Histological Grade Of Hepatocellular Carcinoma Research Articles

Total and High Molecular Weight Adiponectin and Hepatocellular Carcinoma with HCV Infection

BackgroundAdiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection.MethodsA case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI).ResultsThere were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC.ConclusionsOur results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Correlation Between Contrast-Enhanced Intraoperative Ultrasound Using Sonazoid and Histologic Grade of Resected Hepatocellular Carcinoma

Our aim was to accurately assess the correlation between findings of contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of hepatocellular carcinoma (HCC). We enrolled 239 consecutive patients who were undergoing surgery for HCC for this study. Because 33 extensively necrotic HCCs were excluded, a total of 374 histologically proven HCCs were detected in all resected specimens and were the study subjects (71 well-differentiated, 239 moderately differentiated, and 64 poorly differentiated HCCs). After a laparotomy and liver mobilization, contrast-enhanced intraoperative ultrasound in the harmonic mode was performed after a Sonazoid injection. The first minute was defined as the vascular phase, in which the vascularity of the 239 HCCs was assessed. After an approximately 15-minute delay, a thorough liver exploration was performed (Kupffer phase). Preoperative dynamic CT was routinely performed, and the findings were assessed for reference. The proportion of hypervascular tumors during the vascular phase tended to be lower among well-differentiated than among moderately and poorly differentiated HCCs (66% vs 80%, p = 0.058). The proportion of hypoechoic tumors during the Kupffer phase was significantly lower among well-differentiated than among moderately and poorly differentiated HCCs (54% vs 92%, p < 0.0001). In dynamic CT, the proportions of hypervascular tumors during the early phase and hypodense tumors during the late phase were significantly lower among well-differentiated HCCs than among moderately and poorly differentiated HCCs, respectively (early phase, 51% vs 87%, p < 0.0001; late phase, 59% vs 85%, p < 0.0001). Contrast-enhanced intraoperative ultrasound using Sonazoid is useful for estimating the histologic grade of HCC.

Usefulness of Gadobenate Dimeglumine - Enhanced Hepatobiliary Phase MR Imaging on Predicting Histological Grade of Hepatocellular Carcinoma

JKSMRM 15:208-218(2011) Department of Radiology, Research Institute of Radiological Science, Institute of Gastroenterology, Yonsei University College of Medicine Received; October 10, 2011, revised; October 18, 2011, accepted; October 25, 2011 Corresponding author : Myeong-Jin Kim, M.D., Department of Diagnostic Radiology, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea. Tel. 82-2-2228-7400 Fax. 82-2-393-3035 E-mail: kimnex@yuhs.ac Usefulness of Gadobenate Dimeglumine Enhanced Hepatobiliary Phase MR Imaging on Predicting Histological Grade of Hepatocellular Carcinoma

Manganese-enhanced MRI predicts the histological grade of hepatocellular carcinoma in potential surgical candidates

To evaluate the role of manganese-enhanced magnetic resonance (Mn-MRI) in predicting tumour differentiation prior to liver transplant or resection for hepatocellular carcinoma (HCC). The inclusion criteria were patients with HCC who underwent Mn-MRI prior to transplantation or resection from 2001-2008. T1-weighted MRI images were acquired at 0 and 24h after manganese dipyridoxal diphosphate (MnDPDP) intravenous contrast medium and reviewed prospectively. Manganese retention at 24h was correlated with tumour differentiation and disease-free survival. Eighty-six patients underwent Mn-MRI (transplantation 60, resection 26); 114/125 lesions (91%) that were arterialised as evidenced at computed tomography (CT) and had manganese uptake on MRI were HCC. There were 11 false positives (9%) that were regenerative nodules. Ten of fourteen non-manganese-retaining HCC (71%) were poorly differentiated, compared with only 13/114 manganese-retaining HCC (11%) (p<0.0001). Sensitivity, specificity, positive and negative predictive values of non-retention of MnDPDP in predicting poorly differentiated tumours were 0.43, 0.96, 0.71 and 0.88. Median disease-free survival of patients with non-manganese-retaining HCC was less than for patients with manganese-retaining HCC (14±5 months versus 39±3 months, log rank p=0.025). Non-manganese-retaining HCCs are likely to be poorly differentiated and have a poor prognosis. Manganese-enhanced MRI appears to have a role in preoperative assessment of HCC and warrants further evaluation.

Diagnostic performance of apparent diffusion coefficient for predicting histological grade of hepatocellular carcinoma

Objective To investigate whether the histological grade of hepatocellular carcinoma (HCC) can be predicted using the apparent diffusion coefficient (ADC). Materials and Methods This retrospective study group consisted of 80 patients with 85 surgically resected HCCs who underwent preoperative MRI exams including diffusion-weighted imaging. The tumors were histologically classified into five groups as follows: five well (w-), 17 well to moderately (wm-), 37 moderately (m-), 16 moderately to poorly (mp-), and 10 poorly (p-) differentiated HCCs. For ADC measurement of each HCC, the largest possible region of interest was placed on the solid region on the ADC map where ADC was considered to be the lowest. The average ADCs of the five histological grades were compared using Spearman's rank correlation test and Student's t-test, and the diagnostic performance of ADC for mp- and p-HCCs was also evaluated using a receiver operating characteristic-based positive test. Results The average ADC of p-HCC (0.76 ± 0.10 × 10 −3 mm 2/s) was significantly lower than those of the other four histological grades. The average ADC of mp-HCCs (0.99 ± 0.20 × 10 −3 mm 2/s) was significantly lower than those of w-, wm- and m-HCCs. The sensitivity, specificity, PPV, NPV, and accuracy, when an ADC of 0.972 or lower was considered an indicator of mp- and p-HCCs, were 73.1%, 72.9%, 54.3%, 86.0% and 72.9%, respectively. Conclusion ADCs of mp- and p-HCCs were lower than those of w-, wm- and m-HCCs. ADC can contribute to radiological diagnosis of poorly differentiated components in HCCs.

Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow

To retrospectively investigate enhancement patterns of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) in the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced MRI in relation to histological grading and portal blood flow. Sixty-nine consecutive patients with 83 histologically proven HCCs and DNs were studied. To assess Gd-EOB-DTPA uptake, we calculated the EOB enhancement ratio, which is the ratio of the relative intensity of tumorous lesion to surrounding nontumorous area on hepatobiliary phase images (post-contrast EOB ratio) to that on unenhanced images (pre-contrast EOB ratio). Portal blood flow was evaluated by CT during arterial portography. Post-contrast EOB ratios significantly decreased as the degree of differentiation declined in DNs (1.00 ± 0.14) and well, moderately and poorly differentiated HCCs (0.79 ± 0.19, 0.60 ± 0.27, 0.49 ± 0.10 respectively). Gd-EOB-DTPA uptake, assessed by EOB enhancement ratios, deceased slightly in DNs and still more in HCCs, while there was no statistical difference in the decrease between different histological grades of HCC. Reductions in portal blood flow were observed less frequently than decreases in Gd-EOB-DTPA uptake in DNs and well-differentiated HCCs. Reduced Gd-EOB-DTPA uptake might be an early event of hepatocarcinogenesis, preceding portal blood flow reduction. The hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI may help estimate histological grading, although difficulties exist in differentiating HCCs from DNs.

T2-weighted and T1-weighted Dynamic Superparamagnetic Iron Oxide (Ferucarbotran) Enhanced MRI of Hepatocellular Carcinoma and Hyperplastic Nodules

Iron oxide contrast medium (ferucarbotran) shortens both T1 and T2 relaxation time. We used the T2- and the T1-weighted dynamic ferucarbotran-enhanced magnetic resonance (MR) imaging to predict the histologic grade of hepatocellular carcinoma (HCC) and to distinguish HCC from hyperplastic nodules. Forty-three patients with 48 representative hepatic lesions (13 well differentiated HCC, 19 moderately differentiated HCC, 4 poorly differentiated HCC, 12 hyperplastic nodules) were included in the study. T1-weighted image, T2-weighted turbo spin echo, and T2*EPI (echo-planar) images were obtained before and after ferucarbotran injection. The percentage T2 signal intensity loss (T2 PSIL) of the tumors was calculated at 5 minutes and 25 minutes after contrast injection. The enhancement in dynamic T1 images was interpreted by two independent radiologists. The T2 PSIL of well differentiated HCC was 39.5 +/- 8.23%, moderately differentiated HCC was 26.4 +/- 13.78%, poorly differentiated HCC was 4.4 +/- 9.42%, and hyperplastic nodules was 44.3 +/- 11.04%. Comparison of T2 PSIL showed significant differences in the three histologically graded HCCs (p < 0.001), but not between the well differentiated HCCs and hyperplastic nodules (p > 0.05). Delayed post-contrast (25 minutes) T2-weighted images were not necessary and shortened the examination time. In the post contrast dynamic T1 study, no significant differences between all the groups was seen. Ferucarbotran MR images help in differentiating the different histologic grades of HCC but T2 PSIL could not differentiate hyperplastic nodules from well differentiated HCC. Dynamic post contrast T1-weighted images provide no additional information.

Protein expression profile characteristic to hepatocellular carcinoma revealed by 2D-DIGE with supervised learning

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Although several major risks related to HCC, e.g., hepatitis B and/or hepatitis C virus infection, aflatoxin B1 exposure, alcohol drinking and genetic defects have been revealed, the molecular mechanisms leading to the initiation and progression of HCC have not been clarified. To reduce the mortality and improve the effectiveness of therapy, it is important to detect the proteins which are associated with tumor progression and may be useful as potential therapeutic or diagnosis targets. However, previous studies have not yet revealed the associations among HCC cells, histological grade and AFP. Here, we performed two-dimensional difference gel electrophoresis (2D-DIGE) combined with MS for 18 HCC patients. To focus not on individual proteins but on multiple proteins associated with pathogenesis, we introduce the supervised feature selection based on stochastic gradient boosting (SGB) for identifying protein spots that discriminate HCC/non HCC, histological grade of moderate/well and high α-fetoprotein (AFP)/low AFP level without arbitrariness. We detected 18, 25 and 27 protein spots associated with HCC, histological grade and AFP level, respectively. We confirmed that SGB is able to identify the known HCC-related proteins, e.g., heat shock proteins, carbonic anhydrase 2. Moreover, we identified the differentially expressed proteins associated with histological grade of HCC and AFP level and found that aldo-keto reductase 1B10 (AKR1B10) is related to well differentiated HCC, keratin 8 (KRT8) is related to both histological grade and AFP level and protein disulfide isomerase-associated 3 (PDIA3) is associated with both HCC and AFP level. Our pilot study provides new insights on understanding the pathogenesis of HCC, histological grade and AFP level.

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.

Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma: Effect of Histologic Grade on Therapeutic Results

The purpose of our study was to assess the therapeutic results of radiofrequency ablation of hepatocellular carcinoma (HCC) based on the histologic grades of the tumors. Between April 1999 and December 2003, 95 patients with nodular HCC were treated with percutaneous radiofrequency ablation. All tumors were histologically proven by sonography-guided percutaneous biopsy and were classified as Edmondson-Steiner grade I HCC (n = 38) (mean, 2.3 cm) (group 1), grade II HCC (n = 50) (mean, 2.4 cm) (group 2), or grade III HCC (n = 7) (mean, 2.8 cm) (group 3). All patients underwent contrast-enhanced three-phase helical CT examination before and after radiofrequency ablation. After retrospective review of the medical records and follow-up CT examinations, the rates of technique effectiveness, local tumor progression, cumulative survival, and cancer-free survival using a Kaplan-Meier method were calculated and compared among the groups. Technique effectiveness rates in groups 1, 2, and 3 were 87% (27/31), 71% (30/42), and 43% (3/7), respectively, with statistical significance (p = 0.032). Local tumor progression rates in groups 1, 2, and 3 were 16% (5/31), 36% (15/42), and 71% (5/7), respectively, with statistical significance (p = 0.013). Five-year cumulative survival rates in groups 1, 2, and 3 were 71%, 44%, and 43%, respectively, with no statistical significance (p > 0.05). Four-year cancer-free survival rates in groups 1, 2, and 3 were 39%, 10%, and 0%, respectively (p < 0.05 for groups 1 vs 2; p > 0.05 for groups 1 vs 3 and groups 2 vs 3). The histologic grade of HCC is an important factor influencing therapeutic results with survival after radiofrequency ablation.

Bi-dimensional and three-dimensional contrast-enhanced us (2-D and 3-D ceus) and the histological grading of hepatocellular carcinoma (HCC)

Bi-dimensional and three-dimensional contrast-enhanced us (2-D and 3-D ceus) and the histological grading of hepatocellular carcinoma (HCC)

Molecular Changes From Dysplastic Nodule to Hepatocellular Carcinoma Through Gene Expression Profiling *

Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from pre-neoplastic lesions--including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)--to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled t test. Functional assignment of these genes revealed discrete expression clusters representing grade-dependent biological properties of HCC. Using both diagonal linear discriminant analysis and support vector machines, we identified 240 genes that could accurately classify tumors according to histological grade, especially when attempting to discriminate LGDNs, HGDNs, and grade 1 HCC. In conclusion, a clear molecular demarcation between dysplastic nodules and overt HCC exists. The progression from grade 1 through grade 3 HCC is associated with changes in gene expression consistent with plausible functional consequences.

Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma.

Silencing of the suppressor of cytokine signaling ( SOCS-1) by aberrant methylation at the CpG island in the coding region gene has been reported in hepatocellular carcinoma (HCC). However, principally, it is methylation in the 5'-noncoding region but not that in the coding region which determines the regulation of gene expression. Methylation-specific PCR was performed for the analysis of methylation status both in the 5'-noncoding region and the CpG island of SOCS-1 from 22 HCC tissue samples with adjacent non-HCC tissue samples and from two cell lines. Using primers in the CpG island, 9 of 22 HCC samples exhibited aberrant methylation of SOCS-1, while only 1 of 22 adjacent non-HCC samples did so. The unmethylation pattern was detected in 1 of 22 HCC and in 5 of 22 non-HCC samples. Thus, aberrant methylation of SOCS-1 was significantly associated with HCC ( P = 0.0076 by Fisher's exact test). Using primers in the 5'-noncoding region, aberrant methylation was observed in 12 of 22 HCC and in 2 non-HCC samples. The unmethylated pattern was observed in 5 of 22 HCC and in 10 of 22 non-HCC samples ( P = 0.0042). There was no significant correlation between the methylation status of SOCS-1 and clinicopathological findings, such as the presence or absence of cirrhosis or the histological grade of HCC. Aberrant methylation of the SOCS-1 had a significant correlation with HCC. The rate of aberrant methylation was similar in the 5'-noncoding region and in the CpG island. Aberrant methylation of SOCS-1 may be associated with hepatocarcinogenesis, although further studies are necessary.

A study of gene amplification and expression of cyclin D1 in hepatocellular carcinoma

To investigate gene amplification of CCND1 and expression of cyclin D1 in hepatocellular carcinoma (HCC) and to explore the possible relationship between CCND1 gene status and carcinogenesis of HCC. Differential PCR, RT-PCR and immunohistochemistry were used to detect gene amplification, mRNA and protein expression of cyclin D1 in 20 HCC cases respectively. The relationship between the gene amplification rate and the expression level of cyclin D1 and the histological grades of HCC was analyzed. CCND1 gene amplification was detected in 30% of the cases HCC. An overexpression of cyclin D1 mRNA and protein could be demonstrated in 45% and 70% cases respectively. The expression of cyclin D1 mRNA correlated with its gene amplification status (P < 0.05) and was responsible for the protein expression level (P < 0.05). There was a close relationship between the expression level of cyclin D1 protein and HCC histological grades (P < 0.05). CCND1 gene amplification is a common phenomenon in HCC and may be directly responsible for the cyclin D1 mRNA and protein overexpression. Cyclin D1 protein expression level is directly related to HCC histological grades. Therefore, CCND1 amplification and cyclin D1 overexpression may play an important role in development and differentiation of HCC.

Effect of superparamagnetic iron oxide-enhanced MRI of the liver with hepatocellular carcinoma and hyperplastic nodule.

To evaluate the possibility of superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) of the liver in predicting the histologic grade of hepatocellular carcinoma (HCC) and differentiating HCC from benign hyperplastic nodule (HPN). Thirty patients with 31 histologically proved HCC and HPN underwent MRI (1.5 Tesla). HCCs were graded into well-differentiated HCC (HCCw; n = 10) and moderately to poorly differentiated HCC (HCCmp; n = 15). HPN was categorized into dysplastic nodule (DN; n = 1) and focal nodular hyperplasia (FNH; n = 6). T2-weighted fast spin echo images were obtained before and after administration of SPIO. Signal-to-noise ratios (SNR) of the lesion and surrounding liver parenchyma and contrast-to-noise ratios (CNR) were calculated pre- and postcontrast study. Relative enhancement ratios (RER), also known as signal intensity reduction ratios of the lesions, were also calculated. HCCw, HCCmp, DN, and FNH decreased in SNR after injection of SPIO. RER of HCCw was 19.5 +/- 13.3%, that of HCCmp was 6.8 +/- 5.8%, DN was 44.0%, and FNH was 42.9 +/- 4.8%. Significant statistical differences were seen between HCCw and HCCmp and HCC and HPN in RER. HCCw, HCCmp, and DN increased in CNR, and FNH decreased in CNR, but no lesion showed a statistically significant difference in CNR. SPIO-enhanced MR images may help to predict the histologic grade of HCC and distinguish HCC from HPN.

Expression of angiopoietin-2 gene and its receptor Tie2 in hepatocellular carcinoma.

To explore the relationship of angiogenesis-related angiopoietin-2 gene and its receptor Tie2 with angiogenesis and the biology of hepatocellular carcinoma (HCC), angiopoietin-2 gene, Tie2 and CD34 protein expression in 22 resected HCC, 8 cirrhotic and 8 control liver specimens were investigated by in situ hybridization and immunohistochemistry respectively, and the level of angiopoietin-2 and Tie2 expression in HCC were compared in terms of tumor biological parameters. It was found that CD34 was not expressed in control liver, expressed scarcely in cirrhotic liver (17.8 +/- 13.5/HP), but intensively expressed in HCC (86.3 +/- 34.8/HP, P < 0.01). Tie2 receptor was not expressed in controls, expressed at low level in cirrhotic liver (11.3 +/- 8.7/HP), while strongly positive in the microvascular endothelia of HCC (52.4 +/- 16.7/HP, P < 0.01). The level of Tie2 receptor expression in HCC was closely related with tumor diameter, angiogenesis and portal invasion. Angiopoietin-2 gene was not expressed in control liver, expressed mildly in cirrhotic liver (11.2 +/- 9.7/HP), but extensively in tumor zone (36.4 +/- 17.5/HP), the level of angiopoietin-2 expression was closely related with angiogenesis, portal invasion and histological grading of HCC. It is concluded that angiogenesis is increased in HCC; angiopoietin-2/Tie2 expression in human hepatic carcinoma is closely related with angiogenesis, which are probably involved in the HCC angiogenesis regulation, promoting the development and metastasis of human hepatic cancer.

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation

Histological grade of hepatocellular carcinoma (HCC) is an important prognostic factor affecting patient survival after orthotopic liver transplantation (OLT). Retrospective analysis. University-based teaching hospital. Of 952 OLTs performed between June 1991 and January 1999, 56 OLT recipients had histologically proven HCC in the explant liver. Of those, 53 patients with complete clinicopathologic data were analyzed. A single pathologist blinded to the outcome of each patient reviewed all histological specimens. Median follow-up was 709 days. Overall survival for patients with tumors sized 5 cm or less at 1, 3, and 5 years was 87%, 78%, and 71%, respectively (Kaplan-Meier). Univariate analysis revealed the size, number, and distribution of tumors; the presence of microscopic vascular invasion and lymph node metastasis; histological differentiation; and pTNM stage to be statistically significant factors affecting survival. Multivariate analysis revealed histological differentiation and pTNM stage to be the independent and statistically significant factors affecting survival (P =.002 and.03, respectively). When pTNM stage was excluded from multivariate analysis, histological differentiation and size remained the significant independent factors (P =.02 and.03, respectively). Three-year survival for patients with small (</=5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 82% and 67%, respectively. Three-year survival for patients with large (>5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 62.5% and 0%, respectively. In our retrospective experience, histological differentiation had a statistically significant effect on the prognosis of HCC after OLT. However, before altering the current OLT selection criteria for patients with HCC, prospective studies are required to confirm the impact of histological grade on clinical outcome.

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation--Invited Response

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation--Invited Response

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation—Invited Response

Impact of Histological Grade of Hepatocellular Carcinoma on the Outcome of Liver Transplantation—Invited Response

Expression of vascular endothelial growth factor in surgical specimens of hepatocellular carcinoma.

Vascular endothelial growth factor (VEGF) has been reported to play an important role in angiogenesis in hepatocellular carcinoma (HCC). However, there is great variation in reports on the distribution of VEGF expression, especially in non-carcinoma liver cells. Furthermore, some reports have mentioned that endothelial cells were positive for VEGF antibody but have not evaluated its significance. In this study, we focused our attention to these problems and try to solve them. We also analyzed the factors influencing VEGF expression and evaluated the prognostic potential of VEGF protein in HCC. We examined the VEGF expression in specimens surgically removed from 46 HCC patients and 3 patients with liver cancer metastatic from the colon, and in 4 specimens of liver tissue with benign disease, by immunohistochemical methods. VEGF was expressed in HCC cells and hepatocytes and on vascular endothelial cells. Our finding that about seven times more endothelial cells were positive for VEGF antibody in carcinoma areas than in non-carcinoma areas (P < 0.001) suggests that VEGF is a very important angiogenesis factor for HCC growth. VEGF expression in HCC cells and non-carcinoma liver cells and on endothelial cells did not closely correlate with the disease recurrence rate (P > 0.05), suggesting that VEGF expression may not be useful as an individual factor for estimating the prognosis of HCC. A statistical analysis of the relationships between VEGF expression and clinicopathological variables revealed the following: preoperative transcatheter arterial embolization enhanced VEGF expression in both HCC cells and non-carcinoma liver cells. The histological grade of HCC and the level of alanine aminotransferase was related to VEGF expression in non-carcinoma liver cells and on endothelial cells in HCC areas. Tumor size and the histological status of the accompanying chronic hepatitis also influenced the VEGF expression on endothelial cells. Our findings concerning not only HCC but also the surrounding liver and endothelial cells may provide useful information for further research on the role of VEGF expression in HCC patients.