What is the difference between free PSA (Prostate-Specific Antigen) and total PSA in prostate cancer screening?

Free PSA vs Total PSA in Prostate Cancer Screening

Free PSA testing should be used alongside total PSA to improve specificity in prostate cancer detection, particularly in men with total PSA values between 4.0-10.0 ng/mL, as it can reduce unnecessary biopsies by 20% while maintaining 95% sensitivity for cancer detection. 1

Understanding PSA Forms

• Total PSA (tPSA) measures all forms of PSA in the blood, including both bound (complexed) and unbound (free) forms 1
• Free PSA (fPSA) measures only the unbound portion of PSA in circulation 1
• The percentage of free PSA (%fPSA) is calculated as (free PSA ÷ total PSA) × 100 1
• In men with prostate cancer, a higher proportion of PSA is bound to proteins (especially alpha-1-antichymotrypsin), resulting in lower %fPSA compared to men with benign conditions 1, 2

Clinical Utility of Free vs Total PSA

Total PSA

• Serves as the primary screening test for prostate cancer detection 1
• Traditional cutoff of 4.0 ng/mL has a sensitivity of about 20% and specificity of 60-70% 1
• Men with PSA values between 4.0-10.0 ng/mL have approximately 25-30% risk of prostate cancer 1
• PSA values can be elevated in non-cancerous conditions like BPH, prostatitis, and after procedures 1

Free PSA and %fPSA

• FDA approved for use in men with total PSA between 4.0-10.0 ng/mL and normal digital rectal exam 1
• A %fPSA cutoff of ≤25% detects 95% of cancers while avoiding 20% of unnecessary biopsies 1, 3
• Lower %fPSA values correlate with higher risk of prostate cancer 1, 3
• Recent evidence shows %fPSA improves prediction of clinically significant and fatal prostate cancer when added to total PSA 4

Clinical Decision Algorithm

When to Use %fPSA:

1. Primary indication: Men with total PSA between 4.0-10.0 ng/mL and normal digital rectal exam 1
2. Secondary indications:
   • After a negative biopsy with persistent PSA elevation 1
   • Risk stratification in men with PSA ≥2.0 ng/mL 4

Interpreting %fPSA Results:

• ≤10%: High risk of prostate cancer (recommend biopsy) 1
• >10% to ≤25%: Intermediate risk (consider biopsy) 1
• >25%: Lower risk (may consider deferring biopsy) 1

Important Clinical Considerations

• %fPSA should not be used in men undergoing dialysis as free PSA is altered by renal clearance 1
• Laboratory variability can affect PSA measurements; using the same assay for longitudinal monitoring is recommended 1
• 5α-reductase inhibitors (finasteride, dutasteride) lower PSA values by approximately 50% and should be considered when interpreting results 1
• Age-specific PSA reference ranges may be more appropriate than a single cutoff value for all men 1
• Recent research shows that adding %fPSA to total PSA improves prediction of clinically significant prostate cancer and fatal prostate cancer, particularly in men with baseline PSA ≥2 ng/mL 4

Limitations and Caveats

• %fPSA is most useful in the "diagnostic gray zone" of total PSA between 4.0-10.0 ng/mL 1
• The clinical utility of %fPSA may be limited in men with very high PSA values (>10 ng/mL) 1
• Prostatitis can affect PSA levels and confound interpretation 1
• Laboratory variability between different assays can affect results; confirmation of abnormal values is recommended 1
• While %fPSA improves specificity, it should be used as part of a comprehensive approach to prostate cancer risk assessment 1