REVIEWHepatocellular Carcinoma in Keio Affiliated Hospitals– Diagnosis, Treatment, and Prognosis of this Disease –Hidetsugu Saito,1 Tetsuya Masuda,2 Shinichiro Tada,3 Hirotoshi Ebinuma,4Yoshiyuki Yamagishi,4 Keisuke Ojiro,4 Mika Inoue5 and Toshifumi Hibi4

Inaida Research Center for Anti-aging Medicine in Hepato-Gastroenterology,
School of Medicine, Keio University, Tokyo, Japan2
Department of Internal Medicine, Nihon Kohkan Hospital, Kanagawa, Japan
3
Daiwa Shouken Clinic, Tokyo, Japan
4
Division of Gastroenterology and Hepatology,
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
5
Schering-Plough Center for the Study of Chronic Liver Diseases, School of Medicine, Keio University, Tokyo, Japan
1(Received for publication on January 5, 2009)(Accepted for publication on May 21, 2009)

Abstract
We have retrospectively investigated patients with hepatocellular carcinoma (HCC) (912 cases) treated in the Affiliated Hospitals of Keio University (the Keio Association for the Study ofLiver Diseases: KASLD) and here we review the recent diagnosis and treatment of HCC. HCC
is a major cause of death in Japan and a major etiology of this disease is chronic viral infection
such as hepatitis C virus (HCV) and hepatitis B virus (HBV). Screening of HCC by imaging
studies and measurement of serum tumor markers successfully prolonged survival of the patients in Japan. The prognosis of this disease has been determined by both tumor factors anddegree of liver function, and its staging is usually established with a recent system such as Japan Integrated Staging Score (JIS). The 5-year survival rate of JIS stage 0, 1, 2 and 3 were
68.3%, 51.9%, 25.8% and 16.6%, respectively in our cohort. Multivariate analysis using Cox
proportional hazard models showed that age (>65), HCV infection, tumor number, TB (>1.0),
AFP (>20) and PIVKA-II (>40) were significant factors affecting survival among the entire
patients. Major treatment strategies are hepatic resection, radio frequency ablation and transarterial chemo-embolization, but alternative treatments such as radiation, chemotherapy, andtheir combination have been used to reduce tumor sizes resulting prolongation of the survival
or maintenance of patients’ quality of life, while liver transplantation has not been popular inJapan. However, the overall survival continues to decrease from year to year, and does notshow a plateau phase in Kaplan-Mayer curve. These results suggest that the best way to improve survival can be achieved by prevention of the disease. Antiviral therapies have decreased the incidence of HCC, indicating that treatment for chronic hepatitis is the best way toprevent HCC development at present. (Keio J Med 58 (3) : 161－175, September 2009)

Keywords: prognostic scoring system, screening, small hepatocellular carcinoma, prevention, antiviral therapy

Introduction
Hepatocellular carcinoma (HCC) is the third and fourth

leading cause of cancer-related death in Japanese men
and women, respectively, and is the 5t h most common
cause of cancer worldwide. The incidence of HCC has

Reprint requests to: Hidetsugu Saito, MD, PhD, Inaida Research Center for Anti-aging Medicine in Hepato-Gastroenterology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, TEL: +81-3-3353-1211, FAX: +81-3-3351-8705, E-mail: hsaito@a2.keio.jp161Saito H, et al: HCC in Keio Affiliated Hospitals

162

Table 1 Patients and hospitals enrolled in this statistics for the KASLDInstitution

Number of patients

Data completed
Keio University Hospital
Saiseikai Chuo Hospital
Nihon Kohkan Hospital

211
244
106

Subtotal

561

Data incomplete
Kitasato Institute Hospital
Saitama Shakai Hoken Hospital
Keiyu HospitalTachikawa Kyosai HospitalTokyo Dental Ichikawa Hospital
Eiju Sogo Hospital
Kawasaki City Kawasaki Hospital
Subtotal
Total

increased in Japan in the past several decades and has recently increased dramatically in the United States andother Western countries, except for a small group of patients whose mortality showed favorable trends.1 The increase is primarily related to the spread of hepatitis C virus (HCV) infection, which peaked in the 1960s and1980s in Japan and the United States, respectively. Considerable attention has been paid to the emerging HCC
epidemic, which is often associated with hepatitis C andhepatitis B, and end-stage liver cirrhosis (LC) which occurs as a result of repetitive cycles of inflammation andrepair and is associated with the development of HCC.
End-stage liver cirrhosis and HCC can both seriously
impact the quality of life of patients.
In Western countries, liver transplantation has beenused successfully to treat patients with HCC;2 however,the shortage of donor livers and other technical reasons
limit the option for transplantation in some patients.3, 4 In
Japan, liver transplantation for HCC is less common due
to the shortage of cadaveric donor organs.5 Additionally,
strategies to reduce tumor growth are important for patients who are awaiting liver transplantation. For that
purpose, ablation techniques or chemoembolization tocontrol local tumor growth are very useful. Unlike withother cancers, the treatment indication strategy for HCC
depends not only on the surgical staging of cancer
growth and degree of spread but also on residual reserved liver function. These considerations determine
whether treatment modalities other than surgery, such as
local ablation techniques, should be employed. Thus, thetreatment of HCC has progressed dramatically during thepast few decades since our last review,6 and the prognosis of HCC has improved in parallel with our understating of the nature of the disease. Several review articles
on HCC have been published recently7 as well as clinicalguidelines for HCC from several organizations around

161
91
27
27
19
14
12
351
912

the world.8-11
In the present report, we summarized data of patientswith HCC who had been previously admitted to the Keio
University Hospital and the Keio Affiliated Hospitals,
which was integrated as the Keio Association for the
Study of Liver Diseases (KASLD), and review the treatments and prognoses of this disease.
Patients Studied
In 2007, the core members of the fourth KASLD meeting resolved to collect clinical data from HCC patients
through the affiliated hospitals of Keio University to better understand recent trends in HCC treatment. The data
were analyzed retrospectively. Survival rates were analyzed using the Kaplan-Meier product limit survival
method and the log-rank test was used to determine statistical significance. Data from patients in different
groups were compared using the Mann-Whitney U test
for continuous variables. Categorical variables were analyzed by x2 test or Fisher’s exact test. We used Cox proportional hazard models to examine the potential determinants of survival. The start date used for survival analysis was the date of the first diagnosis. All statisticalanalyses were performed using the Statistical Programfor Social Sciences (SPSS 13.0 for Windows; SPSS, Inc.,
Chicago, IL). Statistical significance was defined by a P
value less than 0.05.
The list of the hospitals and the number of patients included are summarized in Table 1. Baseline characteristics of the patients are summarized in Table 2. The age
distribution of patients with HCC (at the time of diagnosis) is shown in Figure 1; a majority of the patients were
elderly, probably because the main cause of HCC is
HCV infection, and progression of liver fibrosis depends
on age and duration of infection.1 2, 1 3 However, elderly

Keio J Med 2009; 58 (3): 161－175

163

Table 2 Baseline characteristics of the patients

Age at diagnosis
GenderHCV-AbHBsAg
BMI
DM
Tumor size (cm)Tumor number
TB (mg/dL)
Alb (g/dL)
PT%
ICG(15) (%)
AFP (ng/mL)
PIVKA-II (pg/mL)Child-Pugh
TNM
CLIP
JIS
Treatment
Milan
Observation period (W)

M/F
–/+
–/+
–/+
1/2/3/4/5/6≤

A/B/C
I/II/III/IVa/IVb
0/1/2/3/4/5/6
0/1/2/3/4/5
Ope/RFA/TACE/others/none
within/out

NumberMedianRange

912
631/251201/538
570/86524
484/299744
449/123/43/18/3/111
628
620
615
162
576
395
422/161/57
144/117/70/24/5
132/112/56/20/10/9/7
89/107/90/40/6/11
86/134/317/189/87
510/227382

68

30 – 9622.7

13.8 – 33.2

2.3

0.7 – 20.0

0.86
3.8
79
22.9
22.0
36

0.20 – 66.0
1.9 – 8.8
29 – 107
2.8 – 89.2
0.5 – 874560
0 – 349000

118.8

0.6 – 702.7

HCV-Ab: hepatitis C virus antibody, HBsAg: hepatitis B virus antigen, BMI: body mass index, DM: diabetes mellitus, TB: serum total
bilirubin level, Alb: serum albumin level, PT: prothrombin time, ICG: indocyanin green test.

patients develop HCC more often than younger patients
despite their lower grade of fibrosis,1 4 suggesting thatthe impact of aging is stronger for fibrosis for development of HCC. It has been said that male gender is themost significant risk factor of HCC. The peak age of female patients was older than male patients and aging factor may be a main causing factor in female patients.
Etiology of HCC
The major clinical risk factor for development of HCC
is cirrhosis of the liver. The major risk factors for the development of LC are HBV- and HCV-infection andchronic heavy alcohol drinking.15 HCV has been previously shown to account for the majority of cases of HCC
in Japan,16 and our findings were similar; the frequency
of HCV was 69% (Fig. 2). Figure 3 shows the proportion of cases with liver diseases due to different causes
among patients admitted to Keio University Hospitalduring the last 4 years. It is clear that HCC was the major cause of admissions due to liver diseases. HBV was
the second leading cause of HCC (seen in 10% of cases)
and the infections were acquired early in life throughtransmission from mother to offspring in most HBV cases (Fig. 2). Chronic alcohol use of greater than 80 g/day
for more than 10 years increased the risk of HCC
5-fold,1 7 and chronic alcohol use in HBV and HCV infection (seen in 1.78% of cases in our study) doubles therisk as compared with either infection alone. Figure 4
shows the causes of LC in patients consulting to Keio
University Hospital. Chronic HCV infection was a major
cause of cirrhosis; this finding is comparable to nation-

wide in Japan, but differs from the trend in Westerncountries, where alcoholic cirrhosis remains a major
cause of LC. Insulin-resistance and the metabolic syndrome are thought to be predisposing factors non-alcoholic steatohepatitis (NASH) and cirrhosis in 10% to
20% of cases, 1 8 and diabetes and obesity have beenshown to double the risk of HCC.19 These patients might
be included in the unknown category in Figure 2. The
cause of LC in 1998 did not include NASH; however, in
2008, NASH was included as one of the causes in ourstudy (Fig. 4).
Screening of HCC
Although potentially curative treatment for early stageof HCC was achieved with a 3-year survival rate in therange of 60-80%, the rate is as low as 10% for late-stage
disease worldwide. These observations strongly suggestthat screening practices allowing for improved diagnosis
at an early stage of this disease could have a large impact
on survival. Recently, prospective cohort studies and arandomized controlled trial (RCT) suggested that HCC
screening of patients with chronic liver diseases can improve survival rates;2 0-2 2 however, this notion remains
controversial.2 3 Many clinicians support screening for
HCC and believe that it would be unethical to perform arandomized controlled trial to demonstrate its efficacy.24
The Japan Society of Hepatology (JSH) recommends
HCC screening by a tumor marker measurement (presence of 2 of 3 markers: alpha-fetoprotein [AFP], lectinbound AFP [AFP-L3] or des-γ carboxy prothrombin,
also known as vitamin K antagonist-II [PIVKA-II]) ev-

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Saito H, et al: HCC in Keio Affiliated Hospitals

Fig. 1 Age distribution of patients with hepatocellular acrcinoma admitted in the affiliated hospitals of Keio University.

Fig. 2 Causes of hepatocellular carcinoma in our cohort.

ery 3 months, in addition to screening once every 6months examination by abdominal ultrasonography (US)and annually by computed tomography (CT) scanningfor patients with chronic hepatitis, and imaging studies
every 3-4 months in patients with LC.2 5 Although theAmerican Association for the Study of Liver Diseases(AASLD) and European Association for the Study ofLiver Diseases (EASL) both recommend HCC screening, the National Cancer Institute (NCI) has not renewed
its statement that “based on fair evidence, screening
would not result in a decrease in mortality from hepatocellular cancer”. Following the rapid increase in thenumber of patients with HCC in Western countries, hepatologists in these countries recognized the importanceof management. The number of HCC cases in Japan
seems to have peaked several decades earlier than inWestern countries.
The effectiveness of US depends on the experience ofthe examiner, the equipment available, the presence ofLC, and the size of the tumor. It has generally been reported that the sensitivity of US for detecting tumor nodules is greater than 60% and the specificity is greaterthan 90%, and that the sensitivity decreases in cirrhotic
livers. A serum AFP level greater than 20 ng/mL (the upper limit of normal) has low sensitivity for detecting
HCC (25-65%) and is not suitable as the sole screening

Fig. 3 Proportion of cases with liver diseases in patients
admitted to Keio University Hospital during the last 4 years.
HCC: hepatocellular carcinoma, LC: liver cirrhosis, CH: chronic
hepatitis, AH: acute hepatitis, ALC: alcoholic liver diseases,
Meta: tumor metastasis from other organs, LD: liver dysfunction,
NAFLD: non-alcoholic fatty liver diseases, DILI: drug-induced
liver injury, AIH: autoimmune hepatitis.

test. Elevated serum AFP levels are sometimes observedin patients with chronic liver disease with a high degreeof hepatocyte regeneration. In such cases, AFP-L3 usually distinguishes true HCC from such a condition described above. Recent studies have reported that HCC
surveillance strategies using both AFP and US improvethe cost-effectiveness (in quality adjusted life years) oftherapy.26, 27 It is thought that high-risk patients for HCC
include all patients with cirrhosis and some HBV-infected patients irrespective of cirrhosis (age >40 years in
men and >50 years in women).
Diagnosis of HCC
Because screening for HCC has recently become common in Japan, small or early-stage HCC is often diagnosed prior to the presentation of specific clinical symptoms. In contrast, right upper quadrant abdominal pain,
early satiety and weight loss are recognized as the textbook manifestations of HCC in Western countries. These
symptoms are thought to occur in more advanced cases.

Keio J Med 2009; 58 (3): 161－175

165

Fig. 4 Causes of liver cirrhosis in patients managed at Keio
University Hospital in 1998 and 2008. NASH (non-alcoholicsteatohepatitis) is a newly recognized disease category. HBV:
hepatitis B virus-related, HCV: hepatitis C virus-related, ALC:
alcoholic liver cirrhosis, PBC: primary biliary cirrhosis, AIH:
autoimmune hepatitis, NASH: non-alcoholic steatohepatitis,
NBNC: non-B, non-C, hepatitis-related.

Histological examination is not usually required for the
diagnosis of HCC, unlike with cancers in other organs. A
consensus statement －that a diagnosis of HCC can bemade based on imaging findings of nodules greater than
2 cm in diameter－ had been previously issued by the
EASL and United Network for Organ Sharing criteria.28
We can diagnose nodules greater than 2 cm in diameteras HCC if any 2 imaging studies, including US, CT,magnetic resonance imaging (MRI) or hepatic angiography, show increased vascularity. Alternatively, 1 positive
imaging result and an AFP level greater than 400 ng/mL
are diagnostic. Tumors enhanced with contrast on rapidsequence imaging with delayed hypointensity in the portal venous phase (Fig. 5) are almost always accurately
diagnosed as HCC; the reported sensitivity and specificity were 100% and 98.8%, respectively.29-31 This finding
originated from previous investigations on the correlation between blood supply and the grade of malignancy
of hepatic nodules.32 The contrast material for US diagnosis of HCC has been recently developed to assist with
the imaging of vascularity and Kupffer cells, in part because Kupffer cell are absent in HCC tissue.33-35
Imaging for lesions less than 2 cm diameter and casesof indeterminate radiologic findings do not have sufficient accuracy to distinguish HCC from other conditions.
Serial US or other radiologic examinations are recommended every 3 months or alternatively, fine needle biopsy can be performed. There is a small but definite risk
(0.003%-5%) of tumor seeding from an invasive biopsy.8
Furthermore, the false-negative rate from biopsy of lesions less than 2 cm diameter is approximately 30% to
40%.8 Contrast materials for MRI imaging have been recently developed, which are captured by Kupffer cells

Fig. 5 Typical small hepatocellular carcinoma detected bycomputed tomography scanning. The tumor is stained at arterial
phase (a) and washed out early at late phase (b). Allows show thetumor.

via phagocytosis and enable imaging of Kupffer cell inclusion.36-38
As was already described above, AFP, AFP-L3, andPIVKA-II are the most commonly used serum tumor
markers. Each marker alone has poor diagnostic ability
for detecting HCC at any level of pretest risk, but can be
useful in combination with imaging criteria.
Natural History of HCC
Prospective studies have shown that HCC most often
develops through a progressive pathway from premalignant nodular lesions in the cirrhotic liver to cancerous lesions.6 The annual risk for HBV, HCV, and alcohol-induced cirrhosis are estimated at 2-3%, 1-8%, and 1%, respectively. HCC can also develop in the absence of cirrhosis in HBV carriers at a rate of 0.26% to 0.6% per
year.
Several risk factors for the development of HCV-related HCC have been identified such as age, degree of liver
fibrosis, male sex, alcohol consumption, positivity for
HBsAg, and high AFP level. Akuta et al. recently reported that amino acid substitutions of the HCV core region

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166

Table 3 Investigated factors and their significance in correlation to the survival of patients with HCC (by log-rank test)
Factors

Categorynp value(log rank)

Age<55/55≤<65/65≤
M/F
none<20/20-60/60?
<60/60≤–/+–/+Alcohol/HBV/HCV/Others
<2/2≤
<3/3≤
<4/4≤
1/2/3/4/5/6≤
Solitary/multiple
≤3/3<
A/B/C
Stage I/II/III/IVa/IVb
0/1/2/3/4/5/6
0/1/2/3/4/5<25/25≤–/+
Ope/RFA/TACE/others/none
within/out of<2/2-3/3≤<1/1≤<2.8<3.5<<3.5<<40/40-70/70≤<70/70≤<15/15-40/40≤<25<<20/20-200/200-400/400≤<20/20≤<40/40-400/400≤<40/40≤679

0.00570.00490.99090.78700.44500.00100.74170.0005<0.0001
0.00040.0123<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001
0.0496
0.3445<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001
0.00090.00050.14070.0845<0.0001<0.0001<0.0001<0.0001

GenderAlcohol (g)
HCV
HBsAg
Etiology
Tumor size (cm)Tumor numberChild-P
TNM
CLIP
JIS
BMI
DM
Treatment
Milan
T.Bil (mg/dL)
Alb (g/dL)
PT (%)ICG15 (%)
AFP (ng/mL)
PIVKA-II (mAU/mL)

651
504
542
476
671
588
594
488
316
285
303
403
617
636
589
478
471
469
107
441
315

n

HCV (+) cases
p value

408
390
365

0.07830.03940.06990.71330.7009320

0.8896352

0.01610.57940.7926<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001<0.00010.2434
0.6338<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001
0.00300.00070.24770.17500.0002<0.0001
0.00350.0310

363
358
239
217
229
299
365
379
362
350
347
341
67
325
218

HCV: hepatitis C virus antibody, HBsAg: hepatitis B virus antigen, BMI: body mass index, DM: diabetes mellitus, TB: serum total
bilirubin level, Alb: serum albumin level, PT: prothrombin time, ICG: indocyanin green test.
: different between whole patients and HCV infected patients.

are correlated with hepatocarcinogenesis.39 Studies haveconfirmed that high HBV viral load is a major risk factor
for the development of HCC in patients with chronic
HBV infection and is also a risk factor for recurrence after resection.40-43 Recent large prospective studies haveconfirmed that coffee consumption decreases the risk ofliver cancer,4 4-4 6 however, it has not been determinedthat coffee drinking really decrease the incidence of
HCC. Other risk factors for development of HCC, including obesity and type 2 diabetes, have been described
elsewhere.47, 48 In our cohort, BMI significantly affected
the survival of patients with HCC; notably, severe obesity (BMI 35-40) was associated with a 5-fold higher
16-year death rate.47
Although treatment intervention was included in thecourse of patients with HCC, we analyzed which factors
affected the survival of patients with HCC (Table 3).
Among the entire cohort of patients, survival was significantly affected by age (<55, <65), HCV+/–, causes of
HCC, tumor size, tumor number, Child-Pugh stage,
TNM stage, CLIP score, JIS stage, BMI (<25), treatment

modality, Milan criteria, total bilirubin levels (TB), albumin level (ALB), prothrombin time, AFP level, and PIVKA-II level. Among patients with HCV infection, age(<55), tumor size (3 cm≤), and BMI did not significantly
impact survival. These findings suggest that HCC patients with HCV infection are older and their tumor sizes
are smaller as compared with patients with HCC associated with other etiologies. The tumors found in HCV-infected patients were smaller because these patients wereintensely screened and the tumors were detected earlier.
Multivariate analysis using Cox proportional hazard
models showed that age (65≤), HCV infection, tumor
number, TB (1.0≤), AFP (20≤) and PIVKA-II (40≤) weresignificant factors affecting survival among the entire
patient cohort (Table 4a). Among patients with HCV infection, tumor number, age (65≤), tumor size, tumor
number, TB (1.0≤), and AFP (20≤) were significant factors (Table 4b). Table 4a shows that survival rates weresignificantly higher among HCC patients with HCV infection versus other etiologies. This finding seems curious, but it suggests that HCC screening was routinely

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167

Table 4 Significant factors affected survival of patients with HCC found by multivariate analyses
a: Whole patients
FactorAge
HCV
Tumor number
TB (mg/dL)
AFP (ng/mL)
PIVKA-II(mAU/mL)

65≤
+
2≤
1.0≤
20≤
40≤

hazard ratio

95% CI

p value

2.703
0.505
2.321
2.007
1.964
1.490

1.668 – 4.381
0.305 – 0.837
1.542 – 3.493
1.328 – 3.031
1.284 – 3.006
0.986 – 2.252<0.0001
0.0080<0.0001
0.00090.00190.0584

hazard ratio

95% CI

2.345
1.940
2.546
1.489
2.107

1.381 – 4.070
1.196 – 3.146
1.579 – 4.105
0.915 – 2.424
1.441 – 4.021

b: HCV infected patients
FactorAge
Tumor size
Tumor number
TB (mg/dL)
AFP (ng/mL)

65≤
2≤
2≤
1.0≤
20≤

0.00260.00730.00010.10940.0008

HCV: hepatitis C virus antibody, TB: serum total bilirubin level.

performed for the HCV-infected patients and that thisscreening system worked well to improve survival.
There were 56 patients with non-B, non-C (NBNC)
HCC. Although number of these patients was insufficient
to conclude the result, survival was significantly affectedby age (65≤), gender and the disease staging (Table 5).
Tumor stage seemed to be more advanced among thesepatients as compared with cases of HCC associated withother etiologies, presumably because they had not beenpreviously screened for HCC. But as shown in this table,
there is no significant characteristic of the patients in thiscategory (no significant high-risk factor); therefore,
screening of these patients is very difficult.
Treatment and Prognosis of HCC
In Japan, the management of HCC involves multiple
disciplines, including hepatology, surgery, diagnostic andinterventional radiology and pathology. Liver transplantation has not been frequently performed so far in Japan,
and surgery and loco-regional treatment, such as ablation, remain the 2 major curative modalities for earlystage HCC. Before choosing a modality of treatment, tumor staging should be evaluated precisely. HCC staging
is also important for the prognosis of HCC. Two disease
processes, namely, the tumor and the underlying cirrhosis, complicate the prognosis of HCC simultaneously,
and many studies have suggested that cirrhosis rather
than the size of the tumor mass is the main determinantof the prognosis. The median survival time of untreatedpatients with newly diagnosed HCC is weeks to months
in Western countries, where screening of HCC only recently became popular. Survival time could be improvedby screening for HCC among high-risk groups. A number of factors are associated with a poor outcome: malesex, advanced age, etiologic agent, presence of morethan 1 risk factor, tumor size, tumor number, doublingtime of nodules, vascular invasion, and distant metastasis. The complicated and heterogeneous nature of HCC
has led to the development of a variety of staging systems.
Overall survival curve in our cohort is shown in
Figure 6a. One-, 3-, and 5-year survival rates were 86%,
64%, and 44%, respectively, which were higher thanthose obtained from the Japanese nationwide surveillance (year 2002-3) made by the Liver Cancer Study
Group of Japan (LCSGJ) including 96,404 HCC cases.
Figure 6b shows the survival curve in patients withchronic HCV infection. The survival rates at 1-, 3-, and5-year were 91%, 70%, and 49%, respectively, whichwere higher than those of whole patients. This result also
indicates that screening of patients with chronic liverdiseases makes better outcome. The measurement of serum AFP and PIVKA-II levels is an easy way of screening. In our case series, elevation of serum levels of AFP(>20; normal limit) (Fig. 7a) and PIVKA-II (>40; normal limit) (Fig. 7b) significantly affected the survival ofpatients with HCC. It was suggested that AFP levels
more than 400 ng/mL and/or PIVKA-II level more than
400 mAU/mL were significant bad prognostic markers.
The 5-year survival rates of these patients were around20%.
The Tumor Node Metastasis (TNM) classification,
mostly used for solid tumors, has extreme limitations because it does not include the severity of underlying cirrhosis or residual liver function. Many prognostic staging systems have been established; the first attempt byProfessor Okuda in Japan,49 followed by systems developed by Cancer of Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), Groupe d’Etude duTreatment du Carcinome Hepatocellulaire (GRETCH),
Chinese University Prognostic System (CUPI), and Ja-

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168

Table 5 Investigated factors and their significance in correlation to the survival of patients with non-B, non-C HCC
Factors

Categorynp valueAge<55/55≤<65/65≤M/F
none/<20/20-60/60≤<60/60≤
<2/2≤
<3/3≤
<4/4≤
1/2/3/4/5/6≤
Solitary/multiple
≤3/3<
A/B/C
Stage I/II/III/IVa/IVb
0/1/2/3/4/5/6
0/1/2/3/4/5<25/25≤–/+
Ope/RFA/TACE/others/none
within/out of<2/2-3/3≤<1/1≤<2.8/2.8-3.5/3.5≤<3.5/3.5≤<40/40-70/70≤<15/15-40/40≤<25/25≤<20/20-200/200-400/400≤<20/20≤<40/40-400/400≤<40/40≤37

0.11910.00710.00220.08090.71220.20250.18900.30470.0006
0.0990<0.0001<0.0001
0.00020.0007<0.0001
0.09180.5941<0.0001
0.01920.00020.00940.01280.02260.04550.44850.17350.07950.1206
0.29970.2706

GenderAlcohol (g)Tumor size (cm)Tumor numberChild-Pugh
TNM
CLIP
JIS
BMI
DM
Treatment
Milan
TB (mg/dL)
Alb (g/dL)
PT (%)ICG 15 (%)
AFP (ng/mL)
PIVKA-II (mAU/mL)

37
33
30
34
31
17
18
16
23
36
36
31
29
29
30
8
26
20

HCV: hepatitis C virus antibody, HBsAg: hepatitis B virus antigen, BMI: body mass index, DM: diabetes mellitus, TB: serum total
bilirubin level, Alb: serum albumin level, PT: prothrombin time, ICG: indocyanin green test.
: Significantly different factors.

pan Integrated Staging Score (JIS). It remains controversial as to which of these systems is best for staging HCC.
The TNM system is popular for surgical patients but
this system is not suitable for staging HCC because it
does not include variables related to liver function. Thissystem was revised in 2002 and the new version has
been demonstrated to be more accurate.50, 51 The prognosis of patients with HCC in our cohort was determinedby Kaplan-Meyer analysis and it differed significantly
according to TNM staging (Fig. 8a) and Child-Pughclassification (Fig. 8b). These findings suggest that the
prognosis of patients with HCC depends not only on tumor progression but also on reserved liver function.
The Okuda staging system49 was the first staging system to include both tumor stage and factors related toliver function, such as tumor size, ascites, bilirubin level
and albumin level. However, while commonly acceptedin Western countries until a few years ago, this system
has proven to be inadequate for patients with early HCC.
The system was first proposed in 1985 based on a retrospective cohort of 850 patients in Japan, where cases
were typically advanced at the time of initial diagnosis.
It failed to include recently identified factors of importance such as vascular invasion, portal vein thrombosis,
and AFP levels. The CLIP system5 2 includes many fac-

tors and was found to be useful even in Japan53, but theinclusion criteria are too broad, which would reduce its
value in cases of early HCC. The prognosis of our cohort
was well correlated with this staging system (Fig. 9).
However, the prognosis of patients in advanced disease,such as CLIP scores 4-6, did not well differentiated eachother. The BCLC system,2 8 derived from the results ofsurgical treatment of early HCC and the natural historyof untreated HCC, has also been validated by several
groups worldwide,5 4-5 6 and in patients who underwent
ablation.57 The CUI system was established based mainly on HBV-associated patients but only 10% of the patients received curative treatment, and it is considered tobe complicated and non-validated.58 The GRETCH system was based on a study in France which included
mainly patients with alcoholic liver disease;59 its validity
appears to be poor.5 5, 5 6, 6 0, 6 1 Lastly the JIS system was
proposed in 2003 by Kudo et al. using a combination of
the Child-Pugh score and the modified TNM classification according to LCSGJ.62 This system is more suitablefor patients with early HCC, and a recently modified JIS
system proposed by Nanashima et al.63 was shown to be
useful for predicting the prognosis of patients receiving
resection.64 In Japan, patients with HCC, who always receive screening at the high-risk stage and the tumor is al-

Keio J Med 2009; 58 (3): 161－175

Fig. 6 Overall survival rates for whole patients (a) and patientswith chronic hepatitis C virus (HCV) infection (b). One year,
3-year, and 5-year survival rates of whole patients were 86%,
64%, and 44%, respectively, while those of HCV-infected patientswere 91%, 70%, and 49%, respectively.

ways diagnosed in its early phase, may be best evaluatedusing the JIS system. Patients with HCC in our cohort
were analyzed according to the JIS scoring system and it
showed that the prognosis was well distinguished, especially in the early stages (Fig. 10). It was suggested thatthe prognosis of HCC is better predicted by the JIS scoring system than the CLIP scoring system in our cohort orJapanese patients with HCC (Fig. 9 and 10).
A treatment modality is selected according to a proposed algorithm for the treatment of HCC.10, 65 Very early HCC, presenting with a single lesion <2 cm, is treatedwith resection and radiofrequency ablation (RFA), which
both offer similar 5-year survival rates. RFA is less invasive and is associated with fewer complications and lower cost.66 The choice of therapy depends on the tumor location, degree of liver function, and the presence of comorbidities. Liver function is preserved in early HCC
when there is a solitary nodule or up to 3 nodules, each ≤3 cm diameter. Such patients are candidates for livertransplantation according to the Milan criteria67 but they169

Fig. 7 Overall survival rates according to alpha-fetoprotein(AFP) levels (a) and vitamin K antagonist (PIVKA)-II levels(b). Statistically significant difference was observed among 4
categories in AFP (p<0.0001 by log-rank test) and among 3
categories in PIVKA-II (p<0.0001 by log-rank-test).

can also be treated by resection or RFA with the possibility of a long-term cure. Patients with compensated cirrhosis and without HCC-related symptoms or vascularinvasion who fall outside of the criteria for very early or
early HCC (intermediate stage) are always treated withtransarterial chemoembolization (TACE), which leads toa 23% improvement in the 2-year survival. Down-staging by single or combined therapy with TACE and RFA
greatly improves posttrasplantation outcome if the patients are carefully selected.68 Patients with vascular invasion or extrahepatic spread are considered to be at anadvanced stage and TACE may increase survival amongsome of these patients. However, insufficient treatment
by TACE seems to increase in the expression of vascularendothelial growth factor (VEGF) and/or basic fibroblast
growth factor (b-FGF) in the liver, inducing the possibility of an active angiogenesis and an extended invasiveness of HCC.6 9 We compared the survival rates of patients in JIS score 0-1 (n=128) according to the firsttreatment modality (Table 6). Five-year survival rates of170

Saito H, et al: HCC in Keio Affiliated Hospitals

Fig. 9 Overall survival rates according to Cancer of Liver Italian
Program (CLIP) scores in whole patients. Statistically significant
difference was observed among 7 categories (p<0.0001 by
log-rank-test).

Fig. 8 Overall survival rates according to Child-Pugh grades (a)and TMN stages (b) in whole patients. Statistically significant
difference was observed among categories in both systems(p<0.0001 by log-rank test).

patients received hepatic resection, RFA, TACE, andpercutaneous ethanol injection (PEI) were 89.3%, 70.8%,
44.6%, and 43.2%, respectively.
Clinical trials for patients with advanced-stage HCC,
which includes progressive liver failure, tumor growthwith vascular involvement, extrahepatic spread, andphysical impairment, have shown no clear benefits.70-75
A recent RCT showed that sorafenib, a multikinase inhibitor of raf kinase, VEGF2, VEGF-receptor (R)3, andplatelet-derived growth factor receptor (PDGFR)-β kinases, improved overall survival by about 3 months
among patients at BCLC stage C as compared with placebo.76 Another option may be focused radiation therapy(hypofractionated stereotactic radiotherapy), which has
also been considered recently for the treatment of HCC,
especially in cases with portal thrombosis or lesions justunder the diaphragm. 7 7 Carbon ion radiotherapy has
been utilized in some institutions in Japan; a favorable

Fig. 10 Overall survival rates according to Japan Integrated
Staging (JIS) scores in whole patients. Statistically significant
difference was observed among 6 categories (p<0.0001 by
log-rank-test).

result was obtained but the procedure is still restricted toa small proportion of HCC.78 Interferon (IFN) is an antitumor drug candidate and is used as systemic treatment
for HCC due to chronic HCV- or HBV-infection. Our invitro studies demonstrated that IFN has an anti-cancer
effect in addition to its viral elimination effect.79-84 Recent studies reported favorable clinical outcomes with
IFN usage in cases of advanced-stage HCC.47, 85, 86 Therapies combining anti-cancer agents, delivered systemically or transarterially, in combination with TACE or thatwithout embolization (TAI) have been utilized in Japan
under institutional ethical approval, but no clear evidence has been reported.

Keio J Med 2009; 58 (3): 161－175

171

Table 6 The survival rates of patients with HCC in the JIS score 0-1
TreatmentnHepatic resection
RFA
TACE
PEI

24
33
44
27

Survival rate
1-year3-year5-year

100%
96.5%
95.2%
96.2%

95.2%
70.8%
79.2%
88.5%

89.3%
70.8%
44.6%
43.2%

RFA: radio frequency ablation therapy, TACE: trasarterial chemo-embolization, PEI: percutaneous ethanol injection therapy.

The Future of HCC Treatment
The mechanisms of HCC pathogenesis are graduallyclarifying. Several tumor suppressors or protooncogenes
are known to be mutated in HCC, including p53, Rb, andinsulin-like growth factor (IGF),4 8, 8 7 and intracellularsignaling pathways, such as VEGF, endothelial growth
factor (EGF), and their down-stream signaling cascades,
have been shown to contribute to the growth of HCC.88
Genome-wide analysis of gene transcription in the liver
has recently revealed that some gene expression profiles
consistently change from chronic hepatitis to HCC,8 9
suggesting that some key molecules to accelerate or inhibit tumor development might be discovered in future.
Imatinib, an inhibitor of several tyrosine kinases, is another agent that targets hepatic cancer progenitor cells.90
These new agents are very encouraging candidates forthe treatment for HCC in the future. Immunologic stimulation may be another future therapeutic candidate for
HCC.91 It has also been demonstrated that it is possible
to predict HCC based on expression-profiling of formalin-fixed, paraffin-embedded liver tissue.9 2 Several possible preventive agents for HCC have been identified,such as retinoids,9 3-9 5 branched-chain amino acid supplementation, 9 6 vitamin K, 9 7 and anti-viral therapies,9 8-1 0 2 and these agents may help to overcome thedifficulties in treating advanced cases of HCC. A recent
investigation has indicated that therapy to resolve hepatic
fibrosis may also be useful for preventing the development of HCC.1 0 3 Among these various therapeutic modalities, resolution of liver cirrhosis using heat shockprotein 47 is the most promising in my opinion,1 0 4 because this therapy may not only prevent HCC development but also improve liver function by resolution of liver cirrhosis.
The overall survival of patients with HCC continues todecrease from year to year, and does not show a plateau
phase in Kaplan-Mayer curve, as was shown in our cohort, which is trend that is quite different from that observed with other types of cancer. These results suggestthat the best way to improve survival of patients with
HCC through prevention of the disease. It has been confirmed that IFN therapy for chronic HCV infection decreases the incidence of HCC. Nucleoside or nucleotide

analogues for chronic HBV infection also decrease theincidence of HCC. This outcome has been encouraging
to hepatologists and we continue to treat patients withchronic liver diseases as we have done for chronic hepatitis C during the last few decades105-111 until HCC is finally eradicated.
Acknowledgements
We thank all the members of the KASLD who offered
their clinical data to establish the clinical trends of the
Keio Medical Society. We especially thank Ms. Mika Inoue for her generous assistance to this work. We also
thank doctors, Nobuhiro Tsukada, Norio Maeda (Saiseikai Chuo Hospital), Yasutaka Inagaki (Nihon Kohkan
Hospital), Satoshi Tsunematasu, Naoki Kumagai, Kanji
Tsuchimoto (Kitasato Institute Hospital), Takeshi Yoshida (Saitama Shakai Hoken Hospital), Hiroshi Nagata,
Shigeyuki Zeki, (Keiyu Hospital), Kazuo Kashiwazaki(Tachikawa Kyosai Hospital), Jiro Nishida (Tokyo Dental Collage Ichikawa Hospital), Yoshinori Horie, Masahiro Kikuchi (Eiju Sogo Hospital), Daisuke Ito, Hanae
Takagi (Kawasaki City Kawasaki Hospital) for their special efforts.
References
1.
2.
3.
4.
5.

6.
7.

Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C:
Trends in mortality from hepatocellular carcinoma in Europe,
1980-2004. Hepatology 2008; 48: 137－145
Fisher RA, Maluf DG, Wolfe L, Williams B, Cotterell A, Stravitz
RT, Heuman D, Posner M: Is hepatic transplantation justified forprimary liver cancer? J Surg Oncol 2007; 95: 674－679
Llovet JM, Schwartz M, Mazzaferro V: Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005;
25: 181－200
Molmenti EP, Klintmalm GB: Liver transplantation in association
with hepatocellular carcinoma: an update of the International Tumor Registry. Liver Transpl 2002; 8: 736－748
Sugawara Y, Makuuchi M: Advances in adult living donor livertransplantation: a review based on reports from the 10th anniversary of the adult-to-adult living donor liver transplantation meeting in Tokyo. Liver Transpl 2004; 10: 715－720
Saito H, Tsuchiya M: Recent advances in the study of hepatocellular carcinoma. Keio J Med 1992; 41: 195－204
El-Serag HB, Marrero JA, Rudolph L, Reddy KR: Diagnosis andtreatment of hepatocellular carcinoma. Gastroenterology 2008;

172
134: 1752－1763
8. Parikh S, Hyman D: Hepatocellular cancer: a guide for the internist. Am J Med 2007; 120: 194－202
9. Bruix J, Sherman M: Management of hepatocellular carcinoma.
Hepatology 2005; 42: 1208－1236
10. Makuuchi M, Kokudo N: Clinical practice guidelines for hepatocellular carcinoma: the first evidence based guidelines from Japan.
World J Gastroenterol 2006; 12: 828－829
11. Kokudo N, Sasaki Y, Nakayama T, Makuuchi M: Disseminationof evidence-based clinical practice guidelines for hepatocellular
carcinoma among Japanese hepatologists, liver surgeons and primary care physicians. Gut 2007; 56: 1020－1021
12. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N,
Arakawa Y, Hashimoto E, Hirota K, Yoshida H, Ohashi Y, Omata
M: Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005; 142: 105－114
13. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, et al: Risk
factors for hepatocellular carcinoma among patients with chronic
liver disease. N Engl J Med 1993; 328: 1797－1801
14. Miki D, Aikata H, Uka K, Saneto H, Kawaoka T, Azakami T,
Takaki S, Jeong SC, Imamura M, Kawakami Y, Takahashi S, Itamoto T, Asahara T, Arihiro K, Chayama K: Clinicopathologicalfeatures of elderly patients with hepatitis C virus-related hepatocellular carcinoma. J Gastroenterol 2008; 43: 550－557
15. Yamagishi Y, Horie Y, Kajihara M, Konishi M, Ebinuma H, Saito
H, Kato S, Yokoyama A, Maruyama K, Ishii H: Hepatocellular
carcinoma in heavy drinkers with negative markers for viral hepatitis. Hepatol Res 2004; 28: 177－183
16. Chiba T, Matsuzaki Y, Abei M, Shoda J, Aikawa T, Tanaka N, Osuga T: Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis. J
Gastroenterol 1996; 31: 552－558
17. Morgan TR, Mandayam S, Jamal MM: Alcohol and hepatocellular
carcinoma. Gastroenterology 2004; 127: S87－96
18. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto
M: Expanding the natural history of nonalcoholic steatohepatitis:from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134－140
19. El-Serag HB, Tran T, Everhart JE: Diabetes increases the risk ofchronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460－468
20. Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP: Screening for hepatocellular carcinoma among veterans with hepatitis C
on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol 2007; 5: 508－512
21. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial ofscreening for hepatocellular carcinoma. J Cancer Res Clin Oncol
2004; 130: 417－422
22. Wong LL, Limm WM, Severino R, Wong LM: Improved survivalwith screening for hepatocellular carcinoma. Liver Transpl 2000;
6: 320－325
23. Pateron D, Ganne N, Trinchet JC, Aurousseau MH, Mal F, Meicler C, Coderc E, Reboullet P, Beaugrand M: Prospective study ofscreening for hepatocellular carcinoma in Caucasian patients withcirrhosis. J Hepatol 1994; 20: 65－71
24. Chalasani N, Said A, Ness R, Hoen H, Lumeng L: Screening forhepatocellular carcinoma in patients with cirrhosis in the UnitedStates: results of a national survey. Am J Gastroenterol 1999; 94:2224－2229
25. Kudo M, Okanoue T: Management of hepatocellular carcinoma inJapan: consensus-based clinical practice manual proposed by theJapan Society of Hepatology. Oncology 2007; 72 Suppl 1: 2－15
26. Patel D, Terrault NA, Yao FY, Bass NM, Ladabaum U: Cost-effectiveness of hepatocellular carcinoma surveillance in patients

Saito H, et al: HCC in Keio Affiliated Hospitals
with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol
2005; 3: 75－84
27. Saab S, Ly D, Nieto J, Kanwal F, Lu D, Raman S, Amado R,
Nuesse B, Durazo F, Han S, Farmer DG, Ghobrial RM, Yersiz H,
Chen P, Schwegel K, Goldstein LI, Tong M, Busuttil RW: Hepatocellular carcinoma screening in patients waiting for liver transplantation: a decision analytic model. Liver Transpl 2003; 9: 672－681
28. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J:
Clinical management of hepatocellular carcinoma. Conclusions of
the Barcelona-2000 EASL conference. European Association for
the Study of the Liver. J Hepatol 2001; 35: 421－430
29. Lim JH, Kim CK, Lee WJ, Park CK, Koh KC, Paik SW, Joh JW:
Detection of hepatocellular carcinomas and dysplastic nodules incirrhotic livers: accuracy of helical CT in transplant patients. AJR
Am J Roentgenol 2000; 175: 693－698
30. Torzilli G, Minagawa M, Takayama T, Inoue K, Hui AM, Kubota
K, Ohtomo K, Makuuchi M: Accurate preoperative evaluation ofliver mass lesions without fine-needle biopsy. Hepatology 1999;
30: 889－893
31. Yu JS, Kim KW, Kim EK, Lee JT, Yoo HS: Contrast enhancementof small hepatocellular carcinoma: usefulness of three successive
early image acquisitions during multiphase dynamic MR imaging.
AJR Am J Roentgenol 1999; 173: 597－604
32. Hayashi M, Matsui O, Ueda K, Kawamori Y, Kadoya M, Yoshikawa J, Gabata T, Takashima T, Nonomura A, Nakanuma Y: Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by
CT during intraarterial injection of contrast medium. AJR Am J
Roentgenol 1999; 172: 969－976
33. Fracanzani AL, Burdick L, Borzio M, Roncalli M, Bonelli N,
Borzio F, Maraschi A, Fiorelli G, Fargion S: Contrast-enhanced
Doppler ultrasonography in the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis. Hepatology 2001; 34: 1109－1112
34. Gaiani S, Celli N, Piscaglia F, Cecilioni L, Losinno F, Giangregorio F, Mancini M, Pini P, Fornari F, Bolondi L: Usefulness of contrast-enhanced perfusional sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography. J Hepatol 2004; 41: 421－426
35. Numata K, Tanaka K, Kiba T, Saito S, Ikeda M, Hara K, Tanaka
N, Morimoto M, Iwase S, Sekihara H: Contrast-enhanced, wideband harmonic gray scale imaging of hepatocellular carcinoma:correlation with helical computed tomographic findings. J Ultrasound Med 2001; 20: 89－98
36. Hammerstingl R, Zangos S, Schwarz W, Rosen T, Bechstein WO,
Balzer T, Vogl TJ: Contrast-enhanced MRI of focal liver tumors
using a hepatobiliary MR contrast agent: detection and differential
diagnosis using Gd-EOB-DTPA-enhanced versus Gd-DTPA-enhanced MRI in the same patient. Acad Radiol 2002; 9 Suppl 1:
S119－120
37. Reimer P, Schneider G, Schima W: Hepatobiliary contrast agentsfor contrast-enhanced MRI of the liver: properties, clinical development and applications. Eur Radiol 2004; 14: 559－578
38. Shimizu M, Iijima H, Horibe T, Yamada M, Suzuki S, Yanagisawa
K, Seki T, Moriyasu F: Usefulness of contrast-enhanced ultrasonography with a new contrast mode, Agent Detection Imaging, inevaluating therapeutic response in hepatocellular carcinoma treated with radio-frequency ablation therapy. Hepatol Res 2004; 29:
235－242
39. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y,
Hosaka T, Kobayashi M, Arase Y, Ikeda K, Kumada H: Aminoacid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 2007; 46:
1357－1364
40. Cheung TK, Lai CL, Wong BC, Fung J, Yuen MF: Clinical fea-

Keio J Med 2009; 58 (3): 161－175
tures, biochemical parameters, and virological profiles of patientswith hepatocellular carcinoma in Hong Kong. Aliment Pharmacol
Ther 2006; 24: 573－583
41. Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF: Recurrenceof hepatitis B-related hepatocellular carcinoma is associated withhigh viral load at the time of resection. Am J Gastroenterol 2008;
103: 1663－1673
42. Ohata K, Hamasaki K, Toriyama K, Ishikawa H, Nakao K, Eguchi
K: High viral load is a risk factor for hepatocellular carcinoma inpatients with chronic hepatitis B virus infection. J Gastroenterol
Hepatol 2004; 19: 670－675
43. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, FungJ, Wong DK, Yuen JC, Mizokami M, Lai CL: Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C,
specific mutations of enhancer II/core promoter/precore regionsand HBV DNA levels. Gut 2008; 57: 98－102
44. Larsson SC, Wolk A: Coffee consumption and risk of liver cancer:
a meta-analysis. Gastroenterology 2007; 132: 1740－1745
45. Inoue M, Yoshimi I, Sobue T, Tsugane S: Influence of coffee
drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J Natl Cancer Inst 2005; 97: 293－300
46. Hu G, Tuomilehto J, Pukkala E, Hakulinen T, Antikainen R, Vartiainen E, Jousilahti P: Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology 2008; 48: 129－136
47. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625－1638
48. El-Serag HB, Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:
2557－2576
49. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, Nakajima Y, Ohnishi K: Natural history of hepatocellular
carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56: 918－928
50. Ramacciato G, Mercantini P, Cautero N, Corigliano N, Di Benedetto F, Quintini C, Ercolani G, Varotti G, Ziparo V, Pinna AD:
Prognostic evaluation of the new American Joint Committee on
Cancer/International Union Against Cancer staging system for hepatocellular carcinoma: analysis of 112 cirrhotic patients resected
for hepatocellular carcinoma. Ann Surg Oncol 2005; 12: 289－297
51. Varotti G, Ramacciato G, Ercolani G, Grazi GL, Vetrone G,
Cescon M, Del Gaudio M, Ravaioli M, Ziparo V, Lauro A, Pinna
A: Comparison between the fifth and sixth editions of the AJCC/UICC TNM staging systems for hepatocellular carcinoma: multicentric study on 393 cirrhotic resected patients. Eur J Surg Oncol
2005; 31: 760－767
52. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998; 28: 751－755
53. Ueno S, Tanabe G, Sako K, Hiwaki T, Hokotate H, Fukukura Y,
Baba Y, Imamura Y, Aikou T: Discrimination value of the newwestern prognostic system (CLIP score) for hepatocellular carcinoma in 662 Japanese patients. Cancer of the Liver Italian Program. Hepatology 2001; 34: 529－534
54. Grieco A, Pompili M, Caminiti G, Miele L, Covino M, Alfei B,
Rapaccini GL, Gasbarrini G: Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC
staging systems in a single Italian centre. Gut 2005; 54: 411－418
55. Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su
GL, Lok AS: Prognosis of hepatocellular carcinoma: comparisonof 7 staging systems in an American cohort. Hepatology 2005; 41:707－716
56. Sala M, Forner A, Varela M, Bruix J: Prognostic prediction in patients with hepatocellular carcinoma. Semin Liver Dis 2005; 25:
171－180

173
57. Guglielmi A, Ruzzenente A, Pachera S, Valdegamberi A, Sandri
M, D’Onofrio M, Iacono C: Comparison of seven staging systems
in cirrhotic patients with hepatocellular carcinoma in a cohort ofpatients who underwent radiofrequency ablation with complete
response. Am J Gastroenterol 2008; 103: 597－604
58. Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, Lau
JT, Yu SC, Johnson PJ: Construction of the Chinese University
Prognostic Index for hepatocellular carcinoma and comparison
with the TNM staging system, the Okuda staging system, and theCancer of the Liver Italian Program staging system: a study basedon 926 patients. Cancer 2002; 94: 1760－1769
59. Chevret S, Trinchet JC, Mathieu D, Rached AA, Beaugrand M,
Chastang C: A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et deTraitement du Carcinome Hepatocellulaire. J Hepatol 1999; 31:
133－14160. Giannini E, Risso D, Botta F, Romagnoli P, Malfatti F, Fumagalli
A, Testa E, Podesta E, Chiarbonello B, Polegato S, Testa R: Prognosis of hepatocellular carcinoma in anti-HCV positive cirrhotic
patients: a single-centre comparison amongst four different staging systems. J Intern Med 2004; 255: 399－408
61. Kudo M, Chung H, Haji S, Osaki Y, Oka H, Seki T, Kasugai H,
Sasaki Y, Matsunaga T: Validation of a new prognostic staging
system for hepatocellular carcinoma: the JIS score compared with
the CLIP score. Hepatology 2004; 40: 1396－1405
62. Kudo M, Chung H, Osaki Y: Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a
proposal for a new staging system, the Japan Integrated Staging
Score (JIS score). J Gastroenterol 2003; 38: 207－215
63. Nanashima A, Sumida Y, Morino S, Yamaguchi H, Tanaka K, Shibasaki S, Ide N, Sawai T, Yasutake T, Nakagoe T, Nagayasu T:
The Japanese integrated staging score using liver damage gradefor hepatocellular carcinoma in patients after hepatectomy. Eur J
Surg Oncol 2004; 30: 765－770
64. Luo KZ, Itamoto T, Amano H, Oshita A, Ushitora Y, Tanimoto Y,
Ohdan H, Tashiro H, Asahara T: Comparative study of the Japan
Integrated Stage (JIS) and modified JIS score as a predictor ofsurvival after hepatectomy for hepatocellular carcinoma. J Gastroenterol 2008; 43: 369－377
65. Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia-Pagan JC,
Visa J, Bru C, Rodes J: Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portalpressure. Gastroenterology 1996; 111: 1018－1022
66. Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C,
Rossi S: Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma
in cirrhosis: Is resection still the treatment of choice? Hepatology
2008; 47: 82－89
67. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L: Livertransplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693－699
68. Yao FY, Kerlan RK, Jr., Hirose R, Davern TJ, 3rd, Bass NM, Feng
S, Peters M, Terrault N, Freise CE, Ascher NL, Roberts JP: Excellent outcome following down-staging of hepatocellular carcinoma
prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008; 48: 819－827
69. Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A,
Girardi L, Cillo U, Burra P, Giacomin A, Farinati F: Transcatheter
arterial chemoembolization (TACE) in hepatocellular carcinoma(HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008; 103: 914－921
70. Tamoxifen in treatment of hepatocellular carcinoma: a randomised
controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet 1998; 352: 17－20
71. Castells A, Bruix J, Bru C, Ayuso C, Roca M, Boix L, Vilana R,
Rodes J: Treatment of hepatocellular carcinoma with tamoxifen: a174
double-blind placebo-controlled trial in 120 patients. Gastroenterology 1995; 109: 917－922
72. Farinati F: Tamoxifen treatment in hepatocellular carcinoma. Gastroenterology 1996; 111: 272－274
73. Grimaldi C, Bleiberg H, Gay F, Messner M, Rougier P, Kok TC,
Cirera L, Cervantes A, De Greve J, Paillot B, Buset M, Nitti D,
Sahmoud T, Duez N, Wils J: Evaluation of antiandrogen therapy
in unresectable hepatocellular carcinoma: results of a European
Organization for Research and Treatment of Cancer multicentric
double-blind trial. J Clin Oncol 1998; 16: 411－417
74. Llovet JM, Sala M, Castells L, Suarez Y, Vilana R, Bianchi L, Ayuso C, Vargas V, Rodes J, Bruix J: Randomized controlled trial ofinterferon treatment for advanced hepatocellular carcinoma. Hepatology 2000; 31: 54－58
75. Yuen MF, Poon RT, Lai CL, Fan ST, Lo CM, Wong KW, Wong
WM, Wong BC: A randomized placebo-controlled study of longacting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 2002; 36: 687－691
76. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, deOliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta
C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath
I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D,
Bruix J: Sorafenib in advanced hepatocellular carcinoma. N Engl
J Med 2008; 359: 378－390
77. Takeda A, Takahashi M, Kunieda E, Takeda T, Sanuki N, Koike Y,
Atsukawa K, Ohashi T, Saito H, Shigematsu N, Kubo A: Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy
and toxicity. Hepatol Res 2008; 38: 60－69
78. Mayahara H, Oda Y, Kawaguchi A, Kagawa K, Murakami M, Hishikawa Y, Igaki H, Tokuuye K, Abe M: A case of hepatocellular
carcinoma initially treated by carbon ions, followed by protons for
marginal recurrence with portal thrombus. Radiat Med 2005; 23:513－519
79. Ebinuma H, Saito H, Kosuga M, Wakabayashi K, Saito Y, Takagi
T, Nakamoto N, Okuyama T, Ishii H: Reduction of c-myc expression by an antisense approach under Cre/loxP switching induces
apoptosis in human liver cancer cells. J Cell Physiol 2001; 188:
56－66
80. Kaneko F, Saito H, Saito Y, Wakabayashi K, Nakamoto N, Tada S,
Suzuki H, Tsunematsu S, Kumagai N, Ishii H: Down-regulation of
matrix-invasive potential of human liver cancer cells by type I interferon and a histone deacetylase inhibitor sodium butyrate. Int J
Oncol 2004; 24: 837－845
81. Masuda T, Saito H, Kaneko F, Atsukawa K, Morita M, Inagaki H,
Kumagai N, Tsuchimoto K, Ishii AH: Up-regulation of E-cadherin
and I-catenin in human hepatocellular carcinoma cell lines by sodium butyrate and interferon-alpha. In vitro Cell Dev Biol Anim
2000; 36: 387－394
82. Nakamura M, Saito H, Ebinuma H, Wakabayashi K, Saito Y, Takagi T, Nakamoto N, Ishii H: Reduction of telomerase activity inhuman liver cancer cells by a histone deacetylase inhibitor. J Cell
Physiol 2001; 187: 392－401
83. Tada S, Saito H, Tsunematsu S, Ebinuma H, Wakabayashi K, Masuda T, Ishii H: Interferon regulatory factor-1 gene abnormality
and loss of growth inhibitory effect of interferon-alpha in humanhepatoma cell lines. Int J Oncol 1998; 13: 1207－1216
84. Wakabayashi K, Saito H, Kaneko F, Nakamoto N, Tada S, Hibi T:
Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor. Int J Oncol 2005; 26: 233－239
85. Feun LG, O’Brien C, Molina E, Rodriguez M, Jeffers L, Schiff
ER, Marini A, Savaraj N, Ardalan B: Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with hepatocellular
carcinoma-A phase II trial. J Cancer Res Clin Oncol 2003; 129:
17－20

Saito H, et al: HCC in Keio Affiliated Hospitals
86. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S,
Koike Y, Yoshida H, Omata M: Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003; 138:299－306
87. Nussbaum T, Samarin J, Ehemann V, Bissinger M, Ryschich E,
Khamidjanov A, Yu X, Gretz N, Schirmacher P, Breuhahn K: Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. Hepatology 2008; 48: 146－156
88. Thomas MB, Abbruzzese JL: Opportunities for targeted therapies
in hepatocellular carcinoma. J Clin Oncol 2005; 23: 8093－8108
89. Furuta K, Sato S, Yamauchi T, Kakumu S: Changes in intrahepatic
gene expression profiles from chronic hepatitis to hepatocellular
carcinoma in patients with hepatitis C virus infection. Hepatol Res
2008; 38: 673－682
90. Knight B, Tirnitz-Parker JE, Olynyk JK: C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits
liver tumor formation in mice. Gastroenterology 2008; 135: 969－
979, 979 e1
91. Gonzalez-Carmona MA, Lukacs-Kornek V, Timmerman A, Shabani S, Kornek M, Vogt A, Yildiz Y, Sievers E, Schmidt-Wolf IG,
Caselmann WH, Sauerbruch T, Schmitz V: CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma
by activating innate and acquired immunity in vivo. Hepatology
2008; 48: 157－168
92. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan
JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone
MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S,
Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR: Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359: 1995－2004
93. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki
KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T: Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma.
Hepatoma Prevention Study Group. N Engl J Med 1996; 334:
1561－1567
94. Muto Y, Moriwaki H, Saito A: Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 1999; 340: 1046－1047
95. Takai K, Okuno M, Yasuda I, Matsushima-Nishiwaki R, Uematsu
T, Tsurumi H, Shiratori Y, Muto Y, Moriwaki H: Prevention of
second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term followup data. Intervirology 2005; 48: 39－45
96. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A,
Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H,
Ohashi Y: Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res
2006; 35: 204－214
97. Mizuta T, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K,
Yamamoto K: The effect of menatetrenone, a vitamin K2 analog,
on disease recurrence and survival in patients with hepatocellular
carcinoma after curative treatment: a pilot study. Cancer 2006;
106: 867－872
98. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F,
Tsubota A, Chayama K, Murashima N, Kumada H: Interferon beta
prevents recurrence of hepatocellular carcinoma after complete
resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology
2000; 32: 228－232
99. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat

Keio J Med 2009; 58 (3): 161－175
J: Lamivudine for patients with chronic hepatitis B and advanced
liver disease. N Engl J Med 2004; 351: 1521－1531
100. Matsumoto A, Tanaka E, Rokuhara A, Kiyosawa K, Kumada H,
Omata M, Okita K, Hayashi N, Okanoue T, Iino S, Tanikawa K:
Efficacy of lamivudine for preventing hepatocellular carcinoma inchronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res 2005; 32: 173－184
101. Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T,
Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A,
Colombo M, Bonino F, Majno P, Llovet JM: Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liverresection in HCV cirrhosis. Hepatology 2006; 44: 1543－1554
102. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S, Seki S, Kobayashi K, Otani S: Randomised trial of effects of interferon-alpha on incidence of hepatocellular
carcinoma in chronic active hepatitis C with cirrhosis. Lancet
1995; 346: 1051－1055
103. Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K, Miyanishi K, Matsunaga T, Takayama T, Niitsu Y:
Resolution of liver cirrhosis using vitamin A-coupled liposomes
to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 2008; 26: 431－442
104. Friedman SL: Targeting siRNA to arrest fibrosis. Nat Biotechnol
2008; 26: 399－400
105. Kagawa T, Morizane T, Saito H, Miyaguchi S, Tsunematsu S,
Tada S, Guevara FM, Kumagai N, Tsuchimoto K, Watanabe T, et
al: A randomized, controlled trial of weekly administration oflymphoblastoid interferon in patients with chronic hepatitis C. J
Hepatol 1993; 17: 91－96

175
106. Saito H, Ebinuma H, Atsukawa K, Takahashi M, Masuda T, Ohishi T, Nojiri O, Mizuoka K, Ishii H: Disappearance of serum hepatitis C virus RNA within two days after one dose interferon administration is predictive for response to high-dose interferon-alpha 2b treatment for chronic hepatitis C. Keio Interferon-alpha 2b
Study Group. Keio J Med 1997; 46: 74－80
107. Saito H, Ebinuma H, Nagata H, Inagaki Y, Saito Y, Wakabayashi
K, Takagi T, Nakamura M, Katsura H, Oguchi Y, Ishii H: Interferon-associated retinopathy in a uniform regimen of natural interferon-alpha therapy for chronic hepatitis C. Liver 2001; 21: 192－197
108. Saito H, Ebinuma H, Satoh I, Miyaguchi S, Tada S, Iwabuchi N,
Kumagai N, Tsuchimoto K, Morizane T, Ishii H: Immunologicaland virological predictors of outcome during interferon-alphatherapy of chronic hepatitis C. J Viral Hepat 2000; 7: 64－74
109. Saito H, Ishii H: Recent understanding of immunological aspects
in alcoholic hepatitis. Hepatol Res 2004; 30: 193－198
110. Saito H, Tada S, Ebinuma H, Ishii H, Kashiwazaki K, Nishida J,
Yoshida T, Zeki S, Yoshida H, Yoshioka M, Inagaki Y, Kumagai
N, Hibi T: Induction therapy with twice-daily interferon-beta does
not improve the therapeutic efficacy of consensus interferon
monotherapy for chronic hepatitis C. Keio J Med 2006; 55: 111－117
111. Saito H, Tada S, Ebinuma H, Ishii H, Kashiwazaki K, Takahashi
M, Tsukada N, Nishida J, Tanaka S, Shiozaki H, Hibi T: Role oferythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections. J Clin Microbiol 2006;
44: 3562－3568