Imaging Lipid Synthesis in Hepatocellular Carcinoma with [Methyl-¹¹C]Choline: Correlation with In Vivo Metabolic Studies

Abstract

PET with [methyl-11 C]-choline ( 11 C-choline) can be useful for detecting well-differentiated hepatocellular carcinoma (HCC) that is not 18 F-FDG-avid. This study was designed to examine the relationship between choline metabolism and choline tracer uptake in HCC for PET with 11 C-choline. Methods: Dynamic PET scans of 11 C-choline were acquired using the woodchuck models of HCC. After imaging, [methyl-14 C]-choline was injected, and metabolites from both HCC tissue samples and the surrounding hepatic tissues were extracted and analyzed by radio-high-performance liquid chromatography. The enzymatic activities of choline kinase and choline-phosphate cytidylyltransferase were assayed for correlation with the imaging and metabolism data. Results: PET with 11 C-choline showed an HCC detection rate of 9 of 10. The tumor-to-liver ratio for the 9 detected HCCs was 1.89 6 0.55. Hematoxylin-eosin staining confirmed that all spots with high tracer uptake were well-differentiated HCCs. Variation of radioactivity distribution within HCCs indicated a heterogeneous uptake of choline. The activities of both choline kinase and choline-phosphate cytidylyltransferase were found to be significantly higher in HCC than in the surrounding hepatic tissues. The major metabolites of 11 C-choline were phosphocholine in HCC and betaine and choline in the surrounding hepatic tissues at 12 min after injection; in HCC, phosphocholine rapidly converted to phosphatidylcholine at 30 min after injection. Conclusion: HCCs display enhanced uptake of radiolabeled choline despite a moderate degree of physiologic uptake in the surrounding hepatic tissues. Initially, increased radiolabeled choline uptake in HCCs is associated with the transport and phosphorylation of choline; as time passes, the increased uptake of radiolabeled choline reflects increased phosphatidylcholine synthesis derived from radiolabeled cytidine 59-diphosphocholine (CDP-choline) in HCCs. In contrast, the surrounding hepatic tissues exhibit extensive oxidation of radiolabeled choline via the phosphatidylethanolamine methylation pathway, a major contributor to the observed physiologic uptake.

Functional imaging techniques in hepatocellular carcinoma

“…11 C and 18 F-F-Cho PET Increased concentrations of choline have been confirmed in surgical HCC specimens [26]. In the hepatitis viral infection-induced woodchuck model it has been shown that HCC is associated with increased transport and phosphorylation of 11 C-Cho and that the increased accumulation of radiolabelled choline reflects increased phosphatidylcholine synthesis [27,28]. A study in the same animal model has shown a small preferential uptake of 11 C-Cho compared to 18 F-fluoroethylcholine in terms of tumour-to-background contrast [29].…”

Use of choline PET for studying hepatocellular carcinoma

“…11 C-acetate instead detected 16/17 HCCs, while 11 C-choline PET detected all HCCs. Kuang et al [26], also in a woodchuck model, observed increased 11 Ccholine uptake in HCC, which was associated with choline transport and phosphorylation; the increased uptake of radiolabelled choline over time reflects increased phosphatidylcholine synthesis from cytidine 5 0 -diphosphocholine. By contrast, the surrounding hepatic tissues exhibited extensive oxidation of radiolabelled choline via the phosphatidylethanolamine methylation pathway, a major contributor to the observed physiological uptake.…”

[18F]-choline PET/CT as an imaging biomarker for primary liver cancers

“…This is actually not obvious by looking at the raw profiles and the image data. Previous preclinical studies hinted that the metabolism of radio-choline in HCC follows mainly the CDP-choline pathway that resulted in adding the saturated fatty acids in PC, while the metabolic fate of the same fluorocholine in the liver parenchymal follows PE-methylation pathway that resulted in getting the longer-chain poly-unsaturated fatty acids in PC (15). Therefore, as shown in Figure 1, not all PCs are the same!…”

“…Patients would normally have their multi-phase contrast enhanced CT or MRI done before the PET scan was ordered. Regarding the advanced HCCs, anecdote results from preclinical studies showed that the imaging signal of choline uptake in these HCCs leveled down comparing to the early stage HCC, but still above liver background suggesting a possible re-partitioning the mixture between CDP-choline and PET methylation pathways in advanced HCCs for the metabolism of the choline tracers (14,15). This is worthwhile for further investigation both preclinically and clinically.…”

“…What is missing in all these previous clinical investigations are cellular characterization and validation. Preclinical studies with a clinically relevant animal model of naturally occurring HCC indicated that the uptake of radio-labeled choline tracers retained in HCC seen on PET images reflects the augmented biosythnesis of phospholipids, mainly phosphatidylcholine (PC) (13–15). This recent clinical study validated the preclinical findings.…”