Comparison of clinicopathologic characteristics among patients with HBV-positive, HCV-positive and Non-B Non-C hepatocellular carcinoma after hepatectomy: a systematic review and meta-analysis.

BACKGROUND: The incidence of HBV-negative and HCV-negative hepatocellular carcinoma (NBNC-HCC) is significantly increasing. However, their clinicopathologic features and prognosis remain elucidated. Our study aimed to compare the clinicopathologic characteristics and survival outcomes of NBNC-HCC with hepatitis virus-related HCC. METHOD: A literature review was performed in several databases, including PubMed, Embase, Cochrane Library and Web of Science, to identify the studies comparing NBNC-HCC with HBV-positive HCV-negative HCC (B-HCC), HBV-negative HCV-positive (C-HCC) and/or HBV-positive HCV-positive HCC (BC-HCC). The clinicopathologic characteristics and survival outcomes were extracted and pooled to access the difference. RESULTS: Thirty-two studies with 26,297 patients were included: 5390 patients in NBNC-HCC group, 9873 patients in B-HCC group, 10,848 patients in C-HCC group and 186 patients in BC-HCC group. Patients in NBNC-HCC group were more liable to be diagnosed at higher ages, but with better liver functions and lighter liver cirrhosis. Comparing to B-HCC and C-HCC groups, although NBNC-HCC group was prone to have larger tumor sizes, it did not have more advanced tumors. Meanwhile, there were no significant differences in both 5-year and 10-year disease-free survival and overall survival between NBNC-HCC group and B-HCC or C-HCC group. CONCLUSIONS: Our meta-analysis revealed patients with NBNC-HCC had as worse prognosis as those with hepatitis virus-related HCC. More attention should be paid on patients with non-alcoholic steatohepatitis or metabolic syndromes to prevent the incidence of NBNC-HCC.

Treatment outcomes after radiofrequency ablation in patients with non-B non-C hepatocellular carcinoma within Milan criteria: comparison with HBV-related hepatocellular carcinoma.

PURPOSE: This study aims to evaluate the treatment outcomes of radiofrequency ablation (RFA) for patients with non-B non-C hepatocellular carcinoma (HCC) (NBNC-HCC) within Milan criteria, as well as to compare them with those of patients with hepatitis B virus (HBV)-related HCC (HBV-HCC). METHODS: From January 2007 to February 2020, 303 patients with primary HCC who underwent RFA were retrospectively reviewed, including 259 patients with HBV-HCC (HBV-HCC group) and 44 patients with NBNC-HCC (NBNC-HCC group). The clinical characteristics and treatment survivals were evaluated and compared. Moreover, the propensity score matching was used to reduce selection bias. RESULTS: A significantly lower proportion of cirrhosis was observed in the NBNC-HCC group (p = .048). Before propensity score matching, local tumor progression, disease-free survival, and overall survival after RFA showed no significant differences between the two groups (all p > .05). After matching, the overall survival rates in the NBNC-HCC group were significantly better than those in the HBV-HCC group (p = .042). Moreover, for patients with NBNC-HCC, tumor size (hazard ratio = 8.749, 95% confidence interval, 1.599-47.849; p = .012) was the only independent predictor of local tumor progression. CONCLUSIONS: Patients with NBNC-HCC within the Milan criteria after RFA had better long-term survival than patients with HBV-HCC, although larger, prospective and multicenter trials are required to validate these results.

Preoperative controlling nutritional status (CONUT) score predicts long-term outcomes in patients with non-B non-C hepatocellular carcinoma after curative hepatic resection.

PURPOSE: The controlling nutritional status (CONUT) score has been reported to predict outcomes in patients with hepatocellular carcinoma (HCC). However, the prognostic significance of the CONUT score in patients with non-B non-C (NBNC) HCC remains to be established. METHODS: The study comprised 246 patients who had undergone elective hepatic resection for HCC between April 2003 and October 2017. We retrospectively investigated the relation between preoperative CONUT score as well as clinicopathological characteristics and disease-free survival (DFS) as well as overall survival (OS). RESULTS: In univariate analyses, CONUT score was associated with DFS and OS in patients with NBNC-HCC (p ≤ 0.01), while there was no significant association of CONUT score with DFS and OS in patients with HBV- and HCV-related HCC (p ≥ 0.1). Of the 111 patients with NBNC-HCC, 97 (87.4%) had CONUT score ≤ 3 (low CONUT score) and the other 14 (12.6%) had CONUT score ≥ 4 (high CONUT score). In the patients with NBNC-HCC, multivariate analysis identified age ≥ 65 years (p = 0.03), multiple tumors (p < 0.01), and high CONUT score (p = 0.03) as the independent and significant predictors of DFS, while multiple tumors (p = 0.01), microvascular invasion (p < 0.01), and high CONUT score (p = 0.01) were the independent and significant predictors of OS. CONCLUSIONS: The CONUT score seems to be a reliable and independent predictor of both DFS and OS after hepatic resection for NBNC-HCC.

The Impact of the Hepatitis B Core Antibody Status on Recurrence in Patients with Non-B Non-C Hepatocellular Carcinoma after Curative Surgery.

BACKGROUND: The serum antibody to hepatitis B core antigen (HBcAb) is considered a risk factor of liver carcinogenesis. This study aimed to reveal whether HBcAb status is a prognostic factor after hepatectomy is performed for treating hepatocellular carcinoma (HCC). METHODS: This retrospective study enrolled 272 patients who underwent hepatectomy as the initial treatment for HCC and who were followed up over 5 years after surgery. The types of HCC were classified into the following 3 types according to the hepatitis virus infection status and the patients without hepatitis virus infection non-B non-C HCC (NBNC-HCC) were further classified into 2 groups. RESULTS: There is no novel finding as a result of the comparison made among hepatitis virus status. Of 90 patients (33.1%) with NBNC-HCC, 10 patients were excluded because the preoperative HBcAb status was not measured. There were 51 patients (63.8%) who were HBcAb-positive and 29 patients (36.2%) who were HBcAb-negative. In multivariate analysis, the presence of HBcAb-negative (hazard ratio 2.10, 95% CI 1.09-4.03, p = 0.026) remained as significant independent risk factors for recurrence in NBNC-HCC. CONCLUSIONS: This study shows that the HBcAb-positive is rather a favorable predictor for recurrence after curative resection in NBNC-HCC.

Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma.

BACKGROUND: While hepatitis B and C viral infection have been suppressed, non-B non-C hepatocellular carcinoma (NBNC-HCC) is considered to be rising in incidence terms in some developed countries where prevalence of those viral infections among HCC patients had been very high (such as Japan, Korea, and Italy). To elucidate critical molecular changes in NBNC-HCC, we integrated three large datasets relating to comprehensive array-based analysis of genome-wide DNA methylation (N = 43 pairs) and mRNA/miRNA expression (N = 15, and 24 pairs, respectively) via statistical modeling. RESULTS: Hierarchical clustering of DNA methylation in miRNA coding regions clearly distinguished NBNC-HCC tissue samples from relevant background tissues, revealing a remarkable tumor-specific hypomethylation cluster. In addition, miRNA clusters were extremely hypomethylated in tumor samples (median methylation change for non-clustered miRNAs: -2.3%, clustered miRNAs: -24.6%). The proportion of CpGs hypomethylated in more than 90% of the samples was 55.9% of all CpGs within miRNA clusters, and the peak methylation level was drastically shifted from 84% to 39%. Following statistical adjustment, the difference in methylation levels within miRNA coding regions was positively associated with their expression change. Receiver operating characteristic (ROC) analysis revealed a great discriminatory ability in respect to cluster-miRNA methylation. Moreover, miRNA methylation change was negatively correlated with corresponding target gene expression amongst conserved and highly matched miRNA sites. CONCLUSIONS: We observed a drastic negative shift of methylation levels in miRNA cluster regions. Changes in methylation status of miRNAs were more indicative of target gene expression and pathological diagnosis than respective miRNA expression changes, suggesting the importance of genome-wide miRNA methylation for tumor development. Our study dynamically summarized global miRNA hypomethylation and its genome-wide scale consequence in NBNC-HCC.

Clinical characteristics and potential aetiologies of non-B non-C hepatocellular carcinoma in hepatitis B virus endemic area.

BACKGROUND & AIMS: We investigated potential aetiologies, clinical characteristics and prognosis of non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients in hepatitis B virus (HBV) endemic area, according to potential causes such as previous HBV exposure, chronic alcohol intake and metabolic syndrome. PATIENTS AND METHODS: Among 4690 HCC patients treated at Asan Medical Center between 2007 and 2009, 523 were newly diagnosed with NBNC HCC, and their medical records and survival data were analyzed retrospectively. RESULTS: Among 321 NBNC HCC patients whose hepatitis B core antibody (anti-HBc) test results were available, 81.0%, 37.1% and 15.5% had anti-HBc positivity, chronic alcohol intake and metabolic syndrome respectively. One-hundred and fifty-two patients (47.4%) had previous exposure to HBV without chronic alcohol intake or metabolic syndrome. Hepatitis B surface antibody (anti-HBs) was positive in 48.0% of the 523 NBNC HCC patients, which was much lower than that in general Korean population, and 52.3% of anti-HBc-positive NBNC HCC patients were negative for anti-HBs. Anti-HBc-negative alcoholic patients presented with more advanced cirrhosis with Child-Pugh class B/C liver function than anti-HBc-positive patients (P = 0.002). In multivariate analysis, baseline liver function, alpha-foetoprotein levels and tumour stage were significant prognostic factors and aetiology did not affect patient survival. CONCLUSIONS: Prior HBV infection could be a potential aetiology in over 40% of NBNC HCC patients in HBV endemic area. Positivity for anti-HBc and negativity for anti-HBs may be a serologic surrogate marker for occult HBV infection in these area. The prognosis of NBNC HCC was determined by tumour stage and underlying liver function.

Impact of occult hepatitis B virus infection on outcome after resection for non-B non-C hepatocellular carcinoma.

BACKGROUND: To investigate the clinicopathologic characteristics of patients with both hepatitis B virus-surface antigen and hepatitis C virus antibody negative hepatocellular carcinoma (non-B non-C HCC [NBNC-HCC]) and examine the impact of occult hepatitis B virus infection (OBI) on patients' survival. METHODS: All patients with OBI were identified from a database of patients with NBNC-HCC who underwent surgical resection between January 1, 2006, and December 31, 2008. Their clinicopathologic and survival characteristics were compared with NBNC-HCC patients without OBI. RESULTS: Out of the 86 NBNC-HCC patients, 59 patients (68.6%) with OBI. A higher prevalence of hepatitis B core antigen positive rate, low platelet count, portal hypertension, and liver cirrhosis were observed in NBNC-HCC patients with OBI. The 1- and 3-y recurrence free survival rates were 66% and 25% in OBI group and 89% and 70% in the no OBI group, respectively (P < 0.001). The 1-, 3-, and 5-y overall survival rates were 86%, 55%, and 51% in OBI group and 93%, 85%, and 66% in no OBI group, respectively (P = 0.112). Multivariate analysis revealed that OBI (hazard ratio [HR] = 2.122; 95% confidence interval [CI], 1.086-4.149; P = 0.028), liver cirrhosis (HR = 2.411; 95% CI, 1.337-4.345; P = 0.003), and vascular invasion (HR = 5.858; 95% CI, 2.799-12.261; P < 0.001) were independent poor prognostic factors for recurrence free survival of patients with NBNC-HCC. CONCLUSIONS: NBNC-HCC patients with OBI had a poorer prognosis. OBI can be a useful predictor for recurrence in patients with NBNC-HCC after surgery.

Current status of liver transplantation for non-B non-C liver cirrhosis and hepatocellular carcinoma.

Recently, non-B non-C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5-5-500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non-B non-C cirrhosis and HCC, are highlighting the importance of peri-transplant management of patients with various comorbidities. The post-LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome-related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome-related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post-LT outcomes. Patient management in the peri-transplant period as well as risk assessment for LT are key to improving post-LT outcomes in the era of a growing number of cases of LT for non-B non-C liver diseases.

Clinicopathological Analysis of Non-B Non-C Hepatocellular Carcinoma Focusing on Cellular Proliferation.

BACKGROUND/AIM: Non-B non-C hepatocellular carcinomas (NBNC-HCCs) are larger than hepatitis virus-related HCCs. We conducted a clinicopathological study of patients who underwent curative NBNC-HCC resection, including proliferative activity assessments, such as nuclear grade and Ki-67 labelling index (LI). MATERIALS AND METHODS: Histopathological findings of 197 patients were examined, including 56 NBNC-HCCs, 45 hepatitis B virus (HBV)-related HCCs (HBV-HCC), and 96 hepatitis C virus (HCV)-related HCCs (HCV-HCC). RESULTS: NBNC-HCCs were significantly larger than HCV-HCCs, but not significantly different from HBV-HCCs. Mitotic counts, nuclear grade, and Ki-67 LI of NBNC-HCCs were not significantly different from those of HCV-HCCs, but were significantly lower than those of HBV-HCCs. Recurrence-free survival was significantly better in the NBNC-HCC group than in the HBV-HCC group in cases with mild liver fibrosis. CONCLUSION: NBNC-HCCs were significantly larger in diameter, but their nuclear grade or Ki-67 LI were not significantly different from those of other HCCs, suggesting that they do not have a higher proliferative activity.

Pre- and Postoperative Models for Prediction of Recurrence in Non-B, Non-C Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The incidence of non-B, non-C hepatocellular carcinoma (NBNC-HCC) is increasing. Like in hepatitis B virus (HBC)/HCV-associated HCC, treatment of NBNC-HCC after resection is challenging due to its high recurrence rate. However, few studies on the recurrence of NBNC-HCC have been published in the past decades. Hence, we aimed to investigate the risk factors for recurrence of NBNC-HCC and construct pre- and postoperative prognostic models for predicting recurrence in these patients who underwent curative resection. METHODS: We retrospectively analyzed 608 patients who underwent liver resection for NBNC-HCC. A multivariate Cox proportional hazard regression analysis was conducted to identify the independent risk factors of recurrence, based on which the prediction nomogram models were constructed and validated. The predictive performance of the models was assessed using the concordance index, time-dependent receiver operating characteristic curve, prediction error cure, and calibration curve. To facilitate clinical use, we stratified the patients into three distinct risk groups based on the score of the models. The cutoff scores of the models were determined by a survival tree analysis. RESULTS: Multivariable analysis identified neutrophil-to-lymphocyte ratio, alpha fetoprotein, tumor number, and tumor diameter as independent preoperative risk factors for recurrence. In addition to these variables, microvascular invasion was an independent postoperative risk factor for recurrence. The pre- and postoperative nomograms were constructed based on these variables. The C-index of the pre- and postoperative nomograms was 0.689 and 0.702 in the training cohort, 0.682 and 0.688 in the validation cohort, respectively, which were both higher than those of the conventional Barcelona Clinic Liver Cancer (BCLC) and 8th edition of the American Joint Committee on Cancer (AJCC8th) staging systems. In addition, the pre- and postoperative nomograms could also re-stratify patients with BCLC stage 0/A or AJCC8th stage IA/IB/II into distinct risk groups. CONCLUSIONS: We constructed pre- and postoperative prognostic models for predicting recurrence in patients with NBNC-HCC who underwent curative resection. They can play a supplementary role to the traditional staging system.

Development and Validation of a Prognostic Nomogram to Predict the Long-Time Prognosis in Non-B, Non-C Hepatocellular Carcinoma.

PURPOSE: To develop and validate a nomogram for individualized prediction of the long-term prognosis of patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC) who underwent hepatectomy. MATERIALS AND METHODS: Five hundred ninety-four patients who met the criteria were included in the research and randomly categorized into the training or validation cohort. The nomogram was constructed on the basis of the independent risk variables that were acquired via multivariate Cox proportional hazard regression analysis. Several complementary methods included the Harrell c-index, time-dependent areas under the receiver operating characteristic curve (tdAUC), and calibration plot, and the Kaplan-Meier curve with Log rank test were used to test predictive performance of the model. The clinical utility of the model was tested by the decision cure analysis (DCA). RESULTS: Tumor diameter, tumor number, elevated serum gamma-glutamyl transpeptidase (GGT) level, microvascular invasion (MVI), and macrovascular invasion were independent risk factors of prognosis of NBNC-HCC. C-indexes of the nomogram were 0.702 (95% confidence interval [CI], 0.662-0.741) in the training cohort and 0.700 (95% CI, 0.643-0.758) in the validation cohort, and median tdAUC values of the nomogram were 0.743 (range, 0.736-0.775) in the training cohort and 0.751 (range, 0.686-0.793) in the validation cohort, which were both higher than those in the conventionally used Barcelona Clinic Liver Cancer staging system, American Joint Committee on Cancer, and eighth edition and the model of Zhang et al. The calibration plot depicted a good consistency between prediction of the model and observed outcome. The Kaplan-Meier curve analysis showed that the model was able to separate patients into three distinct risk subgroups. The DCA analysis also demonstrated that the nomogram was clinically useful. CONCLUSION: We developed and validated a nomogram that was accurate and clinically useful in patients with NBNC-HCC who underwent hepatectomy.

Outcomes of Non-B Non-C Hepatocellular Carcinoma with Reference to Patients with Interferon-Induced Hepatitis C Virus Eradication.

PURPOSE: This study aimed to evaluate survival outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) with reference to patients with HCC achieving sustained virological response (SVR) by preoperative interferon (IFN) treatment for chronic hepatitis C. METHODS: We examined 781 patients who underwent hepatic resection for HCC. They were classified into NBNC-HCC, SVR-HCC, and non-SVR HCC groups. RESULTS: Multivariate analysis for recurrence-free survival (RFS) and overall survival (OS) revealed that the adjusted hazard ratios (HR) of NBNC-HCC and non-SVR HCC groups with reference to the SVR-HCC group were 1.46 (p = 0.10) and 2.10 (p < 0.001), respectively, for RFS, and 1.69 (p = 0.024) and 2.11 (p < 0.001), respectively, for OS. Worsening of Child-Pugh grade at recurrence was confirmed in 21 patients (17.1%) with NBNC-HCC but not in those with SVR-HCC (p = 0.017, SVR vs. NBNC). In the NBNC-HCC group, hepatic resection for intrahepatic recurrence was adopted in 17.4% of patients without worsening of Child-Pugh grade at recurrence, whereas hepatic resection was not adopted in those with grade worsening. Among patients with alcoholic hepatitis, Child-Pugh grade worsening at recurrence was more frequently observed in patients with sobriety than those without sobriety (14.3% vs. 46.2%, p = 0.049). CONCLUSIONS: NBNC-HCC patients had an increased risk for overall death as compared with those with SVR-HCC. Worsening of background liver function may reduce the chances of re-hepatic resection for recurrence and increase the risk for overall death in NBNC-HCC patients. For alcoholic hepatitis patients, sobriety may prevent deterioration of liver function after surgery.

Clinical Features and Outcome of Surgical Patients with Non-B Non-C Hepatocellular Carcinoma.

AIM: To investigate the clinical characteristics and prognosis of surgical patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) compared to those of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-HCC. PATIENTS AND METHODS: Clinical data and outcomes were compared among the three groups. Prognostic factors of patients with NBNC-HCC were investigated. RESULTS: Compared to HBV-HCC, patients with NBNC-HCC had higher chance of hypertension (HTN) (p<0.01), diabetes mellitus (DM) and body mass index (BMI) >25 kg/m2 Compared to HCV-HCC, patients with NBNC-HCC had higher incidence of DM and higher BMI >25 kg/m2 (p<0.01). There were no significant differences in overall survival (OS) rate among the three groups. In patients with NBNC-HCC, albumin (Alb; p<0.05) was an independent prognostic factor of OS, while Alb and α-fetoprotein (AFP) were independent prognostic factors of disease-free survival (DFS; p<0.01 each). CONCLUSION: Surgical patients with NBNC-HCC often have concomitant DM, HTN and high BMI, for whom factors related to prognosis were Alb and AFP.

Age-related clinicopathologic and molecular features of patients receiving curative hepatectomy for hepatocellular carcinoma.

BACKGROUND: Age-related differences of clinicopathologic features, outcomes, and molecular properties of hepatocellular carcinoma remain unclarified. METHODS: We classified patients who underwent hepatectomy for hepatocellular carcinoma into 3 groups by age bracket; younger group (<50 years), middle-aged group (50 to 79 years), and elderly group (≥80 years) and compared age-related features. RESULTS: Hepatitis viral infection was dominant in the younger group (hepatitis B virus [HBV]; 67%) and middle-aged group (hepatitis C virus [HCV]; 56%), whereas the elderly group showed a significantly higher rate without hepatitis virus infection (absence of HBV and HCV infection, 66%; P = .0001). There was a significantly greater proportion of age-associated pre-existing comorbidity in the elderly group (89%; P = .0004). Liver cirrhosis in the elderly group (24%) was significantly lower than other groups (younger, 67%; middle-aged, 50%; P = .0058). There was no significant difference in perioperative and postoperative outcomes among these groups. Microarray analysis revealed age-related upregulation of androgen and phosphatidylinositol 3-kinase pathways in the tumor tissue and downregulation of the fibrosis-related pathways in the noncancerous liver tissue. CONCLUSIONS: Based on increased correlation with the absence of HBV and HCV infection and pre-existing comorbidity, the age-related carcinogenic pathways might play a critical role in elderly hepatocarcinogenesis.

Relation between antibody to hepatitis B core antigen and survival after curative therapy for non-B non-C hepatocellular carcinoma.

BACKGROUND/AIM: We aimed to examine the relationship between antibodies to hepatitis B core antigen (anti-HBc) positivity and survival in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) who underwent curative treatment. PATIENTS AND METHODS: A total of 260 patients with NBNC-HCC who underwent curative therapy were analyzed. They included 124 anti-HBc-positive patients (47.7%) and 136 anti-HBc-negative patients (52.3%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared. RESULTS: The 3-year cumulative OS rates were 75.9% in the anti-HBc-positive group and 82.3% in the anti-HBc-negative group (p=0.069). The corresponding RFS rates were 29.8% in the anti-HBc-positive group and 43.0% in the anti-HBc-negative group (p=0.001). Multivariate analyses identified anti-HBc positivity (p=0.006), aspartate aminotransferase ≥ 40 IU/l (p=0.037) and des-γ-carboxy prothrombin ≥ 100 mAU/ml (p=0.046) as significant adverse predictors were linked to RFS. CONCLUSION: Anti-HBc positivity can be a useful predictor for recurrence in patients with NBNC-HCC after curative therapy.