November 19, 2013

Triple-positive tumor markers predict recurrence and survival in early-stage hepatocellular carcinoma

Hepatology Research

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Shigeki Nakagawa1, Toru Beppu1,2,  Hirohisa Okabe1, Keita Sakamoto1,  Hideyuki Kuroki1, Kosuke Mima1,  Hidetoshi Nitta1, Katsunori Imai1,  Hiromitsu Hayashi1, Yasuo Sakamoto1,2,  Daisuke Hashimoto1, Akira Chikamoto1,  Takatoshi Ishiko1, Masayuki Watanabe1,  Hideo Baba1,*

DOI: 10.1111/hepr.12277

This article is protected by copyright. All rights reserved.This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/hepr.12277

Publication History
Accepted manuscript online: 19 NOV 2013 03:37AM EST
Manuscript Accepted: 11 NOV 2013

Keywords: alpha-Fetoprotein;  DCP;  Hepatocellular Carcinoma;  PIVKA-Ⅱ; prognosis



Hepatectomy is feasible for patients with HCC with good hepatic function who meet the Milan criteria. Several studies have indicated that tumor markers of HCC, AFP, AFP-L3%, and PIVKAII were good predictors of malignant potential. It is important to identify highly malignant cases of HCC, and the aim of this study was to clarify the impact of triple positive tumor markers as the prognostic factors for early-stage HCC within the Milan criteria.


This study investigated 199 patients who underwent hepatectomy for HCC within the Milan criteria between January 2001 and May 2009. Cumulative recurrence-free survival (RFS), overall survival (OS) and clinicopathological parameters were analyzed according to the number of positive tumor markers.


In patients with triple-positive tumor markers, 5-year RFS and OS was poor (17.1 and 61.4%, respectively). Multivariate analyses revealed independent risk factors for recurrence to be HCV-antibody positive (relative risk [RR] 1.65, P=0.0154), non-initial treatment for HCC (RR 1.87, P=0.0047) and triple-positive tumor markers (RR 1.68, P=0.0376), and the independent risk factors for OS were high ICGR15 value (RR 2.46, P = 0.0146), maximum tumor size (RR 2.71, P = 0.0035) and triple-positive tumor markers (RR 2.57, P = 0.0198). Pathologically invasive growth, microvascular invasion and moderate to poor differentiation were significantly related to the number of the three tumor markers.


Triple-positive tumor markers for early-stage HCC within the Milan criteria showed poor prognosis and malignant characteristics. These markers could be a useful predictor for the degree of malignant potential in early-stage HCC.


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