What is the next step for a man with an elevated Prostate-Specific Antigen (PSA) level?

Management of Elevated PSA Levels

For a man with elevated PSA levels, the next step should be a prostate biopsy if PSA is above 4.0 ng/ml or if there is a significant velocity change in PSA levels. 1, 2

Initial Assessment and Referral Criteria

• PSA levels greater than 4.0 ng/ml warrant referral to urology for further evaluation and likely prostate biopsy 3, 2
• Significant PSA velocity changes, specifically increases of 1.0 ng/ml or more in a year, should prompt referral regardless of baseline PSA value 2
• Annual increase of 0.7-0.9 ng/ml warrants repeat PSA measurement in 3-6 months and referral if any further increase is detected 1, 2
• Any abnormality on digital rectal examination (DRE) such as nodules, asymmetry, or areas of increased firmness requires immediate referral regardless of PSA level 1

Diagnostic Algorithm

1. Confirm elevated PSA:

   • Repeat PSA test under standardized conditions before proceeding with invasive testing 3
   • Rule out non-cancer causes of elevated PSA such as prostatitis, which can cause temporary PSA elevation 4, 5

2. Risk stratification:

   • Calculate PSA density (PSA-D; serum PSA divided by prostate volume) as it is one of the strongest predictors for clinically significant prostate cancer 3
   • Consider PSA velocity (rate of change over time) as rapid increases (≥1.0 ng/ml/year) suggest more aggressive disease 1, 2

3. Imaging and biopsy:

   • Order multiparametric MRI (mpMRI) which has high sensitivity (91%) for clinically significant prostate cancer 3
   • Proceed with prostate biopsy for PSA >4.0 ng/ml or significant PSA velocity changes 1
   • Standard biopsy protocol involves 10-12 core samples taken under local anesthesia 1

Special Considerations

• PSA interpretation in men on 5α-reductase inhibitors: For patients taking finasteride, PSA values should be doubled for comparison with normal ranges in untreated men 6
• High-risk populations: African-American men and those with a family history of prostate cancer should be considered for earlier or more aggressive evaluation 1
• PSA "gray zone": Men with PSA values between 2.6-4.0 ng/ml have a substantial risk of cancer (approximately 1 in 7 men with PSA <4.0 ng/ml may have prostate cancer) 1
• Free vs. total PSA: Determination of the proportion of free PSA can improve cancer specificity, especially in men with PSA values in the 4-10 ng/ml range 7

Common Pitfalls to Avoid

• Overlooking PSA velocity: Focusing only on absolute PSA values may miss rapidly growing cancers that still have "normal" PSA levels 1, 2
• Ignoring false positives: Approximately 2 of 3 men with elevated PSA do not have prostate cancer; causes include benign prostatic hyperplasia and prostatitis 1, 5
• Inadequate biopsy: Prostate biopsies sometimes miss cancer when present; consider repeat biopsy if clinical suspicion remains high despite negative initial results 1
• Overtreatment risk: Breaking the compulsory link between diagnosis and active treatment is important to decrease overtreatment while maintaining the potential benefit of early diagnosis 3

Follow-up After Biopsy

• If biopsy confirms cancer, treatment options depend on Gleason score, clinical stage, patient's age, overall health, and preferences 3
• If initial biopsy is negative but clinical suspicion remains high, consider repeat biopsy or continued PSA monitoring 1
• For men with negative biopsies, continued PSA monitoring is recommended with consideration of repeat biopsy if PSA continues to rise 1