Prognostic Factor For Hepatocellular Carcinoma Research Articles

Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma.

Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression. OPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription-polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis. Osteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with alpha-fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high-grade HCC (P < 0.001), late-stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10-year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early-stage HCC, which has no vascular invasion and a lower early tumor recurrence than late-stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003). OPN mRNA overexpression was correlated closely with high-grade, late-stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early-stage HCC.

Tumor vascularity as a prognostic factor for hepatocellular carcinoma: Is there a correlation?

Tumor vascularity as a prognostic factor for hepatocellular carcinoma: Is there a correlation?

Prognostic factors after resection for hepatocellular carcinoma in noncirrhotic livers: univariate and multivariate analysis.

The aim of this study was to investigate the prognostic factors for hepatocellular carcinoma (HCC) in patients without cirrhosis who underwent hepatectomy. Between 1986 and 1998 a total of 197 men and 57 women with noncirrhotic HCC underwent hepatic resection in the Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan. We determined their surgical mortality and the disease-free and overall cumulative survival rates. The surgical mortality was 4.7% and the 5-year disease-free survival rate 24.01%. By Cox regression analysis, serum alkaline phosphatase [relative risk (RR) 1.761; 95% confidence interval (CI) 1.037-2.985)], albumin (RR 2.179; CI 1.215-3.908), multiple tumor status (RR 2.288; CI 1.272-4.115), and blood urea nitrogen (RR 4.651; CI 1.116-19.38) were shown to be independent prognostic factors for the 5-year disease-free survival rates. The 5-year overall cumulative survival rate was 25.91%. By Cox regression analysis, serum albumin (RR 1.656, CI 1.005-2.730), blood transfusion (RR 2.075, CI 1.153-3.731), resection margin (RR 2.562, CI 1.436-4.572), and multiple tumors (RR 2.801, CI 1.727-4.545) were shown to be significant independent factors that influenced cumulative survival rates. Hence in patients with a noncirrhotic HCC who underwent hepatectomy the prognosis depended on preoperative hepatic function, the presence of multiple tumors, the need for blood transfusion, and the surgical resection margin.

C-erb B2 (Her2/neu) is neither overexpressed nor amplified in hepatic neoplasms.

The human c-erb B2 proto-oncogene (Her2/ ) encodes a 185-kD transmembrane putative growth factor receptor of the tyrosine kinase family. Overexpression or amplification of this oncoprotein/oncogene has been established in breast, ovarian, salivary gland, and gastric carcinomas and has been implicated in other neoplasms. Recently, overexpression of c-erb B2 has been demonstrated in hepatocellular carcinoma using enzyme-linked immunosorbent assay. Patients with hepatocellular carcinoma have a poor prognosis, and overexpression of c-erb B2 may have prognostic and treatment implications. The authors evaluated the expression and amplification of c-erb B2 in hepatic neoplasms utilizing routine immunohistochemistry and fluorescence in situ hybridization. Formalin-fixed paraffin-embedded tissue sections from 27 hepatocellular carcinomas and 7 hepatocellular adenomas were immunostained with anti-c-erb B2 utilizing a modified avidin-biotin technique following heat induced antigen retrieval. Ten sections from hepatocellular carcinomas were subjected to fluorescence in situ hybridization assay. Positive and negative controls stained appropriately. Slides were evaluated independently by two pathologists. None of the hepatocellular carcinomas or hepatocellular adenomas was immunoreactive with anti-c-erb B2. Adjacent cirrhotic liver parenchyma, present in 11 cases, was also uniformly negative. None of hepatocellular carcinomas showed any evidence of c-erb B2 amplification by fluorescence in situ hybridization. Immunoreactivity for c-erb B2 was not demonstrated in hepatocellular adenomas, cirrhotic livers, or hepatocellular carcinomas using routine immunohistochemical methods. C-erb B2 amplification was not demonstrated in hepatocellular carcinomas. Neither overexpression nor amplification of c-erb B2 (Her2/ ) can be regarded as a useful prognostic factor in hepatocellular carcinoma.

Hepatitis B or C virus serology as a prognostic factor in patients with hepatocellular carcinoma

It is not clear whether chronic hepatitis B or C virus (HBV or HCV) infection is a prognostic factor for hepatocellular carcinoma. We performed this study to determine if chronic HBV or HCV infection had any impact on postresection survival or affected patterns of failure. The records of 77 patients undergoing surgical resection for hepatocellular carcinoma between January 1990 and December 1998 were reviewed. Forty-four patients (57%) had HCV infection, 18 patients (23%) had HBV infection, and 15 patients (20%) had negative serology. There were no differences in age, sex, or tumor size among the groups, and all patients had margin-negative resections. There was a significantly higher incidence of satellitosis and vascular invasion in patients with HCV infection (32% and 41% respectively; P <0.05 vs. other groups). With a median follow-up of 30 months, a significantly decreased local disease—free survival (LDFS) was seen in HBV-positive (5-year LDFS 26%) or HCV-positive (5-year LDFS 38%) patients compared to those with negative serology (5-year LDFS 79%; P <0.05). There was also a trend toward a decreased overall survival in patients with positive hepatitis serology compared to patients with negative serology (37% vs. 79%; P = 0.12). Univariate analysis revealed that only satellitosis was related to local recurrence and overall survival. Patients with positive serology for hepatitis B or C undergoing resection for hepatocellular carcinoma have a trend toward worse overall prognosis and a significantly decreased LDFS when compared to patients with negative serology.

Grading, P53 and CD44 expression cytoproliferation (MIB1) and tumor morphology as prognostic factors in hepatocellular carcinoma (HCC)

Grading, P53 and CD44 expression cytoproliferation (MIB1) and tumor morphology as prognostic factors in hepatocellular carcinoma (HCC)

Grading, p53 and cd44 expression, cytoproliferation (MIB1) and tumor morphology as prognostic factors in hepatocellular carcinoma (HCC)

Grading, p53 and cd44 expression, cytoproliferation (MIB1) and tumor morphology as prognostic factors in hepatocellular carcinoma (HCC)

Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study.

To evaluate the correlation between serum vascular endothelial growth factor (VEGF) level and the clinicopathologic features in patients with hepatocellular carcinoma (HCC). VEGF is an important angiogenic factor regulating tumor angiogenesis. A high serum VEGF level has been shown to be associated with tumor progression and metastasis in several human cancers, but its significance in HCC is unclear. The correlation between serum VEGF level and tumor pathologic features in patients with HCC has not been studied before. Preoperative serum samples and tumor specimens were prospectively collected in 100 patients undergoing resection of HCC. Serum VEGF level was measured by enzyme-linked immunosorbent assay, and tumor VEGF expression was assessed by immunohistochemical study. Histopathologic examination was performed by a pathologist without prior knowledge of the serum VEGF level or tumor VEGF expression. Preoperative serum VEGF levels ranged from 15 to 1,789 pg/mL (median 269). When serum VEGF levels were compared between groups categorized by different clinicopathologic variables, significant correlation was found between a high serum VEGF level and absence of tumor capsule, presence of intrahepatic metastasis, presence of microscopic venous invasion, and advanced stage. There was a positive correlation between the serum VEGF level and tumor expression of VEGF as well as platelet count. When the 75th percentile serum VEGF level (500 pg/mL) was used as a cutoff level, the frequency of venous invasion in patients with a high serum VEGF level was significantly greater compared with patients with a low serum VEGF level. By multivariate analysis, a serum VEGF level of more than 500 pg/mL and tumor size more than 5 cm were independent preoperative factors predictive of microscopic venous invasion. During a median follow-up of 11.6 months, 48% of patients with a serum VEGF level of more than 500 pg/mL and 27% of those with a serum VEGF level of 500 pg/mL or less developed postoperative recurrence. These results show that a high preoperative serum VEGF level is a predictor of microscopic venous invasion in HCC, suggesting that the serum VEGF level may be useful as a biologic marker of tumor invasiveness and a prognostic factor in HCC.

肝細胞癌切除後他臓器転移例の予後因子の検討

はじめに: 肝細胞癌 (肝癌) 切除後の他臓器転移 (Distant metastasis: DM) 例が増加し, 対応に苦慮することも多い. 今回DM例の再発後生存率 (R-SR) に関与する臨床病理学的因子の解析を行い, DM例に対する治療のあり方を検討した. 対象と方法: 1999年12月までの10年間に教室で初回肝切除の施された肝癌386例中227例が再発した. このうちDM例は61例 (27%) であったが, DM例のR-SRに関与する臨床病理学的因子の単変量, 多変量解析を行った. 結果: 残肝単独再発166例およびDM例の再発後1, 3, 5年生存率はそれぞれ77, 48, 19%および61, 31, 15%(p=0.0042)であった. DM61例中43例に残肝再発が併存したが, DMの内訳は骨28例, 肺20例, リンパ節11例, 脳7例, 副腎7例, 胸腹壁4例, 腹膜3例であった. 今回検討した因子中単変量解析でR-SRに関与する因子は初回肝切除時AFP陰性 (n=39), Stage III以下(n=53), 再発時若齢 (n=32), 残肝再発治療 (n=34), DM巣切除 (n=14) の5因子であった. 多変量解析ではstage III以下, 残肝再発治療, DM巣切除が独立因子であり, 再発時肝機能因子や初回治療因子は関与しなかった. 結語: DM例のR-SRは不良であるが, 残肝再発が治療可能な場合にはDM巣切除がR-SR向上に関与する可能性があるため, 切除も含めた他臓器転移の治療を継続すべきであると思われた.

Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death

BACKGROUNDIn patients with hepatitis C virus (HCV) infection and cirrhosis, long term outcome and the incidence of hepatocellular carcinoma (HCC) are still debated.DESIGNFrom January 1987 to January 1997, 416 patients...

Prognostic factors of hepatocellular carcinoma : Analysis by the proportional hazzard model

Prognostic factors of hepatocellular carcinoma : Analysis by the proportional hazzard model

Review of 336 patients with hepatocellular carcinoma at Songklanagarind Hospital.

AIM:To determine the clinical presentations, survival and prognostic factors of hepatocellular carcinoma (HCC) in Southern Thailand.METHODS:Retrospective analysis was performed on the 336 hepatocellular carcinoma patients treated at Songklanagarind hospital between 1 January 1991 and 31 January 1999.RESULTS:Of these 336 patients, 276 were males and 60 were females. The mean age was 54.4 years. The common symptoms and signs were abdominal pain and hepatomegaly. The most common presentation of tumor was a dominant mass with daughter nodules. Portal vein involvement was found in 50% of total. Extrahepatic metastasis was found in 13%, and the lung was the most common site. There were 65.4% with evidence of cirrhosis and half of them were in Child's class B. HBsAg was positive in 72.6%. Regarding a(c)Okuda's tumor staging, 15%, 61% and 24% were stage I, II and III, respectively. Overall median survival was 2.1 months (11.5 2.6 and 0.7 months for stage I, II and III respectively). Treatments of HCC improved patient survival (5.5 months vs 1.6 months for untreated patients). Most common causes of death were hepatic failure. Using multivariate analysis, the prognostic factors identified were tumor staging, alpha-fetoprotein level above 10000&mgr;gcenter dotL(-1), extrahepatic metastasis, portal vein thrombosis and treatment.CONCLUSION:HCC in Thailand is a fatal disease with poor outcome due to late presentation and high prevalence of liver cirrhosis. Early detection and proper management may improve outcome.

Thymidine phosphorylase (platelet-derived endothelial cell growth factor), microvessel density and clinical outcome in hepatocellular carcinoma

Background/Aims: Angiogenesis plays an important role in tumor growth and metastasis. It is regulated by angiogenic factors. Thymidine phosphorylase (platelet-derived endothelial cell growth factor) is one such factor. Although the significance of platelet-derived endothelial cell growth factor has been studied for several types of tumor, the expression of platelet-derived endothelial cell growth factor and its correlation with microvessel density or clinicopathological factors in hepatocellular carcinoma are unknown. We evaluated microvessel density and platelet-derived endothelial cell growth factor expression in hepatocellular carcinoma to determine whether microvessel density and platelet-derived endothelial cell growth factor expression are correlated with the clinicopathological factors of hepatocellular carcinoma. Methods: Using immunohistochemical staining with anti-platelet-derived endothelial cell growth factor antibody and the ELISA method, we evaluated the correlation among platelet-derived endothelial cell growth factor expression, microvessel density and clinicopathological factors in 84 hepatocellular carcinoma patients. Microvessels were stained with anti-human von Willebrand factor (anti-Factor VIII) and anti-CD34. Results: In the surrounding liver, there was a significant correlation between microvessel density and platelet-derived endothelial cell growth factor expression ( p=0.002), and hepatitis C virus-positive livers had higher microvessel densities than otherwise ( p=0.003). However, this correlation was not found for hepatocellular carcinoma, but hepatitis C virus-positive tumors had higher expression of platelet-derived endothelial cell growth factor ( p=0.018). Microvessel density in hepatocellular carcinoma obtained by Factor VIII staining inversely affected the recurrence-free survival rate ( p=0.0416), but the microvessel density by CD34 staining was not a significant predictor. Conclusion: This study indicates that platelet-derived endothelial cell growth factor may not be a major regulator of angiogenesis of hepatocellular carcinoma, but this enzyme may play an important role in hepatocarcinogenesis cooperating with hepatitis C virus. Also, the density, not of sinusoid-like vessels, but of larger vessels in hepatocellular carcinoma could be a prognostic factor for hepatocellular carcinoma.

Prognostic significance of pathological and biological factors in hepatocellular carcinoma.

Prognostic factors in hepatocellular carcinoma (HCC) conventionally consist of staging with the tumour node metastasis system and grading by tumour cellular differentiation. There are also other factors useful in prognostication but most of them are clinical. With new discoveries in the pathobiology of cancers and introduction of new medical technology, pathological and biological factors of HCC in relation to prognosis have been studied quite extensively. Morphological features of the tumour, both gross and histological, have been found to be significantly related to tumour recurrence and patient survival. Recently, applications of new antibodies and techniques have enabled studies on cellular proliferation using different antibodies such as those for proliferating cell nuclear antigen and Ki-67 protein. These studies on cellular proliferation, as well as assessment of argyrophilic nucleolar organizing regions, have been shown to provide good prognostic significance. Flow cytometric studies on DNA ploidy and studies on expression of genes including the p53 gene, hormone receptors and others show less unanimous results in their prognostic significance. The influence of gender on survival is also reviewed. In conclusion, pathological and biological factors are useful and help to guide clinicians in the management of patients and in assessment of long-term prognosis.

肝細胞癌におけるp53, c-myc染色の予後判定因子としての有用性について

肝細胞癌におけるp53, c-myc染色の予後判定因子としての有用性について

Comparison of Clinical Features and Survival in Patients With Hepatitis B and C Virus-Related Hepatocellular Carcinoma

We analyzed the clinical characteristics and survival of 185 patients with hepatitis B virus-related hepatocellular carcinoma (HBV group) and 1033 with hepatitis C virus-related hepatocellular carcinoma (HCV group) by multi center study. The patients in the HBV group (mean age 52.1 yr) were about 10 years younger than those in the HCV group (mean age 62.9 yr). Liver function, as measured by indocyanine green retention at 15 min, was better in the HBV group (17.5%) than in the HCV group (25.4%). A higher proportion of the HBV group (55%) than the HCV group (44%) had clinical stage I, T-factor differed significantly between the groups: 53% of the HBV group were T3-4 compared with 41% of the HCV group. Furthermore, a higher proportion of the HBV group were graded 2-3 for tumor thrombus in the portal vein (20.3%) and had poorly differentiated hepatocellular carcinoma (7%) compared with the HCV group (7.1% and 5% respectively). Univariate analysis identified poor prognostic factors for hepatocellular carcinoma as HBV, age < or = 50 yr, clinical stage II-III, a high AFP level, higher number of tumors, larger tumor size, tumor thrombus in the portal vein 2-3 and in the hepatic vein 2-3. On multivariate analysis, poor prognostic factors were a high AFP level, higher number of tumors, tumor thrombus in the portal vein 2-3 and in the hepatic vein 2-3, but not HBV, age, clinical stage or tumor size. These results suggest that HBV itself is not a stronger prognostic factor than HCV.

Usefulness of monoclonal antibody Ki-67 as a prognostic factor of hepatocellular carcinoma

We studied the proliferative activity of hepatocellular carcinoma (HCC) by immunohistochemical staining with Ki-67, a monoclonal antibody to nuclear protein observed in the proliferative period of the cell cycle, and evaluated the usefulness of Ki-67 as a prognostic factor. Of the patients who underwent hepatectomy for HCC at our department, 56 cases in which pathological studies for the tumor showed no degeneration or necrosis were selected. Immunohistochemical staining was performed according to the method of Shi et al., using MIB-1 monoclonal antibody (Immunotech, SA) as a primary antibody. Ki-67 L.I. was significantly higher in chronic hepatitis (CH) and liver cirrhosis (LC) than in normal liver, and the L.I. was also significantly higher in non-cancerous tissue of the patients with HCC than in tissues with other liver diseases. In patients with a history of portal hypertension, the L.I. in non-cancerous liver tissue was significantly lower at the previous operation for portal hypertension without HCC than that at the subsequent operation for HCC. The L.I. was significantly higher in patients who showed a high serum AFP level and in those who had intrahepatic metastasis. It also tended to be higher in patients with vessel invasion, infiltration to capsule, aneuploidy tumor cells, and poor differentiation. The cumulative survival rate was significantly lower in patients with the L.I. of 10% or higher than in those with the L.I. of less than 10% in cancerous region. Recurrence was observed earlier after hepatectomy in patients with higher L.I. and the L.I. was significantly higher in those who had recurrence within 12 months. In the patients who could be followed up, the L.I. was significantly higher in those who had multiple recurrence after hepatectomy than in those who had single-lesion recurrence. The incidence of HCC was higher in patients with CH or LC in which the proliferative activity was abnormally enhanced for a prolonged period, suggesting that hepatocyte hyperproliferation triggers hepatic carcinogenesis. In addition, long-term survival was expected even in patients with advanced HCC if the L.I. in preoperative biopsy specimens was low, while in patients with high L.I., postoperative recurrence and distant metastasis may occur more frequently, and postoperative supplementary therapies may be necessary, even when the tumor is completely resectable. In conclusion, Ki-67 staining is considered to be useful for evaluation of the malignant potential of HCC.

HLA class I antigens are possible prognostic factors in hepatocellular carcinoma

Thirty patients who underwent hepatectomy for the treatment of hepatocellular carcinoma (HCC) were examined for expression of HLA class I antigens on HCC cells by flow cytometry. The expression was found significantly lower in cases of stage IV compared with those of stage I or stage II (p<0.05), and in cases of intrahepatic metastases compared with those without metastases (p<0.001). In cases of non-curative hepatectomy, the expression of HLA class I antigens was lower compared with those treated by curative resection. Postoperative cumulative disease-free survival rates were well correlated with the expression rate of HLA class I antigens (p<0.05). Expression of HLA class I antigens on HCC may indicate low malignancy and better prognosis.

Prognostic value of serum alpha-1-antitrypsin in hepatocellular carcinoma

To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female, mean age ± SD 63.0 ± 9.3 years) in whom hepatocellular carcinoma developed with pre-existing cirrhosis. Median survival time was 245 days (range 4–1568+). 30 patients had serum A1AT concentration of ⩽2.20 g/1 (Group A) while 45 (Group B) had alpha-1-antitrypsin > 2.20 g/1. Median survival was 518 days in Group A and 81 days in Group B (Mantel-Cox 20.95, P < 0.0001; hazard ratio 0.26, 95% confidence limits 0.15–0.46). By stepwise survival analysis, alpha-1-antitrypsin together with bilirubin, tumour size and blood urea nitrogen were chosen among 17 variables as the only independent predictors of survival. We conclude that measurement of serum A1AT concentration might be useful as an inexpensive, widely available prognostic marker of hepatocellular carcinoma.

Prognostic significance of nucleolar organizer regions in hepatocellular carcinoma

It has been suggested that the number of argyrophilic nucleolar organizer regions (AgNORs) correlates with cellular activity and the aggressiveness of malignancy. The mean number of AgNORs per nucleus may, therefore, be a prognostic factor for hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the prognostic significance of the number of AgNORs in HCC. The silver-staining technique was applied to surgically resected specimens to indicate AgNORs. Eighty-nine of the specimens were of HCC, 23 were of normal liver adjacent to HCC, and 32 were of cirrhotic liver adjacent to HCC. The number of AgNORs of HCC (mean +/- SD, 3.26 +/- 1.23) was significantly higher than those of normal liver (1.37 +/- 0.13) and cirrhotic liver (1.49 +/- 0.14). The number of AgNORs was significantly correlated with serum alpha-fetoprotein level, tumor size, portal vein invasion, and Edmondson-Steiner histological grade. In patients undergoing curative resection, the survival rate of those with a high number (> 3.04) of AgNORs was significantly worse than that of those with a low number (< or = 3.04) of AgNORs. Multivariate analysis showed that the number of AgNORs was a significant prognostic indicator in patients without portal vein invasion, and portal vein invasion was the only significant variable when all patients undergoing curative resection were assessed together. The results of this study suggest that the number of AgNORs is useful as an indicator of the grade of malignancy and as a predictor of the prognosis of patients with HCC who do not have portal vein involvement.