# PSMA PET/CT in Prostate Cancer

## Overview

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is overexpressed on prostate cancer cells. Its expression increases with higher Gleason grade, metastatic disease, and castration-resistant status. PSMA PET/CT has revolutionized prostate cancer imaging by providing dramatically superior sensitivity and specificity compared with conventional imaging modalities.

## Approved PSMA Radiopharmaceuticals

### Ga-68 PSMA-11

Ga-68 PSMA-11 uses generator-produced Ga-68 with a half-life of 68 minutes. It received FDA approval in 2020 for initial staging of high-risk prostate cancer and biochemical recurrence. It is a small peptide that targets the extracellular domain of PSMA, with imaging performed at 60 minutes post-injection. Excretion is renal, resulting in activity in the kidneys, ureters, and bladder.

### F-18 Piflufolastat (DCFPyL, Pylarify)

F-18 piflufolastat uses cyclotron-produced F-18 with a half-life of 110 minutes. It received FDA approval in 2021 for the same indications as Ga-68 PSMA-11. Its longer half-life allows centralized production and broader distribution, and its lower positron energy produces higher image quality. Imaging is performed at 60 to 120 minutes post-injection.

<image>Comparison of Ga-68 PSMA-11 and F-18 DCFPyL PET/CT in biochemical recurrence showing a PSMA-avid pelvic lymph node metastasis</image>

## Clinical Indications

### Biochemical Recurrence (BCR)

Biochemical recurrence is the most established indication for PSMA PET/CT, and detection rates are strongly dependent on PSA level. At PSA below 0.5 ng/mL, the detection rate is 30 to 50%. At PSA 0.5 to 1.0 ng/mL, it rises to 50 to 70%. At PSA 1.0 to 2.0 ng/mL, it reaches 70 to 80%, and above 2.0 ng/mL, detection exceeds 85%. PSA doubling time and PSA velocity also influence detection rates. PSMA PET dramatically outperforms conventional imaging (bone scan and CT) at low PSA levels and changes management in approximately 50 to 60% of patients, for example by directing targeted salvage radiation versus systemic therapy.

### Initial Staging

PSMA PET/CT is indicated for unfavorable intermediate-risk to high-risk prostate cancer at initial staging. It is superior to conventional imaging for nodal and distant metastatic detection, identifying pelvic lymph node metastases missed by CT size criteria. It may also detect oligometastatic disease amenable to metastasis-directed therapy.

### Pre-Therapy Selection for Lu-177 PSMA

PSMA PET/CT confirms PSMA expression in metastatic disease before lutetium-177 PSMA therapy. All sites of disease should demonstrate PSMA uptake exceeding liver background. Sites that are PSMA-negative or FDG-positive but PSMA-negative suggest dedifferentiated disease that is unlikely to respond to PSMA-targeted therapy.

## PSMA-RADS Classification (Version 1.0)

### Scoring System

The PSMA-RADS classification provides a standardized reporting framework. PSMA-RADS-1 indicates a benign finding with no abnormal uptake. PSMA-RADS-2 indicates likely benign findings with faint uptake in an atypical location for prostate cancer. PSMA-RADS-3 is equivocal, with moderate uptake in an atypical site or faint uptake in a typical site. PSMA-RADS-4 indicates high probability of prostate cancer with intense uptake in a typical location. PSMA-RADS-5 indicates almost certain prostate cancer with intense uptake in a typical location and correlative CT findings.

### Typical vs. Atypical Locations

Typical locations for prostate cancer metastases include the prostate bed, pelvic and retroperitoneal lymph nodes, and bone. Atypical locations include non-regional lymph nodes (such as mediastinal nodes in isolation), visceral organs, and unusual soft tissue sites.

| PSMA-RADS Score | Interpretation | Criteria | Recommended Action |
|---|---|---|---|
| 1 | Benign | No abnormal uptake | No further workup |
| 2 | Likely benign | Faint uptake, atypical site | Observation |
| 3 | Equivocal | Moderate uptake atypical site or faint in typical site | Correlate; consider follow-up |
| 4 | High probability of PCa | Intense uptake, typical location | Treat as metastatic |
| 5 | Almost certain PCa | Intense uptake + correlative CT finding | Treat as metastatic |

<image>PSMA PET/CT maximum intensity projection showing extensive skeletal and lymph node metastatic disease with high PSMA expression in a patient with castration-resistant prostate cancer</image>

## Normal Biodistribution and Pitfalls

### Physiologic Uptake

Normal physiologic PSMA uptake occurs in the kidneys (highest uptake, as PSMA is expressed in proximal tubule cells), salivary glands (parotid and submandibular), lacrimal glands, small bowel (duodenum and jejunum), liver (moderate background), urinary bladder (excreted tracer), and sympathetic ganglia (stellate, celiac, and sacral).

### False Positives (Non-Prostate Cancer Causes of PSMA Uptake)

Celiac ganglion uptake is the most common pitfall, appearing as bilateral, symmetric uptake at a characteristic location. Other malignancies, including renal cell carcinoma, hepatocellular carcinoma, thyroid cancer, and lung cancer, can express PSMA. Benign bone lesions such as Paget disease, healing fractures, and fibrous dysplasia may show uptake. Inflammatory conditions including sarcoidosis and reactive lymph nodes are additional sources of false-positive results. Benign prostatic hyperplasia demonstrates low-level PSMA expression.

### False Negatives

Small lesions below PET resolution (less than 4 to 5 mm) may be missed. Dedifferentiated or neuroendocrine-differentiated prostate cancer can be PSMA-negative. Lesions near the bladder or ureters may be obscured by urinary activity. The effect of recent androgen deprivation therapy on PSMA expression remains controversial, as it may transiently increase or decrease uptake.

<image>Common PSMA PET/CT pitfalls: celiac ganglion uptake mimicking a retroperitoneal lymph node metastasis, and a healing rib fracture mimicking osseous metastasis</image>

## Comparison with Conventional Imaging

### PSMA PET vs. Bone Scan

PSMA PET achieves a sensitivity of approximately 95 to 98% and specificity of approximately 95 to 98% for skeletal metastases, compared with 75 to 85% sensitivity and 70 to 80% specificity for bone scan. PSMA PET detects bone marrow metastases before cortical involvement occurs, during the pre-osteoblastic phase.

### PSMA PET vs. CT

CT relies on size criteria for lymph node assessment, using a short axis of 1 cm or greater as the threshold for abnormality. PSMA PET detects sub-centimeter nodal metastases based on molecular expression, resulting in significantly higher sensitivity for lymph node metastases (40 to 60% versus 8 to 30% for CT).

## E-PSMA Reporting Standards

The European Association of Nuclear Medicine (EANM) has established consensus recommendations for standardized PSMA PET reporting. The miPSMA score provides a visual 5-point scale referenced to blood pool and liver. Structured reporting templates cover findings related to the primary tumor, lymph nodes, bone, and visceral sites.

## Clinical Pearls

PSMA PET/CT has largely replaced conventional bone scan and CT for prostate cancer staging at many institutions.

At very low PSA levels below 0.2 ng/mL, the detection rate may not justify the scan. Shared decision-making with the patient is important.

Celiac ganglion uptake is not metastatic disease. It appears as bilateral, symmetric uptake at the T12-L1 level on sagittal images.

When FDG-positive but PSMA-negative metastases are found, neuroendocrine differentiation should be considered and biopsy pursued.

Androgen deprivation therapy may cause a flare phenomenon on PSMA PET, with transient increased uptake in the first 2 to 4 weeks.

For radiation therapy planning, PSMA PET can define boost volumes for intraprostatic dominant lesions.

## References

- Fendler, W. P., et al. "Ga-68 PSMA-11 PET/CT for Prostate Cancer Biochemical Recurrence." *Journal of Nuclear Medicine*, 2019.
- Pienta, K. J., et al. "CONDOR Trial: F-18 DCFPyL PET/CT for Biochemical Recurrence." *JAMA Oncology*, 2021.
- Rowe, S. P., et al. "PSMA-RADS Classification System." *Journal of Nuclear Medicine*, 2018.
- Hofman, M. S., et al. "ProPSMA Trial: PSMA PET/CT vs. Conventional Imaging." *Lancet*, 2020.