Prostate Cancer - PSA

Prostate cancer is the most frequent malignant neoplasm in men and the second most common cancer death among American men. Prostate-specific antigen (PSA) is used for prostate cancer screening starting at age 50, except in cases of increased risk.

Tabs Content

Clinical Overview

Diagnosis

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 PSA – screening recommendations can be found in Screening

Laboratory Testing

Total PSA (National Comprehensive Cancer Network [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 (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 (American College of Medical Genetics and Genomics [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

Screening

The American Urological Association (AUA), NCCN, American Society of Clinical Oncology (ASCO), and American Cancer Society (ACS) recommend shared decision-making, with discussion of age, life expectancy, and risk factors, to determine when to start screening – refer to table below for specific guidelines
Existing evidence from randomized trials does not support routine screening for prostate cancer (Croswell, 2011)
- Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), 2014 – no difference in overall survival between 76,693 screened and unscreened patients
- European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, 2014 – 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 used for prostate cancer screening starting at age 50, except in cases of increased risk

Screening recommendations (based on guidelines)

Society	Age to start screening	Whom to exclude	Screening frequency	Prostate-specific antigen (PSA)
AAFP (2015)	AAFP recommends against PSA-based screening for prostate cancer	n/a	n/a	n/a
ACP (2013)	55 yrs with shared decision-making 45 yrs – African American, men with first-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
ACPM (2008)	Insufficient evidence to recommend routine population screening with digital rectal exam (DRE) or PSA	n/a	n/a	n/a
ACS (2010)	50 yrs – average risk 45 yrs – African American, men with first-degree relative with prostate cancer at <65 yrs 40 yrs – multiple family members diagnosed at an early age		Shared decision-making for men with 10-yr life span – includes discussion of the risks/benefits of screening and patient preference 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/a	Shared decision-making for men with 10-yr life span – includes discussion of the risks/benefits of screening and patient preference	n/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	Shared decision-making for men with 10-yr life span – includes discussion of the risks/benefits of screening and patient preference 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)	Patient <50 yrs – exception for patients who have a first-degree relative diagnosed with prostate cancer before age 65 yrs 40-45 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 recommended	n/a	n/a	n/a
NCCN (2017)	50 yrs (average risk) Exception for patients <50 yrs with a first-degree relative diagnosed with prostate cancer before age 65 yrs	Patient >65 yrs with life expectancy <10 yrs Patient >75 yrs – average life expectancy at 75 is <10 yrs	Shared decision making for men with 10-yr life span – includes discussion of the risks/benefits of screening and patient preference Annually in conjunction with DRE	n/a
USPSTF (2012)	Screening should not be offered (Grade D recommendation)	n/a	n/a	n/a
AAFP = American Academy of Family Physicians; ACP = American College of Physicians; ACPM = American College of Preventive Medicine; 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, active surveillance
- Every 6 months is adequate for most patients
- 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) – potential for use as biomarker
- 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

Background

Epidemiology

Incidence – >233,000 in 2014 (ACS, 2014)
Age – risk rises steeply with age
- <50 years – low risk
- ≥65 years – 75% of cases
- Median age – 66 years (National Cancer Institute Surveillance, Epidemiology, and End Results Program [SEER], 2017)
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 PSA and acid phosphatase
- Production also increases with tumors, and 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 on imaging

ARUP Lab Tests

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.

Prostate Specific Antigen, Total 0070121
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Preferred initial screening test used in conjunction with digital rectal exam (DRE)

May use to monitor patients for recurrence of cancer

Limitations

Results from different assay methods or kits cannot be used interchangeably

Elevated prostate-specific antigen (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)

Follow-up

DRE and transrectal ultrasonography of the prostate (TRUS)

Serial measurements of PSA required

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

Recommended Use

Acceptable initial test for prostate cancer screening; preferred test is total PSA 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

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

Recommended Use

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

May provide additional prostate cancer risk information for patients with mildly elevated total PSA and a negative DRE

Results include free PSA, PSA, and percent-free PSA

Limitations

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)

Follow-up

DRE and TRUS

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

Recommended Use

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

Aid in the decision of rebiopsy for men ≥50 years who have had ≥1 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 ratio cutoff of 25

Limitations

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, Complexed 2002930
Method: Chemiluminescent Immunoassay

Recommended Use

Aid in detection of prostate cancer in men age ≥50 when used in conjunction with a DRE

May also be used as an aid to manage and monitor prostate cancer patients

Limitations

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)

Prostate Specific Antigen, Ultrasensitive 0098581
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

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

May be used to monitor disease after radical prostatectomy

Limitations

Results from different assay methods or kits cannot be used interchangeably

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

Recommended Use

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

Limitations

Circulating tumor cell count (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

Prostate-Specific Kallikrein, 4Kscore 2014059
Method: Electrochemiluminescent Immunoassay

Recommended Use

Intended for patients 40-80 years

Stratifies risk of aggressive prostate cancer in patients with elevated PSA where biopsy is being considered

Do not order 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

Biomarkers include total PSA, free PSA, percent-free PSA, intact PSA, and human kallikrein 2 (hK2)

PIN4 Prostate Triple Stain by Immunohistochemistry 2010045
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of prostate cancer

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