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Oncology

Oncology 2007;72(suppl 1):5257


DOI: 10.1159/000111707

Published online: December 13, 2007

PIVKA-II Is a Useful Tumor Marker


for Recurrent Hepatocellular Carcinoma
after Surgical Resection
Do Young Kim Yong Han Paik Sang Hoon Ahn Young Jun Youn
Jong Won Choi Ja Kyung Kim Kwan Sik Lee Chae Yoon Chon
Kwang Hyub Han
Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine,
Yonsei Liver Cancer Special Clinic, Severance Hospital, Liver Cirrhosis Clinical Research Center, Seoul, Korea

Key Words
Prothrombin induced by vitamin K absence or antagonist-II
Hepatocellular carcinoma

Abstract
Objectives: The aim of this study is to assess the usefulness
of prothrombin induced by vitamin K absence or antagonistII (PIVKA-II) in monitoring of recurrent hepatocellular carcinoma (HCC) after curative resection. Methods: From April
2001 to March 2004, a total of 245 patients with histologically proven HCC and 267 non-HCC patients were recruited.
Serial follow-up measurements of both alpha-fetoprotein
(AFP) and PIVKA-II were performed in 27 patients who had
recurrent HCC after resection. Results: In the initial HCC
diagnosis, the sensitivity of AFP and PIVKA-II was 48.6%
(119/245) and 75.1% (184/245), respectively, at the cutoff of
20 ng/ml for AFP and 40 mAU/ml for PIVKA-II (p ! 0.01). The
specificity was 81.3% (217/267) and 94.8% (253/267), respectively. When AFP and PIVKA-II were combined, the sensitivity and specificity was 83.3% (204/245) and 77.2% (206/267),
respectively. In 27 patients developing recurrent HCC after
curative surgical resection, the sensitivity of AFP and PIVKAII was 40.7% (11/27) and 74.1% (20/27), respectively. Several
fluctuating patterns of AFP and PIVKA-II were observed from

2007 S. Karger AG, Basel


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initial diagnosis to recurrence. Conclusion: Our data suggest


that PIVKA-II is a useful tumor marker for HCC, complementary to AFP. Serial measurements of both markers after resection might be helpful for early diagnosis of tumor recurrence.
Copyright 2007 S. Karger AG, Basel

Introduction

The prognosis of hepatocellular carcinoma (HCC) is


known to be poor, especially when diagnosed in advanced
stage. However, a favorable outcome could be expected if
early diagnosis and curative treatment such as surgical
resection are feasible. Thus, measurement of serum alpha-fetoprotein (AFP) concentration along with ultrasonography (US) has widely been performed in clinical
practice [1]. Although AFP has served as a representative
tumor marker of HCC for more than 35 years, the reported sensitivity and specificity are not satisfactory for early
diagnosis of HCC [2, 3]. Since the first description by
Liebman et al. in 1984, prothrombin induced by vitamin
K absence or antagonist-II (PIVKA-II), also referred to as
des-gamma-carboxy prothrombin (DCP), has been found
to be another useful tumor marker [4]. Moreover, these
Kwang Hyub Han, MD
Department of Internal Medicine, Yonsei University College of Medicine
Yonsei Liver Cancer Special Clinic, Severance Hospital
Seongsanno 250, Seodaemun-gu, Seoul 120-752 (Korea)
Tel. +82 2 2228 1949, Fax +82 2 393 6884, E-Mail gihankhys@yumc.yonsei.ac.kr

two markers which are supposed to be produced independently by HCC may serve complementarily in the diagnosis of HCC [5, 6].
In contrast to previous reports, recent study demonstrated that the diagnostic accuracy of PIVKA-II seemed
to be higher (sensitivity, 86%; specificity, 93%) compared
to AFP or lectin-bound AFP (AFP-L3) [7]. Clinical utility
of PIVKA-II was further investigated in view of correlation between several factors such as tumor size, intrahepatic metastases, portal vein tumor thrombosis, and histologic activity of tumor tissue [8, 9].
In spite of many studies on the usefulness of PIVKA-II
in the diagnosis of HCC [10, 11], it remains to be determined whether PIVKA-II might play a role in the detection of recurrent HCC after curative resection [6]. As recurrence of HCC is the most important factor influencing survival after resection, it has been an important
issue to search tumor markers for recurrence after resection. Therefore, it would be of considerable interest to
study the role of PIVKA-II as a detection of earlier tumors from HCC patients who are more liable to early recurrence. Thus, we aimed to analyze the fluctuating patterns of AFP and PIVKA-II from the time of initial diagnosis and recurrence.
Patients and Methods
Patients
A total of 257 patients who had been diagnosed with HCC
were enrolled in this study between April 2001 and March 2004.
The HCCs in all patients were histologically confirmed by USguided liver biopsy or surgical specimen. Because PIVKA-II can
falsely appear in a vitamin K-deficient state, we excluded 10 HCC
patients who had received anticoagulants such as warfarin or antibiotics during the prior 4 weeks. Similarly, 2 patients with bile
duct obstruction in US or computed tomography (CT) were also
excluded from this study. Hence, 245 of these HCC patients were
included. For the determination of diagnostic accuracy of each
tumor marker, 267 patients with chronic liver disease, not having
HCC, were selected as control subjects during the same study period. Their diagnosis consisted of chronic hepatitis B, chronic
hepatitis C, liver cirrhosis, and alcoholic liver disease. The absence of HCC in the control subjects was evident by US or CT (or
MRI) findings in cases with AFP 120 ng/ml.
AFP and PIVKA-II Determinations
The serum concentrations of AFP and PIVKA-II were determined by respective enzyme immunoassay (AFP, Bayer, Leverkusen, Germany, cutoff value 20 ng/ml; PIVKA-II, Sanko Junyaku
Co., Tokyo, Japan, cutoff value 40 mAU/ml) according to the manufacturers instructions. Both serum AFP and PIVKA-II were measured when patients were initially diagnosed with HCC, and regular follow-up measurements after treatment were done in some patients. The two markers were also available in control subjects.

PIVKA-II for Evaluation of HCC


Recurrence

Table 1. Clinical backgrounds of HCC and non-HCC patients

Characteristics

HCC
(n = 245)

Non-HCC
(n = 267)

Age, years
Gender, M/F
Underlying liver disease
HBV (%)
HCV (%)
Others (%)
AFP, ng/ml
PIVKA-II, mAU/ml

54.7810
198/47

52.589.5
162/105

198 (80.8)
196 (73.4)
17 (6.9)
42 (15.7)
30 (12.2)
29 (10.9)
2,48689,275 14.5830.3
84681,864
288124

p value
0.01
<0.01
<0.01

<0.01
<0.01

Treatment of HCC and Postresection Follow-Up


Among 245 HCC patients, 155 (63%) underwent surgical resection, and the other 90 (37%) underwent percutaneous ethanol
injection, percutaneous holmium injection or transarterial chemoembolization (TACE) as indicated [12]. The tumor size was
measured with resected specimen in patients who received operation, and by CT or MRI in patients who received nonsurgical
treatments. In 155 patients who underwent surgical resection, serial longitudinal measurement (every 3 months) of tumor marker
along with liver dynamic CT scan was undertaken. Among those,
both AFP and PIVKA-II were serially measured after operation
in 66 (42.6%) patients.
Statistical Analysis
Continuous variables are presented as mean values 8 SD.
2 tests were applied for qualitative variables and Students t test
for the continuous variables. Receiver operating characteristic
(ROC) curves were constructed to compare the performance of
AFP and PIVKA-II. All the tests were performed using SPSS 11.0
(SPSS, Chicago, Ill., USA), and p ! 0.05 was considered as statistically significant.

Results

Demography and Characteristics of Patients


The clinical characteristics of HCC patients and nonHCC control subjects in this study are shown in table 1.
The mean ages of the HCC and non-HCC patients were
55 and 53 years, respectively. The male to female ratio was
significantly higher in HCC than in non-HCC subjects
(p ! 0.001). Hepatitis B virus infection was the most common etiology in both groups.
The mean value for AFP and PIVKA-II at initial diagnosis was 2,486 ng/ml and 846 mAU/ml, respectively. The mean AFP and PIVKA-II concentration in the
non-HCC group was 14.5 ng/ml and 28 mAU/ml, respectively.
Oncology 2007;72(suppl 1):5257

53

Tumor marker level

1.0

0.8
AFP
0.6

0.4

Sensitivity

PIVKA-II

500
AFP

PIVKA-II

400
300
200
100
0
Initial

Post6
resection months

12
18
24
months months months

Time

Fig. 2. An example of changing pattern of AFP and PIVKA-II lev0.2

els in a 38-year-old male patient. At the time of recurrence, only


PIVKA-II abruptly increased to 455 mAU/ml with AFP remaining normal.

0
0

0.2

0.4

0.6

0.8

1.0

1 Specificity

Fig. 1. Receiver operating characteristics (ROS) curves of AFP

and PIVKA-II for the diagnosis of hepatocellular carcinoma. The


area under the ROC curves of PIVKA-II (0.917) was significantly
larger than that of AFP (0.748, p ! 0.001).

Sensitivity and Specificity of Serum AFP and


PIVKA-II
As seen in table 2, the sensitivity and specificity of
PIVKA-II were higher than those of AFP (75.1 vs. 48.6%
for sensitivity, p ! 0.01; 94.8 vs. 81.3% for specificity).
When the two markers were combined, the sensitivity
increased to 83.3%. On the contrary, the specificity of the
combination was lower than that of the single marker.
Figure 1 shows the ROC curves for all patients with HCC
and non-HCC. The area under the ROC curves (AUROC)
for PIVKA-II was significantly larger than that of AFP
(0.917 vs. 0.748, p ! 0.001).
Clinical Utility of PIVKA-II in Recurrent HCC
Of the 155 patients who underwent surgical resection,
serial longitudinal measurements of both tumor markers
were feasible in 27 patients with recurrent HCC. The
changing patterns of AFP or PIVKA-II concentrations in
serum considerably varied from initial diagnosis to the
time of recurrence. These results are summarized in table 3. Of the 7 patterns of tumor marker elevation above
cutoff, the most common was the initial elevation of both
markers followed by elevation of any single marker at recurrence. Conversely, neither AFP nor PIVKA-II in54

Oncology 2007;72(suppl 1):5257

creased at the recurrence despite elevation of any single


marker at initial diagnosis in 6 patients.
At the recurrence, 20 patients (74.1%) showed elevated
serum PIVKA-II level (using cutoff level 1 40 mAU/ml)
and only 11 (40.7%) patients showed elevated serum AFP
level (using cutoff level 120 ng/ml). Of the 39 patients in
whom there was no recurrence for 12 months after operation and serial determination of PIVKA-II concentration was feasible, the value was within the normal range
in 36 patients. Thus, the specificity of PIVKA-II in the
detection of recurrent HCC was 92.3%. As for AFP, it remained normal until 12 months after resection in 34
(87.2%) out of 36 patients without recurrence (table 4).
Figure 2 illustrates one example of tumor marker change
in a 38-year-old male patient who underwent segmentectomy for HCC in segment 8 and was diagnosed with recurrent HCC 24 months after operation. Interestingly,
although both tumor markers had been elevated before
surgery, only PIVKA-II increased abruptly at 24 months
after resection.

Discussion

In fact, the incidence of HCC recurrence is very high


after successful medical and surgical treatments. As recurrence of HCC is the strongest factor influencing survival after curative treatment, it has been an important
issue to search tumor markers for recurrence after treatment. Therefore, it would be of considerable interest to
study the role of several tumor markers for earlier detection of tumors in HCC patients who are more prone to
early recurrence.
Kim/Paik/Ahn/Youn/Choi/Kim/Lee/
Chon/Han

Table 2. Diagnostic accuracy of AFP and PIVKA-II in detection of HCC

Variables

AFP

PIVKA-II

AFP + PIVKA-II

Overall accuracy
Sensitivity
Specificity

65.6%
48.6% (119/245)
81.3% (217/267)

85.4%
75.1% (184/245)
94.8% (253/267)

80.1%
83.3% (204/245)
77.2% (206/267)

p value
NA
<0.01*
NA

* AFP vs. PIVKA-II. NA = Not applicable.

Table 3. Patterns of change in AFP and PIVKA-II concentration in patients with recurrent HCC after surgical
resection

Pattern

At initial diagnosis

At recurrence

1
2
3
4
5
6
7

Increased PIVKA-II and normal AFP


Increased AFP and normal PIVKA-II
Increased both AFP and PIVKA-II
Increased either AFP or PIVKA-II
Increased both AFP and PIVKA-II
Increased either AFP or PIVKA-II
Increased PIVKA-II and normal AFP

Increased AFP and normal PIVKA-II


Increased PIVKA-II and normal AFP
Increased either AFP or PIVKA-II
Increased both AFP and PIVKA-II
Increased both AFP and PIVKA-II
Neither AFP nor PIVKA-II elevation
Increased PIVKA-II and normal AFP

1
0
6
5
5
6
4

Table 4. Sensitivity and specificity of tumor markers at the recurrence of HCC

Variables

AFP

PIVKA-II

AFP + PIVKA-II

Sensitivity
Specificity

40.7% (11/27)
87.2% (34/39)

74.1% (20/27)
92.3% (36/39)

77.8% (21/27)
74.4% (29/39)

p value
<0.01*
NA

The specificity of this table was derived from 39 patients without recurrence for 12 months after curative
resection.
* AFP vs. PIVKA-II. NA = Not applicable.

The current study enrolled 245 HCC patients, all of


whom were diagnosed by liver biopsy or surgical resection to confirm the accurate sensitivity of AFP and
PIVKA-II. The clinical usefulness of PIVKA-II in the detection of HCC has been demonstrated in many studies
[5, 6, 8, 11]. Nevertheless, it is still controversial as to
whether AFP is superior to PIVKA-II in all cases [1315].
In a recent Japanese study recruiting 1,377 HCC patients,
the performance of PIVKA-II was rather lower than AFP;
the AUROC of each marker was 0.812 and 0.887, respectively (p ! 0.0001) [16]. On the other hand, in a Western
study the PIVKA-II showed higher sensitivity and specificity compared to AFP and AFP-L3, irrespective of tu-

mor size [7]. Such different results might come from a


difference in etiologies of underlying liver disease, ethnicity, cutoff value of tumor marker, tumor size or stage,
and so on [17]. In the present study, the sensitivity of
PIVKA-II was found to be higher than that of AFP (75.1
vs. 48.6%, p ! 0.01). Furthermore, the performance of
PIVKA-II was superior to AFP in analysis using ROC
curve; the AUROC of PIVKA-II was significantly higher
than AFP (0.917 vs. 0.748, p ! 0.001). Importantly, the
combined measurement of both AFP and PIVKA-II increased the sensitivity to 83.3% at the expense of lowering
the specificity to 77.2%. Although there is not any convincing evidence to support the combined use of tumor

PIVKA-II for Evaluation of HCC


Recurrence

Oncology 2007;72(suppl 1):5257

55

markers for the purpose of HCC surveillance, further


study will be required to assess the cost-effectiveness of
such a strategy.
Notwithstanding the significant improvements in survival after resection of HCC for the past decades, the longterm prognosis still remains poor in most series [18], with
5-year recurrence rates approaching 100% [19, 20]. Surveillance strategies for recurrent HCC are different between Japan and Western countries. The recommended
postoperative surveillance protocol in Japan is as follows:
monthly or bimonthly measurement of both AFP and
PIVKA-II, US every 23 months, and enhanced CT every
6 months. In contrast to the intense protocol of Japan, the
usual follow-up protocol in Western countries includes
serial CT or US and AFP at 3- to 6-month intervals [21].
Up to now, AFP is known to be an important predictor
of recurrence of HCC, with several tumor markers having been proposed as a complement or substitute for AFP.
However, no studies have compared the predictability of
these tumor markers simultaneously on HCC recurrence
after curative treatment. Although there was no standardized HCC surveillance program after curative resection, combined tumor markers including AFP and
PIVKA-II have been increasingly used as a surveillance
tool in HCC patients who underwent resection. Tateishi
et al. [22] reported that tumor markers pre- and postablation were significant predictors for HCC recurrence and
could complement imaging modalities in the evaluation
of treatment efficacy. In our study, it was clearly demonstrated that the sensitivity of PIVKA-II was higher compared to AFP in the detection of recurrent HCC (74.1 vs.
40.7%). Moreover, the specificity of PIVKA-II in the detection of recurrent HCC was 92.3% compared with
87.2% for AFP. Our results support the usefulness of simultaneous measurement of two markers in monitoring
recurrent HCC after resection. Considering that there is
no solid evidence showing that this type of intensive protocol in Japan confers survival benefit, combined use of
two markers and cautious interpretation along with less
frequent imaging may suffice. However, this issue should
be studied in a randomized controlled trial.
Our data regarding postoperative longitudinal measurements of AFP and PIVKA-II are in agreement with
the previous results by Aoyagi et al. [6]. They categorized
the fluctuating patterns of two markers as follows: (1) elevated AFP at initial diagnosis and elevated PIVKA-II at
recurrence; (2) elevated PIVKA-II at initial and elevated
AFP at recurrence; (3) elevated AFP and PIVKA-II at initial followed by elevation of any single marker at recurrence; (4) elevation of any single marker at initial and
56

Oncology 2007;72(suppl 1):5257

both elevation at recurrence. As seen in table 3, our result


has 3 more patterns in addition to conventional 4 patterns in the previous one. Five patients with elevation of
both AFP and PIVKA-II at initial diagnosis also had increase of both markers. Four patients only had PIVKA-II
elevation at initial and recurrence. In 6 patients, there was
no tumor marker increase at recurrence in spite of elevation of any single marker at initial diagnosis. According
to our results, a clinician may fail to detect recurrence of
HCC earlier if only a single tumor marker is applied despite elevation of both initial tumor markers before treatment. The above observation is not surprising since cell
clone can recur, producing tumor marker different from
that produced in initial HCC, according to multicentric
carcinogenesis theory [6].
In conclusion, PIVKA-II might be a useful tumor
marker in the diagnosis of HCC, complementary to AFP,
and in the monitoring of recurrence after curative resection. Simultaneous measurement of AFP and PIVKA-II
could enhance the rate of early HCC diagnosis and detection of recurrence after curative resection.

Acknowledgement
This study was supported by a grant (No. A050021) from the
Korea Health 21 R&D project from the Ministry of Health and
Welfare, Republic of Korea.

Disclosure Statement
The authors declare that they have no financial conflict of
interest.

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