Lung cancer remains a leading cause of mortality worldwide. PET/CT with ¹⁸F-FDG is widely used for detecting, staging, and monitoring lung cancer by assessing increased glycolytic metabolism in tumor cells. Prostate-specific membrane antigen (PSMA), although primarily a marker for prostate cancer, is also associated with tumor neoangiogenesis and has shown uptake in various malignancies, including lung cancer, suggesting potential theranostic applications.

This study aims to compare the uptake of ¹⁸F-FDG and ¹⁸F-PSMA in primary and metastatic lung cancer lesions, analyzing differences between adenocarcinoma and squamous cell carcinoma (SCC) subtypes.

Fourteen patients (9 men and 5 women), aged 55–82 years and diagnosed with lung cancer (10 adenocarcinoma, 4 SCC), underwent PET/CT scans on two separate days: 60 minutes after intravenous administration of 0.1 mCi/kg of ¹⁸F-FDG and 90 minutes after intravenous administration of 0.1 mCi/kg of ¹⁸F-PSMA. Images were assessed by two nuclear medicine physicians and one radiologist. The maximum standardized uptake value (SUVmax) was measured for both tracers in primary tumors, regional lymph nodes, and distant metastatic lesions. The lesions were defined in both tracers by an SUVmax uptake above the background and visual analysis.

A total of 288 lesions were analyzed (247 adenocarcinoma, 41 SCC). In adenocarcinoma, ¹⁸F-PSMA identified 215 lesions, compared to 237 detected by ¹⁸F-FDG. Nine lesions were exclusive to ¹⁸F-PSMA, while 32 were detected only by ¹⁸F-FDG. Forty-five lesions showed higher ¹⁸F-PSMA uptake, while 174 exhibited predominant ¹⁸F-FDG uptake. The median SUVmax for ¹⁸F-FDG was 6.5 (range: 1.8–24.5), compared to 4.0 (range: 0.7–24.8) for ¹⁸F-PSMA. In SCC, ¹⁸F-PSMA identified 36 lesions, while ¹⁸F-FDG detected 41. No lesions showed predominant ¹⁸F-PSMA uptake, and SUVmax values were higher for ¹⁸F-FDG (median: 8.8; range: 1.3–36.6) compared to ¹⁸F-PSMA (median: 2.5; range: 0.9–10.4).We found that SUV values for ¹⁸F-PSMA are statistically different between SCC and adenocarcinoma subtypes in the lesions that showed uptake of both radiotracers (Mann-Whitney U test, p-value < 0.0001). Also, a positive correlation was observed for ¹⁸F-FDG and ¹⁸F-PSMA SUVs in both histological subtypes, being strong for SCC (r = 0.0,8140, p-value < 0.0001) and moderate for adenocarcinoma (r = 0.4278, p-value < 0.0001).

These findings highlight distinct uptake patterns between adenocarcinoma and SCC using ¹⁸F-FDG and ¹⁸F-PSMA PET/CT. SCC demonstrated markedly higher ¹⁸F-FDG uptake with minimal ¹⁸F-PSMA uptake, indicating limited utility of ¹⁸F-PSMA in this subtype. In contrast, adenocarcinoma showed higher ¹⁸F-FDG uptake in most lesions, but a subset exhibited significant ¹⁸F-PSMA uptake, suggesting a potential link between neoangiogenesis and glycolytic metabolism. These results support a complementary role for ¹⁸F-PSMA in adenocarcinoma evaluation, particularly in cases with high PSMA expression. Further studies are needed to determine its clinical impact on personalized treatment strategies and theranostic applications.