Metabolic characteristics distinguishing intrahepatic cholangiocarcinoma: a negative pilot study of 18F-fluorocholine PET/CT clarified by transcriptomic analysis

PET using fluorine-18 fluorocholine ( 18 F-fluorocholine) may detect malignancies that involve altered choline metabolism. While 18 F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than 18 F-fluoro-D-deoxyglucose (FDG) PET/CT, it is not known whether it can also detect intrahepatic cholangiocarcinoma (ICC), a less common form of primary liver cancer. Clinical, radiographic, and histopathologic data from 5 patients with ICC and 23 patients with HCC from a diagnostic trial of liver 18 F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate 18 F-fluorocholine PET/CT for ICC. Imaging was correlated with whole-genome expression profiling to identify molecular pathways associated with tumor phenotypes. On PET/CT, all ICC tumors demonstrated low 18 F-fluorocholine uptake with a significantly lower tumor to mean background uptake ratio than HCC tumors (0.69 vs. 1.64, p < 0.0001), but no corresponding significant difference in liver parenchyma uptake of 18 F-fluorocholine between ICC and HCC patients (8.0 vs. 7.7, p = 0.74). Two ICC patients demonstrated increased tumor metabolism on FDG PET/CT, while immunohistochemical analysis of ICC tumors revealed overexpression of glucose transporter 1 (GLUT-1) and hexokinase indicating a hyper-glycolytic phenotype. Gene expression analysis revealed down-regulation of farnesoid-X-receptor and other lipid pathways in ICC relative to HCC, and up-regulation of glycolytic pathways and GLUT-1 by HIF1α. These results imply limited utility of 18 F-fluorocholine in ICC, however, significant metabolic differences between ICC, HCC, and parenchymal liver tissue may still provide clues about the underlying liver pathology. Gene and protein expression analysis support hyperglycolysis as a more dominant metabolic trait of ICC.