Iwao Ikai

Tumor size predicts vascular invasion and histologic grade : Implications for selection of surgical treatment for hepatocellular carcinoma

Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (≤3 cm, 25%; 3.1‐5 cm, 40%; 5.1‐6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm (P = 0.01). High histologic grade, an alpha‐fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients. (Liver Transpl 2005;11:1086–1092.)

Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey

Advances in the diagnosis and surgical treatment of hepatocellular carcinoma (HCC) have improved the prognosis for patients with HCC who undergo liver resection. The objective of this study was to evaluate prognostic predictors for patients with HCC who underwent liver resection in a Japanese nationwide data base.

Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan.

In the 17th Nationwide Follow‐up Survey of Primary Liver Cancer in Japan, 18 213 individuals were newly registered as patients with primary liver cancer at 645 medical institutions over a period of 2 years (from 1 January 2002 to 31 December 2003). Of these patients, 94.2% had hepatocellular carcinoma (HCC) and 4.1% had intrahepatic cholangiocarcinoma (ICC). In addition, 24 705 follow‐up patients were registered in the survey. Epidemiological and clinicopathological factors, diagnosis and treatment were investigated in the newly registered patients, and the cumulative survival rates of newly registered patients in the 12th to 17th follow‐up surveys conducted between 1992 and 2003 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified by background factors and treatment. The data obtained in this follow‐up survey should contribute to future research and medical practice for primary liver cancer.

Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a Japanese nationwide survey.

BACKGROUND Although a surgical resection is an important modality for the treatment of hepatocellular carcinoma (HCC), the impact of the operative method on both the patient survival and disease-free survival (DFS) still remains controversial. METHODS Using a nationwide Japanese database, 72,744 patients with HCC who underwent a curative liver resection between 1994 and 2001 were divided into two groups based on whether an anatomical subsegmentectomy (AS) or a non-anatomical minor hepatectomy (MH) was performed. A total of 5,781 patients with single HCCs were selected for the study and divided into 3 subgroups based on the size of the HCCs (less than 2 cm, 2 to 5 cm, and greater than 5 cm in diameter). An AS was performed for 2,267 patients while an MH was performed for 3,514 patients. RESULTS The overall DFS was significantly better after an AS (P = .0089). When the patients were stratified according to the size of the HCC, a better DFS was seen in the patients with HCC from 2 to 5 cm after an AS (P < .0005). Further stratification according to liver damage did not show any significant differences between an AS and an MH. CONCLUSION An AS is therefore recommended, especially when the size of HCC ranges from 2 to 5 cm.

Aberrant Methylation of Multiple Tumor Suppressor Genes in Aging Liver, Chronic Hepatitis, and Hepatocellular Carcinoma

Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human liver tissue specimens. A total of 176 liver tissues, including 77 pairs of HCCs and matching noncancerous liver and 22 normal livers, were analyzed for methylation. Methylation of 19 epigenetic markers was quantified, and the results were correlated with different disease states and the presence or absence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Based on methylation profiles, the 19 loci were categorized into 3 groups. Normal liver tissues showed methylation primarily in group 1 loci (HIC‐1, CASP8, GSTP1, SOCS1, RASSF1A, p16, APC), which was significantly higher than group 2 (CDH1, RUNX3, RIZ1, SFRP2, MINT31) and group 3 markers (COX2, MINT1, CACNA1G, RASSF2, MINT2, Reprimo, DCC) (P < 0.0001). Noncancerous livers demonstrated increased methylation in both group 1 and group 2 loci. Methylation was significantly more abundant in HCV‐positive livers compared with normal liver tissues. Conversely, HCC showed frequent methylation at each locus investigated in all 3 groups. However, the group 3 loci showed more dense and frequent methylation in HCV‐positive cancers compared with both HBV‐positive cancers and virus‐negative cancers (P < 0.0001). Conclusion: Methylation in HCC is frequent but occurs in a gene‐specific and disease‐specific manner. Methylation profiling allowed us to determine that aberrant methylation is commonly present in normal aging livers, and sequentially progresses with advancing stages of chronic viral infection. Finally, our data provide evidence that HCV infection may accelerate the methylation process and suggests a continuum of increasing methylation with persistent viral infection and carcinogenesis in the liver. (HEPATOLOGY 2008.)

Staging of hepatocellular carcinoma: Assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan

Objective:The aims of this study were to present evidence to develop and validate the Japanese Tumor-Node-Metastasis (TNM) staging system for primary liver cancer and to compare its discriminatory ability and predictive power with those of Vautheys simplified staging, which was adopted as the TNM staging system of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC). Summary Background Data:Among many staging systems for hepatocellular carcinoma, the Japanese TNM staging system and the AJCC/UICC staging system were developed based on a survival analysis of surgical patients. These 2 staging systems have not been compared in large series. Methods:The Liver Cancer Study Group of Japan (LCSGJ) prospectively collected clinicopathologic data of 63,736 patients with primary liver cancer from 1995 to 2001. Among them, 13,772 patients received curative hepatic resection. Based on univariate and multivariate survival analyses, the Japanese TNM staging system was developed. The accuracy of the Japanese TNM staging system for predicting patient survival was compared with that of the AJCC/UICC staging system using the cross-validation method. Results:The independent prognostic factors (relative risk; 95% confidence interval) were vascular or bile duct invasion (1.36;1.29–1.43), liver cirrhosis (1.26;1.20–1.32), diameter (≤2 cm or >2 cm) (1.21;1.14–1.28), alpha-fetoprotein (1.20;1.15–1.25), single/multiple (1.18;1.12–1.23), liver damage (1.15;1.10–1.20), hepatic involvement (1.14;1.09–1.19), histologic differentiation (1.14;1.08–1.20), gross classification (1.13;1.08–1.18), and esophageal varices (1.07;1.02–1.13). Based on these results, 3 criteria (vascular or bile duct invasion, diameter, and single/multiple) were selected. Patients with none of these 3 factors were considered T1, and those with 1, 2, and 3 factors were T2, T3, and T4, respectively. The number of patients and 5-year survival rates for T1, T2, T3, and T4 were 2078, 70%; 6853, 58%; 3021, 41%; and 582, 24% (P < 0.0001), respectively, while those for the AJCC-T were 8457, 61% in T1, 2888, 46% in T2, and 1189, 30% in T3 (P < 0.0001). While both the LCSGJ-T and the AJCC-T had good discriminating ability, the former was significantly superior (P = 0.0007). Conclusions:Our findings support the development of LCSG stage. While both staging systems allow for the clear stratification of patients into prognostic groups, the LCSGJ staging may be more appropriate for stratifying patients with early-stage HCC.

Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis

BACKGROUND & AIMS Although angiogenesis is closely associated with liver fibrosis, the angiogenic factors involved in liver fibrosis are not well characterized. Angiopoietin 1 is an angiogenic cytokine indispensable for vascular development and remodeling. It functions as an agonist for the receptor tyrosine kinase with immunoglobulin G-like and endothelial growth factor-like domains 2 (Tie2) and counteracts apoptosis, promotes vascular sprouting or branching, and stabilizes vessels. METHODS Liver samples from patients with liver fibrosis were evaluated for mRNA expression of angiogenic cytokines. Liver fibrosis was induced in BALB/c mice by either carbon tetrachloride (CCl(4)) or bile duct ligation (BDL). Hepatic stellate cells (HSCs) were isolated from BALB/c mice. We used an adenovirus expressing the extracellular domain of Tie2 (AdsTie2) to block angiopoietin signaling in mice and evaluated its effect on liver fibrosis. RESULTS mRNA expression level of angiopoietin 1 was increased in human fibrotic livers and correlated with the expression level of CD31, an endothelial cell marker. During experimental models of murine liver fibrosis, angiopoietin 1 was expressed by activated HSCs. In primary cultures, activated HSCs express and secrete angiopoietin 1 more abundantly than quiescent HSCs, and the inflammatory cytokine tumor necrosis factor-alpha stimulates its expression in an nuclear factor-kappaB-dependent manner. AdsTie2 inhibits angiogenesis and liver fibrosis induced by either CCl(4) or BDL. CONCLUSIONS These results reveal an angiogenic role of HSCs mediated by angiopoietin 1, which contributes to development of liver fibrosis. Thus, angiogenesis and hepatic fibrosis are mutually stimulatory, such that fibrosis requires angiogenesis and angiogenesis requires angiopoietin 1 from activated HSCs.

Is Hepatic Resection for Large or Multinodular Hepatocellular Carcinoma Justified? Results From a Multi-Institutional Database

BackgroundThe role of surgical resection in patients with large or multinodular hepatocellular carcinoma (HCC) remains unclear. This study evaluated the long-term outcome of patients with hepatic resection for large (>5 cm in diameter) or multinodular (more than three nodules) HCC by using a multi-institutional database.MethodsThe perioperative and long-term outcomes of 404 patients with small HCC (<5 cm in diameter; group 1) were compared with those of 380 patients with large or multinodular HCC (group 2). The prognostic factors in the latter group were analyzed.ResultsThe postoperative complication rate (27% vs. 23%; P = .16) and hospital mortality rate (2.4% vs. 2.7%; P = .82) were similar between groups. The overall survival rates were significantly higher in group 1 than group 2 (1 year, 88% vs. 74%; 3 years, 76% vs. 50%; 5 years, 58% vs. 39%; P < .001). Among patients in group 2, five independent prognostic factors were identified to be associated with a worse overall survival: namely, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, and positive histological margin.ConclusionsHepatic resection can be safely performed in patients with large or multinodular HCC, with an overall 5-year survival rate of 39%. Symptomatic disease, the presence of cirrhosis, a multinodular tumor, microvascular invasion, and a positive histological margin are independently associated with a less favorable survival outcome.

Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma

HYPOTHESIS A subset of patients can be identified who will survive without recurrence beyond 5 years after hepatic resection for hepatocellular carcinoma (HCC). DESIGN A retrospective review of a multi-institutional database of 591 patients who had undergone hepatic resection for HCC and on-site reviews of clinical records and pathology slides. SETTING All patients had been treated in academic referral centers within university-based hospitals. PATIENTS We identified 145 patients who had survived for 5 years or longer after hepatic resection for HCC. MAIN OUTCOME MEASURES Clinical and pathologic factors, as well as scoring of hepatitis and fibrosis in the surrounding liver parenchyma, were assessed for possible association with survival beyond 5 years and cause of death among the 145 five-year survivors. RESULTS Median additional survival duration longer than 5 years was 4.1 years. Women had significantly longer median additional survival durations than did men (81 months vs 38 months, respectively, after the 5-year mark) (P =.008). Surgical margins, type of resection, an elevated preoperative alpha-fetoprotein level, and the presence of multiple tumors or microscopic vascular invasion had no bearing on survival longer than 5 years. However, patients who survived for 5 years who also had normal underlying liver or minimal fibrosis (score, 0-2) at surgery had significantly longer additional survival than did patients with moderate fibrosis (score, 3-4) or severe fibrosis/cirrhosis (score, 5-6) (P<.001). CONCLUSIONS Death caused by HCC is rare beyond 5 years after resection of HCC in the absence of fibrosis or cirrhosis. The data suggest that chronic liver disease acts as a field of cancerization contributing to new HCC. These patients may benefit from therapies directed at the underlying liver disease.

Preoperative Predictors of Survival After Resection of Small Hepatocellular Carcinomas

ObjectiveTo determine preoperative predictors of survival that can guide the choice of treatment for patients with small hepatocellular cancers (HCCs). Summary Background DataThe treatment of patients with small (≤5 cm in diameter) HCCs is controversial. MethodsA cohort of 249 patients (69 women, 180 men; median age 62 years) who underwent resection with curative intent for small HCC was identified from a multiinstitutional database. For each patient, the clinical data and pathology slides were reviewed. Six clinical factors (age, gender, preoperative &agr;-fetoprotein level, hepatitis serology, number of tumors [single vs. multiple], and Child-Pugh score) and three pathologic factors (hepatitis activity score, fibrosis score, and Edmondson-Steiner tumor grade) that can be determined before surgery were correlated with survival. Log-rank tests and Cox proportional hazards modeling were used to determine factors influencing survival. ResultsThe median overall survival for the entire cohort was 4.2 years. The estimated overall 5- and 8-year survival rates were 41.1% and 19.8%, respectively. Multivariate Cox analysis indicated that fibrosis score, Edmondson-Steiner grade, and Child-Pugh score were simultaneously significant predictors of survival after resection. A prognostic scoring system based on these covariates was derived and applied to the entire cohort. Patients lacking all three risk factors were assigned a score of 1, patients with one risk factor were assigned a score of 2, and patients with two or three risk factors were assigned a score of 3. Pairwise log-rank tests indicated significant differences in survival between scores 1 and 2, scores 2 and 3, and scores 1 and 3. This scoring system retained its prognostic significance when a subset of 98 patients with positive hepatitis C serology was analyzed separately. ConclusionsPatients with small HCCs who will derive the least benefit from resection can be identified before surgery using a score based on tumor grade and the severity of underlying liver disease. In these patients, transplantation and/or ablation should be considered as possible alternative therapies.