Research ArticleClinical Studies

Prognostic Impact of Hepatectomy for Patients with Non-hepatitis B, Non-hepatitis C Hepatocellular Carcinoma

TOSHIYA OCHIAI, SHINPEI OGINO, TAKESHI ISHIMOTO, ATSUSHI TOMA, YUSUKE YAMAMOTO, RYO MORIMURA, HISASHI IKOMA and EIGO OTSUJI
Anticancer Research August 2014, 34 (8) 4399-4410;

Abstract

Back ground/Aim: The purpose of the present study was to clarify the clinicopathological features of non-hepatitis B and -C (NBNC) hepatocellular carcinoma (HCC), the incidence of which has been increasing. Patients and Methods: Two hundred and eighty-four patients with HCC were classified into three groups according to viral hepatitis status, namely NBNC, hepatitis B, and hepatitis C. We compared the three groups and studied related risk factors. Results: Patients without cirrhosis who had increased number of platelets and diabetes mellitus, and a serum alpha-feto-protein (AFP) level <100 ng/dl were more common in the NBNC group. The cumulative survival and disease-free survival were better in the NBNC group than in the other groups. The tumor size and hepatitis B or C viral status were found to be independent risk factors of disease-free survival and the presence of multiple lesions was the only independent risk factor of survival. Conclusion: Close follow-up of NBNC liver cirrhosis and early detection of NBNC-HCC can improve the prognosis after surgery.

Liver cirrhosis is significantly associated with hepatocarcinogenesis. In the pathology of hepatitis B virus (HBV), the integration of cancer genes into host genomic DNA is the first step in carcinogenesis from a normal liver to cirrhosis to hepatocellular carcinoma (HCC) (1, 2). In addition, in the setting of hepatitis C virus (HCV), persistent infection and continuous inflammation affects genomic changes and induces the progression of liver cirrhosis and HCC (3, 4). Therefore, most cases of HCV related to HCC are associated with cirrhosis. Previously, almost all patients with HCC in Japan were found to exhibit viral hepatitis and liver cirrhosis. As a result, conditions associated with liver cirrhosis have an impact on the prognosis of patients with HCC. However, the incidence of B and C hepatitis viruses as a cause of liver cirrhosis and HCC has been decreasing due to treatment with vaccines, nucleoside/nucleotide analogs and interferon.

The rate of negativity in patients with HCC for markers of HBV surface antigens (HBsAg) and HCV, i.e. non-hepatitis B and -C (NBNC)-HCC, is 5-15%, and the number of cases of NBNC-HCC has been gradually increasing (5-10). So-called NBNC liver disease includes alcoholic steatohepatitis, non-alcoholic steatohepatitis, collagen diseases inducing hepatitis and viral hepatitis of unknown origin, etc. The most common form of chronic liver disease in Japan and developed countries is non-alcoholic fatty liver disease (NAFLD), including the more aggressive non-alcoholic steatohepatitis (NASH) (11). However, clinically, it is difficult to precisely discriminate between these diseases as a certain cause of liver cirrhosis or HCC. In the future, new categories of NBNC liver disease may be identified; however, the clinical features of HCC originating from NBNC liver cirrhosis or hepatitis should be promptly clarified, as the number of such cases has remarkably increased and therefore effective surgical strategies for treating such cases are strongly needed. Furthermore, in patients with NBNC liver cirrhosis, differences between cases of hepatitis B core antibody (HBcAb)-positive and -negative hepatitis remain unclear.

In the present article, we analyzed the clinicopathological features and surgical strategies regarding NBNC liver cirrhosis and HCC.

Patients and Methods

Between February 1990 and May 2011, 292 patients with HCC underwent primary hepatic resection at the Department of Surgery, Division of Digestive Surgery, the Kyoto Prefectural University of Medicine. Among them, clinicopathological data including viral hepatitis status were available for 284 patients with HCC who underwent R0 resection for HCC. Patients were classified according to viral hepatitis status: 49 patients were HBsAg-positive and HCV-negative (B-HCC group), 174 patients were HCV-positive and HBsAg-negative (C-HCC group), and 61 patients had neither hepatitis B surface antigen nor hepatitis C antibody (NBNC-HCC group). We compared the groups in order to clarify the difference among NBNC-HCC, B-HCC and C-HCC. Moreover, we evaluated the differences between 17 cases of HBcAb-positive NBNC and 22 cases of HBcAb-negative NBNC. We also studied risk factors of viral hepatitis among the three groups of patients using univariate and multivariate analyses.

View this table:
Table I.

Clinicopathological characteristics of groups.

Curative resection (R0) is defined as complete removal of macroscopic tumor which is not exposed on the cut surface. Basically, resection of primary HCC at our institution was carried out by anatomic hepatectomy (12). For patients who also have liver cirrhosis or impaired liver function, however, limited (non anatomical) resection may be carried-out in some cases as a second-choice procedure. Indications for hepatic resection and the operative method were determined based on tumor progression and Makuuchi's criteria, i.e. presence or absence of ascites, serum total bilirubin levels, and indocyanin green retention rate at 15 minutes (ICG R15) (13). Patients with HCC with serum total bilirubin levels >1.0 mg/dl or ICG R15>29% underwent limited (non anatomical) resection.

All resected liver specimens were cut at a thickness of approximately 5 mm and microscopic sections were viewed after staining with hematoxylin and eosin. Pathological diagnosis and classification of resected HCC tissues were carried out according to The General Rules for the Clinical and Pathological Study of Primary Liver Cancer (14). Tumor was staged using the definition of TNM Stages by the Liver Cancer Study Group of Japan (LCSGJ), which is concordant with TNM classification by the International Hepato-Pancreato-Biliary Association and the International Union Against Cancer (Table I) (15).

Follow-up. Patients were followed up by hepatic ultrasonography, computed tomography, and assessment of serum alpha-fetoprotein (AFP) levels and serum protein induced by vitamin K absence II levels every 3-6 months. Disease-free survival (DFS) was defined as the interval between surgery and the date of diagnosis of the first recurrence or the last follow-up. Survival (OS) was also defined as the interval between surgery and the date of death caused by HCC recurrence or the last follow-up. Post-recurrent survival (PRS) was defined as the interval between the date of the first recurrence and the date of death caused by HCC recurrence or the last follow-up. We treated the date of death caused by liver dysfunction or rupture of varices the same as the date of the last follow-up. The median follow-up duration was 36 months (range=1-220 months); there were no statistically significant differences between the NBNC, B and C HCC groups (NBNC=39.30±42.43 months, B=49.74±40.93 months C=46.76±39.68 months).

View this table:
Table II.

Perioperative data of groups since 2000.

Statistics. Statistical analysis was carried-out with a Mann–Whitney U-test for unpaired observations and the Chi-square test for the frequency of various attributes among groups. OS and DFS were estimated by the Kaplan–Meier method and checked for statistical significance with the Wilcoxon and log-rank test. A Cox's hazard proportional analysis was performed to identify the risk factors of post operative DFS and OS. Differences with a p-value less than 0.05 were considered significant.

Results

Clinical features. Regarding the host-related factors, patients without cirrhosis who had many platelets and diabetes mellitus were more common in the NBNC group than in the other groups (p<0.01, p<0.01 and p<0.05, respectively). Compared to the C-HCC group, the NBNC-HCC group had lower ICG retention rates (p<0.01). Moreover, in both the NBNC-HCC and B-HCC groups, male patients who had higher serum albumin levels were more common than in the C-HCC group (p<0.05 and p<0.05, respectively). Regarding tumor-related factors, patients with a serum AFP level <100 ng/dl were more common in the NBNC-HCC group than in the other groups (p<0.01). The mean tumor size in the NBNC-HCC group was larger than that of the C-HCC group (p<0.01). Infiltrative large tumors with intra-hepatic metastasis were significantly more common in the B-HCC group than in the other groups (p<0.05 and p<0.01). Moreover, the B group had greater ductal invasion rates and more tumors located beyond one sub-segment (p<0.01 and p<0.01, respectively). Regarding treatment-related factors, more blood transfusions were performed in the NBNC-HCC group than in the C-HCC group (p<0.01). The patients in the C-HCC group underwent a small hepatectomy more often than did those in the other groups (p<0.05). However, the curability of the C-HCC group was better than that of the B-HCC group (p<0.05) (Table I).

There were no differences in perioperative data between the groups (Table II).

In the NBNC-HCC group, fewer patients developed recurrence compared to those observed in the B-HCC or C-HCC group during the follow-up period. As a result, the cumulative OS and DFS were better in the NBNC-HCC group than in the other groups (Figure 1). However, there were no significant differences in recurrence patterns among the groups (Table II).

Prognostic factors. For the 284 patients overall, the risk factors affecting DFS were tumor size, ductal infiltration, presence of multiple lesions, curability B (no residual cancer, but stage >II, or cancer invasion at the surgical margin), and HBV or HCV infection, as determined by the univariate analysis. Out of these, the tumor size and HBV or HCV were found to be independent risk factors by the multivariate analysis using risk factors determined by the univariate analysis (Table IV). The risk factors for OS were the same as the five factors for DFS as determined by the univariate analysis. Out of these, the presence of multiple lesions was the only independent risk factor identified by the multivariate analysis using risk factors determined by the univariate analysis (Table IV).

Regarding prognostic factors, among NBNC-HCC patients, greater tumor size, presence of ductal invasion and curability B status were found to be risk factors for poorer DFS according to a univariate analysis. However, no factors were identified as risk factors for OS (Table V). On the other hand, among B-HCC patients, a surgical curability B status, greater tumor size, ductal invasion, and multiple lesions were found to be risk factors for poorer DFS. In addition to these factors, resection of two or three segments was identified to be a risk factor for survival. However, no independent risk factors were identified in the NBNC and B-HCC patients (Table VI). Among C-HCC patients, a surgical curability B status, greater tumor size, ductal invasion, and multiple lesions were also found to be risk factors for disease-free survival. Out of these, greater tumor size was the only independent risk factor identified by the multivariate analysis using the risk factors determined by the univariate analysis. For survival, a surgical curability B status and multiple lesions were identified as risk factors, but multiple lesions were the only independent risk factor according to the multivariate analysis (Table VII).

Figure 1.
Figure 1.

Cumulative overall survival (a) and disease-free survival (b) in the NBNC-, B- and C-HCC groups.

Figure 2.
Figure 2.

Cumulative overall survival (a) and disease-free survival (b) of the HBcAb-positive and -negative patients among the NBNC group.

Comparison between HBAb-positive and -negative NBNC-HCC. There were no significant differences in any of the clinicopathological factors, perioperative data, OS status or DFS between the HBcAb-positive and -negative patients among the NBNC group in our study, although there was a small number of cases (Figure 2) (Table VIII).

Discussion

NBNC-HCC arises from various kinds of background liver disease. According to the report of the Japan Non-B, Non-C Liver Cirrhosis Study Group (16), NBNC liver cirrhosis is caused by 11 etiological agents, i.e., 14.5% of cases are caused by NASH, 55.1% of cases are caused by alcoholic liver disease (ALD), 2.5% of cases are caused by fatty liver disease, with the exception of NASH, ALD and other known etiologies, 8.0% of cases are caused by primary biliary cirrhosis, 0.8% of cases are caused by other types of biliary cirrhosis, 6.8% of cases are caused by autoimmune hepatitis, 0.6% of cases are caused by metabolic disease, 0.8% of cases are caused by congestive disease, 0.2% of cases are caused by parasitic disease, 0.2% of cases are caused by other known etiologies and 10.5% of cases are caused by an unknown etiology. Cirrhosis is detected in 65%, 81% and 15% of patients with NASH-HCC, ALD-HCC and liver disease of unknown etiology (17). As a cause of NBNC liver cirrhosis in Japan, NASH has been increasing.

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Table III.

Recurrence patterns for each group.

NASH can progress to cirrhosis and HCC due to diabetes and obesity. Moreover, aging, an elevated γ-GTP level, iron deposition and progression of fibrosis are risk factors for hepatocarcinogenesis in patients with NASH liver cirrhosis (18-22). Insulin resistance and the subsequent inflammatory cascade associated with the development of NASH cause hepatocarcinogenesis (11). According to the literature (23-27), 26-37% of patients with NASH demonstrate progression of fibrosis over a period of up to 5.6 years, with up to 9% of patients progressing to liver cirrhosis. Moreover, 4-27% of NASH patients progress to HCC after developing liver cirrhosis. Therefore, providing scheduled observation is necessary for patients with NASH in order to detect HCC or liver dysfunction. With regard to the incidence of HCC, most reports maintain that the rate of ALD liver cirrhosis is higher than that of NASH liver cirrhosis (28, 29). However, one report has documented opposite findings (30). Ascha et al. maintained that regular alcohol consumption is a significant risk factor for the development of HCC in patients with NBNC liver cirrhosis (31). Unfortunately, we do not have data about NASH, but diabetes mellitus was more common in the NBNC group than in the other groups in this study. There were no significant differences in the alcohol intake among the groups.

In comparison to that observed in B-, C- and NBNC-HCC groups, host-related factors such as an elderly age, a non-cirrhotic status, a male gender, an increased platelet count, hypertension and hyperlipidemia are significantly more frequent in patients with NBNC-HCC. Diabetes mellitus is more common in patients with NBNC, particularly NASH and NAFLD, than in those with other types of viral diseases. Moreover, the serum albumin levels in both patients with NBNC and HBV are increased compared to those observed in patients with HCV (32-34). Compared to patients with viral hepatitis, patients with NBNC-HCC have a better liver function (35). Li et al. (36) reported that NBNC-HCC is associated with a much lower ratio of males-to-females compared to our data, and that the cumulative incidence of HCC-specific death among females with NBNC-HCC is significantly greater than that observed among males with NBNC-HCC, when comparing NBNC and HBV patients.

Comparing ALD-HCC and non-ALD-HCC groups, the latter have a higher prevalence of diabetes, a larger tumor size and higher tumor marker levels (37). In addition, elderly individuals with a greater body-mass index and higher platelet count are more common among patients with non-ALD-HCC. Meanwhile, cirrhotic liver and a high AFP level are common among patients with ALD-HCC (35,38). The liver function tends to be worse among patients with ALD-HCC than among patients with non-ALD HCC. With regard to prognosis, patients with ALD-HCC have a higher tendency toward recurrence than patients with non-ALD-HCC, although the survival rates are similar for the groups (37).

According to reports of HBcAb in patients with NBNC-HCC, an HBcAb-positive status is an independent adverse predictor linked to recurrence-free survival after curative therapy (39). Moreover, Yano et al. reported that an HBcAb-positive status in patients with NBNC-HCC is significantly associated with an elderly age, a lower serum AFP level and a family history of liver disease compared to that observed in patients with B-HCC (40). However, they suggested the clinical features of positivity for anti-HBc alone are similar to those of HBsAg-positive. Some differences may be explained by differences in the time of first exposure to HBV. In our study, there were no significant differences in the clinical characteristics, including the prognosis, between HBcAb-positive and -negative cases. However, all our patients underwent curative hepatectomy. This may be the reason for the different results, or the differences may have been due to the limitation of the small sample size examined.

View this table:
Table IV.

The pre-and intra-operative predicted risk factors for disease-free and overall survival in patients with hepatocellular carcinoma.

Regarding tumor-related factors, a lower serum AFP level is more common in patients with NBNC-HCC than in patients with others types of viral hepatitis, and the tumor size is larger in patients with NBNC-HCC than in those of other viral groups (32,36). Moreover, patients with NBNC-HCC exhibit greater ductal invasion than patients with C-HCC (32). This is thought to be due to the fact that fewer patients with NBNC-HCC receive regular follow-up for liver diseases, since such patients are negative for both HBV and HCV. Most patients lack awareness that they are suffering from a liver disease.

View this table:
Table V.

The pre-and intra-operative predicted risk factors for disease-free and overall survival in patients with non-B, non-C hepatocellular carcinoma.

In 20 meta-analyses of NBNC-HCC, patients with HBV or HCV infection more frequently developed recurrence during follow-up (41). However, the recurrence rate of NBNC-HCC is not low because an advanced stage of disease is often present at the initial detection. Wakai et al. reported that the cumulative probability of intra-hepatic recurrence reached a plateau at 2.4 years after resection in the NBNC-HCC group, whereas it continued to increase gradually in the B- and C-HCC groups (42). The cumulative survival of the NBNC_HCC group was better than that of the B- and C-HCC groups. Patients with NBNC-HCC have more opportunities for repeat-resection or other treatments of intra-hepatic recurrence, which may lead to a favorable outcome (35). Meanwhile, Nishikawa et al. reported that there were no differences in OS or recurrence-free survival among patients who met the Milan criteria (32).

Among patients with NBNC-HCC, identified independent risk factors for DFS include the presence of a tumor capsule and vascular invasion (36). Tomimaru et al. reported that only the degree of fibrosis is a significant prognostic factor for NBNC and HBcAb-negative HCC (43). In that study, intra-hepatic recurrence diagnosed according to the new Inuyama Classification (44) was frequently observed in both lobes in the fibrotic liver group within two years after the initial hepatectomy, while recurrence more than two years after the initial hepatectomy was primarily seen in the contralateral lobe.

View this table:
Table VI.

The pre-and intra-operative predicted risk factors for disease-free and overall survival in patients with hepatitis B viral hepatocellular carcinoma.

There are no differences in treatment-related factors, regardless of the viral status in the literature. The ultimate surgical treatment for liver cirrhosis and HCC is liver transplantation. However, the number of such transplantations for NBNC liver cirrhosis is small because the liver function of patients with NBNC liver cirrhosis is relatively good compared to that of patients with viral liver cirrhosis. In order to perform curative transplantation for NBNC-HCC, Kawaguchi et al. identified six factors independently associated with the Milan criteria in patients with NBNC-HCC, i.e. the year of HCC diagnosis, liver cirrhosis and the serum aspartate aminotransferase, alanine aminotransferase, AFP and des-gamma-carboxyl prothrombin levels (45).

View this table:
Table VII.

The pre-and intra-operative predicted risk factors for disease-free and overall survival in patients with hepatitis C viral hepatocellular carcinoma.

Patients who undergo liver transplantation for NASH liver cirrhosis frequently go on to develop NAFLD and NASH (46). Wang et al. reported that patients with NASH are more likely to die from cardiovascular complications or sepsis based on the results of a meta-analysis (47). Additionally, ALD is generally not an indication for liver transplantation, even living donor ones from relatives. Moreover, one report found that the incidence of de novo tumors of the upper aerodigestive tract after liver transplantation is higher among patients who received a transplant for alcoholic cirrhosis (48).

Previously, most cases of non-A non-B liver cirrhosis originated from HCV. Following the detection of HCV, the clinicopathological features of HCV liver cirrhosis were analyzed and effective strategies for treating both HCV and C-HCC were established. As a result, the number of patients with HCV liver cirrhosis and HCC has been decreasing.

View this table:
Table VIII.

Clinicopathological characteristics of groups.

In conclusion, the number of patients with NBNC liver cirrhosis and HCC has increased remarkably in Japan. Most patients with HCC are diagnosed at an advanced stage. However, such patients have a good liver function and can undergo large anatomical hepatectomy and repeated hepatectomy for intra-hepatic recurrence. Moreover, the prognosis of these patients is better than that of patients with viral HCC. Regarding the surgical strategy for NBNC-HCC, close follow-up of NBNC liver cirrhosis and early detection of NBNC-HCC are important. In the near future, novel concepts of NBNC liver cirrhosis and HCC will be proposed, and effective treatments and preventive therapies must be developed.

Footnotes

  • Conflicts of Interest

    None.

  • Received March 10, 2014.
  • Revision received May 19, 2014.
  • Accepted May 20, 2014.

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Prognostic Impact of Hepatectomy for Patients with Non-hepatitis B, Non-hepatitis C Hepatocellular Carcinoma
TOSHIYA OCHIAI, SHINPEI OGINO, TAKESHI ISHIMOTO, ATSUSHI TOMA, YUSUKE YAMAMOTO, RYO MORIMURA, HISASHI IKOMA, EIGO OTSUJI
Anticancer Research Aug 2014, 34 (8) 4399-4410;
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