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

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. 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.