Positron Emission Tomography (PET) Imaging in HCC

Abstract

The advent of hybrid-Positron Emission Tomography (PET) imaging modalities have provided unprecedented opportunities for imaging to play a key role in the advancement of molecular medicine towards optimal, personalized diagnosis and therapy. Molecular imaging allows the non-invasive characterization and quantitation of molecules and molecular events in cells and tissue that are fundamental to the pathophysiology of human disease. In oncology, targeted probes are developed to unravel tumour biology, develop predictive biomarkers, identify therapeutic targets and advance the use of theranostics. Based on clinical PET studies of HCC, it is well-recognized that 18F-Fluorodeoxyglucose (FDG), by far the most commonly used radiotracer in clinical practice, lacks sensitivity for primary HCC lesion detection (≈50%) [1, 2]. This is attributed to the relatively high glucose-6-phosphatase in liver cells and some HCC tumors. K4, the rate constant for dephosphorylation by glucose 6-phosphatase, is similar to the surrounding liver tissue in 45% of HCCs. The uptake of FDG in HCC is depends on the relative ratio of k3 and k4, k3 being the rate constant for phosphorylation of FDG by Hexokinase, which is upregulated in many cancers [3]. In experimental studies on HCC, hexokinase activity increases during carcinogenesis and glucose 6-phosphatase activity decreases finally to zero. Hence, the degree of differentiation of HCC may be assessed using k3 and k4 as indices, and 18F-FDG has a unique role in prognostication by the ability of tracer avidity to predict HCC recurrence and survival [4–6]. On the other hand, 11C-acetate has been found superior in sensitivity (≈90%) [1, 2]. Translational studies have found that HCC tumors utilize exogenous Acetate by upregulation of acetyl-co-A synthetase 1 (ACSS1) and ACSS2, and one study found in particular, ACSS1 was associated with tumor growth and malignancy under hypoxic conditions in human HCC [7]. Based on our experience in the clinics, we have found combined dual-tracer PET scans to provide the highest sensitivity (93%) compared to 18F-FDG and 11C-Acetate alone (51.2% and 81.4% respectively). However, the specificity was poor (46.2%). Moreover, the utilization of 11C-Acetate is limited by the requirement of an on-site cyclotron due to its short half-life, and radiation dose and costs are important considerations. Understanding the role of dual-tracer PET scans in HCC and the complementary patterns of FDG and Acetate uptake, their respective metabolic pathways and how they interact, are important in patient management and to further the understanding of cancer metabolism with therapeutic implications.