Risk factors for postoperative recurrence of non-B non-C hepatocellular carcinoma

Background/purpose

The majority of hepatocellular carcinomas are associated with chronic infection with hepatitis B or C virus. Recently, however, the proportion of non-B non-C hepatocellular carcinomas has been increasing. It is necessary to determine the optimal surgical approach for non-B non-C hepatocellular carcinoma.

Methods

Seventy-seven patients with non-B non-C hepatocellular carcinoma who underwent curative hepatic resection were included in this study. Univariate and multivariate analyses were performed to clarify risk factors for postoperative recurrence of non-B non-C hepatocellular carcinoma.

Results

On univariate analysis, surgical margin <5?mm (P?=?0.001) and the presence of multiple tumors (P?=?0.002) were significantly associated with lower disease-free survival rate. On multivariate analysis, surgical margin <5?mm and the presence of multiple tumors were independent risk factors for postoperative recurrence.

Conclusion

Curative resection with adequate surgical margins for single non-B non-C hepatocellular carcinoma can achieve a good outcome.     

Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta‐analysis

Background: The association between occult hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) remains controversial. Aims: We conducted a meta‐analysis of prospective studies and retrospective studies to examine whether occult HBV infection increases the risk of HCC. Methods: Two independent reviewers searched databases for eligible studies published in English or Chinese dated from 1966 to 6 April 2010. The odds ratios or the relative risks (RRs) of each study were considered respectively. Results: We identified 16 eligible studies. A significantly increased risk of HCC was found in subjects with occult HBV infection in comparison with non‐infected controls in both retrospective [OR_unadjusted=6.08, 95% confidence interval (CI)=3.45–10.72] and prospective studies (RR_adjusted=2.86, 95% CI=1.59–4.13), and occult HBV increased the risk for HCC in both hepatitis C virus (HCV)‐infected populations (summary RR=2.83, 95% CI=1.56–4.10) and in non‐infected populations (OR_unadjusted=10.65, 95% CI=5.94–19.08). A higher prevalence of occult HBV was observed in individuals who were positive for anti‐HBs and anti‐HBc (OR_unadjusted=1.81, 95% CI=1.06, 3.09). Conclusion: Our findings suggest that occult HBV infection was associated with an increased risk of HCC. Occult HBV may serve as a cofactor in the development of HCV‐related HCC, and it may also play a direct role in promoting Non‐B and Non‐C HCC growth. Suggestive evidence indicates that individuals with a concomitant presence of anti‐HBs and anti‐HBc had an increased risk of occult HBV infection. However, further studies are needed to clarify these observations.     

Clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse: a retrospective study of patients undergoing hepatic resection

Background This study was carried out to clarify the etiology and clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse.Methods HCC patients who underwent resection were divided into three groups: a non-B non-C (NBNC) group (n = 13), who were seronegative for hepatitis B surface antigen (HBs Ag) and anti-hepatitis C antibody (HCV Ab), excluding a history of alcohol abuse; a B group (n = 25), who were seropositive for HBs Ag only; and a C group (n = 116), who were seropositive for HCV Ab only. We analyzed the features of tumor- and host-related factors and the outcome of the NBNC group.Results Hepatic inflammation and fibrosis were less severe in the NBNC group than in the other groups. There were no significant differences in tumor-related factors, except for higher serum levels of -fetoprotein in the NBNC group. Recurrence rates and disease-free survivals were comparable among the three groups. The NBNC group comprised a greater population with one or two recurrent hepatic lesions (P < 0.05), and indocyanine green retention rates and fibrosis scores were preserved after the initial hepatectomy. The NBNC group had higher resection rates for intrahepatic recurrences (75.0%) than the other groups (21.1% and 22.2% in groups B and C, respectively; P < 0.05 and P < 0.05). The survival rate after the initial hepatectomy or detection of the recurrent lesions was significantly better in the NBNC group (both 100% at 5 years) than those in groups B and C (P < 0.05).Conclusions NBNC patients maintained good liver function following the initial hepatectomy, and tended to have one or two recurrent lesions. These biological advantages provided NBNC patients more opportunities for repeat resection of intrahepatic recurrences, which may lead to a favorable outcome.     

Preliminary results of HBV DNA testing of Polish haemophilia patients – lack of occult HBV infection

Identification of hepatitis B virus (HBV) infection in the absence of surface antigen (HbsAg) became possible with the introduction of HBV DNA detection methods. Such occult HBV infection was diagnosed recently in about half of the Japanese HBsAg-negative haemophilia patients. The aim of our study was to assess the prevalence of occult HBV infection in Polish severe haemophilia population on the sample of 115 haemophilia A and B patients (mean age 34.9 +/- 10.9) treated with non-virus inactivated clotting factor preparations before 1995. HBV DNA was detected in nine HBsAg-positive patients (7.8%). The mean HBV DNA load was 72,800 IU mL(-1) (250-400,000 IU mL(-1)). Hepatitis C virus (HCV) RNA was found in six out of nine HBV-positive patients. In conclusion, HBV DNA was identified only in HBsAg-positive patients. Unlike in Japan, the frequency of occult HBV infection in Polish haemophilia population seems extremely rare or absent.     

Primary hepatocellular carcinoma following nonspecific non-B hepatitis with tumor DNA negative for HBV DNA

Summary An association between non-A, non-B hepatitis and hepatocellular carcinoma has been made on the basis of negative serological markers for hepatitis B virus (HBV); however, hepatocellular carcinomas have been found to contain hepatitis B virus deoxyribonucleic acid (HBV DNA) in individuals who lack serological markers of HBV infection. Therefore, reports which ascribed a hepatocellular carcinoma to non-A, non-B hepatitis but did not examine the tumor for HBV DNA are open to question. We describe a case of chronic active hepatitis with primary hepatocellular carcinoma that lacked HBV DNA in the tumor, the nontumorous liver tissue, and serum. The individual lacked all serological markers for HBV infection. This report more fairly supports the association between hepatocellular carcinoma, and chronic hepatitis not due to hepatitis B. Whether this is related specifically to a non-A, non-B hepatitis agent requires identification of the viral agents that cause non-A, non-B hepatitis.     

Juvenile Hepatocellular Carcinoma in a Healthy Liver

Primary hepatocellular carcinoma (HCC) in patients ＜30 years old is extremely rare. In younger patients, HCC develops against a background of persistent hepatitis B virus infection. We herein report a 23-year-old woman with HCC with all-negative hepatitis virus markers developing in an apparently healthy liver. Imaging studies showed a 50-mm hypervascular mass in segment 4 of the left liver lobe, compatible with HCC. The patient underwent surgical resection. A histological examination showed the presence of poorly differentiated HCC. The patient was diagnosed with HCC developing in a healthy liver. This is an extremely rare case of non-B non-C HCC.     

Possible contribution of prior hepatitis B virus infection to the development of hepatocellular carcinoma

BACKGROUND: The prevalence of prior hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients and its role in hepatocarcinogenesis are not clear. The aim of the present study is to clarify the importance of prior HBV infection in development of HCC. METHODS: Of 1288 consecutive HCC patients between January 1999 and October 2002, 1008 patients were enrolled. To determine the influence of prior HBV infection in hepatitis B surface antigen (HBsAg)-negative HCC, the prevalence of antibody to hepatitis B core antigen (anti-HBc) was examined according to age, and the clinical features were compared between the anti-HBc positive and the negative groups. RESULTS: The proportion of HBsAg-negative HCC patients, HCC patients with antibody to hepatitis C virus (anti-HCV; C-HCC) and HCC patients negative for both HBsAg and anti-HCV (nBnC-HCC), increased with age. The anti-HBc-positive rates in C-HCC patients also increased with age. Those rates in nBnC-HCC patients were >50% in all age groups. Furthermore, it was found that the anti-HBc-positive rates of these patients were higher than those of corresponding control patients. Tumor size and a positive rate for vessel involvement both in C-HCC and nBnC-HCC patients were larger and higher, respectively, in anti-HBc-positive patients compared with anti-HBc-negative patients, although the difference in nBnC-HCC did not reach statistical significance because of the small numbers. These tumor characteristics were similar to those of B-HCC patients. CONCLUSION: A possible contribution of prior HBV infection to the development of HCC is indicated.     

Lack of evidence for hepatitis B virus (HBV) infection in fulminant non-A,non-B hepatitis

We studied eight patients who had orthotopic liver transplantation for fulminant hepatic failure in the course of acute non-A, non-B hepatitis. HBV DNA was searched for extensively in the liver tissue by PCR using several sets of primers in conventional and heminested reactions. All patients were negative for HBV DNA in liver tissue by all assays employed; furthermore, they were negative for HEV RNA, HCV RNA, and HBV DNA in serum. Although the causative role of HEV and HCV in fulminant non-A, non-B hepatitis cannot be excluded, our data do not support a causative association between this syndrome and HBV infection.This study was supported by Grant CR20 from the Mayo Clinic and Foundation. D.H.P. is supported by Public Health Service grants AI 32403, AR 41497, and AI 30548 from the National Institutes of Health.     

Liver biopsy features of acute hepatitis C compared with hepatitis A,B, and non-A,non-B,non-C

ABSTRACT— The diagnosis of acute hepatitis C (AHC) often can only be suspected because current serologic tests remain negative for over 3 months. Because histologic features might provide useful clues, we reviewed 85 liver biopsy specimens from 85 patients with acute viral hepatitis, comparing 22 cases of AHC with 23 cases of acute hepatitis A (AHA), 30 cases of acute hepatitis B (AHB), and 10 cases of acute hepatitis non-A, non-B, non-C (AHNC). AHC was characterized by dense portal lymphoid aggregates (7 cases) and Poulsen-Christoffersen-type cholangitis (8 cases); these lesions were not found in any other type of acute viral hepatitis, and thus appeared to be diagnostic. Sinusoidal inflammatory infiltrates also were common in AHC, particularly in biopsy specimens obtained during the early phase of the disease. These inflammatory infiltrates did not appear to affect adjacent hepatocytes. Necrosis in AHC usually was spotty and accompanied by mixed inflammatory cells. In AHNC, necrosis was also spotty but, as an added feature, pigmented macrophages predominated in them. In AHA, necrosis was predominantly periportal, whereas in AHB, severe zone-3 necrosis predominated. Fatty changes were predominantly microvesicular; they were common in AHC but were also found in other groups. Collectively, the described histologic features allowed diagnosis of AHC in biopsy specimens with reasonable confidence. However, histologic findings failed to predict the prognosis in individual cases.     

Non-B,Non-C Hepatocellular Carcinoma in an HBV- and HCV-Endemic Area: A Community-Based Prospective Longitudinal Study

A large community cohort of adults who participated in a health screening program from 2003 to 2013 were prospectively analyzed for the risk factors of non-B, non-C (NBNC) hepatocellular carcinoma (HCC). The serostatus of hepatitis B and C of 52,642 participants was linked to the mortality and cancer registration data of the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. During a median follow-up of 6 years, 35 of the 43,545 participants who were negative for both HBsAg and anti-HCV antibody developed HCC. Multivariate Cox regression analysis revealed that old age (hazard ratio, 95% CI: 1.058, 1.019–1.098, p = 0.003); male sex (2.446, 1.200–4.985, p = 0.014); high aspartate aminotransferase levels (6.816, 2.945–15.779, p < 0.001); fibrosis index based on four factor score (1.262, 1.154–1.381, p < 0.001); blood sugar (1.009, 1.002–1.015, p = 0.006); and alpha-fetoprotein ≥15 ng/mL (143.938, 43.094–480.760, p < 0.001) were independent risk factors for HCC. By contrast, triglyceride >150 mg/dL was associated with a decreased risk of HCC (0.216, 0.074–0.625, p = 0.005). This prospective community-based study provided insights into the potential HCC risk factors which may shed some light in HCC prevention and screening.     

Clinicopathological studies and operative results of hepatocellular carcinoma with liver cirrhosis,comparing HB-associated cirrhosis to alcoholic and post-transfusion cirrhosis

The present study was undertaken to elucidate clinicopathological findings and operative results of HCC with HB-associated cirrhosis, compared with those in HCC patients with alcoholic and post-transfusion cirrhosis. The number of the HBV group was 26 cases, consisting of 17 in sAg(+), 4 in eAg(+) and 5 in eAb(+) subgroups. The number of the post-transfusion group was 7 and that of alcoholic group was 12. A high incidence of hypersplenism and esophageal varix in the eAg(+) subgroup was found. ICG R₁₅ was the highest, K_icg and ICG R_max were the lowest in the eAg(+) subgroup. The mean diameter of tumors was the largest, 6.6±3.9 cm, in the sAg(+) subgroup and was the smallest, 2.2+1.7 cm, in the eAg(+) subgroup. The incidence of postoperative jaundice, hyperammoninemia and live dysfunction were the highest in the sAg(+) and eAg(+) subgroup. One and three-year survival rate were 76.9% and 48.1% in the sAg(+) subgroup, 60.0% and 30.0% in the eAb(+) subgroup, and the oneyear survival rate in the eAg(+) subgroup was 50.0%. The three-year survival rate could not be calculated because 3 years had not passed since the operation. The prognosis was the poorest in the HBV group among all groups. This study suggests that in HBV-associated cirrhosis, hepatectomy might induce “acute on chronic” changes (acute hepatitis and fulminant hepatitis). Therefore we should select operative procedures by considering surgical risk and the etiology of liver cirrhosis in hepatectomy.     

Impact of occult hepatitis B virus infection on efficacy and prognosis of interferon-alpha therapy for patients with chronic hepatitis C.

BACKGROUND/AIMS: It is reported that some patients with undetectable hepatitis B surface antigen (HBsAg) have serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis C (HCV). The aim of this study was to elucidate the impact of occult HBV infection on the efficacy and prognosis of interferon-alpha (IFN) therapy in HCV patients. METHODS: One hundred and forty HCV patients without HBsAg who received IFN therapy were studied. Serum HBV DNA was quantified by real-time detection polymerase chain reaction. RESULTS: Of 140 patients, 11 (7.9%) were HBV DNA-positive before IFN therapy. The serum HBV DNA levels ranged from 106 to 884 copies/ml. Four of these 11 patients showed a sustained virologic response by IFN, compared with 39 of 129 without HBV DNA (P = NS). Interestingly, two of the 11 patients developed hepatocellular carcinoma (HCC) after therapy, compared with 16 of 129 without HBV DNA (P = NS). In the serial study, serum HBV DNA was transiently undetectable during and after IFN; however, most became positive during follow-up. CONCLUSIONS: Occult HBV infection may not have a significant impact on response to IFN therapy for chronic HCV and development of HCC after therapy. Occult HBV may be sensitive to IFN although HBV is not completely eradicated.     

Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study

Summary.  An impact of serum hepatitis B virus (HBV) DNA on hepatocarcinogenesis has not been investigated in a cohort of patients with non-B, non-C cirrhosis. Eighty-two consecutive Japanese patients with cirrhosis, who showed negative hepatitis B surface antigen and negative anti-hepatitis C virus, were observed for a median of 5.8 years. Hepatitis B virus core (HBc) region and HBx region were assayed with nested polymerase chain reaction. Both of HBc and HBx DNA were positive in 9 patients (11.0%) and both were negative in 73. Carcinogenesis rates in the whole patients were 13.5% at the end of the 5th year and 24.6% at the 10th year. The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively ( P  =   0.0078). Multivariate analysis showed that men ( P  =   0.04), presence of HBc and HBx DNA (hazard ratio: 8.25, P  =   0.003), less total alcohol intake ( P  =   0.010), older age ( P  =   0.010), and association of diabetes ( P  =   0.005) were independently associated with hepatocellular carcinogenesis. Existence of serum HBV DNA predicted a high hepatocellular carcinogenesis rate in a cohort of patients with non-B, non-C cirrhosis.     

HBV感染对原发性肝细胞癌生物学行为及p53蛋白的表达影响

探讨在原发性肝细胞癌(HCC)中乙型肝炎病毒(HBV)的感染对肿瘤生物学行为以及突变型p53蛋白的表达影响。利用血清学指标检测60例HCC的HBV感染情况,采用抗生蛋白链霉素-过氧化酶法(S-P)检测癌组织中突变p53蛋白的表达。38例HBV感染HCC中突变p53蛋白的表达率为73.68%(28/38),22例非HBV感染表达率为45.45%(10/22),两者有显著差异(P<0.05)。在HCC中,HBV感染与肿瘤的Edmondson分级、AFP值增高、门静脉癌栓形成、肝内转移以及转氨酶增高相关(P<0.05)。HBV的感染可能与p53基因的突变共同作用导致HCC的发生及发展。同时检测以上二种指标可以为认识HCC的生物学特性,制定合理的综合治疗方案提供依据。     

肝癌患者血清中乙型肝炎病毒基因分型及临床意义

目的:探讨血清中乙型肝炎病毒(HBV)基因型及HBV DNA水平与肝细胞癌的关系。方法:应用巢式聚合酶链反应扩增乙型肝炎病毒与基因,用末端标记方法对PCR产物标记并直接测序,测序结果和GenBank中登录的标准基因型序列相比较,应用荧光定量PCR法检测HBV DNA水平。对61例肝癌、65例慢性乙型肝炎、10例乙型肝炎病毒携带者进行了检测。结果:136例中B基因型59例(43.4%)、C基因型77例(56.6%),随着病情加重,C基因型比例逐渐增高;不同基因型HBV感染的肝癌患者间HBV DNA水平差异有显著意义,P<0.05;在慢性乙型肝炎患者中,HBV DNA水平差异无显著性意义。结论:本地区乙型肝炎病毒以B、C基因型为主,乙型肝炎病毒C基因型及高水平的HBV DNA感染与肝癌的发生相关。     

Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review

Occult hepatitis B (OHB) infection has been reported to play an important role in the development of hepatocellular carcinoma (HCC). In this systematic review, a significantly higher prevalence of OHB was observed in patients with HCC in the presence or absence of HCV infection when compared with control populations without HCC. Correspondingly, among adequately designed prospective studies, the cumulative probability of developing HCC was significantly greater among patients with OHB than among HBV DNA‐negative patients in the presence or absence of HCV infection. Study design, inclusion criteria, treatment options, methodology and potential confounding variables were evaluated, and immunopathogenic mechanisms that could be involved in OHB as a risk factor in HCC were reviewed. From this analysis, we conclude that although OHB is an independent risk factor in HCC development in anti‐HCV‐negative patients, a synergistic or additive role in the occurrence of HCC in HCV‐coinfected patients is more problematic due to the HCC risk attributable to HCV alone, especially in patients with advanced fibrosis and cirrhosis.