What is Prostate-Specific Antigen (PSA) and how is it interpreted?

Understanding Prostate-Specific Antigen (PSA) and Its Interpretation

Prostate-Specific Antigen (PSA) is a serine protease produced by prostatic epithelial cells that functions primarily to liquefy seminal coagulum, and its blood level measurement serves as an important but imperfect biomarker for prostate cancer detection, with interpretation requiring consideration of multiple factors including age, prostate size, and medication use. 1, 2

What is PSA?

• PSA is a 34-kDa glycoprotein (240 amino acids) produced exclusively by prostatic epithelial cells and is a member of the kallikrein gene family 3
• It functions primarily in semen where it digests the gel forming after ejaculation by cleaving semenogelins in the seminal coagulum 1, 2
• PSA is secreted into prostatic ducts as an inactive proenzyme (proPSA) that becomes activated through enzymatic cleavage 2
• In blood, PSA circulates in two main forms:
  • Complexed PSA (cPSA): Bound to serum proteins, primarily alpha-1-antichymotrypsin (70-90% of total PSA) 1, 4
  • Free PSA (fPSA): Unbound form (5-40% of total PSA) 1
• PSA production is regulated by androgens acting through androgen receptors 3

PSA Interpretation

Normal Values and Thresholds

• Traditionally, a PSA threshold of 4.0 ng/ml has been used as a cutoff for prostate cancer suspicion 4, 5
• However, significant prostate cancer can occur in men with PSA levels below 4.0 ng/ml 4
• Recent studies have shown that 15-24% of men with PSA in the 2.5-4.0 ng/ml range may have prostate cancer 4
• Using the 4.0 ng/ml threshold:
  • Approximately 70% of prostate cancers can be detected 4
  • False-negative rate is 20-25% (missed cancers) 4
  • False-positive rate is 65% (unnecessary biopsies) 4

Factors Affecting PSA Levels

• Prostate conditions that elevate PSA:

  • Prostate cancer 4, 6
  • Benign prostatic hyperplasia (BPH) 4, 6
  • Prostatitis (inflammation) 6
  • Urethral or prostatic trauma 6

• Medical procedures that can elevate PSA:

  • Prostate biopsy (significant elevation) 3
  • Cystoscopic examination 3
  • Prostate massage 3
  • Transrectal ultrasound 3
  • Digital rectal examination (minimal effect) 3

• Medications affecting PSA:

  • 5α-reductase inhibitors (finasteride, dutasteride) reduce PSA by approximately 50% within 6 months 7, 6
  • For patients on 5α-reductase inhibitors, PSA values should be doubled for comparison with normal ranges, though this rule becomes less accurate after 3 years of treatment 7, 4

• Other factors:

  • Laboratory variability in PSA testing can range from 20-25% 6
  • Renal failure can affect PSA levels (free PSA is cleared by kidneys) 4, 6

Improving PSA Specificity

• Free PSA percentage:

  • The proportion of free PSA is typically smaller in prostate cancer than in BPH 1
  • Measuring the ratio of free to total PSA can improve specificity and reduce unnecessary biopsies 1, 4

• PSA velocity:

  • The rate of PSA change over time can help distinguish cancer from benign conditions 4
  • A yearly PSA velocity greater than 0.75 ng/ml may predict malignancy even when total PSA remains within normal range 4
  • At least 3 PSA measurements over 18 months are recommended for accurate PSA velocity interpretation 4

• PSA density:

  • Accounts for the relationship between PSA level and prostate size 4
  • Helps differentiate between BPH and cancer as causes of elevated PSA 4

• PSA nadir and changes from nadir:

  • For men on 5α-reductase inhibitors, monitoring changes from PSA nadir can be valuable 4
  • An increase of 0.3 ng/ml or greater from nadir may indicate prostate cancer with 71% sensitivity and 60% specificity 4

Clinical Recommendations for PSA Testing

• Current guidelines suggest against systematic PSA-based screening for prostate cancer due to uncertain benefit on mortality and potential harms from overdiagnosis and overtreatment 4
• Shared decision making is recommended for men considering screening, taking into account individual values and preferences 4
• For men who choose screening:
  • Begin at age 50 for average-risk men 4
  • Begin at age 45 for high-risk men (African Americans, family history) 4
  • A mildly elevated PSA should be rechecked in 3-6 months before proceeding to biopsy 6
  • Use the same laboratory assay for serial PSA measurements 6

Common Pitfalls in PSA Interpretation

• Relying solely on PSA without considering other clinical factors 4
• Failing to account for medication effects, particularly 5α-reductase inhibitors 7, 6
• Using different laboratory assays for serial measurements 6
• Applying the simple "doubling rule" for patients on 5α-reductase inhibitors beyond 3 years of treatment 4, 6
• Not considering age-specific PSA reference ranges 4
• Ignoring PSA velocity in men with normal PSA levels 4