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 velocity testing, PSA free percentage, or PCA3
      •  A range of 2.5-10 ng/mL may be preferred in some cases
    • >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 Prevention trial); age-specific reference ranges should not be used for PSA
      • PSA values and percentage of individuals with cancer

        PSA Value

        Percentage of Individuals with 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 velocity (PSAV)
    • 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], 2014)
    • PSA velocity = (PSA test #2-PSA test #1)/time elapsed
  • PSA free percentage
    • Aids in distinguishing prostate cancer from benign conditions
    • Use if PSA concentrations are 4–10 ng/mL and digital rectal exam (DRE) is negative
      • A range of 2.5-10 ng/mL may be preferred in some cases
    • Risk is age dependent – the older the patient and the lower the value, the higher the risk
    • PSA free percentage >25% – associated with low risk
    • PSA free percentage ≤10% – associated with ≥49% risk, regardless of age
    • PSA free percentage <25% – recommend biopsy
  • PSA density (PSAD)
    • PSA/ultrasound volume of prostate gland
    • Higher value (typically >0.1 or 0.15) associated with increased risk of cancer
  • PCA3 (urine)
    • Indications
      • 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
    • Specimen
      • Collect 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 – current means of diagnosis
    • Recommended if PSA >10 ng/mL or if PSA is 4-10 ng/mL with a free percentage between 10% and 25%
    • Tumors assigned Gleason score based on gland architecture
  • Biopsy results determine next step
    • 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
    • Cancer – discuss options
  • Immunohistochemistry
    • P504S (AMACR); p63; PSA; keratin 903
  • Molecular testing
    • BRCA1 and BRCA2 genes
      • If aggressive prostate cancer (Gleason ≥7) diagnosed at any age
      • If ≥2 close relatives with breast, ovarian, aggressive prostate, or pancreatic cancer at any age

Imaging Studies

  • Transrectal ultrasound (TRUS) – measure prostate volume (PV)
    • Divide PSA value by PV to obtain PSAD

Prognosis

  • Future risk of cancer
    • PSA baseline above median for age at 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 a finding of metastatic disease at the time of diagnosis
    • Indications of aggressive tumor
      • Higher PSAD (low PSAD defined as <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)
    • The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial – no difference in overall survival between 76,693 screened and unscreened patients
    • The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial – no difference in overall survival between 162,243 screened and unscreened patients
      • Significant improvement in survival with screening but at high risk for overtreatment
  • PSA is the main tumor marker approved for use as a prostate cancer screening test
    • Prostatic acid phosphatase (PAP) has little screening value and is not currently recommended
  • Screening recommendations

    Society

    Age to start screening

    Who to exclude

    Screening frequency

    PSA

    USPTF (2012)

    Does not endorse PSA screening for healthy men regardless of age (Grade D recommendation)

    PSA screening does not reduce prostate cancer-specific related death and often leads to unnecessary tests and treatments associated with significant morbidity

    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

    NCCN

    50 yrs (for men of average risk)

    EAU (2010)

    40-45 yrs

    ACS

    50 yrs (for men of 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

    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

    AUA (2013)

    55 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 <10-15 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

    USPTF = U.S. Preventive Services Task Force; NCCN = National Comprehensive Cancer Network; EUA = European Association of Urology; ACS = American Cancer Society; AUA = American Urological Association

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 
    • Subsequent rise in concentrations is indicative of residual disease, metastasis, or PSA bounce
    • Independent predictor of progression-free survival and overall survival
    • Cutoff point – >5 CTCs/7.5 ml of blood
  • 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 sixth most common neoplasm worldwide. Prostate cancer is the second most common cause of cancer death among American men.

Epidemiology

  • Incidence – 160/100,000
  • 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 <65 years
  • Elderly males

Pathophysiology

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

Clinical Presentation

  • May have signs and symptoms of enlarged prostate – urgency and frequency of urination
  • Frequently asymptomatic
  • Metastatic disease
    • Bone pain – pelvis, spine
    • Osteoblastic lesions seen by x-ray

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 for prostate cancer in conjunction with DRE

Aid in prognosis and in therapy management

Results from different assay methods or kits cannot be used interchangeably

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

PSA levels can also be elevated in benign prostatic hyperplasia and inflammatory conditions such as 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

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

PSA levels can also be elevated in benign prostatic hyperplasia and inflammatory conditions such as prostatitis  

DRE and TRUS

Prostate Specific Antigen, Ultrasensitive 0098581
Method: Quantitative Electrochemiluminescent Immunoassay

Monitor disease after radical prostatectomy

Results from different assay methods or kits cannot be used interchangeably

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

Aids in the decision of rebiopsy for 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

Sensitivity and specificity

  • 77.5% and 57.1% respectively – relative to prostate biopsy outcome
  • Based on a PCA3 score cut-off value of 25

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

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

Results should be interpreted in correlation with clinical history and other relevant data

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

Use to determine prognosis, assess treatment efficacy, and aid in treatment decisions for patients with prostate cancer

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; CTCs that express EpCAM but not cytokeratins 8, 18, and 19

 
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

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

If PSA total is between 3.0-10.0 ng/mL, free PSA will be added

Prostatic Acid Phosphatase 0070120
Method: Quantitative Chemiluminescent Immunoassay

Limited clinical utility

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