Prostate-specific antigen (PSA) test

Prostate-Specific Antigen (PSA) Overview

Prostate-Specific Antigen (PSA) is a protein produced primarily by cells within the prostate gland (both normal and cancerous cells). It is a glycoprotein with enzymatic activity (a serine protease belonging to the kallikrein family) whose main physiological function is to liquefy semen, helping sperm motility.

Small amounts of PSA normally leak into the bloodstream. Elevated levels of PSA in the blood can indicate prostate abnormalities, including prostate cancer, but also benign conditions like Benign Prostatic Hyperplasia (BPH) and prostatitis. Therefore, PSA testing is used primarily in the context of prostate cancer screening, diagnosis support, and monitoring.

PSA Biology and Forms

PSA is a single-chain glycoprotein with a molecular weight of approximately 33,000 Daltons (33 kDa).

In the blood serum, PSA exists mainly in two forms:

• Complexed PSA (cPSA): Bound to plasma protease inhibitors, primarily alpha-1-antichymotrypsin (ACT) and alpha-2-macroglobulin (A2M). The PSA-ACT complex (molecular weight ~100 kDa) is the major form. PSA bound to A2M is generally not detected by standard assays.
• Free PSA (fPSA): Unbound, enzymatically inactive forms of PSA (molecular weight ~33 kDa).

The standard clinical PSA test typically measures Total PSA (tPSA), which represents the sum of free PSA and PSA complexed mainly to ACT.

Clinical Indications for PSA Testing

The main indications for measuring PSA levels include:

1. Prostate Cancer Screening: Used, often in conjunction with a Digital Rectal Exam (DRE), to screen asymptomatic men for prostate cancer. The benefits versus harms of routine screening are debated (see Screening Controversy below). Decisions about screening should be individualized based on age, race, family history, and patient preferences after discussion with a healthcare provider.
2. Diagnosis Support: An elevated PSA level prompts further investigation (e.g., repeat PSA, free PSA, imaging, biopsy) to determine the cause, which may be cancer or a benign condition.
3. Prognosis and Staging: Higher PSA levels at diagnosis generally correlate with a higher likelihood of more advanced or aggressive prostate cancer.
4. Monitoring After Diagnosis:
   • Tracking PSA levels before treatment helps assess the disease status.
   • Monitoring PSA levels after treatment (surgery, radiation, hormone therapy) is crucial for assessing treatment effectiveness and detecting recurrence. A rising PSA after definitive treatment (biochemical recurrence) often precedes clinical evidence of relapse.
5. Monitoring Patients with Benign Prostatic Hyperplasia (BPH): Although not its primary use, serial PSA monitoring might sometimes be done in men with BPH, partly to watch for potential concurrent development of cancer, though changes are often related to BPH itself.

Interpretation of PSA Levels

Interpreting PSA levels requires careful consideration of multiple factors:

• "Normal" Range: There isn't a single PSA level below which a man is guaranteed not to have prostate cancer. Historically, a cutoff of 4.0 ng/mL was often used, but cancer can be found below this level, and benign conditions can cause levels above it.
• Age-Specific Ranges: Some guidelines use age-adjusted reference ranges, as PSA levels tend to increase naturally with age due to prostate growth (BPH). For example:
  • Age 40-49: < 2.5 ng/mL
  • Age 50-59: < 3.5 ng/mL
  • Age 60-69: < 4.5 ng/mL
  • Age 70+: < 6.5 ng/mL
  • These are examples and vary between guidelines.
• PSA Velocity: The rate of change in PSA over time. A rapid increase (e.g., > 0.35-0.75 ng/mL per year, depending on baseline PSA) may be more suspicious for cancer than a slow rise, even if the absolute level is still within the "normal" range. Requires at least 2-3 measurements over 18-24 months.
• PSA Density (PSAD): PSA level divided by the prostate volume (measured by ultrasound). Higher density suggests a greater likelihood that an elevated PSA is due to cancer rather than just BPH.
• Significance of Elevated PSA: An elevated PSA level (above age-specific range or > 4.0 ng/mL) or a significant PSA velocity increases the suspicion of prostate cancer but is not diagnostic. It warrants further evaluation.
• Post-Treatment Interpretation: After radical prostatectomy (prostate removal), PSA should become undetectable (< 0.1 or < 0.2 ng/mL). A detectable or rising level indicates biochemical recurrence. After radiation therapy, PSA levels decrease more slowly, and nadir (lowest point) + 2 ng/mL is often used to define biochemical recurrence.

It is crucial to understand that PSA dynamics (the pattern of change over time) are often more important than any single value, especially for monitoring.

Factors Affecting PSA Levels

Besides prostate cancer, several factors can influence PSA levels:

• Benign Prostatic Hyperplasia (BPH): Enlargement of the prostate gland, common with aging, leads to higher PSA production. This is the most common cause of elevated PSA in older men. (Prostatic Hypertrophy / BPH)
• Prostatitis: Inflammation or infection of the prostate gland can cause significant, sometimes temporary, increases in PSA. (Prostate Inflammatory Diseases)
• Age: PSA levels naturally tend to increase slowly with age.
• Prostate Procedures/Manipulation:
  • Digital Rectal Exam (DRE): Can cause a small, temporary increase, although usually not clinically significant for most assays.
  • Prostate Biopsy: Causes a significant, prolonged increase (wait several weeks before re-testing).
  • Cystoscopy, Colonoscopy, Transurethral Resection of the Prostate (TURP), Laser Therapy, Catheterization: Can temporarily elevate PSA levels.
  • Ejaculation: Can cause a temporary, mild increase (often advised to abstain for ~48 hours before testing).
  Recommendation: Blood for PSA testing should ideally be drawn *before* performing procedures like DRE, biopsy, cystoscopy, or within a week *after* such procedures (longer after biopsy).
• Medications:
  • 5-alpha-reductase inhibitors (finasteride, dutasteride - used for BPH/hair loss): Can lower PSA levels by about 50% after 6-12 months of use; results need to be adjusted (doubled) for interpretation.
  • Other drugs: Some evidence suggests statins or NSAIDs might slightly lower PSA, but this is generally not clinically significant.
• Race: Men of African ancestry may have slightly higher baseline PSA levels.
• Obesity: May be associated with slightly lower PSA levels (hemodilution effect).

Free PSA and Percent Free PSA (%fPSA)

Measuring the proportion of free PSA relative to total PSA can help differentiate between BPH and prostate cancer, especially when the total PSA is in the borderline range (e.g., 4-10 ng/mL).

• Prostate cancer tends to produce more complexed PSA, leading to a lower percentage of free PSA (%fPSA).
• BPH tends to produce relatively more free PSA, resulting in a higher %fPSA.

The %fPSA is calculated as: (%fPSA) = [Free PSA / Total PSA] * 100.

• A %fPSA > 25% suggests a lower likelihood of cancer (more likely BPH).
• A %fPSA < 10% suggests a higher likelihood of cancer.
• Values between 10-25% fall into an intermediate range.

Measuring %fPSA is most useful when the total PSA is between 4 and 10 ng/mL to help guide decisions about prostate biopsy.

PSA Screening Controversy

Routine PSA screening for prostate cancer in all men is controversial because:

• Overdiagnosis: It can detect slow-growing, low-risk cancers that might never cause symptoms or affect lifespan, potentially leading to unnecessary anxiety and treatment side effects (e.g., incontinence, erectile dysfunction).
• False Positives: Elevated PSA is often caused by benign conditions (BPH, prostatitis), leading to unnecessary biopsies.
• Unclear Mortality Benefit: Large clinical trials have shown conflicting results regarding whether routine screening significantly reduces overall prostate cancer mortality compared to detecting cancers when symptoms arise.

Current guidelines generally recommend shared decision-making between men and their doctors regarding PSA screening, starting around age 50-55 (or earlier for higher-risk individuals like African American men or those with a strong family history). The discussion should include the potential benefits (early detection of potentially aggressive cancer) and harms (overdiagnosis, overtreatment, side effects) of screening.

The PSA Blood Test Procedure

• Sample Type: Blood serum.
• Preparation: No fasting required. Avoid ejaculation for ~48 hours before the test. Inform your doctor about recent prostate procedures or manipulations.
• Collection: Standard venipuncture (blood draw from a vein in the arm).
• Analysis: Measured using immunoassays in a clinical laboratory. Total PSA is standard; Free PSA may be ordered concurrently or reflexively if Total PSA is elevated.

References

1. National Cancer Institute (NCI). (n.d.). Prostate-Specific Antigen (PSA) Test. Retrieved from https://www.cancer.gov/types/prostate/psa-fact-sheet
2. American Cancer Society (ACS). (n.d.). Screening Tests for Prostate Cancer. Retrieved from https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/acs-recommendations.html
3. Mayo Clinic Staff. (n.d.). PSA test. Mayo Clinic Patient Care & Health Information. Retrieved from https://www.mayoclinic.org/tests-procedures/psa-test/about/pac-20384731
4. U.S. Preventive Services Task Force (USPSTF). (2018). Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. *JAMA*, 319(18), 1901–1913. https://doi.org/10.1001/jama.2018.3710
5. Catalona, W. J., Partin, A. W., Slawin, K. M., Brawer, M. K., Flanigan, R. C., Patel, A., ... & Southwick, P. C. (1998). Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. *JAMA*, 279(19), 1542–1547. https://doi.org/10.1001/jama.279.19.1542
6. Lab Tests Online. (n.d.). Prostate Specific Antigen (PSA). Retrieved from https://labtestsonline.org/tests/prostate-specific-antigen-psa