Background:⁶⁸Ga-Prostate Specific Membrane Antigen (⁶⁸Ga-PSMA), a positron emission tomography (PET) tracer that was recently introduce for imaging of prostate cancer, may accumulate in other solid tumors including Hepatocellular Carcinoma (HCC). The aim of the study was to assess the potential role of ⁶⁸Ga-PSMA PET-Computed Tomography (CT) for imaging of HCC. Material and Methods: A prospective pilot study in seven patients with HCC with 41 liver lesions: 37 suspected malignant lesions (tumor lesions) and 4 regenerative nodules. For each liver lesion, uptake of ⁶⁸Ga-PSMA and ¹⁸F-FDG uptake were measured [standard uptake value (SUV) and lesion-to-liver background ratios (TBR-SUV)], and correlated with dynamic characteristics (HU and TBR-HU) obtained on contrast enhanced CT data. Immunohistochemistry staining of PSMA in the tumor tissue was analyzed in samples obtained from 5 patients with HCC and compared to control samples from 3 patients with prostate cancer. Results: Thirty-six of the 37 tumor lesions and none of the regenerative nodules showed increased ⁶⁸Ga-PSMA uptake while only 10 lesions were ¹⁸F-FDG avid. Based on contrast enhancement, tumor lesions were categorized into 27 homogeneously enhancing lesions, nine lesions with "mosaic" enhancement composed of enhancing and non-enhancing regions in the same lesion and a single non-enhancing lesion, the latter being the only non-⁶⁸Ga-PSMA avid lesion. Using the Mann-Whitney test, ⁶⁸Ga-PSMA uptake was found significantly higher in enhancing tumor areas compared to non-enhancing areas and in contrast, ¹⁸F-FDG uptake was higher in non-enhancing areas, P<0.001 for both. ⁶⁸Ga-PSMA uptake (TBR SUV_max) was found to correlate with vascularity (TBR-HU) (Spearman r=0.866, p<0.001). Immunohistochemistry showed intense intra-tumoral microvessel staining for PSMA in HCC, in contrast with cytoplasmic and membranous staining, mainly in the luminal border, in prostate cancer samples. In two of the study patients ⁶⁸Ga-PSMA PET-CT identified unexpected extrahepatic metastases. Four regenerative liver nodules showed no increased uptake of either of the PET tracers. Conclusion:⁶⁸Ga-PSMA PET-CT is superior to ¹⁸F-FDG PET-CT in imaging patients with HCC. HCC lesions are more commonly hypervascular taking up ⁶⁸Ga-PSMA in tumoral micro-vessels. ⁶⁸Ga-PSMA PET-CT is a potential novel modality for imaging patients with HCC.

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