Intrahepatic cholangiocarcinoma in cirrhosis presents granulocyte and granulocyte-macrophage colony-stimulating factor

Hum Pathol. 2003 Dec;34(12):1337-44. doi: 10.1016/j.humpath.2003.07.012.


Intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (HC-CC) are known to arise occasionally in hepatitis-related cirrhosis, although their clinicopathological features remain unclarified. In this study, we characterized the ICC (9 cases) and ICC elements of HC-CC (11 cases) arising in nonbiliary cirrhosis. Thirty-three hepatocellular carcinomas (HCC) associated with nonbiliary cirrhosis and 24 ICC without cirrhosis were used as controls. Prominent neutrophilic infiltration was frequent in ICC with cirrhosis (78%) and ICC elements of combined HC-CC (72%). Neutrophilic infiltration-related cytokines (interleukin 8, granulocyte colony-stimulating factor [G-CSF], and granulocyte macrophage colony-stimulating factor [GM-CSF]) were expressed frequently and intensely in carcinoma cells of ICC with cirrhosis (40%, 80%, and 60%, respectively) and in ICC elements of the combined one (13%, 38%, and 63%, respectively). Interleukin 8 was expressed in 18% of ICC without cirrhosis, irrespective of neutrophilic infiltration. Neutrophilic infiltration and expression of G-CSF and GM-CSF were in parallel (P < 0.05). G-CSF and GM-CSF mRNA were detected by RT-PCR in tissue specimens expressing G-CSF and GM-CSF at the protein level. Such neutrophilic infiltration and expression of G-CSF and GM-CSF were not evident in controls. The expressions of c-kit and c-Met, as a hematopoietic and hepatic stem cell marker, were seen frequently in ICC with cirrhosis (80% and 80%, respectively) and ICC elements of the combined one (63% and 50%, respectively). The present study revealed that the frequent expression of G-CSF and GM-CSF is a characteristic of ICC with cirrhosis and ICC in combined carcinoma, probably representing a phenotype of fetal hepatic parenchymal cell. The expression of these cytokines may be causally related to prominent neutrophilic infiltration.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bile Duct Neoplasms / complications*
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology*
  • Cholangiocarcinoma / complications*
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Female
  • Fibrosis / complications*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Granulocyte Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Humans
  • Immunohistochemistry
  • Interleukin-8 / biosynthesis
  • Male
  • Middle Aged
  • Neutrophils / metabolism*
  • Phenotype
  • Proto-Oncogene Proteins c-met / biosynthesis
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cell Factor / biosynthesis
  • Stem Cells / physiology


  • Interleukin-8
  • RNA, Messenger
  • Stem Cell Factor
  • Granulocyte Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins c-met