How to cite: Rowe SP. “Pitfalls of PSMA PET Imaging: False Positive, Equivocal, False Negative, Intraprostatic Uptake.” October, 2025. Accessed Oct 2026. https://grandroundsinurology.com/pitfalls-of-psma-pet-imaging-false-positive-equivocal-false-negative-intraprostatic-uptake/
Summary
Steven P. Rowe, MD, PhD, Professor of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, explains the biochemical properties of prostate-specific membrane antigen (PSMA) and how small-molecule prostate-specific membrane antigen positron emission tomography (PSMA PET) radiotracers bind to its extracellular active site. He describes heterogeneity in PSMA expression within prostate tumors and emphasizes that most primary cancers express sufficient PSMA for detection. He contrasts small-molecule tracers with antibody-based agents and explains why current FDA-approved tracers are all small molecules.
Dr. Rowe discusses key differences among PSMA PET agents. He explains how hydrophilicity, hydrophobicity, and structure influence urinary excretion, off-target binding, and false positive bone uptake. Despite chemical differences, registrational clinical trials show similar patterns across agents, with moderate sensitivity and very high specificity for detecting pelvic lymph node metastases in high-risk and very-high-risk patients undergoing radical prostatectomy.
He summarizes the findings from studies on biochemical recurrence, explaining that detection efficiency increases with the prostate-specific antigen (PSA) level, but the positive predictive value remains high even at low PSA levels. PSA doubling time does not consistently predict detection efficiency across datasets. He cautions that inter-reader variability may contribute to potential false positives in evaluating suspected local recurrence.
Dr. Rowe also focuses on intraprostatic uptake. He notes that most primary cancers demonstrate identifiable PSMA uptake, but segmentation methods remain unreliable. Threshold-based volume estimation poorly correlates with histopathologic tumor volume, limiting claims that PSMA PET can outperform magnetic resonance imaging (MRI) in assessing extracapsular extension or seminal vesicle invasion.
He reviews emerging PSMA-specific scoring systems, including the PRIMARY score, P-score, PSMA-RADS, and the SPARK framework, highlighting trade-offs between precision and clinical practicality. He highlights physiologic uptake in neural ganglia, benign fractures, fibro-osseous lesions, Paget’s disease, and uptake changes after radiation as common pitfalls, and false negatives in neuroendocrine prostate cancer due to loss of PSMA expression.
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ABOUT THE AUTHOR
Steven P. Rowe, MD, PhD, is an Professor of Radiology at University of Texas Southwestern Medical Center, Dallas, Texas. He clinically practices both diagnostic radiology and nuclear medicine, and his research work focuses on applications of novel molecular imaging agents for positron emission tomography (PET) and single-photon emission computed tomography (SPECT). He is particularly interested in the use of prostate-specific membrane antigen (PSMA)-targeted PET agents in prostate cancer and renal cell carcinoma, as well as the clinical utilization of 99mTc-sestamibi SPECT for non-invasive characterization of renal masses. He and his colleagues recently developed and validated a structured reporting system for delineating and codifying findings on PSMA PET known as PSMA Reporting and Data System (PSMA-RADS).
