Background progenitor activation is associated with recurrence after hepatectomy of combined hepatocellular-cholangiocarcinoma

Authors

  • Xiong Cai,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
    2. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
    3. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
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    • These authors contributed equally to this work.

  • Jian Zhai,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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    • These authors contributed equally to this work.

  • David E. Kaplan,

    1. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
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  • Yijun Zhang,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Lining Zhou,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Xutao Chen,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Guangyang Qian,

    1. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Qiudong Zhao,

    1. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Yonghai Li,

    1. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
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  • Lu Gao,

    1. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
    2. Departments of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Wenming Cong,

    1. Departments of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Minghua Zhu,

    1. Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China
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  • Zhenlin Yan,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Lehua Shi,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Dong Wu,

    Corresponding author
    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
    • Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
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  • Lixin Wei,

    Corresponding author
    1. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
    • Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
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  • Feng Shen,

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Mengchao Wu

    1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Potential conflict of interest: Nothing to report.

  • Supported by the Grant 2008ZX10002-025 from the State Key Project on Infectious Diseases of China. Additional support was provided by National Natural Science Foundation of China (No. 81030041), Key Basic Research Project of China (No. 2010CB945600, 2011CB966200), and China Scholarship Council (No. 2010658011).

Abstract

Hepatic progenitor cells (HPC) play important roles in both liver regeneration and carcinogenesis. Combined hepatocellular-cholangiocarcinoma (CHC), a malignant primary liver tumor with poor prognosis, is thought to be of HPC origin. However, the prognostic significance of this etiology is not well defined. Therefore, we retrospectively investigated the relationship of HPC-related pathological features and long-term outcome in patients with CHC in our department. In a cohort of 80 patients identified between 1997 and 2003, including 70 patients who underwent resection with curative intent, overall survival (OS) and disease-free survival (DFS) were correlated with the proliferative activity of nontumor ductular reaction (DR) and the expression levels of HPC and biliary markers including α-fetoprotein (AFP), keratin 7 (K7), keratin 19 (K19), oval cell (OV)-6, epithelial cell adhesion molecule (EpCAM), and c-Kit in both tumor and nontumor liver. We found that nontumor ductular reactions (DRs), specifically the proliferating cell nuclear antigen (PCNA) labeling index of the ductular reaction (PI-DR), a surrogate for transit-amplifying compartments, was an independent prognostic factor for both OS and DFS. By contrast, intratumoral expression of only one marker, absence of AFP, was associated with OS. PI-DR was also independently associated with synchronous “multicentric occurrence” in hepatocellular carcinoma components, a feature of CHC that may predispose to metachronous multifocal tumorigenesis. Conclusion: Proliferative ductular reaction related to HPC activation is associated with recurrence of CHC. Background HPC activation is strongly associated with multifocal occurrence and related tumor recurrence, highlighting the critical role of background liver disease, a “field effect,” in the recurrence of CHC. (Hepatology 2012;56:1804–1816)

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