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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
Introduction
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.
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
Results
53
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
0
0
0.2
0.4
0.6
0.8
1.0
1 Specificity
Discussion
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
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
1
0
6
5
5
6
4
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.
55
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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