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1509
Correlation of Hepatitis Virus Serologic Status with
Clinicopathologic Features in Patients Undergoing
Hepatectomy for Hepatocellular Carcinoma
Naoki Yamanaka, M.D.
Tsuneo Tanaka, M.D.
Wataru Tanaka, M.D.
Junichi Yamanaka, M.D.
Chiaki Yasui, M.D.
Nobukazu Kuroda, M.D.
Masafumi Takada, M.D.
Eizo Okamoto, M.D.
BACKGROUND. This study investigated the relationship between clinicopathologic
features and various viral serologies in patients who underwent hepatectomy in
the treatment of hepatocellular carcinoma (HCC).
METHODS. Two hundred two patients were allocated to four groups, according to
First Department of Surgery, Hyogo College of
Medicine, Nishinomiya, Japan.
their positivity or negativity for hepatitis B surface antigen (HBsAg) and hepatitis
C virus antibody (HCVAb): Group I (HBsAg[0], HCVAb[/], n Å 151), Group II
(HBsAg[/], HCVAb[0], n Å 27), Group III (HBsAg[0], HCVAb[0], n Å 20), or Group
IV (HBsAg[/], HCVAb[0], n Å 4). The mean age of the HBsAg positive patients
(Groups II and IV) was 10 years younger than that of the HBsAg negative patients
(Groups I and III).
RESULTS. The male-to-female ratio was higher in HCVAb negative groups (II and
III). The HCVAb positive groups (I and IV) had a significantly poorer hepatic
reserve and smaller resections than the HCVAb negative groups. Because the
tumors were more advanced (as determined by TNM staging) in Group II, the
3-year crude and disease free survival rates were lower in Group II than in Group
I. However, HCVAb negative groups (II and III), when compared at 5 years with
the limited subsets of patients who had tumors at earlier stages or a curative
resection, had significantly better crude and disease free 5-year survival rates
than the HCVAb positive group (I).
CONCLUSIONS. Clinicopathologic features differ from one another in accordance
with the viral seromarkers in HCC patients. Significantly better crude and disease
free survival after complete resection were promising results for patients with nonHCV-related HCC. By comparison, for patients with HCV-related HCC, the risk of
intrahepatic recurrences never subsided even in later years after complete resection.
Therefore, posthepatectomy follow-up management should be individualized depending on the viral serologic status of HCC patients. Cancer 1997;79:1509–15.
q 1997 American Cancer Society.
KEYWORDS: hepatitis B virus, hepatitis C virus, viral seromarker, hepatocellular
carcinoma, hepatectomy, survival rate.
I
Address for reprints: Naoki Yamanaka, M.D.,
First Department of Surgery, Hyogo College of
Medicine, 1-1, Mukogawa-cho, Nishinomiya
663, Japan.
Received August 13, 1996; revision received
December 30, 1996; accepted January 8, 1997.
t is well known that patients with a chronic viral hepatitic infection
have an increased risk of developing hepatocellular carcinoma
(HCC).1 In 1989, Choo et al.2 reported having cloned the agent of
hepatitis C virus (HCV) and having developed a technique of specific
serologic assay to detect this agent.3 Since then, several studies4 have
been conducted to investigate differences in the mechanism and frequency of carcinogenesis between HCV-related and hepatitis B virus
(HBV) – related liver diseases. With regard to surgery, it is also important to determine whether or not the clinicopathologic features
q 1997 American Cancer Society
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TABLE 1
Clinical Backgrounds
Group
(n)
HBsAg/HCVAb
Gender
(M:F)
Age
(yrs)
ALT (U)
AST (U)
Albumin
(g/dL)
ICG R15
(%)
Clinical stage I/I
/ II / III (%)
Transfusion
history (%)
I (151)
II (27)
III (20)
IV (4)
0//
//0
0/0
///
4.8:1
8:1
9:1
3:1
63 { 6.3
51 { 10
63 { 6.4
52 { 8.2
71 { 41
53 { 34b
43 { 29a
63 { 41
70 { 44
57 { 40
42 { 20a
51 { 21
3.6 { 0.5
3.9 { 0.5a
3.9 { 0.6a
3.7 { 0.3
20 { 9.0
12 { 4.7a
14 { 7.7a
15 { 11
35
67b
63b
25
38/151 (25)
5/27 (19)
3/20 (15)
1/4 (25)
HBsAg: hepatic B surface antigen; HCVAb: hepatitis C virus antibody; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ICG R15: indocyanine green retention rate at 15 minutes.
a
P õ 0.01 (I vs. II, I vs. III).
b
P õ 0.05 (I vs. II, I vs. III).
TABLE 2
Liver Histopathology
Group
Normal
(%)
Fibrosis
(%)
Chronic
hepatitis (%)
Precirrhosis
(%)
Cirrhosis
(%)
I
II
III
IV
1.3
3.7
0
0
2.7
3.7
0
0
13
22
42
25
28
30
16
25
55
40.6
42
50
and the recurrence pattern or prognosis after hepatectomy differ according to the type of hepatitis virus.
There is one report5 documenting clinicopathologic
differences between HCV antibody (HCVAb) positive
and hepatitis B surface antigen (HbsAg) positive hepatectomized patients. However, there has been no detailed study of patients with the various combinations
of HCV and HBV seromarkers. The aim of this study
was to analyze the clinicopathologic implications of
viral seromarkers in HCC patients after a hepatectomy.
linked immunoadsorbent assay. The clinical features
and regional characteristics of the tumors of the four
groups were compared.
The pathohistologic findings in the liver were categorized into four grades: cirrhosis, precirrhosis,
chronic hepatitis, and normal liver. Precirrhosis was
characterized by the presence of piecemeal necrosis
and incomplete bridging fibrosis. The cumulative
crude and disease free survival rates were determined
for all the groups except Group IV, due to the small
number of patients in that group. The analysis was
performed for the entire group as well as for subsets
of patients who had undergone curative resection or
had an earlier stage of tumor (Stage I or II, according
to TNM staging6). Student’s t test was used for the
statistical analysis. The cumulative survival rates were
determined by the Kaplan – Meier method, and statistical differences were determined by the standard error
test. A P value of õ0.05 was considered statistically
significant.
RESULTS
PATIENTS AND METHODS
Clinical Features
A total of 202 patients with HCC who had undergone
hepatic resection between January 1991 and December 1994 were enrolled in this study. These patients
were categorized into Group I (HBsAg[0] and
HCVAb[/], n Å 151), Group II (HBsAg[/] and
HCVAb[0], n Å 27), Group III (HBsAg[0] HCVAb[0],
n Å 20), and Group IV (HBsAg[/] and HCVAb[/], n Å
4). The patients in these groups accounted for 75%,
13%, 9.9%, and 2.1%, respectively, of the total number
of patients. Hepatitis B envelope antigen (HBeAg) was
positive in 18.5% (5 of 27) of the Group II patients,
and either anti-hepatitis B core antigen (HBcAb) or
anti-hepatitis B surface antigen (HBeAg) was positive
in 85% (17 of 20) of the Group III patients. HCVAb
was determined by a new second-generation enzyme-
The patients’ ages, male-to-female ratio, histopathology of the liver, and liver function parameters are
shown in Tables 1 and 2. The mean age was significantly lower, by 10 years, in the HBsAg positive patients (Groups II and IV) than in HBsAg negative patients (Groups I and III), irrespective of HCVAb seropositivity or seronegativity. The male-to-female ratio
was higher in the HCVAb negative groups (II, III) than
in the HCVAb positive groups (I, IV). Liver function,
as determined by tests such as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT),
serum albumin, and the indocyanine green retention
rate at 15 minutes (ICG R15), was significantly better
in the HCVAb negative Groups (II, III) than in Group
I. The clinical stage, an index of the severity of liver
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1511
TABLE 3
Tumor Backgrounds
Histologic grade (%)
Portal invasion (%)
No. of tumors (%)
Group
Tumor
size (cm)
Well
Moderate
Poor
(0)
(/)
Single
Multiple
TNM staging I / II/
overall (%)
I
II
III
IV
3.9 { 2.5
6.3 { 5.2a
5.7 { 4.7
4.1 { 1.7
13
5
11
0
74
79
61
100
13
16
28
0
141
24
18
4
10 (7)
3 (11)
2 (10)
0 (0)
92 (61)
13 (48)
11 (55)
4 (100)
59
14
9
0
89/151 (59)
13/27 (48)
12/20 (60)
3/4 (75)
a
P õ 0.05 (I vs. II).
disease7 as graded by five factors, i.e., ascites, albumin,
total bilirubin, prothrombin time, and ICG R15, was
also significantly better in the HCVAb negative groups.
The proportion of patients at clinical Stage I was significantly higher in Groups II and III than in Group I.
A history of blood transfusion was more frequently
observed in the HCVAb positive groups than in the
HCVAb negative groups, although the differences were
not statistically significant. The incidence of coexisting
type B or B* cirrhosis was highest (83%) in Group I,
whereas Group III showed the lowest rate (58%) (Table
2). In other words, the presence of coexisting cirrhosis
tended to be less frequent in the HCVAb negative patients, particularly those who were also negative for
HBsAg. Thus, in terms of liver pathology and function,
the condition of the HCVAb positive patients was more
severe.
Tumor Background
The four groups were compared with regard to tumor
size, alpha fetoprotein (AFP) level, histologic grade of
cell differentiation, frequency of macroscopic portal
thrombus, number of HCC nodules, and TNM staging
(Table 3). The mean tumor size was significantly larger
in Group II than in Group I (6.3 { 5.2 cm vs. 3.9 { 2.5
cm, P õ 0.05). The AFP level was higher in Group II
(7707 { 22072 ng/mL) than in the other three groups
(I, 1374 { 7037; III, 1544 { 2931; IV, 338 { 569 ng/
mL), although the difference was not statistically different. The incidence of portal thrombus was similar
in all the groups except Group IV, and was about 10%.
The percentages of patients who had a single HCC
nodule or a tumor at an early stage (Stage I or II,
according to TNM staging6) was the lowest in Group
II, i.e., the HCCs in Group II tended to be more advanced than those in Group I.
Resection Range
The extent of resection was expressed as follows:
wedge resection (Hr-O), subsegmentectomy (Hr-S),
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TABLE 4
Extent of Hepatectomy
Group
Hr0, S
Hr1
Hr2, 3
Hr1, 2, 3/
overall (%)
I
II
III
IV
84
9
6
2
52
10
6
2
15
8
8
0
(44)
(67)a
(70)a
(50)
HrO: wedge resection; HrS: subsegmentectomy; Hr1: segmentectomy; Hr2: lobectomy; Hr3: trisegmentectomy.
a
P õ 0.05 (I vs. II, I vs. III).
segmentectomy (Hr-1), or bi- or trisegmentectomy
(Hr-2 or Hr-3) (Table 4). An Hr-1 or a more extensive
resection was performed in 44%, 65%, 70%, and 50%
of the patients in Groups I, II, III, and IV, respectively.
The extent of resection was significantly (P õ 0.05)
limited in the HCVAb positive patients, who had a
lower hepatic reserve, than in the HCVAb negative patients.
Crude Survival Rates
Overall
During the 3 years after surgery, survival rates were
lowest for patients in Group II, who had more advanced tumors (Fig. 1). At 5 years, the cumulative survival rate was highest in Group III (64%), followed by
Groups II (54%) and I (42%).
Comparison by Tumor Stage and Curability
When the analysis was limited to those whose tumors
were at a stage of I or II (Fig. 2), the cumulative survival
rates for these subsets of patients were similar until 4
years after surgery. However, the 5-year survival rate
was highest in Group II (82%) and was significantly
better than in Group I (48%). In the patients who had
a curative resection,7 the 5-year survival rate was high-
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CANCER April 15, 1997 / Volume 79 / Number 8
FIGURE 2. Prognosis by virus marker for patients with Stage I and II
FIGURE 1. Overall prognosis by virus marker is represented. The crude
survival rate after hepatectomy is shown, according to the serologic state
of the hepatitis virus. B: hepatitis B surface antigen; C: hepatitis C virus
antibody.
tumors is represented. The disease-free survival rate, after hepatectomy
is shown, according to the serologic state of the hepatitis virus. B: hepatitis
B surface antigen; C: hepatitis C virus antibody.
FIGURE 4. Overall prognosis by virus marker is represented. The disease
FIGURE 3. Prognosis by virus marker for patients who had a curative
resection is represented. The crude survival rate after hepatectomy for
patients with tumors at Stage I or II (TNM) is shown, according to the
serologic state of the hepatitis virus. B: hepatitis B surface antigen; C:
hepatitis C virus antibody.
est in Group III (74%), which was significantly better
than in Group I (45%) (Fig. 3).
Disease Free Survival
Overall disease free survival
No significant difference was observed in the overall
cumulative disease free survival rates among Groups
I, II, and III during the first 3 years after surgery (Fig.
4). On the other hand, the survival rate at 5 years was
significantly lower in Group I than in Group II.
Comparison by tumor stage and curability
For the patients with tumors at Stage I or II, the disease
free survival rate constantly decreased even after the
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free survival rate after hepatectomy for patients at Stage I or II (TNM) is
shown, according to the serologic state of the hepatitis virus. B: hepatitis
B surface antigen; C: hepatitis C virus antibody.
second postoperative year in Group I, whereas there
was only a slight decrease in the survival rate for the
HCVAb negative patients (Groups II and III) irrespective of the HBsAg status (Fig. 5). Therefore, the disease
free survival rate at 5 years was significantly higher for
Group III than for Group I. For the patients who had
a curative resection, there was no significant difference in the 3-year survival rate among the three
groups. At 5 years, however, the disease free survival
rate was significantly lower for Group I than for Groups
II and III (Fig. 6).
DISCUSSION
After an assay for HCVAb became widely available
in 1990, a survey conducted by the Liver Cancer
Study Group of Japan revealed that HCVAb is detectable in 72% of Japanese HCC patients and
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Viral Serotype in Hepatoma/Yamanaka et al.
FIGURE 5. Prognosis by virus marker for patients with Stage I and II
tumors is represented. The crude survival rate after curative hepatectomy
is shown, according to the serologic state of the hepatitis virus. B: hepatitis
B surface antigen; C: hepatitis C virus antibody.
FIGURE 6. Prognosis by virus marker for patients who had a curative
resection is represented. The disease free survival rate after hepatectomy
is shown, according to the serologic state of the hepatitis virus. B: hepatitis
B surface antigen; C: hepatitis C virus antibody.
HBsAg is detectable in 18%.8 It is well known that
the natural history of a viral infection, from its onset
to the development of liver cancer, differs between
hepatitis B and hepatitis C.4 Our study found certain clinicopathologic differences according to the
viral serologic status of patients who developed
HCC and underwent a hepatectomy.
An accurate determination of the presence or
absence of HBV infection requires checking for the
incorporation of HBV DNA into liver cell genomic
DNA. In fact, low levels of HBV DNA have been
detected by the polymerase chain reaction technique in the serum or liver tissue of hepatitis B or
HCC patients whose serum had lost HBsAg.9,10 In
addition, it has recently been reported that hepatitis B developed in the recipients of liver grafts from
donors who were negative for HBsAg but positive
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1513
for HBsAb or HBcAb.11,12 It seems likely that our
Group III patients, who were seronegative for both
HBsAg and HCVAb, had persistent HBV DNA in
their liver tissue, because 85% of them were positive
for an HBV-related antibody. Therefore, there may
be little difference at the molecular level between
the HCVAb negative patients with and without
HBsAg positivity. However, the age at HCC diagnosis was 10 years younger, and the tumor stage was
more advanced in Group II than in Group III.
There was a conspicuous male predominance
in the patients with HCC unrelated to HCV, regardless of whether they were positive or negative for
HBsAg. The hepatic reserve was also better in the
HCVAb negative patients than in the HCVAb positive ones. In particular, the patients negative for
both HBsAg and HCVAb had a higher proportion
(42%) of noncirrhotic livers. Consequently, the safe
extent of resection13,14 was significantly limited due
to the poorer hepatic reserve in the HCVAb positive
patients than in the HCVAb negative patients.
The 3-year survival rates after hepatectomy
were lower for the HBsAg positive patients due to
the higher proportion of patients with higher tumor
stage, where there should be a high rate of association with unrecognized intrahepatic lesions left unresected. Intrahepatic recurrences after a hepatectomy originate from the growths of either residual,
minute, intrahepatic metastatic foci or metachronous multicentric foci. The risk factors for recurrence include tumor size, growth type,15 portal invasion, intrahepatic metastasis,16,17 intracapsular
infiltration of tumor cells,18 tumor capsule,19 histologic grade,20,21 DNA ploidy pattern,22 and serum
AFP level.23 Operative procedure-related risk factors include tumor location,24 surgical margin,21
and limitation of the extent of resection.17 All these
tumor-related or operative procedure – related factors may contribute to the intrahepatic recurrences
originating from unrecognized minute foci, which
are more likely to occur within a few postoperative
years.
Host liver-related risk factors include liver
function parameters such as albumin, ALT25 and
ICG retention rate,4 and the inflammatory activity
in the nontumorous portion of the liver.5,25 Additionally, DNA synthesis activity in the liver with virus-induced cirrhosis,26 age, 4 and the AFP value,
which may serve as an parameter of inflammatory
activity of hepatitis,25 have been cited as carcinogenic factors.
The development of hepatocellular carcinoma
in patients suffering from HCV-related chronic liver
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CANCER April 15, 1997 / Volume 79 / Number 8
diseases is reported to be significantly higher than
that in patients with HBV infection.4 In HBsAg-related chronic liver diseases, the hepatitis subsides
with seroconversion in about 90% of patients, and
subsequently the viremia diminishes with age. In
contrast, in HCV-related chronic liver diseases, inflammatory activity tends to persist,27 and the carcinogenic potential barely subsides at all.4
In fact, the HCVAb-positive patients, who
showed higher serum liver enzyme levels before
surgery, had a linear increase in recurrence during
the postoperative period despite the higher proportion of patients with tumors at earlier stages. As a
result, 5-year crude and disease free survival rates
became lower. In contrast, the later intrahepatic
recurrences after the third postoperative year was
only slight in the HCVAb negative patients, although there was a higher proportion of more advanced tumors. In the patients with a lower probability of having unrecognized minute lesions, i.e.,
those treated at the earlier tumor stage or who had
a curative resection, the aforementioned trends became especially pronounced.
In conclusion, if the tumor is recognized early
and completely removed, better crude and disease
free survival can be expected for patients with HCVunrelated HCCs irrespective of HBsAg status. In
light of this, reresection of solitary posthepatectomy recurrences of HCV-unrelated HCC would be
meaningful. On the other hand, for HCV-related
HCCs, metachronous multicentric growth hardly
subsides at all, even 3 or more years after complete
removal; therefore, closer and more careful followup is necessary.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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