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Japanese Journal of Clinical Oncology Pages 67-70

Comparison of Clinical Features and Survival in Patients with Hepatitis B and C Virus-Related Hepatocellular Carcinoma
Introduction
Subjects And Methods
Results
References
Comparison of Clinical Features and Survival in Patients with Hepatitis B and C Virus-Related Hepatocellular Carcinoma

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

Hiroshi Tanizaki1, Munemasa Ryu1, Taira Kinoshita1, Noriaki Kawano1, Masaru Konishi1, Akihiro Cho1, Tetsuya Nakatsura11, Toshiyuki Natsume1, Shinichiro Takahashi1, Mitsutaka Sugita1, Kunihiko Izuishi1, Masahiro Yoshino2, Junji Furuse2, Masahiko Iwasaki2 and Yoshitaka Tsubono3

Departments of 1Surgery and 2Internal Medicine, National Cancer Center Hospital East and 3Epidemiology and Biostatistics Division, National Cancer Center Research Institute East, Kashiwa, Chiba, Japan

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 v50 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.

Key words: hepatocellular carcinoma - hepatitis B virus - hepatitis C virus

INTRODUCTION

Measurements of antigen and antibody levels have shown that hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in the development of hepatocellular carcinoma (HCC) (1-4). According to the Liver Cancer Study Group of Japan in 1988 (5), hepatitis B surface antigen (HBsAg) was positive in 24.6% of patients with HCC. However, by 1993 the percentage of patients positive for HBsAg had decreased to 18.2%, while that of patients positive for HCV antibody had increased to 71.7%. It has been reported that many cases of HCC are related to viral infection (6).

In the present multi-center study, we attempted to clarify the clinical features of HBV-related (HBV group) and HCV-related (HCV group) HCC, and analyzed prognostic factors in cases of infection by each hepatitis virus.

SUBJECTS AND METHODS

We compared the clinical features of patients treated between 1991 and 1993 through a multicenter study with 17 participating institutions. One hundred eighty-five patients with HBs-antigen-positive, HCV-antibody-negative HCC (HBV group) and 1033 patients with HBs-antigen-negative, HCV-antibody-positive HCC (HCV group) were evaluated. Patients positive for both HBs antigen and HCV antibody were excluded. The treatments received by the HBV and HCV groups were surgical resection in 57% and 53% of cases, transarterial embolization (TAE) in 27% and 21%, percutaneous ethanol injection (PEI) in 11% and 22%, and other treatments in 5% and 4% respectively. There were no significant differences in treatment between the two groups. The clinical features of the patients were also examined. These included age, sex, liver function as reflected by indocyanine green retention at 15 minutes (ICG-R15), clinical stage according to the General Rules for the Clinical and Pathological Study of Primary Liver Cancer in Japan, AFP (alpha-fetoprotein) level , T3-4/1-2 ratio, tumor number, tumor size, presence of tumor thrombus in the portal vein (Vp) and hepatic vein (Vv), and the degree of tumor cell differentiation. Patient survival was determined in August 1995.

The c2 test was used to analyze differences between the groups and the Kaplan-Meier method was used to produce survival curves. The log rank method was used to analyze differences in probability of survival. Cox's proportional hazards model was employed to analyze factors affecting differences in survival probability. The risk ratio (RR) of HCC was calculated by both univariate and multivariate analysis.

Table 1. Comparison of clinical features between the HBV and HCV groups.
Clinical feature HBV group HCV group [chi]2 test
No. of patients 185 1033  
1. Mean age (yr) 52.1 ± 10.5 62.9 ± 7.15 P < 0.01
2. Sex (male/female) 152/33 786/247 NS
3. Mean ICG-R15 (%) 17.5 ± 11.8 25.4 ± 14.7 P < 0.01
4. Clinical stage
I/II+III		 93/75

 437/539

 P < 0.05
5. Mean AFP level (ng/ml) 13 791 ± 60 246 3896 ± 40 292 P < 0.01
6. T-factor
T1-2/T3-4		 76/86

 499/343

 P < 0.05
7. No. of tumors 1.47 ± 0.81 1.58 ± 0.90 NS
8. Tumor size (mm) 56.6 ± 43.1 35.0 ± 26.8 P < 0.01
9. Vp0-1/Vp2-3 130/33 724/55 P < 0.01
10. Vv0-1/Vv2-3 155/7 753/17 P < 0.05
11.Tumor cell differentiation
well + moderately/poor		 74/27 470/61 P < 0.05
Treatment
resection/TAE/PEI (%)		 57/27/16

 53/21/22

 NS
HBV group, patients with hepatitis B virus-related hepatocellular carcinoma; HCV group, patients with hepatitis C virus-related hepatocellular carcinoma; ICG-R15, indocyanine green retention at 15 min; TAE, transarterial embolization, PEI, percutaneous ethanol injection; Vp, tumor thrombus in the portal vein, Vv, tumor thrombus in the hepatic vein.

HBV group, patients with hepatitis B virus-related hepatocellular carcinoma; HCV group, patients with hepatitis C virus-related hepatocellular carcinoma; ICG-R15, indocyanine green retention at 15 min; TAE, transarterial embolization, PEI, percutaneous ethanol injection; Vp, tumor thrombus in the portal vein, Vv, tumor thrombus in the hepatic vein.

RESULTS

Clinical features (Table 1 )

1. Age. The mean age of patients in the HBV group (52.1 yr) was approximately 10 years younger than that of patients in the HCV group (62.9 yr, P < 0.01).

2. Sex. There was no significant difference in sex ratio between the HBV group (152 [82.1%] men and 33 [17.9%] women) and the HCV group (786 [76.1%] men and 247 [23.9%] women).

3. Indocyanine green retention at 15 min. The mean ICG-R15 was significantly higher in the HCV group (25.4 + 14.7%) than in the HBV group (17.5 + 11.8%; P < 0.01).

4. Clinical stage. A significantly higher proportion of the HBV group (55%) had clinical stage I compared with the HCV group (45%; P < 0.05).

5. Alpha-fetoprotein (AFP). There was a significant difference in the mean serum level of AFP between the HBV group (13 791 + 60 246 ng/ml) and the HCV group (3896 + 40 292 ng/ml; P < 0.01).

6. T-factor. There was significant difference in the T3-4 ratio between the HBV group (53%) and the HCV group (41%; P < 0.05).

7. Number of tumors. There was no significant difference in the mean number of tumors between the HBV group (1.47) and the HCV group (1.58).

8. Tumor size. There was a significant difference in tumor size between the HBV group (56.6 + 43.1 mm) and the HCV group (35.0 + 26.8 mm; P < 0.01).

9. Tumor thrombus in the portal vein (Vp). The Vp2-3 ratio in the HBV group (20.3%) was significantly higher than that in the HCV group (7.1%; P < 0.01).

10. Tumor thrombus in the hepatic vein (Vv). The Vv2-3 ratio in the HBV group (4.3%) was significantly higher than that in the HCV group (2.2%; P < 0.05).

11. Degree of tumor cell differentiation. A significantly higher proportion of the HBV group (7%) had poorly differentiated tumors, compared with the HCV group (5%; P < 0.05).

Survival

1. Survival of the HBV and HCV groups (Fig. 1). The 3-year survival rate of the HBV group (56%) was significantly poorer than that of the HCV group (63%; P < 0.05).

Figure 1.


2. Survival according to T-factor (Fig. 2). The 3-year survival rates of the HBV group patients with T1-2 and T3-4 were 78% and 31% respectively, compared with corresponding rates of 77% and 41% for the HCV group. The 3-year survival of the HBV group patients with T3-4 was thus worse than that of the corresponding HCV group patients, but not significantly.

Figure 2.


3. Survival of patients after surgical resection (Fig. 3). The ratio of patients treated surgically did not differ significantly between groups, although the 3-year survival rate after surgical resection was significantly worse in the HBV group (62%) than in the HCV group (71%; P < 0.05).

Figure 3.


4. Univariate and multivariate analysis (Table 2 ). We performed univariate analysis of factors associated with prognosis. The significant prognostic factors for HCC were HBV, age, clinical stage, AFP level, number of tumors, tumor size, and presence of tumor thrombus in portal vein and hepatic vein. We then performed multivariate analysis of clinical characteristics that were identified as significant prognostic factors by univariate analysis. Especially significant prognostic factors were the serum AFP level, number of tumors, portal vein tumor thrombus and hepatic vein tumor thrombus. The risk ratio of HCC for HBV compared with HCV was 0.91; HBV was therefore shown by multivariate analysis not to be a significant prognostic factor.

Table 2. Univariate and multivariate analysis of prognostic factors
Variable Univariate analysis Multivariate analysis
  RR (95% CI) P RR (95% CI) P
HCV/HBV 0.63 (0.49-0.83) 0.0008 0.91 (0.58-1.42) 0.68
Sex (female/male) 0.81 (0.62-1.06) 0.12 1.01 (0.70-1.47) 0.94
Age (<50 yr/[ge]50 yr) 0.68 (0.49-0.93) 0.016 0.66 (0.39-1.14) 0.13
Clinical stage
(II + III/I)		 1.74

 (1.38-2.19)

 0.0001

 1.50

 (1.10-2.06)

 0.01
AFP (<500/.500[ge]) 3.11 (2.47-3.90) 0.0001 1.88 (1.33-2.66) 0.0004
No. of tumors
(3[le]/>3)		 1.83

 (1.35-2.49)

 0.0001

 2.00

 (1.37-2.91)

 0.0003
Tumor size
([le]30mm/>30mm)		 2.77

 (2.22-3.45)

 0.0001

 1.38

 (0.99-1.91)

 0.06
Vp2-3/0-1 6.17 (4.68-8.13) 0.0001 3.00 (1.81-4.97) 0.0001
Vv2-3/0-1 7.08 (4.41-11.35) 0.0001 3.11 (1.52-6.37) 0.002
RR, risk ratio; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; Vp, tumor thrombus in the portal vein; Vv, tumor thrombus in the hepatic vein.

Discussion

It is generally accepted that hepatocellular carcinoma develops against a background of chronic liver disease (7)). However, after Choo (8)) isolated the HCV genome in 1989, some authors suggested that persistent HBV or HCV infection might cause both chronic liver disease and hepatocellular carcinoma. Because HBV is a DNA virus and HCV is an RNA virus, the clinical features of chronic liver disease caused by each virus and the natural courses of the virus-related HCCs are assumed to differ (9)).

Kamiya (10) reported that HBV- and HCV-related HCCs differed significantly in terms of patient age, degree of liver dysfunction, maximal tumor size and AFP level. As a result, patients with HBV-related HCC had progressive disease but good liver function. Lee (11) reported that HBV-related HCC developed in relatively younger patients than was the case for HCV-related HCC. In the present study, patients with HBV-related HCC were about 10 years younger than those with HCV-related HCC. Zaman (12) reported that the risk factors for HCC were age and sex. A study by the Liver Cancer Study Group of Japan found that in cases treated by surgical resection, the risk factors were serum AFP level, tumor size, number of tumors, degree of liver function, age, operable curability and presence of tumor thrombus in the portal vein. Univariate analysis in the present study showed that significant risk factors were HBV infection, younger age, clinical stage II-III, a serum AFP level of .500 ng/ml, number of tumors, tumor size and presence of tumor thrombus in the portal vein (Vp2-3) and hepatic vein (Vv2-3).

Multivariate analysis of these significant prognostic factors showed that the serum AFP level, number of tumors and presence of tumor thrombi in the portal vein and hepatic vein were factors associated with HCC progression. HBV itself was not shown to be a stronger prognostic factor than HCV. Survival of HCC patients was determined by progressive factors, and not only by the type of hepatitis virus present. In other words, it is thought that the clinical characteristics of each virus-related HCC are responsible for differences in survival.

These results suggest that if further improvements in diagnostic imaging were made and thorough mass screening performed, patients with HBV-related HCC could be identified while the tumors were still small. For this reason, it is expected that the prognosis of patients with HBV-related HCC is similar to that of patients with HCV-related HCC.

References

1. Beasley R P, Hwang L Y, Lin C C, Chien C S. Hepatocellular carcinoma and hepatitis Bvirus: a prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129-33.MEDLINE Abstract

2. Beasley R P. Hepatitis B virus as the etiologic agentin hepatocellular carcinoma. Epidemiologic consideration. Hepatology 1982;2:21-6.

3. Brechot C, Nalpas B, Courouce A M, Duhamel G, Callard P, Carnot F et al. Evidence that hepatitis B virus has a role in liver- cell carcinoma in alcoholic liver disease. N Engl J Med 1982;306:1384-7.MEDLINE Abstract

4. Kiyosawa K, Sodemaya T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671-5.MEDLINE Abstract

5. The Liver Cancer Study Group of Japan: Primary liver cancer in Japan - report 8. Acta Hepatologica Japonica 1988;29:1619-26.

6. The Liver Cancer Study Group of Japan: Primary liver cancer in Japan - report 10. Acta Hepatologica Japonica 1993;34:805-13.

7. Chen C J, Liang K Y, Chang A S, Chang Y C, Lu S n, Liaw Y F et al. Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology 1991;13:398-406.

8. Choo Q-L, Kuo G, Weiner A J, Overby L R,Bradley D W, Houghton M. Isolation of a cDNA clone derived from a blood-borne non- A, non-B viral hepatitis genome. Science 1989;244:359-62.

9. Hopf U, Moller B, Kuther D, Stemerowicz R, Lobeck H, Ludtke-Handjery A et al. Long-term follow-up of posttransfusion and sporadic chronic hepatitis non-A, non-B and frequency of circulating antibodies to hepatitis C virus (HCV). J Hepatol 1990;10:69-76.MEDLINE Abstract

10. Kamiya S. Clinical features and prognoses of small hepatocellular carcinomas based on viral markers and etiologic factors. Chiba Med J 1995;71:133-40.

11. Lee HS, Han CJ, Kim C. Predominant etiologic association of hepatitis C virus with hepatocellular carcinoma compared with hepatitis B virus in elderly patients in a hepatitis B-endemic area. Cancer 1993;72:2564-7.MEDLINE Abstract

12. Zaman S N, Melia W M, Johnson R D, Portmann B C, Johnson P J, Williams R. Risk factors in development of hepatocellular carcinoma in cirrhosis: Prospective study of 613 patients. Lancet 1985;1:1357-60.

Received May 20, 1996; accepted November 20, 1996
For reprints and all correspondence: Hiroshi Tanizaki, Department of Surgery, National Cancer Center Hospital East, 5-1 Kashiwanoha 6-chome, Kashiwa, Chiba 277, Japan
Abbreviations: HBV group, patients with hepatitis B virus-related hepatocellular carcinoma; HCV group, patients with hepatitis C virus-related hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HBsAg, hepatitis B surface antigen; TAE, transarterial embolization; PEI, percutaneous ethanol injection; ICG-R15, indocyanine green retention at 15 min; Vp, (tumor thrombus in the) portal vein; Vv, (tumor thrombus in the) hepatic vein; RR, risk ratio

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