Prostate Cancer - PSA

Indications for Testing

• Lower urinary tract symptoms (eg, urinary frequency, hesitancy, incomplete emptying, and nocturia)
• Urinary tract infection in males with appropriate risk factors
• New prostate nodule or hypertrophy
• Follow-up of previously elevated prostate-specific antigen (PSA) – screening recommendations can be found in the Screening section

Laboratory Testing

• Total PSA (NCCN, 2016)
  • <1 ng/mL – repeat testing at 2-4 year intervals
  • 1-3 ng/mL – repeat testing at 1-2 year intervals
  • >3 ng/mL – repeat testing and digital rectal exam (DRE); workup for benign disease
  • Normal PSA values do not rule out prostate cancer
  • PSA values and associated risk of developing cancer

    PSA Value	Risk of Developing Cancer
    <0.5 ng/mL	6.6%
    0.6-1.0 ng/mL	10.1%
    1.1-2.0 ng/mL	17%
    2.1-3.0 ng/mL	23.9%
    3.1-4.0 ng/mL	26.9%
    Thompson, 2004
  • PSA can be elevated in benign conditions affecting the prostate
• PSA free percentage
  • Premise – the ratio of free (unbound) PSA to total PSA is reduced in prostate cancer
  • Free PSA expressed as a percentage of total PSA – both values need to be measured concurrently
  • Most useful for PSA concentrations 4-10 ng/mL with normal DRE (Sturgeon, 2008)
  • Risk is age dependent – the older the patient and the lower the percentage, the higher the risk for prostate cancer
  • PSA free percentage >25% – associated with low risk (considered normal)
  • PSA free percentage ≤10% – associated with >50% risk, regardless of age
  • PSA free percentage <25% – consider biopsy based on clinical circumstance
• PSA velocity (PSAV)
  • Premise – PSAV increases more rapidly in men with prostate cancer
  • Defined as rate of increase in PSA over time
    • PSAV = (PSA test #2-PSA test #1)/time elapsed
  • Requires at least 3 serial measurements (Noguez, 2014)
  • Biopsy may be considered, based on individual risk factors, if PSAV result is ≥0.35 ng/mL/year and PSA concentration is >2.6-4 ng/mL (National Comprehensive Cancer Network [NCCN], 2017)
• PSA density (PSAD)
  • Premise – prostate cancer is more dense than benign conditions
  • PSA divided by ultrasound volume of prostate gland (using transrectal ultrasound)
    • Normalizes for large glands that produce increased amounts of PSA
  • Higher value (typically >0.1-0.15 ng/mL) associated with increased risk of cancer
• PCA3 (urine)
  • Premise – PCA3 is overexpressed in prostate cancer but not in benign hypertrophy
  • PCA3 is a prostate-specific noncoding mRNA
  • Specimen
    • Collect urine sample after DRE
  • Test methodology
    • In vitro nucleic acid amplification test
    • Utilizes
      • Target capture transcription-mediated amplification
      • Hybridization-protection assay for amplicon detection
    • PCA3 score – calculated as the ratio of PCA3 RNA copies to PSA RNA copies, multiplied by 1,000
  • Sensitivity and specificity
    • 77.5% and 57.1% respectively – relative to prostate biopsy outcome
    • Based on a PCA3 score cutoff value of 25
  • PCA3 scoring results interpretation

    PCA3 Ratio	Result	Interpretation
    0-17	Negative	Associated with decreased likelihood of a positive biopsy for prostate cancer
    18-24	Negative	Interpret with caution – due to normal test variability, specimens with PCA3 scores near the cutoff may yield a different overall interpretation upon repeat testing
    25-31	Positive	Interpret with caution – due to normal test variability, specimens with PCA3 scores near the cutoff may yield a different overall interpretation upon repeat testing
    >31	Positive	Associated with increased probability of a positive biopsy for prostate cancer

• Prostate health index (PHI)
  • Combination of  total PSA,  free PSA, and a subcategory of free PSA called pro-PSA (also referred to as p2PSA)
  • Multicenter study determined PHI may increase sensitivity of cancer detection for men with indeterminate serum PSA
  • Optimal cutoff of test appears to be 24, which should lead to 36% of biopsies avoided with ~2.5% trade-off of high-grade cancers missed (NCCN, 2016)
• Laboratory developed tests – not FDA approved
  • Prostate-specific kallikrein (4Kscore) (NCCN, 2016)
    • Combination score of total PSA, free PSA, percent-free PSA, intact PSA, and human kallikrein 2 (hK2)
    • Intended for patients 40-80 years
    • Stratifies risk of aggressive prostate cancer in patients with elevated PSA where biopsy is being considered
    • Test should not be ordered if
      • Prostate cancer was previously diagnosed
      • DRE was performed within the last 4 days
      • Any procedure or therapy was used to treat symptomatic benign prostatic hyperplasia (BPH) within the past 6 months
      • Any invasive, urologic procedure that may be associated with a secondary PSA evaluation was done within the past 6 months
      • 5-alpha reductase inhibitor (5-ARI) therapy (eg, Avodart [dutasteride] or Proscar [finasteride]) was administered within the past 6 months
    • Avoids 58% of inappropriate biopsies with 4.7% trade-off of missed high-grade cancers; however, no cutoff threshold has been established
  • ConfirmMDx (NCCN, 2016) (not available at ARUP Labs)
    • Tissue-based, multiplex epigenetic assay
    • Assesses hypermethylation of promoter regions of GSTP1, APC, and RASSF1 genes
    • Consider when repeat biopsy is contemplated; test may identify higher risk of prostate cancer (NCCN, 2016)

Histology

• Sonographically guided biopsy for tissue sample
• Biopsy results determine subsequent recommendations (NCCN, 2016)
  • Atypia, suspicious for cancer – extended pattern rebiopsy within 6 months
  • High-grade prostatic intraepithelial neoplasia (PIN)
    • Multifocal >2 sites
      • Extended pattern rebiopsy within 6 months
    • Focal
      • PSA and DRE at 6-24 month interval
      • Consider percent-free PSA, 4Kscore, PHI, PCA3, or ConfirmMDx and/or multiparametric MRI and/or refined prostate biopsy techniques
  • Benign
    • Refer to focal follow-up recommendations
  • Adenocarcinoma detected – proceed based on life expectancy, Gleason score, and patient preference
• Immunohistochemistry (Epstein, 2014) – useful for determination of primary disease for metastatic tissue samples
  • P504S (AMACR); p63; cytokeratin 5/6; keratin 903 (high molecular weight)
  • ARUP’s PIN4 prostate triple stain includes most relevant markers – P504S, p63, 34βE12
• Molecular testing
  • BRCA1 and BRCA2 gene testing should be considered
    • For aggressive prostate cancer (Gleason ≥7) diagnosed at any age
    • If ≥2 close relatives with breast, ovarian, aggressive prostate, or pancreatic cancer at any age

Genetic Testing

• Genetic testing should be considered (ACMG, 2015)
  • For aggressive prostate cancer (Gleason ≥7) diagnosed at any age and ≥2 close relatives with breast, ovarian, aggressive prostate, or pancreatic cancer at any age
  • ≥2 cases of prostate cancer at ≤55 years in close relatives
  • ≥3 first-degree relatives with prostate cancer

Prognosis

• Future risk of cancer
  • Baseline PSA above median for age (40-55 years) in absence of other etiology (prostatitis) is a strong predictor of future cancer risk
• Current cancer
  • Higher initial PSA concentration correlates with increased risk of tumor progression over 10 years and with metastatic disease at the time of future diagnosis
  • Aggressive tumor behavior is suggested by
    • Higher PSAD (>0.10-0.15)
    • Higher PSAV (>2 ng/mL/year)
    • High Gleason score

Differential Diagnosis

• Prostatitis – bacterial, fungal, Mycobacterium tuberculosis
• Benign prostatic hypertrophy
• Urinary tract infection