Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers

// Satoshi Seino 1 , Atsunori Tsuchiya 1 , Yusuke Watanabe 1 , Yuzo Kawata 1 , Yuichi Kojima 1 , Shunzo Ikarashi 1 , Hiroyuki Yanai 2 , Koji Nakamura 2 , Daisuke Kumaki 3 , Masaaki Hirano 3 , Kazuhiro Funakoshi 3 , Takashi Aono 4 , Takeshi Sakai 5 , Jun Sakata 6 , Masaaki Takamura 1 , Hirokazu Kawai 1 , Satoshi Yamagiwa 1 , Toshifumi Wakai 6 and Shuji Terai 1 1 Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan 2 Drug Discovery Laboratories, Chiome Bioscience Inc., 907 Nogawa, Miyamae-Ku, Kawasaki-Shi, Kanagawa 216-0001, Japan 3 Division of Gastroenterology and Hepatology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan 4 Division of Surgery, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan 5 Division of Diagnostic Pathology, Niigata Prefectural Central Hospital, Joetsu-Shi, Niigata 943-0147, Japan 6 Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-Ku, Niigata 951-8510, Japan Correspondence to: Atsunori Tsuchiya, email: atsunori@med.niigata-u.ac.jp Shuji Terai, email: terais@med.niigata-u.ac.jp Keywords: hepatocellular carcinoma; hepatic progenitor cell; epithelial cell adhesion molecule; lectin-reactive α-fetoprotein; des-γ-carboxy prothrombin Received: July 11, 2017      Accepted: March 22, 2018      Published: April 24, 2018 ABSTRACT The high heterogeneity of hepatocellular carcinomas (HCCs) complicates stratification of HCC patients for treatment. Therefore, it is necessary to establish a comprehensive panel of HCC biomarkers related to tumour behaviour and cancer prognosis. Resected HCCs from 251 patients were stained for hepatic progenitor cell (HPC) markers epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), delta-like 1 homolog (DLK1), and cytokeratin 19 (CK19). Staining patterns were analysed for their prognostic association with relapse-free survival and overall survival. α-Fetoprotein (AFP), lectin-reactive α-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin (DCP) were assessed as indicators of HPC protein expression. Expression pattern of HPC markers correlated with tumour malignancy indicated by high AFP/AFP-L3 serum levels, more frequent vascular invasion, and poorer tumour differentiation. EpCAM expression, DCP ≥300 mAU/ml, age ≥60, and Child-Pugh score grade B or C were independent prognostic factors of poor outcome and were used in a new scoring system for HCC prognosis after operation. Expression of two or more HPC markers was a significant predictor of poor HCC outcome and serum levels of AFP/AFP-L3 correlated with the expression of HPC proteins. Our study paved the way for further elucidation of the association among HPC markers, serum tumour markers, and HCC clinical outcome for precision medicine.