PSMA PET/CT: Normal Biodistribution, Benign Variants, and Non-Prostatic Uptake Pitfalls

Purpose: Prostate-specific membrane antigen (PSMA) PET/CT has become a cornerstone imaging modality for the detection, staging, and restaging of prostate cancer due to its high sensitivity and specificity. PSMA is a transmembrane glycoprotein markedly overexpressed in prostate cancer cells and tumor neovasculature, particularly in high-grade and metastatic disease. Radiotracers such as Ga-68 PSMA-11 and F-18–labeled PSMA agents enable superior lesion detection compared with conventional imaging.

Methods/Materials: This educational exhibit reviews the biologic mechanism of PSMA-targeted radiotracer uptake and illustrates normal physiologic biodistribution patterns on PSMA PET/CT. Representative clinical cases are used to demonstrate common sites and imaging characteristics of focal abnormal uptake, including prostate bed recurrence, nodal disease, osseous metastases, and visceral involvement. Common interpretive pitfalls, such as sympathetic ganglia uptake and benign musculoskeletal findings, are highlighted. Correlation with CT morphology and clinical context is emphasized to aid in accurate diagnosis.

Results: Normal PSMA biodistribution demonstrates intense physiologic uptake in the salivary and lacrimal glands, kidneys, and urinary bladder; moderate uptake in the liver, spleen, and small bowel; and variable mild uptake in sympathetic ganglia, adrenal glands, and nasopharynx. Abnormal uptake patterns suspicious for malignancy include focal tracer activity exceeding background liver uptake, asymmetric distribution, uptake in unexpected locations, and correlation with structural abnormalities on CT. While prostate cancer remains the most common cause of pathologic PSMA uptake, non-prostatic malignancies and benign or inflammatory conditions may also demonstrate PSMA avidity, representing important diagnostic pitfalls.

Conclusions: PSMA PET/CT offers exceptional sensitivity for detecting prostate cancer and its metastatic spread; however, PSMA expression is not entirely specific. Familiarity with normal physiologic uptake patterns, benign variants, and non-prostatic causes of PSMA avidity is essential for accurate image interpretation.