Surgical results in patients with dual hepatitis B– and C–related hepatocellular carcinoma compared with hepatitis B– or C–related hepatocellular carcinoma

Surgical results in patients with dual hepatitis B– and C–related hepatocellular carcinoma compared with hepatitis B– or C–related hepatocellular carcinoma Miin-Fu Chen, MD, FACS, Long-Bin Jeng, MD, Wei-Chen Lee, MD, and Tse-Ching Chen, MD, Taipei, Taiwan

Background. The purpose of our study was to report on the surgical outcomes of patients with hepatocellular carcinoma (HCC) with dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and to assess the differences in the surgical results between those patients and the patients with hepatitis B– or hepatitis C–related HCC. Methods. The operative outcomes of 13 patients with hepatitis B surface antigen (HBsAg)–positive and hepatitis C antibody (HCV Ab)–positive (the BC-HCC group) results, 57 patients with HBsAg-positive and HCV Ab–negative (the B-HCC group) results, and 34 patients with HBsAg-negative and HCV Ab–positive (the C-HCC group) results, who had undergone hepatic resection from 1991 to 1995, were compared. Results. The operative mortality rate within 1 month after operation for patients with BC-HCC was 7.7%. No statistically significant difference was found compared with the patients with B-HCC and CHCC (5.3% and 5.9%, respectively). The postoperative course of patients with BC-HCC was complicated by liver failure, postoperative ascites, and wound infection in one patient each. Also, no statistically significant difference was found among the groups (23.1%, 22.8%, and 20.5% for patients with BCHCC, B-HCC, and C-HCC, respectively). The overall 1-, 3-, and 5-year survival rates of patients with BC-HCC in this series were 75%, 50%, and 40%, respectively. The postoperative recurrence rate was 66.7%. No statistically significant differences were found between the various groups of the virus-related HCC on the overall survival rate and disease-free survival rate. Conclusions. Hepatic resection for HCC in patients with dual HBV and HCV infections was associated with slightly higher operative morbidity and mortality rates, but there were no statistical differences compared with hepatitis B– or C–related HCC regarding the survival and recurrence rates. (Surgery 1998;123:554-9.) From the Departments of Surgery and Pathology, Chang Gung University, Chang Gung Memorial Hospital, Taipei, Taiwan

HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE most common malignant tumors throughout the world. Chronic viral hepatitis and cirrhosis have long been suggested to play an important role in the development of HCC.1-5 In Taiwan the hepatitis B virus (HBV) infection rate is high, and most patients with HCC have positive results to hepatitis B surface antigen, but the prevalence of positive results to hepatitis C virus (HCV) is low.6,7 The advent of HCV assays has enabled investigators to Accepted for publication Oct. 22, 1997. Reprint requests: Miin-Fu Chen, MD, FACS, Department of Surgery, Chang Gung Memorial Hospital, 199, Tung Hwa N. Rd., Taipei, Taiwan. Copyright © 1998 by Mosby, Inc. 0039-6060/98/$5.00 + 0 11/56/87237

554 SURGERY

examine the issues of HCV coinfection or superinfection more precisely.8-10 Furthermore, case-control studies have indicated that dual infection with HCV and HBV represents a much higher relative risk for the occurrence of HCC.11-13 Information on the comparative study of surgical outcomes of HCC between patients with HBV infection and those with HCV infection was available.14 However, the report on the surgical results in patients with HCC with dual HBV and HCV infection has not yet been carried out. The aim of this study was to report the surgical outcomes of patients with HCC with dual HBV and HCV infection. The surgical results were compared with those of patients with HCC with HBV or HCV infection regarding their clinical features,

Chen et al. 555

Surgery Volume 123, Number 5 Table I. Clinical features of patients with hepatitis virus–related HCC BC-HCC Total no. of patients Age (yr)* Gender (no. male/female) History of blood transfusion Child’ s class (%) A B C Liver cirrhosis (%) Total bilirubin (mg/dl)* Serum AST (IU/L)* Serum ALT (IU/L)* Prothrombin time* (INR) Platelets (×104) α-Fetoprotein (%) <10 µg/L >400 µg/L

B-HCC

C-HCC

p Value

13 49.8 ± 14.9 11:2 0

57 51.6 ± 12.3 40:17 0

34 61.9 ± 10.0 22:12 5 (14.7%)

90.9 9.1 0 76.9 0.84 ± 0.45 72.4 ± 53.7 65.5 ± 71.0 1.03 ± 0.06 24.3 ± 21.0

78.9 19.3 1.8 54.4 0.97 ± 1.75 67.5 ± 57.0 53.9 ± 61.0 1.07 ± 0.11 17.8 ± 9.8

79.4 20.6 0 64.7 0.96 ± 0.43 86.2 ± 62.7 76.6 ± 58.1 1.08 ± 0.13 13.2 ± 8.3

NS NS NS NS NS NS NS NS NS

7.7 76.9

19.3 45.6

28.1 38.2

NS NS

<0.05 NS <0.05

NS, Statistically not significant; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalization ratio. *Expressed as mean ± SD.

Table II. Types of hepatectomy of patients with hepatitis virus–related HCC BC-HCC (n) Total patients Right lobectomy Left lobectomy

B-HCC (n)

C-HCC (n)

13

57

34

5 3

15 8

15 4

(69.2%)

(50.9%)

1 0

2 4

0 3

Partial hepatectomy Segmentectomy

2 2

11 15

2 9

Wedge excision

0

(49.1%) 2

NS (64.7%)

Right trisegmentectomy Left lateral segmentectomy

(30.8%)

p Value

NS (35.3%)

1

NS, Statistically not significant.

morbidity, survival, and tumor recurrence after operation. MATERIAL AND METHODS From 1991 to 1995, among the 227 patients who had undergone hepatic resection for HCC in the Chang Gung Memorial Hospital, Taipei, Taiwan, after the establishment of an assay method for HCV antibodies, 104 patients were entered into this study. Eighty-four patients were excluded in whom both an HCV and HBV infection were not found, 20 patients in whom the tumor was incompletely resected, and 16 patients in whom the incomplete clinical records were found. Of the 104 patients with hepatitis virus–related HCC, 13 had dual HBV and HCV infection (the BC-HCC group), 57 had positive results to hepatitis B surface antigen anti-

bodies (the B-HCC group), and 34 had positive results to anti-HCV antibodies (the C-HCC group). The clinical features for the background factor analysis are listed in Table I. The mean age of the patients in the BC-HCC group was lower than that of the patients in the B-HCC or C-HCC groups, with a statistically significant difference (p < 0.05, chi-squared test). There were no statistically significant differences among the three groups regarding gender and the association rate of cirrhosis. The preoperative serum α-fetoprotein levels in the patients with BC-HCC were higher than those of the patients in the B-HCC or C-HCC groups; there were no statistically significant differences. No patient in the BC-HCC group had a history of blood transfusions. The status of liver function was almost identical among the three groups. The operative procedures for the three groups of

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Table III. Histopathologic features of patients with hepatitis virus–related HCC Total no. of patients Size of tumor (cm)* <2 cm (%) >5 cm (%) No. of tumors Single (%) Multiple (%) Capsule of tumor(+) (%) Vascular invasion(+) (%) Edmondson class (%) I II III IV

BC-HCC

B-HCC

C-HCC

p Value

13 6.00 ± 4.30 7.6 46.2

57 7.34 ± 5.12 5.3 49.1

34 5.04 ± 2.86 2.9 38.3

92.3 7.7 61.5 30.8

91.2 8.8 36.8 49.1

91.2 8.8 64.7 35.3

NS

46.2 38.5 38.5 15.4

36.8 45.6 37.6 7.0

23.5 32.3 41.2 9.1

NS NS NS NS

NS NS

NS NS

NS, Statistically not significant. *Expressed as mean ± SD.

Table IV. Postoperative complications of patients with hepatitis virus–related HCC Total no. of patients No. of patients with complications Postoperative complications (%) Intraabdominal abscess Atelectasis Liver failure Ascites Bile leak Wound infection

BC-HCC

B-HCC

C-HCC

p Value

13 3 (23.1%)

57 13(22.8%)

34 7 (20.5%)

NS

0 0 7.7 7.7 0 7.7

4.0 1.8 3.5 5.3 1.8 3.5

2.9 2.9 5.9 2.9 0 5.9

NS NS NS NS NS NS

NS, Statistically not significant.

patients are listed in Table II; no statistically significant differences were found among the groups. Table III shows the histopathologic features in patients with hepatitis virus–related HCC. Postoperative complications were monitored carefully. Operative death means that the patient died within 30 days after the operation. A statistical analysis was carried out among the three groups with both the Mann-Whitney U test and the chisquared test. Survival was analyzed by the KaplanMeier method, and survival curves were compared by the generalized Wilcoxon test. A value of p < 0.05 was considered statistically significant. RESULTS Mortality and morbidity rates. The major postoperative complications were liver failure, postoperative ascites, and wound infection in one patient each. The morbidity rate for patients with BC-HCC was 23.1%. Postoperative complications and morbidity rates of the patients with B-HCC and C-HCC are listed in Table IV. Although the morbidity rate

of patients with BC-HCC was slightly higher compared with the patients with B-HCC and C-HCC, the difference was not statistically significant. Also, no statistically significant differences were observed regarding the occurrence of each specific complication among the groups (Table IV). One patient in the BC-HCC group died of liver failure 22 days after right lobectomy. He was found to have HCC in association with liver cirrhosis. The surgical mortality rate of the patients with BC-HCC was 7.7%. Three of the patients with B-HCC and two of the patients with C-HCC also died within 1 month of operation, resulting in a surgical mortality rate of 5.3% and 5.9% for patients with B-HCC and CHCC, respectively. Although a higher overall mortality rate was observed for the patients with BCHCC, the difference was not statistically significant. Follow-up results and survival. Of the 98 patients with hepatitis virus–related HCC who were discharged from the hospital, eight were lost to follow-up. Ninety patients (86.5%) were available for late assessment. The number of patients observed

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Table V. Follow-up results of patients with hepatitis virus–related HCC undergoing hepatic resection BC-HCC No. of patients followed up 12 No. of patients with intrahepatic recurrence 8 (66.7%) No. of different treatment modalities after recurrence Re-resection 0 TACE 4 Chemotherapy 3

B-HCC 49 33 (67.3%) 3 16 6

C-HCC

Total no. of patients

29 19 (65.5%)

90 60

2 8 3

5 28 12

TACE, Transarterial chemoembolization.

who had BC-HCC, B-HCC, and C-HCC was 12, 49, and 29, respectively. The follow-up period for the surviving patients ranged from 6 to 72 months (median 12.2 months). Recurrence of intrahepatic disease was found in 60 of 62 patients with postoperative recurrence. The other two patients, one with BC-HCC and other with B-HCC, were found to have died of pulmonary metastasis. The postoperative recurrence rates were similar among the groups. Of the eight patients in the BC-HCC group with postoperative recurrence, four patients underwent transhepatic arterial embolization and three underwent systemic chemotherapy (Table V). Overall, the 1-, 3-, and 5-year cumulative survival rates of the 13 patients with BC-HCC in this series were 75%, 50%, and 40%, respectively. The diseasefree survival rates after operation were 52%, 40%, and 28%, respectively. No statistically significant differences were found among the groups on the overall survival rate and disease-free survival rate (Figs. 1 and 2). DISCUSSION In Taiwan, liver cirrhosis and HCC are relatively prevalent, and 80% to 85% of the patients with these conditions have positive results for hepatitis B surface antigen.1-5 The rate of positive results for HCV antibodies in patients with HCC was found to be 12.6% and 33.3% by two independent studies from Taiwan.6,7 In this study the positive rate of anti-HCV antibody was 45.2% (47/104) in patients with HCC who had undergone hepatic resection. The reported studies on seroprevalence of HCV indicate that HCV is found in more than 10% to 15% of patients infected with HBV worldwide.10,15 Dual hepatitis viral infections are associated with viral interference.10 HCV superinfection can cause a much more severe liver disease in patients with chronic HBV infection in terms of histologic findings and clinical decompensation.16-19 Dual hepatitis B surface antigen and anti-HCV positivity in patients with cirrhosis is an independent and sig-

nificant determinant for the development of HCC, as reported by Benvegnu et al.20 In this series there was a higher incidence of total postoperative complications and death within 1 month of operation in the patients with BC-HCC; however, the differences were not statistically significant compared with the B-HCC or C-HCC groups. Liver failure was one of the most common postoperative complications and the major cause of death. Several factors may contribute to the occurrence of this particular complication. Earlier studies have already shown that patients with dual infection involving HCV (i.e., those who have coreplication of viruses) tend to have severe and progressive liver disease.16-19 However, in this series we did not identify any more depressed liver function clinically or more inflammatory changes in liver parenchyma histopathologically in these patients. On the other hand, this report indicated that patients with HCV-related HCC had a relatively smaller tumor size, but they underwent more major hepatectomy (p > 0.05). In our previous reports we found that the type of hepatectomy (major or minor) was not a significant factor in evaluating postoperative recurrence and long-term survival.21,22 However, it should not be denied that a major hepatectomy performed for a relative, identified small tumor is a relative risk factor for the development of postoperative liver failure in patients with BC-HCC. In this series the long-term survival rate after operation in the patients with BC-HCC was lower than that of the patients with either C-HCC or BHCC but was not statistically different among them. However, the recurrence rate of the patients with BC-HCC was lower than that of the patients with B-HCC, with a significant difference, but it was higher than that of the patients with C-HCC (p > 0.05). The 4-year disease-free survival rate of the patients with BC-HCC was also lower than that of the patients with C-HCC but higher than that of the patients with B-HCC. Nonetheless, the observa-

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Fig. 1. Overall survival rates of patients with hepatitis virus–related HCC who have undergone hepatic resection.

Fig. 2. Crude disease-free survival rates after hepatic resection for HCC.

tion period after the operation was too short to make any conclusions from these data. Histopathologic examinations for portal vein invasion of the tumor, the presence of intrahepatic metastasis, the absence of a fibrous tumor capsule, the tumor infiltration into the capsule, and a poor differentiation of cancer cells are prognostic factors after resection of HCC.22-25 There are conflicting data regarding the ploidy of HCC being a useful predictor of survival.26,27 The results of our previous study demonstrated no significant correlation between the DNA ploidy and survival rates in

patients with HCC who underwent hepatic resection.28 Recurrence was located mostly in the remnant liver and might be the result of inadequate resection of the original tumor, unrecognized multifocal HCC, a multicentric origin of HCC in patients with liver cirrhosis, and portal vein invasion by HCC, or it might be spread intrahepatically from the portal vein during operation.22,29 In conclusion, hepatic resection for HCC in patients with dual HBV and HCV infections was associated with only slightly higher postoperative morbidity and mortality rates than in those with

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either virus infection; thus the risks were such that we recommend that the operation should not be denied to well-selected patients.

16.

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