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When PSMA is not enough: the diagnostic blind spots of PSMA PET/CT and the added value of [¹⁸F]FDG in high-risk prostate cancer: dual-tracer cohort study
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DOI：10.1186/s40644-026-01084-y.png)
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Abstract
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PSMA PET/CT has transformed prostate cancer management, yet its diagnostic utility is not absolute. It fails to detect PSMA-suppressed disease variants, including treatment-induced neuroendocrine prostate cancer (t-NEPC) and dedifferentiated tumors, and is inherently blind to second primary malignancies (SPMs). This study evaluated the additional diagnostic yield and direct clinical impact of incorporating [¹⁸F]FDG PET/CT into a systematic, indication-driven dual-tracer protocol in high-risk prostate cancer patients. In this retrospective, STROBE-compliant, single-center cohort study, 82 patients with histologically confirmed prostate cancer who underwent both [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]FDG PET/CT were analyzed. Clinical indications encompassed suspected SPM, suspected dedifferentiation or t-NEPC, initial staging of very high-risk disease, pre-[¹⁷⁷Lu]Lu-PSMA therapy evaluation, and equivocal PSMA findings. The primary endpoint was the proportion of patients in whom [¹⁸F]FDG PET/CT provided additional diagnostic information. Secondary endpoints included concordance analysis and the rate of management changes. Median age was 72 years (IQR 65–75). [⁶⁸Ga]Ga-PSMA-11 demonstrated superior prostate cancer detection compared to [¹⁸F]FDG (70.7% vs. 25.6%; McNemar’s p < 0.0001). However, [¹⁸F]FDG PET/CT provided clinically critical additional information and directly altered management in 51.2% of patients (95% CI: 40.6–61.7%). The most impactful contributions were histopathologically confirmed SPM detection (30.5%, predominantly lung and colorectal adenocarcinomas) and identification of PSMA-negative/FDG-positive discordant disease signaling dedifferentiation. No significant correlation was found between PSMA and FDG SUVmax values (Spearman rho = 0.149, p = 0.422), underscoring their biologically distinct and complementary targets. [¹⁸F]FDG PET/CT is not a redundant adjunct to PSMA imaging; it fills a critical diagnostic blind spot. When applied through an indication-driven framework, dual-tracer imaging directly reshapes clinical decision-making in more than half of selected high-risk prostate cancer patients, enabling detection of occult malignancies and guiding pivotal treatment decisions that PSMA PET/CT alone cannot support.
Keywords:
Prostate cancer
Dual-tracer imaging
Dedifferentiation
Neuroendocrine prostate cancer
Treatment-induced NEPC
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