ANTICANCER RESEARCH 35: 2157-2164 (2015)

Scoring System Based on Tumor Markers and Child-Pugh

Classification for HCC Patients who Underwent Liver Resection
SHIGEKI NAKAGAWA1, HIROMITSU HAYASHI1, HIDETOSHI NITTA1, HIROHISA OKABE1,
KEITA SAKAMOTO1, TAKAAKI HIGASHI1, HIDEYUKI KUROKI1, KATSUNORI IMAI1,
DAISUKE HASHIMOTO1, YASUO SAKAMOTO1,2, AKIRA CHIKAMOTO1, TORU BEPPU1,2 and HIDEO BABA1

1Department of Gastroenterological Surgery, Graduate School of Life Sciences,

Kumamoto University, Kumamoto, Japan;
2Department of Multidisciplinary Treatment for Gastroenterological Cancer,

Kumamoto University Hospital, Kumamoto, Japan

Abstract. Background: The long-term prognosis of
hepatocellular carcinoma (HCC) patients after hepatic
resection (HR) remains poor because of limited liver
function and frequent recurrences. We created a prognostic
system of HCC based on tumor markers and Child-Pugh
classification. Patients and Methods: This study investigated
427 HCC patients and three tumor markers (alpha-
fetoprotein (AFP), Lens culinaris agglutinin-reactive
fraction of AFP (AFP-L3), des-γ -carboxyprothrombin
(DCP)) in relation to Child-Pugh classification by the
stepwise Cox regression model for establishing a tumor
marker staging (TMS). Results: The TMS shows four levels
(0/1/2/3) with 5-year recurrence rate of each stage of 76.7,
72.3, 80.9 and 100%, respectively, and 5-year overall
survival of 77.0, 68.7, 52.1 and 28.9%, respectively. This
TMS appears to be a better model to predict the recurrence
and survival of HCC patients after hepatectomy than only
the number of positive tumor markers. Conclusion: TMS is a
useful staging system to evaluate biological status and
background liver function.
Hepatocellular carcinoma (HCC) is a common malignancy
worldwide, especially in Asian countries with an increasing
incidence in Western countries (1, 2). Development of
devices for diagnosis, such as computed tomography (CT),
Correspondence to: Professor Hideo Baba, MD, Ph.D., Department
of Gastroenterological Surgery, Graduate School of Life Sciences,
Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Tel: +81 963735211, Fax: +81 963714378, e-mail: hdobaba@
kumamoto-u.ac.jp
Key Words: Hepatocellular carcinoma (HCC), alpha-fetoprotein
(AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3),
des-γ-carboxyprothrombin (DCP), tumor marker.
angiography, vascular imaging, ultrasonography and
magnetic resonance imaging (MRI) enables for detection of
early stages of HCC. The development of therapeutic
modalities, including liver transplantation, hepatic resection,
trans-arterial chemoembolization and localized ablation
therapy has improved the prognosis of HCC patients (3-5).
Nevertheless, short- and long-term prognoses remain a
difficult task to accomplish.
For the diagnosis of HCC, three tumor markers, alpha-
fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction
of AFP (AFP-L3) and des-γ-carboxyprothrombin (DCP), are
usually being examined in addition to the diagnostic
imaging. These tumor markers are useful tools not only for
the diagnosis but also for the evaluation of the the malignant
potential of HCC and prediction of prognosis (6-10).
Recently, the examination of all three tumor markers was
proven useful in predicting the prognosis of curatively-
resected HCC (11-13).
To predict the prognosis of HCC patients, the tumor-node-
metastasis (TMN) staging, which proposed by the
International Union against Cancer (UICC) (14) or the Liver
Cancer Study Group of Japan are being followed. However,
new staging systems that combined tumor malignancy and
liver function, such as the Cancer of the Liver Italian
Program (CLIP) (15, 16) and Japan Integrated Staging (JIS)
(17) system, have been created and clarified the usefulness
to predict the prognosis of HCC patients. Not only tumor
factors, such as TNM staging and tumor markers, but also
liver function is also important to define the prognosis (18)
in HCC patients as HCC may occur from cirrhotic liver or
liver with inflammation. Thus, in the present study, we
attempted to predict HCC prognosis by combining both liver
function and expression of tumor markers. This approach
involved the combination of the Child-Pugh score as “liver
function” and the number of tumor markers expressed in
HCC as “tumor malignancy”.

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Table I. Patients’ background and clinicopathological findings of the study. imaging studies, such as ultrasonography, dynamic CT and
enhanced MRI, as well as CT angiography for diagnosis and staging
Variable n=427 of HCC before surgery. The final diagnosis was confirmed
pathologically in the resected specimens. The severity of liver
Sex (Male/Female) 350/77 disease (liver fibrosis staging and hepatitis activity grading) was also
Age 67 (30-83) evaluated according to the criteria proposed by the Inuyama
Etiology (HBV/HCV/NBNC/HBV+HCV) 109/195/113/10 classification (19). This was a retrospective, non-interventional,
Child-Pugh Classification (A/B) 353/74 observational study, approved by the institutional ethics committee
Albumin 3.9 (1.8-5.1)
of Kumamoto University Hospital and performed in accordance
Total bilirubin 0.8 (0.2-2.4)
with the Helsinki Declaration of 1975. Written informed consent
Prothrombin activity 91 (13.4-140)
was obtained from all patients.
PLT(×104/mm3) 14.0 (4.2-37.9)
ICG R15 (%) 12.7 (2.9-73.9)
Number of tumors; median (range) 1 (1-9) Measurement of hepatocellular carcinoma tumor markers. AFP,
Single/Multiple 274/153 AFP-L3 and DCP were measured immediately before hepatic
Tumor size (cm) 3.5 (1.0-20) resection. The serum AFP level was determined by a
Macroscopic vascular invasion (-/+) 372/55 chemiluminescent enzyme immunoassay (Siemens Immulite AFP
Microscopic vascular invasion (-/+) 206/221 IV; Mitsubishi Chemical Medience, Tokyo, Japan) and the serum
Differentiation (well-mod/include poor) 327/100 AFP-L3 level was expressed as a percentage of the total AFP (AFP-
Growth pattern (expansive/infiltrative) 286/41 L3/ total AFP×100) by lectin affinity electrophoresis coupled with
AFP (ng/ml); median (range) 16.4 (0-474000) antibody-affinity blotting (AFP-L3 Test Wako; Wako Pure Chemical
≥20 ng/ml/<20 ng/ml 206/221 Industries Ltd., Osaka, Japan). Serum DCP was determined by a
AFP-L3 (%); median (range) 0.5 (0.0-89.1) chemiluminescent enzyme immunoassay (Lumipulse PIVKA-II
≥10 %/<10 % 117/310 Eisai; Eisai, Tokyo, Japan). The upper limits of the normal range of
DCP (mAU/ml); median (range) 80 (0-298050) AFP, AFPL3 and DCP in our institution were 20 ng/ml, 10 % and
≥40 mAU/ml/<40 mAU/ml 268/159 40 mAU/ml, respectively. Tumor markers higher than the upper
Liver resection (Anatomical/Non-anatomical) 279/148 limit of the normal range were defined as positive.
Treatment for HCC (initial/non-initial) 119/308
Treatment and surveillance. The surgical procedure was selected
HBV, Hepatitis B virus; HCV, hepatitis C virus; NBNC, non-B non-C;
based on the tumor location, extent of the tumor, parenchymal liver
PLT, platelet count; ICG R15, Indocyanine Green Retention rate at 15
function and the patients' general condition. Hepatic resection (HR)
min; AFP; alpha-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive
was considered as the first choice treatment for patients with good
fraction of AFP; DCP, des-γ -carboxyprothrombin.
liver functional reserve (20). If the liver function allowed,
anatomical resection was employed. The reasons for undergoing
radiofrequency risk associated with general condition and refusal of
HR. The follow-up program included AFP, AFP-L3 and DCP assays
Patients and Methods every 1-2 months, as well as ultrasonography, dynamic CT or
dynamic MRI every 3-4 months after surgery. When a recurrence of
Patients and diagnosis. The study population consisted of 427 HCC HCC was detected, patients received further treatment for HCC,
patients who underwent curative hepatic resection at the Department such as repeated hepatectomy, ablation therapy or trans-arterial
of Gastroenterological Surgery, Kumamoto University Hospital, chemoembolization (TACE). After treatment for recurrent lesions,
between January 2001 and May 2009. The patients underwent the same surveillance was continued.

Table II. The weight of number of positive tumor markers and Child-Pugh score for predicting overall survival.

Univariate analysis Multivariate analysis

RR 95%CI p-Value RR 95%CI p-Value β-Value

Number of positive
tumor markers
0 1 1
1 1.33 0.75-2.44 0.3289 1.40 0.79-2.57 0.2567 0.093
2 2.27 1.29-4.13 0.0040** 2.38 1.35-4.36 0.0024** 0.127
3 3.56 2.04-6.46 <0.0001*** 3.72 2.14-6.78 <0.0001*** 0.242
Child-Pugh classification
A 1 1
B 1.29 0.80-2.00 0.2791 1.43 0.88-2.23 0.1351 0.095

RR, Relative risk; CI, confidence interval. *p<0.05, **p<0.01, ***p<0.001

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 Nakagawa et al: Staging Based on Tumor Marker and Child-Pugh
Table III. Tumor marker staging classification.
Parameter/score 0 1
Number of positive tumor markers 0 1 or 2
Child-Pugh stage A B
Statistical analysis. Dichotomous variables were compared using
the χ2 test, where as continuous variables were compared using
t-tests. The univariate and multivariate analysis based on the Cox
regression model was used to estimate risk factors related to
recurrence-free survival (RFS) and overall survival (OS), continuous
variables were converted into binary. All p values of <0.05 were
considered to be significant. The stepwise Cox regression model
was used to provide the coefficient for Child-Pugh classification and
the number of tumor markers. All analyses were performed using
the JMP program (SAS Institute, Cary, NC, USA).
Results
Patients’ characteristics. Table I shows the patients’
background and clinicopathological characteristics of this
study. Among the 427 patients, there were 350 men and 77
women ranging in age from 30-83 years. More than three
quarters (82.7%) of the patients belonged to Child-Pugh class
A and 17.3% belonged to class B. The median values of serum
AFP, AFP-L3 and DCP levels were 16.4 ng/ml, less than 0.5%
and 80.0 mAU/mL, respectively. Serum AFP, AFP-L3 and DCP
levels over the upper limits of normal range were observed in
48.2% of the patients, 27.4% and 62.8%, respectively.
Univariate analysis of the perioperative risk factors associated
with recurrence rate and overall survival. The recurrence rates
of all patients at 1, 3 and 5 years were 32.1, 60.3 and 77.0%,
while the OS rates at 1, 3 and 5 years were 90.6, 72.0 and
64.8%. Multivariate analysis revealed that low serum albumin
level (relative risk (RR)=1.49, p=0.0084), decreased platelet
(PLT) count (RR=1.51, p=0.0086), multiple tumor (RR=1.93,
p<0.0001) and tumor size >3.5cm (RR=1.55, p=0.0034) were
the independent risk factors to predict high recurrence rate.
Low serum albumin (RR=1.72, p=0.0163), multiple tumor
(RR=1.62, p=0.0232) and tumor size >3.5cm (RR=2.28,
p=0.0002) were the independent risk factors for poor OS by
multivariate analysis.
Coefficient weighting of tumor markers and Child-Pugh
classification for predicting overall survival and newly-
proposed prognostic scoring system; Tumor Marker Score
(TMS) Stage. Table II shows the univariate and multivariate
analysis of the number of tumor markers and Child-Pugh
classification for OS and coefficient score (β value). The
number of tumor markers and Child Pugh classification
showed various scores that ranged from 0-2 of the Cox
regression model, which is a rounded value based on
“10×coefficients”(Table III). Then, we added each score and
2
classified HCC patients into four levels, thus establishing TMS
3 stages 0 to 3. In each stage, recurrence rates at 1, 3 and 5 years
were as follows: 14.9, 47.9 and 76.7% in TMS stage 0; 34.1,
58.7 and 72.3% in TMS stage 1; 39.9, 64.5 and 80.9% in TMS
stage 2; and 63.9, 82.0 and 100% in TMS stage 3. OS in each
stage was as follows: 99.7, 83.0 and 77.0% in TMS stage 0;
95.1, 76.5 and 68.7% in TMS stage 1; 79.6, 59.6 and 51.2% in
TMS stage 2; and 53.9, 28.9 and 28.9% in TMS stage 3. The
Kaplan-Meyer curves are shown in Figure 1.
Comparison of scoring systems. The Kaplan-Meier survival
curves for recurrence and OS by the TMS staging, number
of tumor markers and CLIP scoring system are shown in
Figures 1-3, respectively. The RRs for recurrence of TMS
stage 0, 1, 2 and 3 are 1, 1.30, 1.92 and 2.80. As shown in
Table IVa, the RRs of only the number of tumor markers 0,
1, 2 and 3 are 1, 1.26, 2.53 and 1.97. The RRs of CLIP 0 1,
2 and 3-5 are 1, 1.47, 2.51 and 5.58. Of note about OS, as
shown in Tabke IVb, the RR of CLIP 0. 1, 2, and 3-5 are 1,
2.53, 3.00 and 4.52. The RR of only the number of tumor
markers 0, 1, 2 and 3 are 1, 1.33, 2.27 and 3.56. The RR for
OS of TMS staging are 1, 1.41, 2.66 and 6.00.
Discussion
AFP is the most widely used tumor marker for HCC and its
high serum levels correlate with poor prognosis (21-28)
and, as we have previously reported, the doubling time of
preoperative AFP is a significant predictor for both DFS
and OD (10). AFP-L3-positive status has been demonstra-
ted to correlate with a large number of HCC tumors or
those with a high malignant potential (7). A high level of
serum DCP was reported to correlate with portal vein
invasion and indicates a poor prognosis in HCC patients
(25, 29). An elevated preoperative DCP has been
demonstrated to be associated with a high recurrence rate
after liver transplantation (30-32). However, the efficacies
of preoperative levels of each tumor marker were not clear
in the present study.
Recently, the utility of the combined measurement of
these three tumor markers (AFP, AFP-L3 and DCP) was
demonstrated in predicting the outcome and recurrence for
HCC patients treated with HR (11, 12). As we previously
discussed (13), tumor markers evaluated before and after HR
are used in these studies and examining their levels and
postoperative levels seems imperative. However, predicting
the patients’ prognosis before surgery is very important
because we can choose the appropriate treatment modality
based on the patient’s own prognostic profile. Therefore, in
this study, we attempted to predict prognosis by using only
preoperative parameters.
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Table IVa. Comparison of the relative risk for recurrence of each classification.

CLIP Number of tumor markers TMS

Score RR p-Value Number RR p-Value Stage RR p-Value

0 1 0 1 0 1
1 1.47 0.0357* 1 1.26 0.1724 1 1.30 0.1389
2 2.51 <0.0001*** 2 1.53 0.0217* 2 1.92 0.0008**
3-5 2.58 <0.0001*** 3 1.97 0.0004** 3 2.80 0.0127*

CLIP, Cancer of the liver Italian program; TMS, tumor marker staging; RR, relative risk. *p<0.05, **p<0.01, ***p<0.001.

Table IVb. Comparison of the relative risk for OS of each classification.

CLIP Number of tumor markers TMS

Score RR p-Value Number RR p-Value Stage RR p-Value

0 1 0 1 0 1
1 2.53 0.0039* 1 1.33 0.3289 1 1.41 0.2213
2 3.00 0.0001*** 2 2.27 0.0040** 2 2.66 0.0007***
3-5 4.52 <0.0001*** 3 3.56 <0.0001*** 3 6.00 <0.0001***

OS, Overall survival; CLIP, Cancer of the Liver Italian Program; TMS, tumor marker staging; RR, relative risk. *p<0.05, **p<0.01, ***p<0.001.

Figure 1. Recurrence rate and overall survival curves according to the TMS staging are shown. p-values and relative risk are shown in table IVa and b.

Bruinx et al. reviewed that four main factors affect the
prognosis of patients with HCC: (i) tumor characteristics,
such as stage, aggressiveness and growth rate of the tumor;
(ii) general health; (iii) liver function; and (iv) specific
intervention. We considered the number of positive tumor
markers as tumor characteristics and the Child-Pugh score
as a liver function status. The staging system to estimate the
patients’ prognosis is simple and based on factors that are
easy to collect and should be constant between each
participating institution. The herein presented TMS system
can be calculated only from laboratory data and patient
interview without any means of diagnostic imaging. The
TMS system is also based on the cutoff line as a standard
value and, therefore, it is universally useful if the measuring
procedure is different between each institute even if cut-off
values were different between several hospitals.

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Figure 2. Recurrence rate and overall survival curves according to the number of positive tumor markers are shown. p-values and relative risk are
shown in table IVa and b.

Figure 3. Recurrence rate and overall survival curves according to the CLIP score are shown. p-values and relative risk are shown in table IVa and b.

In the present study, we created a new tumor marker
staging (TMS) system that combines the number of positive
tumor markers, as well as the Child-Pugh classification and
is compared with the number of positive tumor markers and
CLIP scoring system. The CLIP score was organized by
variables that are examined for the HCC diagnosis routinely
and based on laboratory data, Child-Pugh classification and
imaging studies. The TMS system shows a similar or better
analysis power compared with the CILP score for predicting
RFS and OS of HCC patients after HR, even though TMS
does not contain any imaging evaluation. Compared with the
number of tumor markers only, TMS also exhibited better
analysis power. However, it is clinically necessary to evaluate
imaging findings for an in-depth look at diagnosis for
decision-making on treatment for HCC patients, especially
in the planning of surgical resection. Useful ways for further
classification, in addition to imaging findings, include TMN,
Okuda, BCLC and JIS staging (17, 33, 34). These staging
systems favor prediction of prognosis of HCC patients with
or without surgery and, in fact, many reports have shown
their usefulness and the availability of other systems as well
(17, 33-37). However, there exist some points to be improved
as these systems do not include the measurement of
biological factors, such as tumor markers. Sometimes,
however, imaging findings do not reflect the gravity of the
malignancy. It has been reported that it is difficult to

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diagnose small intrahepatic metastasis or microscopic portal
vein invasion correctly by imaging features alone, especially
when the tumors are small (29, 38). A few papers have
confirmed that tumor markers are useful to predict the
pathological malignancy of the HCC tumor, such as micro-
vascular invasion or poor differentiation (11, 13). In order to
evaluate tumor malignancy, including intrahepatic metastasis
or microvascular invasion, it appears better to evaluate the
positivity of tumor markers in addition to the staging systems
based on imaging findings.
In the present study, we showed that the TMS system was
useful to predict the RFS and OS of HCC patients who
underwent curative surgery. Its effectiveness should be
validated in relation with the other staging systems currently
employed and based on diagnostic imaging findings.
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Received December 12, 2014
Revised January 12, 2015
Accepted January 16, 2015
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