expression, moderate hypointensity on in-phase T1-weighted, heterogeneous mild hyperintensity on T2-weighted, and heterogeneous mild enhancement on hepatic arterial dominant phase images. Child-Pugh grade was B. In-phase T1-weighted spoiled gradient-recalled echo (GRE) (TR/TE, 150/4.2) axial image shows hepatocellular carcinoma as moderately hypointense lesion (arrow) without internal heterogeneity. Likewise, opposed-phase T1-weighted spoiled GRE (150/1.6) axial image (not shown here) showed hepatocellular carcinoma as moderately hypointense lesion without internal heterogeneity.

View larger version (117K): [in a new window]   Fig. 5C. —70-year-old man with cirrhosis due to chronic type C viral hepatitis and moderately differentiated 7.4-cm hepatocellular carcinoma showing mild vascular endothelial growth factor (VEGF) expression, moderate hypointensity on in-phase T1-weighted, heterogeneous mild hyperintensity on T2-weighted, and heterogeneous mild enhancement on hepatic arterial dominant phase images. Child-Pugh grade was B. Fat-suppressed T2-weighted fast spin-echo (4,286/80) axial image shows hepatocellular carcinoma as mildly hyperintense lesion (arrow) with internal areas of slightly higher signal intensity (arrowhead).

View larger version (117K): [in a new window]   Fig. 5D. —70-year-old man with cirrhosis due to chronic type C viral hepatitis and moderately differentiated 7.4-cm hepatocellular carcinoma showing mild vascular endothelial growth factor (VEGF) expression, moderate hypointensity on in-phase T1-weighted, heterogeneous mild hyperintensity on T2-weighted, and heterogeneous mild enhancement on hepatic arterial dominant phase images. Child-Pugh grade was B. On gadolinium-enhanced hepatic arterial phase T1-weighted spoiled GRE (150/1.6) axial image, hepatocellular carcinoma exhibits heterogeneous, moderate enhancement (arrow).

View larger version (54K): [in a new window]   Fig. 6A. —59-year-old man with chronic type C viral hepatitis and moderately differentiated 2.4-cm hepatocellular carcinoma showing weak vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, subtle hyperintensity on T2-weighted, and moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Schematic shows electrophoretic bands and corresponding histograms in this patient. VEGF solution (1.25 mg/mL) was used for calibration. Area of histogram was 902 pixels for calibration band, 1,174 pixels for hepatocellular carcinoma band (HCC), and 930 pixels for surrounding liver band. VEGF expression index (VEGFIND) was 1.30 in hepatocellular carcinoma and 1.03 in surrounding liver, giving VEGFIND difference of 0.27.

View larger version (123K): [in a new window]   Fig. 6B. —59-year-old man with chronic type C viral hepatitis and moderately differentiated 2.4-cm hepatocellular carcinoma showing weak vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, subtle hyperintensity on T2-weighted, and moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. In-phase T1-weighted spoiled gradient-recalled echo (GRE) (TR/TE, 150/4.2) axial image shows no abnormal imaging findings for hepatocellular carcinoma. Opposed-phase T1-weighted spoiled GRE (150/1.6) axial image (not shown here) shows hepatocellular carcinoma as area of partly decreased signal intensity, which was not seen in B, indicating that this tumor harbors internal fat.

View larger version (99K): [in a new window]   Fig. 6C. —59-year-old man with chronic type C viral hepatitis and moderately differentiated 2.4-cm hepatocellular carcinoma showing weak vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, subtle hyperintensity on T2-weighted, and moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. Fat-suppressed T2-weighted fast spin-echo (6,000/80) axial image shows hepatocellular carcinoma as homogeneous area of faintly increased signal intensity (arrow).

View larger version (111K): [in a new window]   Fig. 6D. —59-year-old man with chronic type C viral hepatitis and moderately differentiated 2.4-cm hepatocellular carcinoma showing weak vascular endothelial growth factor (VEGF) expression, isointensity on in-phase T1-weighted, subtle hyperintensity on T2-weighted, and moderate enhancement on hepatic arterial dominant phase images. Child-Pugh grade was A. On gadolinium-enhanced hepatic arterial phase T1-weighted spoiled GRE (150/1.6) axial image, hepatocellular carcinoma exhibits slightly heterogeneous, mild enhancement (arrow).

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