Value of [⁶⁸Ga]Ga-PSMA-11 PET/CT in Reflecting the Intra- and Intertumor Heterogeneity of Neovascularization in Clear Cell Renal Cell Carcinoma

Prostate-specific membrane antigen (PSMA) is a potential target for the diagnosis and treatment of angiogenesis in clear cell renal cell carcinoma (ccRCC). We aimed to investigate the degree of PSMA signal variability in ccRCC and assess its correlation with neovascularization in the tumor microenvironment. We included 120 patients with suspected renal tumors who underwent [⁶⁸Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) scan before surgery in this retrospective study, including 98 ccRCC, 17 non-ccRCC, and 5 benign diseases. We compared the maximum standard uptake value (SUVmax) and tumor-to-liver ratio (TLR) of primary lesions in different groups and analyzed the diagnostic efficacy of PSMA imaging for ccRCC. The coefficient of variation (CV) of SUVmax, which reflects intertumor heterogeneity, and volume ratio (VR), which reflects intratumor heterogeneity, were obtained from PET imaging. We analyzed the correlation between SUVmax, PSMA immunohistiochemical (IHC) staining, microvessel density (MVD), and serum vascular endothelial growth factor (VEGF) and compared the inter- and intratumor heterogeneity of primary lesions and metastases. In our study, ccRCC showed significantly higher SUVmax and TLR compared to non-ccRCC and benign diseases (<i>F</i> = 14.48, <i>p</i> < 0.001; <i>F</i> = 14.49, <i>p</i> < 0.001). PSMA IHC staining exhibited moderate correlation with SUVmax (<i>r</i> = 0.421, <i>p</i> = 0.021) and MVD (<i>r</i> = 0.518, <i>p</i> = 0.003), but it was not correlated with serum VEGF (<i>r</i> = -0.003, <i>p</i> = 0.989). SUVmax had a moderate correlation with MVD (<i>r</i> = 0.448, <i>p</i> = 0.013) and serum VEGF (<i>r</i> = 0.345, <i>p</i> = 0.020). Serum VEGF exhibited a weak correlation with MVD (<i>r</i> = 0.338, <i>p</i> = 0.145). Based on the correlation, the SUVmax-to-angiogenesis model was validated. The mean SUVmax values of primary lesions, bone metastases, and tumor thrombi were 16.13, 18.69, and 6.02, respectively. The CV of the mean SUVmax was 58.5%, 55.9%, and 80.6%. The mean VR values of primary lesions, bone metastases, and tumor thrombi were 0.33, 0.46, and 0.75, respectively. The CV of the mean VR was 81.8%, 41.3%, and 26.7%. The SUVmax of primary lesions was significantly correlated with corresponding bone metastases and tumor thrombi (<i>r</i> = 0.52, <i>p</i> = 0.011; <i>r</i> = 0.87, <i>p</i> = 0.024). The SUVmax of primary lesion in localized ccRCC and advanced ccRCC showed no significant difference (<i>p</i> = 0.251), while the VR was significantly different (<i>p</i> = 0.049). In conclusion, [⁶⁸Ga]Ga-PSMA-11 PET/CT is an effective molecular imaging tool for assessing angiogenesis and its heterogeneity and differentiating ccRCC. The SUVmax of primary lesions was significantly correlated with PSMA IHC staining, MVD, and serum VEGF. The intertumor heterogeneity of tumor thrombi was significantly higher than that of primary lesions and bone metastases. Primary lesions exhibited the highest intratumor heterogeneity, and lesions with high intratumor heterogeneity showed invasive behavior. PSMA uptake by primary lesions has a positive effect on metastasis.