Prostate-Specific Antigen (PSA)

What Is PSA?

Biochemistry

1. Pre-pro-PSA - initial zymogen with a 17-amino acid leader sequence
2. Pro-PSA (proPSA) - inactive 244-amino acid proenzyme after leader sequence cleavage
3. Active PSA - produced by cleavage of proPSA by hK2

• Complexed PSA (cPSA) - 70-90% of total; bound mainly to alpha-1-antichymotrypsin (ACT) and alpha-2-macroglobulin. The PSA-ACT complex is detectable by most immunoassays; the PSA-A2M complex is NOT detected by standard assays.
• Free PSA (fPSA) - 10-30% of total; unbound, biologically inactive form

Campbell-Walsh-Wein Urology, block 83 | Tietz Textbook of Laboratory Medicine, p. 1050

Normal Reference Values

Tietz Textbook of Laboratory Medicine, p. 1050

Causes of Elevated PSA

• Benign prostatic hyperplasia (BPH)
• Prostatitis
• Urinary tract infections (UTI)
• Acute urinary retention
• Catheterization
• Prostatic biopsy (significant transient rise)
• Prostatic massage, bicycle riding, ejaculation (minor, transient rises)
• Digital rectal examination (DRE) - minor rise

• Prostate cancer (primary use)
• Rarely, ectopic PSA expression in breast cancer and other malignancies at lower concentrations

Tietz Textbook of Laboratory Medicine, pp. 1050-1051 | Schwartz's Principles of Surgery, p. 1813

PSA Derivatives and Reflex Tests

1. Free PSA (fPSA) and Percent-Free PSA (%fPSA)

• %fPSA = (fPSA / total PSA) × 100
• Inverse relationship with prostate cancer risk: lower %fPSA = higher cancer probability
• Most useful in the "gray zone" (total PSA 4-10 µg/L) with a normal DRE
• At a 25% cutoff, detects 95% of prostate cancers
• Reduces unnecessary biopsies in men with BPH

2. Complexed PSA (cPSA)

• Direct measurement of cPSA provides information analogous to %fPSA (ratio of cPSA to total PSA)
• May improve differentiation of BPH from cancer

3. PSA Density (PSAD)

• PSA level divided by prostate volume (measured by TRUS)
• Adjusts for benign gland enlargement; higher density suggests cancer

4. PSA Velocity (PSAV)

• Rate of change in PSA over time (ng/mL/year)
• Controversial as an independent indication for biopsy
• Current consensus: high PSAV alone is NOT an indication for biopsy; men with elevated PSA already meeting biopsy thresholds should proceed regardless of velocity
• Smooth, fast exponential PSA growth above a baseline predicts increased prostate cancer probability

5. PSA Doubling Time (PSADT)

• Time for PSA to double; shorter PSADT suggests more aggressive disease
• Used mainly in monitoring recurrence post-treatment

6. proPSA and phi (Prostate Health Index)

• phi = combines total PSA, free PSA, and [-2]proPSA
• Improves cancer detection specificity compared to total PSA alone

Henry's Clinical Diagnosis, p. 2853-2870 | Tietz, p. 1050-1051

Clinical Uses

1. Screening (Controversial)

• The USPSTF (2012) concluded harms outweigh benefits and recommended against universal screening - this was later revised (2018) to allow shared decision-making for men 55-69 years
• The ACS and EAU recommend informed, shared decision-making for men with >10-year life expectancy
• EAU and Memorial Sloan Kettering recommend a baseline PSA at age 45 for risk stratification
• Benefit of screening is modest and largely limited to men aged 55-69 years
• ~75% of biopsies triggered by PSA do not find cancer; ~70% of found cancers are low-grade/indolent (ERSPC trial data)

2. Diagnosis Aid

• Higher PSA = greater likelihood of prostate cancer, after excluding confounders
• A single elevated PSA should NOT prompt biopsy - confirm with a second measurement
• Definitive diagnosis requires prostatic biopsy and histopathology
• Exception: PSA >100 µg/L with clinical evidence of bone metastases - biopsy may not be essential

3. Staging and Prognosis

• Pretreatment PSA is used in conjunction with Gleason score and clinical stage for risk stratification
• Nomograms (e.g., Partin tables) incorporate PSA for predicting pathologic stage

4. Treatment Monitoring and Recurrence Surveillance

• PSA is the most important serum tumor marker for prostate cancer management
• After radical prostatectomy: PSA should fall to undetectable levels
• Biochemical recurrence (BCR) = confirmed PSA ≥ 0.2 ng/mL post-prostatectomy (or rising PSA after radiotherapy)
• A trend of increasing PSA is more significant than a single absolute elevated value for detecting recurrence
• PSA also used to monitor response to androgen deprivation therapy (ADT)

Schwartz's Principles of Surgery, p. 1813-1815 | Tietz, pp. 1050-1052

Combination Testing