Prostate-Specific Antigen

Prostate specific antigen (PSA) is a serine protease (kallikrein-3) made by prostatic epithelial cells that liquefies semen. Small amounts leak into the blood, mostly bound to alpha-1 antichymotrypsin (complexed PSA), and about 10 to 30% circulates unbound (free PSA). Total PSA is measured by immunoassay in serum and reported in ng/mL (microg/L). PSA is organ specific but not cancer specific, and any process that disrupts prostatic architecture raises it.

The test is used to assess men with symptoms or an abnormal digital rectal examination, to monitor treatment and detect recurrence after prostatectomy, radiotherapy or hormone therapy, and, after informed discussion, for early detection in asymptomatic men. Its main weakness is overdiagnosis of indolent cancer.

Prostate cancer is the commonest cancer in men in many countries, with about 1.4 million new cases and 375 000 deaths each year worldwide. Lifetime risk is about 1 in 8, higher in men of African ancestry (about 1 in 6) and with a family history or BRCA2 variants. Benign prostatic enlargement affects over half of men over 60 years.

Indications. Lower urinary tract symptoms, bone pain or pathological fracture in an older man, abnormal digital rectal examination, unexplained weight loss, monitoring of known prostate cancer, risk informed detection in selected asymptomatic men (usually from 50 years, or from 40 to 45 years in high risk groups), and assessment of response to treatment.

Specimen. Serum, taken before a digital rectal examination or at least 1 week after. Avoid sampling within 48 hours of ejaculation, 6 weeks of prostatic biopsy or urinary tract instrumentation, 4 to 6 weeks of urinary tract infection or prostatitis, and after vigorous cycling. Samples are stable for days at 2 to 8 °C, and serum should be separated within a few hours.

Ranges are assay specific, and the same assay should be used for serial results.

Total PSA. Age related median values: under 2.5 ng/mL at 40 to 49 years, under 3.5 at 50 to 59, under 4.5 at 60 to 69, and under 6.5 at 70 to 79 years. A fixed cut off of 4.0 ng/mL is commonly used for referral, with lower thresholds (over 3.0 ng/mL, or over 1.0 ng/mL at 40 to 50 years as a risk predictor) in many programmes.

• Under 1.0 ng/mL at 40 to 50 years: low long term risk.
• 3 to 4 ng/mL: a chance of cancer of about 20 to 25%.
• 4 to 10 ng/mL: a chance of cancer of about 25%.
• Over 10 ng/mL: a chance of cancer of 50% or more.
• Over 20 ng/mL: high chance of locally advanced disease, and over 100 ng/mL usually indicates metastases.

Free to total PSA ratio. In men with total PSA of 4 to 10 ng/mL and a normal examination, a free fraction under 10% suggests cancer (chance 55 to 56%), 10 to 25% an intermediate chance, and over 25% suggests benign disease (chance 8%). It reduces unnecessary biopsies.

PSA density. Total PSA divided by prostate volume (from ultrasound or MRI). A density over 0.15 ng/mL per mL increases the likelihood of clinically significant cancer.

PSA velocity and doubling time. A rise of over 0.75 ng/mL a year, or 2 ng/mL in the 12 months before diagnosis, is associated with cancer, but these measures add little to single values in detection. Doubling time is used after treatment.

Other markers. The Prostate Health Index (total, free and [-2]proPSA), 4Kscore and urinary tests (PCA3, TMPRSS2-ERG) improve selection for biopsy. Multiparametric MRI before biopsy is now used to find and target significant tumours.

Causes of raised PSA.

• Prostate cancer.
• Benign prostatic hyperplasia (usually 0.5 to 1 ng/mL for each 10 mL of volume).
• Prostatitis, urinary tract infection and acute urinary retention (values can exceed 100 ng/mL).
• Prostatic manipulation: biopsy, transurethral resection, catheterisation, cystoscopy, vigorous digital examination.
• Ejaculation within 24 to 48 hours, prolonged cycling, and prostatic infarction.
• Increasing age and prostate volume.

Causes of low PSA. 5-alpha-reductase inhibitors (finasteride and dutasteride lower PSA by about 50% after 6 to 12 months, so the measured value is doubled), androgen deprivation, obesity (haemodilution), and some aggressive poorly differentiated cancers.

Monitoring after treatment.

• After radical prostatectomy, PSA should fall to undetectable (under 0.1 ng/mL) within 6 weeks. A confirmed value of 0.2 ng/mL or more indicates biochemical recurrence.
• After radiotherapy, the nadir is reached over months to years, and a rise of 2 ng/mL over the nadir defines failure.
• On androgen deprivation, nadir under 0.2 ng/mL predicts better outcome, and a rising PSA with castrate testosterone defines castration resistant disease.
• Ultrasensitive assays detect recurrence earlier, and PSMA PET locates the site.

Critical values and findings needing immediate action.

• PSA over 100 ng/mL, or any raised PSA with bone pain, neurological deficit, spinal cord compression symptoms, anaemia, hydronephrosis or acute urinary retention.
• A rapidly rising PSA during hormone therapy with new symptoms.
• Raised PSA in a man with fever, dysuria or perineal pain (treat infection, and repeat in 6 weeks).

Interferences and pitfalls.

• A single mildly raised value is repeated after 4 to 6 weeks before action, since transient causes are frequent.
• Different assays give different results, and results from different laboratories are not interchangeable.
• Biotin supplements interfere with some immunoassays (falsely low result in sandwich assays).
• Heterophile antibodies cause false elevations.
• The test misses about 15% of cancers at a cut off of 4 ng/mL, including some high grade cancers.
• PSA cannot distinguish indolent from aggressive cancer. MRI, biopsy grade and genomic tests decide management.
• Testosterone therapy can raise PSA in hypogonadal men, and baseline and follow up values are taken.
• Women and children have trace levels, and PSA has no role in them except in rare tumours.

Special groups.

• Men of African ancestry: higher risk of earlier and more aggressive disease, and baseline testing from 40 to 45 years is discussed.
• Men with BRCA2 variants or Lynch syndrome: higher risk and earlier screening.
• Older adults: screening beyond 70 years or with a life expectancy under 10 years has little benefit and carries harm.
• Transgender women: PSA is lower on oestrogen, and the prostate remains at risk.
• Regions: advanced presentation is more frequent where screening is limited.

Follow up tests. Repeat PSA, free to total ratio, digital rectal examination, multiparametric MRI of the prostate, targeted and systematic biopsy, urinalysis and culture, testosterone, bone scan or PSMA PET, alkaline phosphatase, calcium, creatinine, full blood count, and genetic testing (BRCA1, BRCA2, mismatch repair genes) in advanced or familial disease.