Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma.

Angiogenesis is important for tumor growth, and is regulated by angiogenetic factors such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether or not expression of VEGF receptors (VEGFRs) is related to the proliferation of tumor cells in hepatocellular carcinoma (HCC). We simultaneously stained proliferation marker Ki-67 antigen and either VEGFR1 (Flt-1) or VEGFR2 (Flk-1) on paraffin-embedded tissue sections from 50 cases of surgically resected human HCC. Based on the staining pattern of VEGFRs, we classified the cases into 4 categories; receptor double-negative, Flt-1 single-positive, Flk-1 single-positive, receptor double-positive. Interestingly, the Ki-67 index was significantly lower in receptor double-negative cases in comparison to that in either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0491, P = 0.0196, respectively). Moreover, the index was also significantly lower in receptor double-positive cases in comparison to either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0026, P < 0.0001, respectively). We further investigated 35 cases showing a Ki67 index > 10% to determine the expression of VEGFRs on Ki-67 antigen-positive proliferating cells. Surprisingly, the histological grade of HCC and the expression pattern of VEGFRs showed a characteristic relation; the well-differentiated HCC cases were all distributed in the Flk-1-positive group (7/7), moderately differentiated HCC cases were distributed in either the Flt-1 or Flk-1 single-positive group (20/21), and poorly differentiated HCC cases were predominantly distributed in either the receptor double-negative or double-positive group (6/7). These findings suggest that the expression pattern of VEGFRs influences the histological differentiation of HCC.

Magnetic resonance imaging and expression of vascular endothelial growth factor in hepatocellular nodules in cirrhosis and hepatocellular carcinomas.

We summarized and discussed our previous research results on correlation between magnetic resonance (MR) imaging findings and vascular endothelial growth factor (VEGF) expression in benign or borderline hepatocellular nodules in cirrhosis, hepatocellular carcinomas (HCCs), and in the surrounding liver. Magnetic resonance images were retrospectively correlated quantitatively and qualitatively with VEGF expression in hepatic nodules and in the surrounding liver. By immunohistochemistry, hepatic nodules with moderate to strong immunoreactivity for VEGF showed higher T1 signal intensity, and those with intense immunoreactivity for VEGF showed higher T2 signal intensity. By Western blotting, HCC-to-liver contrast-to-noise ratio correlated with VEGF indices (VEGFs) of hepatocellular carcinomas inversely on opposed-phase T1-weighted, directly on T2-weighted, and marginally and inversely on gadolinium-enhanced hepatic arterial-phase images. On T2-weighted images, standard-deviation ratio of hepatocellular carcinomas correlated directly with VEGFs of hepatocellular carcinomas. Heterogeneities of hepatocellular carcinomas on MR images correlated directly with VEGFs of HCCs on opposed-phase T1-weighted, T2-weighted, hepatic arterial-phase, and equilibrium-phase images. Our results may reflect that MR signal intensity, hepatic arterial vascularity, and heterogeneity of hepatocellular nodules on MR images are closely related to the intensity of VEGF expression as up-regulated by hyper- or hypoxia in the nodules. Gadolinium-enhanced MR imaging may be useful to monitor ischemic state of hepatocelluar nodules. Although real impacts of our results on radiologic practice have been still debatable, we believe that our results may help future radiologic practice in conjunction with biomolecular or genetic treatments for hepatocellular carcinomas.

[Percutaneous cryoablation therapy under local anesthesia for unresectable metastatic liver tumors].

Even though liver resection is the first choice against metastatic liver tumors, oncologists are often obliged to include other treatment modalities depending on metastatic tumor size, number of metastatic nodules, location of tumors, patient's general condition, and so on. Among others we selected cryoablation therapy against unresectable tumors and examined its usefulness clinically in 5 patients. Under local anesthesia, the cryoprobe, which was 3 mm in diameter, was introduced into the center of the tumor by use of an ultrasonographic guiding technique. In the middle of the freezing process, through ultrasonography we could clearly monitor the target tumor, which would change into an ice ball. It was noteworthy that not only the treated tumor but also untreated tumors were reduced in 2 cases. Because of extra-hepatic metastases, 3 patients died within 1 year after the therapy, while 2 patients are alive. This modality was easily repeatable and was minimally invasive with little toxic effect. In addition, it did not worsen quality of life (QOL). The above results indicate that cryoablation therapy could be a feasible modality against unresectable metastatic liver tumors.

Clinicopathological features of hepatocellular carcinoma evaluated by vascular endothelial growth factor expression.

AIM: To evaluate the significance of the expression of vascular endothelial growth factor (VEGF), its correlation with clinicopathological variables were studied in the tissue of hepatocellular carcinoma (HCC) and surrounding liver. METHODS: In 56 samples (tumor and non-tumor liver tissue) collected from 28 patients, VEGF expression was examined by immunohistochemistry and western blot analysis. RESULTS: The value of VEGF expression by western blotting was correlated with immunohistochemical staining grade. In tumor tissue, the value of VEGF expression correlated with tumor size (P = 0.034), á-fetoprotein (P = 0.036) and protein induced by vitamin K absence-II by simple regression, and histological grade (P = 0.0132) by the unpaired t-test. The level of VEGF expression in non-tumor liver was found to correlate with the value of serum albumin (P = 0.008), cholinesterase (P = 0.012) and prothrombin activity (P = 0.046). The frequency of simple nodular type in gross appearance decreased in cases with high tumor/non-tumor (T/N) ratio (P = 0.022), and the degree of portal vein invasion progressed with an increase in the T/N ratio (P = 0.008). The T/N ratio was significantly higher in early recurrence cases (P = 0.0081). CONCLUSION: This study on the expression of VEGF might be useful to estimate the liver condition and the clinicopathological features of HCC.

Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver and correlation with MRI findings.

OBJECTIVE: The purpose of our study was to assess the correlation between the quantitative and qualitative imaging findings on unenhanced and gadolinium-enhanced MR images and the intensity of vascular endothelial growth factor (VEGF) expression in hepatocellular carcinomas and in the surrounding nontumorous liver. MATERIALS AND METHODS: The intensities of VEGF expression in hepatocellular carcinoma and in the surrounding liver by Western blot analysis were converted to VEGF expression indexes (VEGF(IND)) in 22 surgical specimens ranging in size from 14 to 126 mm (mean, 47.6 +/- 29.5 mm) that were resected in 22 patients (17 men and five women; age range, 41-85 years [mean, 64 years]) between April 2000 and October 2002. MR images were retrospectively evaluated to determine contrast-to-noise ratios (CNRs), signal intensity SD ratios, and phase-shift indexes. Signal intensity characteristics of hepatocellular carcinomas were reviewed independently by two experienced radiologists who were unaware of the pathologic diagnosis or the results of immunoblotting. CNRs, SD ratios, and phase-shift indexes were correlated with VEGF(IND) using a simple regression test, and signal intensity characteristics were correlated with VEGF(IND) using the Spearman's rank correlation test. RESULTS: On opposed-phase T1-weighted spoiled gradient-recalled echo (GRE) images, CNRs correlated inversely with the VEGF(IND) of hepatocellular carcinomas (r = -0.46, p = 0.038). CNRs on T2-weighted fast spin-echo images correlated directly with the VEGF(IND) of hepatocellular carcinomas (r = 0.49, p = 0.025), and on gadolinium-enhanced hepatic arterial phase GRE images marginally and inversely correlated with VEGF(IND) (r = -0.39, p = 0.081). On T2-weighted fast spin-echo images, SD ratios correlated directly with the VEGF(IND) of hepatocellular carcinomas (r = 0.44, p = 0.044). No correlation was found between phase-shift indexes and VEGF expression. The qualitatively assessed signal intensity heterogeneities of hepatocellular carcinomas correlated directly with the VEGF(IND) of hepatocellular carcinomas on opposed-phase T1-weighted GRE, T2-weighted fast spin-echo, hepatic arterial phase GRE, and equilibrium phase GRE images. CONCLUSION: Our results indicate that the signal intensity and heterogeneity of hepatocellular carcinomas on MR images correlate with the degree of VEGF expression in hepatocellular carcinomas.

Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver: correlation with angiographically assisted CT.

OBJECTIVE: The purpose of our study was to assess the correlation between the intensity and characteristics of contrast enhancement on angiographically assisted CT and the intensity of vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HCC) and in the surrounding nontumorous liver. MATERIALS AND METHODS: The intensity of VEGF expression in HCC and in the surrounding liver was expressed as a VEGF expression index by Western blot analysis in 20 surgical specimens resected in 20 patients between March 2000 and August 2002. Findings on CT during arterial portography (n = 20) and CT hepatic arteriography (n = 17) were retrospectively evaluated to determine contrast enhancement indexes and the enhancement characteristics of HCCs and of the surrounding liver. Contrast enhancement indexes and VEGF expression indexes were correlated using a simple regression test, and enhancement characteristics and VEGF expression indexes were correlated using the Spearman's rank correlation test. RESULTS: On CT hepatic arteriography, the contrast enhancement indexes of HCCs showed moderate inverse correlation with the VEGF expression indexes of HCCs (r = -0.57, p = 0.017) and high inverse correlation with the differences between the VEGF expression indexes of HCCs and those of livers (difference in the VEGF expression index, -0.80; p = 0.0001). The contrast enhancement index of the liver showed marginal moderate direct correlation with the VEGF expression index of the liver (0.44, p = 0.076) and high inverse correlation with the difference in the VEGF expression index (-0.71, p = 0.0013). On CT during arterial portography, the contrast enhancement indexes of HCCs showed moderate inverse correlation with the difference in the VEGF expression index (-0.51, p = 0.023). The qualitative degree of heterogeneity of hepatic artery enhancement in HCC on CT hepatic arteriography showed moderate direct correlation with the VEGF expression indexes of HCCs (0.55, p = 0.033) and high direct correlation with the difference in the VEGF expression indexes (0.73, p = 0.004). CONCLUSION: Our results indicated that the intensity and heterogeneity of hepatic artery enhancement of HCCs on CT hepatic arteriography correlated with the degree of VEGF expression in HCCs.

Minute gastric carcinoid tumor with regional lymph node metastasis.

We report a patient with a minute gastric carcinoid tumor with lymph node metastasis, and a small gastric cancer. A 50-year-old man having a diagnosis of an elevated lesion on the anterior wall of the gastric body, detected by a series of upper gastrointestinal examinations, was referred to the Cancer Institute Hospital. Careful upper fluoroscopy disclosed a small superficial depressed lesion with converging folds and a superficial elevated lesion covered with nonspecific gastric mucosa. With a final preoperative diagnosis of depressed early cancer and minute carcinoid tumor of the stomach, made by upper gastrointestinal examinations including biopsy, the patient underwent segmental gastrectomy and perigastric lymph node dissection. Histological examination of the resected specimen revealed a lymph node metastasis from a gastric carcinoid tumor of 5-mm diameter, in addition to an early gastric cancer of poorly differentiated adenocarcinoma. Small gastric carcinoid tumors have been regarded as being benign neoplasms biologically. However, the case we present suggests that attention should be paid to the possibility of metastasis at the time of treatment for a minute sporadic gastric carcinoid tumor. We therefore discuss the malignant potential of these tumors, mainly from the viewpoint of histopathological classification, to gain understanding so that the patients can be treated adequately.