Diagnostic Potential of Supplemental Static and Dynamic ⁶⁸Ga-FAPI-46 PET for Primary ¹⁸F-FDG-Negative Pulmonary...

PET using ⁶⁸Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, ¹⁸F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently ¹⁸F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic ⁶⁸Ga-FAPI-46 PET in the ¹⁸F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic ⁶⁸Ga-FAPI-46 PET in addition to ¹⁸F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUV_max, SUV_mean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (⁶⁸Ga-FAPI-46 in relation to¹⁸F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k ₁, k ₂, k ₃, and k ₄) were extracted from dynamic ⁶⁸Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated ⁶⁸Ga-FAPI-46 uptake, higher TBRs, and higher ⁶⁸Ga-FAPI-46-to-¹⁸F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative ⁶⁸Ga-FAPI-46-to-¹⁸F-FDG ratios regarding SUV_max and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: ⁶⁸Ga-FAPI-46 PET is a powerful new tool for the assessment of single ¹⁸F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.