The combination of immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF) inhibitors has become a standard first-line therapy for patients with unresectable hepatocellular carcinoma (HCC), highlighting the importance of ICIs in treatment strategies. However, around one-fifth of patients fail to respond, often due to activating mutations in the Wnt/β-catenin signaling pathway, which are associated with primary resistance. Detecting Wnt/β-catenin activation through non-invasive methods could therefore be crucial for guiding clinical management in advanced HCC. Mutations in this pathway manifest in two distinct tumor behaviors: the “Jekyll phenotype,” which shows limited vascular invasion, low metastatic potential, and favorable prognosis, and the “Hyde phenotype,” a more aggressive form characterized by poor differentiation, frequent metastasis, cancer stem cell characteristics, and elevated serum alpha-fetoprotein levels. Differentiation between these phenotypes may be achieved using a combination of hepatobiliary phase Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI), which highlights the Jekyll phenotype via increased nodule enhancement, and FDG-PET/CT, which identifies the Hyde phenotype through elevated glucose uptake.
