What type of Prostate-Specific Antigen (PSA) test is recommended to evaluate for prostate cancer?

What PSA Test to Order for Prostate Cancer Evaluation

Order a total PSA (tPSA) test as the initial screening test, and if the total PSA is in the 4-10 ng/mL range with a normal digital rectal exam, add a free PSA to calculate the percent free PSA (free/total PSA ratio) to improve specificity and reduce unnecessary biopsies. 1

Initial Testing Approach

• Total PSA (tPSA) is the standard first-line test for prostate cancer screening and should be combined with digital rectal examination for optimal detection 2
• A single elevated PSA should never prompt immediate biopsy—always verify with a second value before proceeding 1
• Use the same PSA assay for all longitudinal monitoring, as different assays are not interchangeable and can vary by 20-25% depending on standardization methods 2

When to Add Percent Free PSA

The percent free PSA (%fPSA) is FDA-approved and clinically indicated when:

• Total PSA is between 4-10 ng/mL (the "diagnostic gray zone") 1
• Digital rectal examination is normal 1
• You need to decide whether to proceed with biopsy 1

Key performance characteristics:

• A 25% free PSA cutoff detects 95% of prostate cancers while avoiding 20% of unnecessary biopsies 1
• Men with prostate cancer have significantly lower percent free PSA compared to those with benign prostatic hyperplasia 1, 3
• A 16% cutoff provides optimal diagnostic accuracy (sensitivity 80%, specificity 61.5%, overall accuracy 84.5%) 4

Other PSA Forms (Less Commonly Used)

Complexed PSA (cPSA):

• Measures PSA bound to alpha-1-antichymotrypsin 1
• FDA-approved but has not gained widespread clinical acceptance 1
• Provides similar information to percent free PSA but is not routinely incorporated into practice 1

PSA Density (PSAD):

• Requires transrectal ultrasound to measure prostate volume 1
• Calculated as PSA value (ng/mL) divided by prostate volume (cc) 1
• Utility not fully established and adds complexity without clear benefit 5

PSA Velocity:

• Requires at least 3 PSA measurements over 18 months for accurate interpretation 2
• Predictive value remains controversial 1, 5
• Most PSA variation is physiologic, limiting clinical utility 1

Critical Interpretation Factors

Factors that can falsely elevate PSA (must consider before interpretation):

• Prostatitis or urinary tract infection 5, 2
• Recent urinary catheterization (especially traumatic) 1
• Benign prostatic hyperplasia 1, 5
• Recent ejaculation or prostatic trauma 5

Factors that lower PSA:

• 5α-reductase inhibitors (finasteride, dutasteride) decrease PSA by approximately 50% in 6-12 months 1, 5, 2
• Critical pitfall: Multiply the PSA by 2.3 for men taking these medications to determine true PSA value 1

Risk Stratification by PSA Level

• PSA 0-2 ng/mL: 1% probability of prostate cancer 1
• PSA 4-10 ng/mL: 25-35% probability of cancer 5, 3
• PSA >10 ng/mL: >50-67% probability of cancer 1, 5

Important caveat: The Prostate Cancer Prevention Trial demonstrated that prostate cancer can be detected at all PSA levels, even below 1.0 ng/mL, with higher PSA levels conferring higher risk of aggressive disease 5

Decision-Making Algorithm

1. Order total PSA as initial test 2
2. If PSA 4-10 ng/mL with normal DRE: Add percent free PSA 1
   • If %fPSA <25% (or <16% for higher specificity): Consider biopsy 1, 4
   • If %fPSA ≥25%: May avoid immediate biopsy, continue monitoring 1
3. Consider additional factors before biopsy decision: age, ethnicity, family history, prior biopsy results, comorbidities, and patient values 1, 2
4. Verify abnormal results with repeat testing before proceeding to biopsy 1