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. 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)

Combined hepatocellular-cholangiocarcinoma: A population-level analysis of an uncommon primary liver tumor

“…Our analyses showed that men were more commonly affected than women (66%), and patients were older than 60 years at the time of diagnosis (mean age at diagnosis = 62.7 years). Data regarding hepatitis virus infections, background liver status, and biomarkers such as alpha‐fetoprotein were not captured in the SEER database before 2004 and, consequently, were not included in the present analysis; they have been analyzed in the literature with contrasting results …”

and Functional Significance in the NewClassification of Primary Liver Cancers

“…Non-tumoral ductular reaction and its proliferative index, which signifies HPC activation, were independent prognostic factors for overall and disease-free survival in CHCC-CC patients after resection [27]. In addition, soluble NCAM in patient sera was shown to be associated with poor prognosis [28].…”

Hepatic Progenitor Cells in Action

“…2 During chronic liver injury, the normally quiescent resident hepatic HPCs are activated and expanded from the periportal to the pericentral zone of the liver, producing reactive ductules in humans. 4,5 Reactive ductules or ductular reactions (DRs) refer to an increased number of ductules (the finest ramifications of the biliary tree), represent a regenerative response of the liver, and, thus, are a source of hepatocellular restoration during its damage or senescence. The contribution of HPCs to parenchymal restoration during liver injury is directly proportional to diminishing hepatocyte replicative potential and increasing senescence.…”