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Hepatobiliary & Pancreatic Diseases International

162 Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com


Original Article / Liver
Author Afliations: Center of General Surgery and Liver Transplant,
Fundeni Clinical Institute, Fundeni Street No. 258, 022328, Bucharest,
Romania (Tanase AM, Dumitrascu T, Dima S, Grigorie R and Popescu
I); Unit "Organisation nuclaire et oncogense", INSERM U993, Institut
Pasteur, 28, rue du Docteur Roux, 75724 Paris cedex 15, France (Marchio A
and Pineau P)
Corresponding Author: Irinel Popescu, MD, PhD, FACS, FEBS, Center of
General Surgery and Liver Transplant, Fundeni Clinical Institute, Fundeni
Street No. 258, 022328, Bucharest, Romania (Tel/Fax: 004-021-3180417;
Email: irinel.popescu220@gmail.com)
2014, Hepatobiliary Pancreat Dis Int. All rights reserved.
doi: 10.1016/S1499-3872(14)60026-6
BACKGROUND: The global risk of hepatocellular carcinoma
(HCC) is largely due to hepatitis B virus (HBV) and hepatitis C
virus (HCV) infections. In recent years, however, an increased
prevalence of non-viral HCC has been noted. The clinical impact
of the presence/absence of viral infections in HCC remains
controversial. The present study aimed to assess the effect of
hepatitis viruses on demographics, clinical and pathological
features and long-term outcome in a large cohort of Romanian
patients who underwent surgery for HCC.
METHODS: The study included 404 patients with HCC who
had undergone resection, transplantation or radiofrequency
ablation at a single institution between 2001 and 2010. The
patients were divided into four groups: 85 patients with hepatitis
B virus infection (HBV group), 164 patients with hepatitis C
virus infection (HCV group), 39 patients with hepatitis B and C
virus co-infection (HBCV group), and 116 patients without viral
infection (non-BC group).
RESULTS: The patients of both HBV (56.011.3 years) and
HBCV groups (56.09.9 years) were signicantly younger than
those of the HCV (61.08.5 years, P=0.001) and non-BC groups
(61.013.0 years, P=0.002). Interestingly, the prevalence of liver
cirrhosis was signicantly lower in the non-BC group (47%)
than in any other subsets (72%-90%, P<0.002). Furthermore,
the non-BC patients were more advanced according to the
Barcelona Clinic Liver Cancer stages than the patients of the
HCV or HBCV groups (P<0.020); accordingly, they were more
frequently assessed beyond the Milan criteria than any other
groups (P=0.001). No signicant differences in the disease-free
or overall survival rates were observed among these groups.
CONCLUSIONS: Patients with non-viral HCC are diagnosed at
advanced ages and stages, a situation plausibly due to the poor
effectiveness of cancer surveillance in community practice. The
presence of viral infections does not appear to impair the long-
term prognosis after surgical treatment in patients with HCC;
however, there is a trend for worse disease-free survival rates in
HBCV patients, though statistical signicance was not reached.
(Hepatobiliary Pancreat Dis Int 2014;13:162-172)
KEY WORDS: hepatitis B virus;
hepatitis C virus;
hepatocellular carcinoma;
recurrence;
prognosis
Introduction
H
epatocellular carcinoma (HCC) is the seventh
most common cancer and the third leading
cause of cancer-related death worldwide.
[1]
Thus,
HCC is not only common but also very deadly, with a
5-year survival rate of less than 10%.
[2]
According to
the age-adjusted HCC incidence per 100 000 habitants,
different areas are classied as low (<5), intermediate
(5-15) and high (>15).
[3]
Romania is considered to be at
an intermediate incidence (8 HCC/100 000 habitants).
[4]
For the past century, the global risk of HCC was
largely due to hepatitis B virus (HBV) and hepatitis
Inuence of hepatitis viruses on clinico-
pathological proles and long-term outcome
in patients undergoing surgery for
hepatocellular carcinoma
Anna-Maria Tanase, Traian Dumitrascu, Simona Dima, Razvan Grigorie,
Agnes Marchio, Pascal Pineau and Irinel Popescu
Bucharest, Romania
Hepatitis viruses and hepatocellular carcinoma
Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com 163
C virus (HCV) infections, along with aatoxin
intoxication, excessive alcohol consumption, obesity
and diabetes.
[5, 6]
Furthermore, diabetes mellitus has
a negative impact on both overall and disease-free
survival after curative-intent treatments for HCC.
[7]

Chronic hepatitis B and C, mostly in the cirrhotic stage,
are responsible for the great majority of cases of HCC
worldwide,
[8]
as appears to be the case in Romania.
[4, 9]

Co-infection with both viruses is often noticed in HCC
patients due to their similar ways of transmission; this
situation has signicantly impacted the overall burden
of chronic liver disease.
[10]
HBV and HCV co-infection
is associated with more severe forms of liver disease
compared with chronic hepatitis caused by a single
virus.
[11]
At the molecular level, distinct chromosomal
abnormality patterns and transcriptomic signatures
were observed in HCC without viral infection.
[12, 13]

Therefore, there should be some clinico-pathological
differences between HCC in patients without viral
infection and those associated with hepatitis viruses.
With regards to its natural history and its clinical
presentation, HCC is a heterogeneous disease. The
incidence of HCC varies across the world due to
geographic differences in the prevalence of risk
factors.
[14]
Furthermore, in addition to different etiology
rates, other signicant differences among countries are
commonly noticed regarding patient age, gender ratio,
tumor size or degree of underlying liver damage.
[15]

Nevertheless, biological characteristics appear to affect
the natural history of HCC.
[16]

Curative-intent treatment options for HCC include
liver resection, liver transplantation and ablative
therapy, depending on the tumor stage and functional
status of the liver.
[17-20]
However, despite the above-
mentioned heterogeneity, no differences regarding long-
term survival were observed between Western and
Eastern centers when adjusted for clinico-pathological
factors.
[15]
Early detection and curative resection are
considered the most important factors for long-term
outcome.
[21]
The effect of HBV and HCV infection on
clinico-pathological features and long-term outcome
in HCC-treated patients has been previously studied;
however, most of these studies are from Eastern Asia.
[22]

In Eastern Europe there is a conspicuous paucity of
reports regarding the epidemiology
[23-25]
and surgical
management
[17, 26]
of HCC. Furthermore, none of the
works published thus far have addressed the effect
of hepatitis on long-term prognosis. We assessed the
potential differences determined by the presence of HBV
or HCV in a large cohort of HCC patients from a single
surgical center of an Eastern European country. Only
patients who were surgically treated with liver resection,
liver transplantation or radiofrequency ablation were
considered.
Methods
Patients
The data from 404 patients who had been treated from
January 2001 to November 2010 with a nal pathological
diagnosis of HCC were retrospectively reviewed from
a prospective-gathered electronic database established
at the Center of General Surgery and Liver Transplant
from the Fundeni Clinical Institute (Bucharest,
Romania). Only patients who underwent surgical
treatment (i.e., liver resection, liver transplantation or
radiofrequency ablation) were considered. Informed
consent was obtained from each patient, and the study
was approved by the Local Ethics Committee.
The preoperative work-up included a serologic
examination for HBV (hepatitis B surface antigen)
and HCV (hepatitis C antibody) for all patients. The
serum tumor marker alpha-fetoprotein (AFP) was
preoperatively assessed in 207 patients (51%); the cut-off
value was <32 ng/dL. Computed tomography (CT) and/
or magnetic resonance imaging (MRI) examinations
were performed to evaluate the extent of the disease,
tumor location and characteristics. For patients who
underwent ablation, the size and number of tumors
were noted with imaging examinations and the tumor
type was established through biopsy (patients without
a positive biopsy for HCC were excluded). The choice
of treatment modality was performed according to the
patient status [Child-Pugh score or Barcelona Clinic
Liver Cancer (BCLC) classication] and tumor features
(localization, size, number and stage).
The patients with HCC were divided into four
groups: 85 patients with only hepatitis B virus infection
(HBV group), 164 patients with only hepatitis C virus
infection (HCV group), 39 patients with hepatitis B and
C virus infection (HBCV group), and 116 patients with
no viral infection (non-BC group). The comparative
analyses included demographics (age, gender and
residence), serum AFP level, Child-Pugh score, staging
systems such as Okuda, BCLC, the Cancer of the
Liver Italian Program (CLIP), Milan criteria, type of
treatment, pathology data (number and size of the
tumors, underlying liver cirrhosis, Edmonson-Steiner
grading system), disease-free and overall survival rates.
The follow-up protocol included clinical
examination, serum AFP level and ultrasound and/or
CT and/or MRI every 3 months in the rst year and
every 6 months thereafter. Data for AFP were available
for 48 patients in the HBV group (56%), 90 patients in
Hepatobiliary & Pancreatic Diseases International
164 Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com
the HCV group (55%), 20 patients in the HBCV group
(51%) and 49 patients in the non-BC group (42%). The
last follow-up was April 1, 2011.
Statistical analysis
All statistical analyses were performed using SPSS
version 17.0 software (SPSS Inc., Chicago, IL, USA). The
data were expressed as the number (percentage) and
median (range), except for age, which was expressed by
the meanSD. Fisher's exact test (two-tailed) was used
to compare the categorical variables, and the Mann-
Whitney U test (two-tailed) was used for continuous
variables. The median disease-free and overall survival
rates were estimated using the Kaplan-Meier method,
and the median follow-up time was estimated using
reversed Kaplan-Meier curves. Comparisons were
made using the log-rank test (for univariate analysis).
Multivariate analysis used a forward stepwise Cox
proportional hazards model and variables from the
univariate analysis with P values less than 0.10 were
included. A P value less than 0.05 was considered
statistically signicant.
Results
Patient demographics and geographical distribution
Of the 404 patients with HCC, 288 (71%) had viral
infection. Among them, 124 patients (31%) had HBV
infection and 203 patients (50%) had HCV infection
(Table 1).
Both patients in the HBV (56.011.3 years) and
HBCV groups (56.09.9 years) were signicantly
younger than those in the HCV (61.08.5 years,
P=0.001 and P=0.002) or non-BC groups (61.013.0
years, both P=0.001). No differences regarding patient
age were observed between the HBV and HBCV groups
(P=0.970) or between the HCV and non-BC groups
(P=0.061) (Fig. 1A). Patients were predominantly male
in all groups. Signicant differences were observed
between the HBV and HCV groups (P<0.001), the HCV
and HBCV groups (P=0.010) and the HBV and non-
BC groups (P=0.002), respectively. No differences were
noted between the HCV and non-BC groups (P=0.362),
the HBV and HBCV groups (P=0.763) or the non-
BC and HBCV groups (P=0.054) (Fig. 1B). Regarding
the origins, patients in the non-BC group were more
frequently from rural areas than those in the HBV
(P=0.005) and HCV groups (P=0.056). Overall, the non-
BC patients were more frequently from a rural area than
from an urban neighborhood in comparison with all
viral etiologies (P=0.009) (Fig. 1C). In addition, patients
from outside Bucharest were more prevalent in the non-
BC group than in the HBCV group (P=0.042). The city-
countryside distribution was not different among the
groups of virus-infected patients (Fig. 1C, D).
Histopathological features
Liver cirrhosis was present in 289 patients (72%)
and was less frequent in the non-BC group (52/116,
47%) than in the HBV (61/85, 72%; P=0.002), HCV
(141/164, 86%; P=0.001) or HBCV groups (35/39, 90%;
P=0.001). Liver cirrhosis was also less frequent in the
HBV group than in the HCV (P=0.009) and HBCV
groups (P=0.036). No differences in the prevalence of
liver cirrhosis (P=0.792) were observed between the
HCV and HBCV groups, nor differences in Child-Pugh
scores (P0.199) among the groups (Table 1).
In these groups, there was no signicant difference
in the number of patients with multicentric tumors, the
size of the tumor, or the Edmonson-Steiner grading
system (Table 2).
The median serum AFP level was 30.2 ng/dL (range
2.0-60490.0) in the HBV group, 83.7 ng/dL (range 2.1-
5741.0) in the HCV group, 47.1 ng/dL (range 1.4-991.0)
in the HBCV group, and 12.0 ng/dL (range 1.1-35500.0)
in the non-BC group. But no statistical differences were
observed among all the groups (P0.476).
Clinical staging
At the time of initial diagnosis, more patients in
the non-BC group (83/116, 72%) were assessed beyond
Table 1. Clinical and laboratory characteristics of 404 patients
undergoing surgery for HCC
Parameters
HBV patients
(n=85)
HCV patients
(n=164)
HBCV patients
(n=39)
Non-BC
patients
(n=116)
Child-Pugh
*
A 44 87 23 36
B 16 51 11 16
C 1 3 1 0
Okuda
#
I 40 81 22 47
II 43 76 16 65
III 2 7 1 4
CLIP

0 31 60 17 29
1 18 55 10 26
2 22 26 6 38
3 10 15 4 14
4 4 7 2 9
5 0 1 0 0
6 0 0 0 0
*: P0.199; #: P0.095; : P0.324. CLIP: Cancer of the Liver Italian
Program.
Hepatitis viruses and hepatocellular carcinoma
Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com 165
Fig. 1. Demographic data in 404 patients with HCC. A: age
distribution; B: gender ratios; C: living places of patients attending
surgery in Fundeni Clinical Institute (urban vs rural); D:
distribution in or outside the Romanian capital, Bucharest.
Table 2. Pathological data of 404 patients undergoing surgery for HCC
Parameters
HBV
patients
HCV
patients
HBCV
patients
Non-BC
patients
Multicentric
*

Yes 12 33 7 19
No 73 131 32 97
Tumor diameter
#
(cm) 5 (2-19) 4 (0.8-14) 4 (2-12) 7 (1-14)
Edmonson-Steiner

Grade I 9 16 6 12
Grade II 64 125 29 74
Grade III 0 1 1 2
Grade IV 4 9 1 11
Unknown 8 13 2 17
*: Multicentric means 2 nodules, P0.224; #: P0.224; : P0.115.
Table 3. Surgical treatment of 404 patients with HCC
Treatment
HBV
patients
(n, %)
HCV
patients
(n, %)
HBCV
patients
(n, %)
Non-BC
patients
(n, %)
Liver resection 53 (62) 98 (60) 16 (41) 103 (89)
Transplantation 8 (9) 15 (9) 12 (31) 31 (2)
RFA 24 (28) 51 (31) 11 (28) 10 (9)
RFA: radiofrequency ablation.
the Milan criteria than those in the HBV (44/85, 52%;
P=0.004), HCV (65/164, 40%; P=0.001) or HBCV
groups (14/39, 36%; P=0.001). But there were no
differences in this regard between the HBV and HCV
groups (P=0.080), the HBV and HBCV groups (P=0.122)
or between the HCV and HBCV groups (P=0.717),
respectively.
With regard to clinical staging, no differences were
observed in the Okuda or CLIP staging systems among
the groups (Table 1). As expected, however, patients in
the non-BC group had more advanced BCLC stages (62
patients with C/D stages, 53%) than those in the HCV
(63 with C/D stages, 38%; P=0.020) or HBCV groups
(12 with C/D stages, 31%; P=0.017). But there were no
differences between the HBV (38 with C/D stages, 45%)
and HCV (P=0.344), HBCV (P=0.169) and non-BC
groups (P=0.257), nor differences between the HCV and
HBCV groups (P=0.461).
Type of treatment
The types of treatment given to each group are
shown in Table 3. Liver resection was more frequently
performed in the non-BC group than in the HCV
(P=0.001), HBV or HBCV groups (P=0.005). But no
differences in this regard were observed between the
HBV and HCV groups (P=0.665), the HCV and HBCV
groups (P=0.847) or the HBV and HBCV groups
(P=1.000), respectively.
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Disease-free and overall survival rate analysis
The median time of follow-up was 44 months (range
4-123 months). A total of 103 patients were excluded
from the survival analysis because of postoperative
deaths or loss from follow-up: 19 (22%) in the HBV
group, 42 (26%) in the HCV group, 5 (13%) in the HBCV
group and 37 (32%) in the non-BC group. Postoperative
mortality was 4.5% (18 patients), and there were no
differences between the groups (data not shown).
No differences were observed in the disease-free or
overall survival rates of the groups (Fig. 2). Furthermore,
survival analysis was made after adjustment of age and
Fig. 2. Kaplan-Meier survival curves for patients undergoing surgery for HCC. DFS: disease-free survival; OS: overall survival.
Hepatitis viruses and hepatocellular carcinoma
Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com 167
the presence or absence of liver cirrhosis. The median
(60 years) and the rst quartile (53 years) were used
as cut-off points of age. No differences in the disease-
free (P0.642) or overall survival rates (P0.654) were
observed among the groups when the presence/absence
of cirrhosis was adjusted (data not shown). Finally,
no differences were observed among the groups after
adjustment of age (disease-free survival P0.547; overall
survival P0.702) (data not shown).
The following potential risk factors for disease-
free and overall survival rates were considered upon
univariate analysis: age, area of residence (urban
vs rural/Bucharest and suburbs vs outside), gender,
cirrhosis, the Milan criteria, Okuda, CLIP and BCLC
classications, tumor diameter and number, Edmonson-
Steiner grading, HBV, HCV, and HBV and HCV viral
co-infections, and different types of treatment (partial
liver resection, liver transplantation and radiofrequency
ablation). For overall survival, the Milan criteria,
Okuda and BCLC classications, number of tumors,
Edmonson-Steiner grading and radiofrequency ablation
were identied as statistically signicant prognostic
factors by the univariate analysis. For disease-free
Table 5. Multivariate analysis for overall survival in 301 patients
undergoing surgery for HCC
Parameters
Hazard
ratio
95% condence
interval
P value
Single tumor 0.711 0.530-0.954 0.023
Outside Milan criteria 1.059 0.777-1.444 0.718
Edmonson-Steiner grade I-II 0.528 0.366-0.760 0.001
Okuda I 0.740 0.533-1.028 0.073
CLIP 0-3 0.762 0.415-1.401 0.382
BCLC stage A-B 0.753 0.568-0.999 0.049
Radiofrequency ablation 1.287 0.976-1.697 0.074
Table 4. Multivariate analysis for disease-free survival in 301
patients undergoing surgery for HCC
Parameters
Hazard
ratio
95% condence
interval
P value
Single tumor 0.76 0.551-1.048 0.094
Outside Milan criteria 1.061 0.753-1.495 0.733
Edmonson-Steiner grade I-II 0.569 0.388-0.835 0.004
Okuda I 0.663 0.495-0.887 0.006
BCLC stage A-B 0.594 0.448-0.789 <0.001
Radiofrequency ablation 1.134 0.850-1.512 0.394
Transplantation 0.552 0.307-0.991 0.046
Tumor diameter 4.8 cm 1.025 0.956-1.099 0.489
Presence of cirrhosis 1.682 1.255-2.253 <0.001
Area of living outside Bucharest
and suburbs
1.090 0.820-1.447 0.550
survival, in addition to the above-mentioned factors,
liver transplantation was identied as a prognostic
factor in the univariate analysis. HBV infection, HCV
infection, and a co-infection of HBV and HCV were not
identied as prognostic factors after surgery for HCC
in the univariate analyses for disease-free (P0.311) or
overall survival (P0.128). The multivariate analyses for
potential risk factors are shown in Tables 4 (for disease-
free survival) and 5 (for overall survival).
Discussion
A recently study
[22]
has addressed the effect of viral
hepatitis status on clinico-pathological features and
patient survival after surgical treatment of HCC. Notably,
only a single study included European patients.
[27]

Moreover, few studies included a comparative analysis
among all four groups of patients: HBV-only, HCV-
only, HBV and HCV co-infection and non-viral HCC.
[22]

It is well-known that both HBV and HCV carriages
are highly prevalent in the Romanian population and
therefore represent a serious public health problem.
[28-33]

A similarly worrying situation is not encountered in
Western Europe
[31]
and can only be compared with
what is observed in neighboring countries such as the
Republic of Moldova
[34]
and perhaps Bulgaria.
[35]

Most (71%) of the HCC cases in the present series
are related to viral infections, primarily to HCV
infection and secondarily to HBV infection. Similar
features were previously reported in another smaller
series of Romanian patients with HCC.
[9]
The prevalence
of viral infection in HCC cases worldwide is reported to
range between 13%-90.5% for HBV and 4%-88% for
HCV.
[36-38]
Although we have previously shown that the
molecular epidemiology of HCC in Romania appears
to be slightly different from that observed in Western
Europe,
[25]
the association of HCC with HBV (31%)
or HCV (50%) in the present study is similar to that
reported in Western Europe
[39-42]
but differs from the
situation in Greece, where HBV continues to dominate
HCC causes.
[43]
HBV-associated HCC incidence is
currently decreasing in the autochthonous European
population because of systematic immunization policies
implemented in the European Union. Thus, it is highly
probable that Romania will follow this trend because
there is a decrease in HBV prevalence because of
immunizations.
[44]
The HCV-related HCC incidence was
predicted to rise until 2015-2020 and decrease thereafter
because of preventive measures taken during the 1990s
to control the spread of HCV.
[42]
A similar situation will
occur in Romania, in which the health care system has
greatly improved in the past two decades.
[45, 46]
Thus,
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the non-BC subset of HCC patients will be increasingly
important in the future, as is the case in Northern
Europe.
[43]
Patients in the present series without viral infections
were older than those with HBV-only or co-infection
of HBV and HCV. A similar trend was observed in the
HCV-only-infected patients. An older age was shown in
non-viral HCC patients compared with HBV- or HCV-
only patients.
[22, 47, 48]
However, a younger age was seen in
patients without viral infection.
[15]
In our study, a small
number of non-BC patients were younger than the rest
of the population. This nding suggests the presence of
alleles predisposing to liver cancer in early-onset HCC
patients or in 2%-3% of the Romanian population.
[49-51]
In the present study, patients with HCV-only were
older than those with HBV-only or a co-infection
of HBV and HCV. Previous studies
[52-54]
have shown
a signicant older age in patients with HCV-only
compared with those with HBV-only HCC. This
situation could be explained by a dominating role of
HBV over HCV, with HBV setting the pace of a fast
liver disease progression. Alternatively, this situation
could merely reect an age difference at contamination,
with HBV acquired earlier in a patient's life span and
thereby triggering earlier complications of chronic
infection. In Romania, the mode of HBV infection is
known to be predominantly horizontal, thus occurring
later in life than in the Far Eastern countries where HBV
transmission was previously vertical/perinatal.
[29, 55, 56]

This may explain why the mean age difference between
those who are HBV- and HCV-infected is only 5 years,
whereas the difference in Taiwan region is 12 years.
[57]
The present study have shown that patients with
HCC without viral infection are more frequently from
rural areas compared with HBV-only patients; a similar
trend was observed compared with HCV-only patients;
however, statistical signicance was not reached. These
ndings are surprising because previous studies have
shown a higher prevalence of HBV and HCV in rural
areas of Romania compared with urban areas.
[28, 29]

However, data from the literature are controversial. A
report from Poland indicated that urban dwellers were
more likely to be carriers of hepatitis viruses than those
who live in rural areas.
[58]
However, symmetric studies
showed no differences in Asian countries
[59]
or even an
increased prevalence of HBV in rural areas in Western
Europe, China or Africa.
[52, 60]
Alternatively, the cause
of the larger non-BC proportion among rural dwellers
could be linked to the presence of specic environmental
or lifestyle HCC risk factors. In such settings, an excess
of HCC cases should be observed in some regions of
Romania. Several risk factors for non-viral HCC, such as
excessive alcohol consumption and diabetes were found
to prevail in rural areas of Romania.
[61, 62]
Interestingly,
Central European surveys have reported increased rates
of cancers affecting rural populations.
[63, 64]
Further
epidemiological studies are warranted to conrm this
hypothesis. Furthermore, non-BC HCC patients are
more frequently from outside Bucharest areas compared
with HBCV patients. HBV and HCV were recently
found to have the highest prevalence in the south of
Romania,
[28, 29]
including the Bucharest area.
[32]
Liver cirrhosis was present in a large number of
patients of the present series (72%). The prevalence
of liver cirrhosis in HCC patients displays some
geographical variability and is high everywhere (more
than 80%), except in sub-Saharan Africa.
[3, 65]
Although
rare in Europe, HCC on a non-brotic liver may result
from hepatitis B, alcohol abuse and infrequently from
chronic hepatitis C.
[66]
In the present series of patients
and as shown previously, liver cirrhosis was signicantly
less frequent in HCC without viral infection compared
with all other patient groups.
[47, 67]
This situation suggests
that some of the patients within the non-BC subset
were submitted to a more directly tumorigenic process
(either genetic or environmental). Liver cirrhosis
prevalence was signicantly lower in the HBV-only
patients compared with HCV-only or HBCV patients.
This nding conrms that HBV does not require
cirrhosis to systematically induce carcinogenesis.
[66]
The
highest rate of liver cirrhosis (90%) was observed in the
present study in patients with a co-infection of HBV
and HCV. Co-infection is known to generate intense
hepatic inammation that induces the stimulation of
brogenesis by cytokines, resulting in an accelerated
pathophysiologic process.
[15, 39, 57, 68, 69]
As a consequence,
co-infection is more strongly associated with HCC than
either single infection, suggesting a synergistic effect for
brogenicity and carcinogenicity.
[70]
HBV and HCV are
non-redundant inducers of hepatocarcinogenesis: HBV
is a DNA virus that is able to integrate into host genomic
DNA and may generate genomic instability or encode
proteins important in carcinogenesis, whereas HCV is a
strictly cytoplasmatic RNA virus endowed with different
tumor-promoting activities either indirectly through
chronic liver inammation or more directly through
viral products interacting with onco-suppressive or
oncogenic proteins.
[5]

Although no differences were observed between
the groups of the present series regarding the Child-
Pugh score, serum AFP level, Okuda or CLIP staging
systems, uninfected HCC patients were more frequently
assessed outside the Milan criteria compared with HBV-
and HCV-only/HBCV patients. Furthermore, patients
Hepatitis viruses and hepatocellular carcinoma
Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com 169
without viral hepatitis had signicantly more advanced
BCLC stages at diagnosis compared with HCV-only
or HBCV patients. It was previously shown that more
advanced CLIP and BCLC stages prevailed in patients
with HBV-only compared with HCV-only HCC.
[52]

Regarding the pathology characteristics, we observed
that in the present series, patients without viral
infection tend to have larger tumors compared with
all other groups (7 vs 4-5 cm), though these ndings
did not reach statistical signicance. Larger
[47, 69]
and
less differentiated
[69, 71]
tumors in patients with HCC
in the absence of viral infection have been previously
described. Because of their advanced ages and stages at
diagnosis combined with their larger tumors, one may
speculate that these HCC may have followed an indolent
growth for years. Nevertheless, further studies are
needed to demonstrate this feature. A more appropriate
explanation for advanced ages, stages at diagnosis and
larger tumors in the uninfected HCC patients of the
present series could be due to the poor effectiveness
of cancer surveillance in community practice, delayed
presentation or low-quality medical care. These features
must be corroborated with the fact that non-viral
HCC patients are more frequently from rural areas
where there is a lack of specialized medical centers and
where people are more reluctant to seek medical help.
Nevertheless, in the present study, the disease-free and
overall survival rates do not appear to be impaired for
patients from rural/outside Bucharest areas (Fig. 2).
However, a non-signicant trend towards a better
prognosis in patients coming from the Bucharest area
should be noted.
The impact of viral status on long-term outcome in
patients with HCC is controversial. Thus, some studies
have shown a signicantly poorer disease-free
[6, 27, 53, 72]

and overall survival rates in patients with HBV-/HCV-
only or co-infection,
[47, 72]
whereas other investigators did
not identify differences regarding the recurrence
[52, 69]

or overall survival rates
[15, 52, 53, 73]
between HCC patients
with or without viral infection or between HBV and
HCV patients
[15, 47, 54]
as appears to be the case in the
present series. Postoperative antiviral therapy may
potentially reduce the recurrence rates
[74]
and improve
overall survival
[38, 75]
after surgery for HCC with viral
infection. Nevertheless, interferon-alpha appears to
suppress tumor growth in HCC but promotes metastasis
capacity.
[76, 77]

Although statistical signicance was not reached,
the data of the present study showed a trend for better
disease-free and overall survival rates in HBV-only
patients compared with all other groups of patients;
a trend towards a worse long-term outcome was
observed in the HBCV group of patients with HCC.
This observation is at odds with a recent meta-analysis
that showed a tendency for better overall survival
rates in HCC patients without viral infection and an
impaired disease-free survival for HBV or HCV.
[22]
The
differences between the reported meta-analysis and the
outcome of the present study may be explained either
by the fact that uninfected HCC patients had more
advanced disease in Romania than in reported countries
or because the risk factors and clinico-biological
features of the tumors differ widely between different
patient cohorts.
The lack of a signicant difference in overall survival
between groups may be explained by the fact that there
were no signicant differences in regard to the most
important independent prognostic factors for overall
survival identied in the present series (i.e., number of
tumors and Edmonson-Steiner grading). Furthermore,
based on the identied independent prognostic factors
for disease-free survival in the present series, one could
expect to have a worse survival in the non-BC group
(because of the increased rates of advanced BCLC
stages). However, this feature could be balanced by the
signicantly reduced rates of liver cirrhosis compared
with all other groups. The trend for a worse disease-
free survival in the HBCV group could be explained
by the highest rate of liver cirrhosis (90%) in this
group compared with all other groups. The presence
of cirrhosis was identied as an independent risk factor
for poor disease-free survival in the present study. The
lack of statistical signicance for disease-free survival
rates in the HBCV group compared with all other
groups could be explained by the highest rate of liver
transplantations (31%); liver transplantation has been
identied as an independent prognostic factor for better
disease-free survival.
The present study is limited by its retrospective
design and should be interpreted with caution. Thus,
some data regarding clinics or pathology with a
potential impact on long-term outcome after surgery for
HCC were overlooked.
In conclusion, despite a lower incidence of liver
cirrhosis, uninfected patients with HCC are diagnosed
at advanced ages and stages, and these patients are
likely to have larger tumors. This nding could be
explained by the low effectiveness of cancer surveillance
in community practice. A careful denition of liver
cancer-prone individuals among the population free of
viral hepatitis should be developed, and a surveillance
program should be implemented either in community
or tertiary care facilities. Furthermore, an improvement
in the quality of medical care in rural areas, along with
Hepatobiliary & Pancreatic Diseases International
170 Hepatobiliary Pancreat Dis IntVol 13No 2 April 152014 www.hbpdint.com
the implementation of medical educational programs
for the general population, could contribute to an earlier
diagnosis in patients with HCC without viral infection.
The issue of the subset of young patients (<45 years)
developing HCC without viral infections should be
investigated in appropriate epidemiological studies.
Contributors: TAM and DT contributed equally to the paper. DT
and PI made the study concept and design. DS and GR acquired
the data. TAM, DT and PP made the interpretation of data.
TAM and DT made the analysis and drafted the manuscript. All
authors made the critical review of the manuscript for important
intellectual content. PI is the guarantor.
Funding: None.
Ethical approval: This study was approved by the Local Ethics
Committee.
Competing interest: No benets in any form have been received
or will be received from a commercial party related directly or
indirectly to the subject of this article.
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Received February 19, 2013
Accepted after revision September 10, 2013