Prostate Cancer - PSA

Diagnosis

Indications for Testing

  • Follow up previously elevated PSA (screening recommendations can be found in the Screening section)
  • New prostate nodule or hypertrophy

Laboratory Testing

  • PSA
    • 4-10 ng/mL – indeterminate; consider PSA free percentage, PSA velocity (PSAV) testing, or PCA3
    • >10 ng/mL – recommend biopsy
    • <3 ng/mL – repeat PSA in 1 year
    • Normal PSA values do not rule out prostate cancer (substantiated by the Prostate Cancer Screening trial); age-specific reference ranges should not be used for PSA
    • 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%

    • PSA can be elevated in benign conditions
  • PSA free percentage
    • 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 digital rectal exam (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
  • PSAV
    • 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], 2015)
  • PSA density (PSAD)
    • 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)
    • PCA3 is a prostate-specific noncoding mRNA
    • Aids in decision for rebiopsy of individuals >50 years who have had
      • One or more negative prostate biopsies AND
      • For whom a repeat biopsy would be recommended by a urologist based on current standard of care (FDA, 2012)
    • 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 1000
    • Sensitivity and specificity
      • 77.5% and 57.1% respectively – relative to prostate biopsy outcome
      • Based on a PCA3 score cut-off 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 cut-off 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 cut-off may yield a different overall interpretation upon repeat testing

      >31

      Positive

      Associated with increased probability of a positive biopsy for prostate cancer

Histology

  • Sonographically guided biopsy for tissue sample recommended if  
    • PSA >10 ng/mL
    • PSA is 4-10 ng/mL with a free percentage <25%
  • Biopsy results determine subsequent recommendations
    • Atypical small acinar proliferation – repeat PSA and DRE in 3 months
    • High-grade intraepithelial dysplasia (PIN 3) – repeat PSA and DRE in 3 months and every 3 months for 1 year
    • Malignancy detected – recommendations as per urologist
  • Immunohistochemistry (Epstein, 2014)
    • 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

Prognosis

  • Future risk of cancer
    • Baseline PSA above median for age (40-55 years) 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

Screening

  • Existing evidence from randomized trials does not support routine screening for prostate cancer (Croswell, 2011)
  • PSA is the main tumor marker for prostate cancer screening
    • Prostatic acid phosphatase (PAP) is not recommended
  • Screening recommendations

    Society

    Age to start screening

    Who to exclude

    Screening frequency

    PSA

    ACP (2013)

    55 yrs with shared decision making

    45 yrs – African American, men with 1st degree relative with prostate cancer at <65 yrs

    40 yrs – multiple family members diagnosed at <65 yrs

    Patient ≥70 yrs

    Patients with life expectancy <10-15 yrs

    Consider longer intervals (>1 yr)

    n/a

    ACS (2010)

    50 yrs – average risk

    45 yrs – African American,  men with 1st degree relative with prostate cancer at <65 yrs

    40 yrs – multiple family members diagnosed at <65 yrs

    Patient <50 yrs

    Annually in conjunction with DRE if PSA ≥2.5 ng/mL; biannually if PSA <2.5 ng/mL

    Use PSA free percentage test in cases where total PSA 4-10 ng/mL (2.5-10 ng/mL may be preferred in some cases)

    No interpretive guidelines available for PSA free percentage when total PSA is <2.5 ng/mL or >10 ng/mL

    ASCO (2012)

    Men with life expectancy >10 yrs

    n/an/an/a

    AUA (2013)

    55 yrs – average risk

    Higher risk patients – individualize approach and consider earlier age to screen

    Patient >65 yrs with life expectancy <10-15 yrs

    Patient ≥70 yrs of age

    Every 2 yrs in conjunction with DRE

    Use PSA free percentage test only in cases where total PSA 4-10 ng/mL (2.5-10 ng/mL may be preferred in some cases)

    No interpretive guidelines available for PSA free percentage when total PSA is <2.5 ng/mL or >10 ng/mL

    EAU (2013)

    40-45 yrs

    Patient <50 yrs – exception for patients who have a first-degree relative diagnosed with prostate cancer <65 yrs

    Patient >65 yrs with life expectancy <10 yrs

    Patient >75 yrs – average life expectancy at 75 is <10 yrs

    Intervals every 2-4 yrs for PSA >1.0 ng/mL and up to 8 yrs if PSA <1 ng/mL at baseline screen

    n/a

    ESMO (2015)Population based screening is not recommendedPatients >70yrs  

    NCCN (2015)

    50 yrs (average risk)

    Patient <50 yrs – exception for patients who have a first-degree relative diagnosed with prostate cancer <65 yrs

    Patient >65 yrs with life expectancy <10 yrs

    Patient >75 yrs – average life expectancy at 75 is <10 yrs

    Annually in conjunction with DRE

    n/a

    USPSTF (2012)

    Screening should not be offered (Grade D recommendation)

    n/a

    n/a

    n/a

    ACP = American College of Physicians; ACS = American Cancer Society; ASCO = American Society of Clinical Oncology; AUA = American Urological Association; EAU = European Association of Urology; ESMO = European Society for Medical Oncology; NCCN = National Comprehensive Cancer Network; USPSTF = U.S. Preventive Services Task Force

Monitoring

  • PSA concentrations – recommended for monitoring disease progression
    • As often as every 3 months, but at least every 6 months
    • Successful surgical resection should lead to PSA concentrations <0.05 ng/mL
      • Radiation therapy may not result in concentrations equally low
    • Subsequent rise in concentrations is indicative of residual disease, metastasis, or PSA bounce
  • Circulating tumor cell count (CTC)
    • Use in metastatic tumors in conjunction with clinical data and imaging to monitor response to therapy and disease progression 
    • Cutoff point – >5 CTCs/7.5 ml of blood
    • Independent predictor of progression-free survival and overall survival
    • Subsequent rise in concentrations is indicative of residual disease or metastasis
  • DRE – as often as every 6 months, but at least every 12 months

Clinical Background

Prostate cancer is the most frequent malignant neoplasm in men and the second most common cancer death among American men.

Epidemiology

  • Incidence – >233,000 in 2014 (American Cancer Society, 2014)
  • Age – risk rises steeply with age
    • <50 years – low risk
    • ≥65 years – 75% of cases
  • Sex – exclusively male
  • Ethnicity – higher occurrence in African Americans

Risk Factors

  • African American ethnicity
  • Family history – 5- to 11-fold increase in risk with a first-degree relative diagnosed with prostate cancer at <65 years
  • Older age
  • BRCA1 or BRCA2 mutation

Pathophysiology

  • Tumors are usually adenocarcinomas that depend on androgens for growth
  • Epithelial cells of prostate produce prostate-specific antigen (PSA) and acid phosphatase
    • Production also increased with tumors and also with inflammation and hyperplasia – lacks specificity for diagnosis of cancer
  • Most tumors develop in peripheral zone of prostate, commonly in the posterior aspect

Clinical Presentation

  • Frequently asymptomatic
  • Signs and symptoms of enlarged prostate – urgency, frequency of urination, nocturia
  • Metastatic disease
    • Bone pain – pelvis, spine most common sites
    • Osteoblastic lesions are on imaging

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Prostate Specific Antigen, Total 0070121
Method: Quantitative Electrochemiluminescent Immunoassay

Initial screening test used with DRE

Aid in prognosis and in therapy management

May use to monitor patients for recurrence of cancer

Results from different assay methods or kits cannot be used interchangeably

Elevated PSA concentrations only suggest the presence of prostate cancer; biopsy confirmation required

False-positive results occur in benign prostatic hyperplasia and inflammatory conditions (eg, prostatitis)

DRE and TRUS

Serial measurements of PSA required

Prostate Specific Antigen, Free Percentage (Includes Free PSA and Total PSA) 0080206
Method: Quantitative Electrochemiluminescent Immunoassay

Use for individuals with significant increases in PSA values

Percentage of free PSA to total PSA

Alternative to PCA3 testing in indeterminate PSA cases (4-10 ng/mL)

Results from different assay methods or kits cannot be used interchangeably

Elevated PSA concentrations only suggest the presence of prostate cancer; biopsy confirmation required

False-positive results occur in benign prostatic hyperplasia and inflammatory conditions (eg, prostatitis)

DRE and TRUS

PCA3 - Prostate Cancer Biomarker by Transcription-Mediated Amplification 2010102
Method: Qualitative Transcription-Mediated Amplification

Aids in the decision of rebiopsy for men ≥50 years who have had one or more negative prostate biopsies AND for whom a repeat biopsy would be recommended by a urologist based on current standard of care

Collect after DRE

Clinical sensitivity/specificity – 77.5% and 57.1% respectively (relative to prostate biopsy outcome), based on a PCA3 score cut-off value of 25

Values obtained with different assay methods or kits cannot be used interchangeably

Sufficient number of prostate cells must be present in the urine for analysis

PCA3 testing should not be used for men with atypical small acinar proliferation (ASAP) on their most recent biopsy

 
Prostate Specific Antigen, Ultrasensitive 0098581
Method: Quantitative Electrochemiluminescent Immunoassay

Do not use for initial prostate cancer screening

Preferred test is total prostate specific antigen in conjunction with digital rectal exam

May be used to monitor disease after radical prostatectomy

Results from different assay methods or kits cannot be used interchangeably

 
Circulating Tumor Cell Count 0093399
Method: Immunomagnetic Separation/Immunofluorescent Stain/Computer Assisted Analysis

Use for patients with metastatic prostate cancer in conjunction with clinical data and imaging to monitor response to therapy and disease progression

Cutoffs vary by tumor cell type

CTC is not as accurate as imaging in assessing whether a patient has progressive disease

Doxorubicin therapy patients – allow at least 7 days following administration of a dose before testing

Not detected – CTCs that do not express EpCAM or CTCs that express EpCAM but not cytokeratins 8, 18, and 19

Serial CTCs should be performed in the same laboratory

 
PIN4 Prostate Triple Stain by Immunohistochemistry 2010045
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Antibodies  included in this triple stain – p504S, p63, and 34βE12

Stained and returned to client pathologist; consultation available if needed

   
P504S (AMACR) by Immunohistochemistry 2004076
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
Prostatic Acid Phosphatase (PAP) by Immunohistochemistry 2004079
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
Prostate Specific Antigen by Immunohistochemistry 2004112
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
PTEN by Immunohistochemistry 2004115
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
PTEN with Interpretation by Immunohistochemistry 2007031
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Includes interpretation

   
Cytokeratin 5,6  (CK 5,6) by Immunohistochemistry 2003851
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
Keratin 903 (K903) High Molecular Weight by Immunohistochemistry 2003978
Method: Immunohistochemistry

Aid in histologic diagnosis of prostate cancer

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Prostate Specific Antigen, Total - Medicare Screening 0070234
Method: Quantitative Electrochemiluminescent Immunoassay

Preferred initial screening test for prostate cancer in conjunction with digital rectal exam

May use to monitor patients for recurrence of cancer

Prostate Specific Antigen, Total with Reflex to Free PSA (Includes Free Percentage) 0080264
Method: Quantitative Electrochemiluminescent Immunoassay

Do not use for initial prostate cancer screening; preferred test is total PSA antigen in conjunction with DRE

May be useful in distinguishing cancer from benign conditions in patients with mildly elevated total PSA and negative DRE

Reflex pattern – if PSA total is between 3.0-10.0 ng/mL, free PSA will be added

Prostatic Acid Phosphatase 0070120
Method: Quantitative Chemiluminescent Immunoassay

Obsolete test for prostate cancer screening; preferred test is total PSA in conjunction with DRE

Benign prostatic hyperplasia, prostate massage, and prostatic infarction may result in elevated PAP concentrations; the PAP assay value, regardless of level, should not be interpreted as absolute evidence for the presence or absence of malignant disease