What is the approach to follow-up on an elevated Prostate-Specific Antigen (PSA) result?

Approach to Follow-Up on an Abnormal PSA

For an elevated PSA, confirm the elevation with a repeat test in 3-6 months before proceeding to invasive workup, but refer immediately to urology if PSA is >4.0 ng/mL with abnormal digital rectal examination, or if PSA velocity is ≥1.0 ng/mL per year regardless of absolute value. 1

Initial Assessment and Confirmation

Exclude Confounding Factors

• Do not test PSA during active urinary tract infections or prostatitis, as approximately 2 of 3 men with elevated PSA do not have prostate cancer 1
• Avoid PSA testing within 48 hours of ejaculation, vigorous exercise, or recent prostate manipulation (digital rectal examination, cystoscopy, or prostate biopsy) 1
• If patient is on 5-alpha reductase inhibitors (finasteride or dutasteride), PSA is reduced by approximately 50% within 6 months; any confirmed increase from the lowest PSA value while on these medications may signal prostate cancer and requires evaluation, even if levels remain within "normal" range for untreated men 2, 3

Repeat PSA Testing

• For mildly elevated PSA (4.0-10.0 ng/mL), recheck PSA in 3-6 months to confirm elevation before proceeding to biopsy 4
• Use the same PSA assay for longitudinal monitoring, as different assays are not interchangeable due to different calibration standards 1
• Short-term PSA decreases can occur in men with prostate cancer, including high-grade cancer, and should not influence the decision to proceed to biopsy if initial PSA was elevated 5

Risk Stratification

Immediate Referral Criteria (Do Not Wait for Repeat Testing)

• PSA >4.0 ng/mL with any abnormality on digital rectal examination (nodule, asymmetry, or increased firmness) 6, 1
• PSA velocity ≥1.0 ng/mL per year, even if absolute PSA is within normal range 1
• PSA >10 ng/mL regardless of digital rectal examination findings 6

Perform Digital Rectal Examination

• Digital rectal examination must be performed when PSA is elevated, as it may identify high-risk cancers with "normal" PSA values 1
• Any nodule, asymmetry, or areas of increased firmness require immediate referral regardless of PSA level 6, 1

Calculate PSA Density

• PSA density (PSA divided by prostate volume) is one of the strongest predictors for clinically significant prostate cancer, with a cut-off of 0.15 ng/mL/cc 1, 7
• Prostate volume can be estimated by transrectal ultrasound or multiparametric MRI 1

Additional Risk Assessment Tools

• For PSA 4-10 ng/mL, order percent free PSA: <10% suggests higher cancer risk (30-35% probability of cancer on biopsy), while >25% suggests benign disease 1, 7
• Consider PSA velocity: for men with PSA <4 ng/mL, velocity of 0.35 ng/mL per year is suspicious; for PSA 4-10 ng/mL, velocity of 0.75 ng/mL per year is suspicious 6
• Alternative biomarkers include phi (>35 suggests higher risk) or 4Kscore for further risk stratification 1

Diagnostic Workup

Multiparametric MRI

• Order multiparametric MRI before biopsy in most cases, as it has high sensitivity (91% for clinically significant prostate cancer) and can guide targeted biopsies while reducing detection of clinically insignificant cancers 1, 7
• For very high PSA (>50 ng/mL), proceed directly to prostate biopsy without preliminary MRI, as this represents high-risk disease 1

Prostate Biopsy

• Perform extended-pattern biopsy (12 cores minimum) including sextant cores, lateral peripheral zone cores, and lesion-directed cores at palpable nodules or suspicious MRI findings 6
• For PI-RADS 4-5 lesions on MRI with PSA density >0.20 ng/mL, proceed with targeted biopsy plus perilesional sampling 7
• After 2 negative extended TRUS biopsies, prostate cancer is not commonly found at repeat biopsy 6

Biopsy Results Requiring Repeat Sampling

• High-grade prostatic intraepithelial neoplasia (HGPIN): If extended pattern used initially, consider delayed repeat biopsy (1 year); if sextant biopsy used, rebiopsy using extended pattern 6
• Atypia suspicious for cancer: Extended pattern rebiopsy within 3 months with increased sampling of atypia site and adjacent areas 6
• Negative biopsy with PSA >10 ng/mL: Repeat biopsy at 3-12 month interval based on discussion with patient 6

Surveillance Strategy for Confirmed Benign Elevation

PSA 4-10 ng/mL with Negative Workup

• If free PSA >25%, follow with PSA and digital rectal examination every 6-12 months 6
• If free PSA 10-25%, consider repeat biopsy or close follow-up with PSA every 6 months 6

PSA Normalizes (<4.0 ng/mL)

• Continue surveillance with PSA testing at 2-4 year intervals 1
• Men aged ≥60 years with PSA <1.0 ng/mL have very low risk of metastases or death from prostate cancer 1

Post-Treatment PSA Elevation

After Radical Prostatectomy

• PSA should be undetectable within 6-8 weeks after surgery (wait this period before assessing PSA due to long half-life) 6
• Biochemical recurrence is defined as PSA ≥0.2 ng/mL confirmed on two successive assays 6, 1
• Exclude metastatic disease with CT (or MRI) and bone scan 1

After Radiation Therapy

• Biochemical recurrence requires minimum of three PSA determinations ≥2 weeks apart, with minimum value >1.5 ng/dL 6, 1
• Measure testosterone levels: should be ≥150 ng/dL, and patient should not be receiving hormonal therapy for minimum 1 year 6, 1

Critical Pitfalls to Avoid

• Do not delay referral for significant PSA velocity changes (≥1.0 ng/mL/year) even if absolute PSA is within normal range, as rapidly growing cancers may have "normal" PSA levels 1
• Do not assume negative biopsy excludes cancer: prostate biopsies can miss cancer; continue PSA monitoring with consideration of repeat biopsy if PSA continues to rise 1
• Do not focus only on absolute PSA values: PSA velocity is crucial for detecting aggressive disease 1
• Do not use different laboratory assays for serial PSA measurements, as they are not interchangeable 4
• Men with <15 years life expectancy are unlikely to benefit from early diagnosis, so consider overall health status and patient preferences 7