Prostate Cancer - PSA

Prostate cancer is the most frequent malignant neoplasm in men and the second most common cancer to cause death among American men. Serum prostate specific antigen (PSA) testing is currently recommended for early detection of prostate cancer; digital rectal examination (DRE) should be used in men with an increased PSA but is not recommended for use as a stand-alone test (National Comprehensive Cancer Network [NCCN] Prostate Cancer Early Detection guideline, 2018). Other biomarkers are used to stratify 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 male with applicable risk factors for cancer
New prostate nodule or hypertrophy
Men who elect to participate in early detection screening for prostate cancer
Follow-up for previously elevated PSA

Laboratory Testing

Total PSA (NCCN Prostate Cancer Early Detection guideline, 2018)

Premise – PSA production increases with tumors, inflammation, and hyperplasia; while not specific to cancer, PSA levels may guide decision-making about need for biopsy, prognosis, and disease monitoring

PSA Test Result Interpretation
PSA Test Result (ng/mL)	Follow-Up
<4	Repeat testing in select patients (those with normal DRE and no other indications for biopsy) at 1-4 yr intervals
<1	Repeat testing at 2-4 yr intervals
1-3	Repeat testing at 1-2 yr intervals
>3	Repeat testing and perform DRE if not already performed; workup for benign disease
Source: NCCN, 2018

Normal PSA values do not rule out prostate cancer
PSA can be elevated in benign conditions affecting the prostate
Results of DRE (if performed), age, and estimated life expectancy should be considered along with PSA result

Additional biomarkers that may assist with risk stratification

PSA free percentage

Premise – the ratio of free (unbound) PSA to total PSA is reduced in prostate cancer
Free PSA is 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 Test Result Interpretation
PSA Free Percentage Test Result (%)	Interpretation of Result
>25	Associated with low risk
≤10	Associated with >50% risk, regardless of age
<25	Consider biopsy based on clinical circumstance
Source: NCCN, 2018

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 three 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 Prostate Cancer Early Detection guideline, 2018)
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
- Offers limited benefit over other tests; may be useful in patients with previous prostate volume measurements (NCCN Prostate Cancer Early Detection guideline, 2018)

PCA3 (urine)

Premise – PCA3 is overexpressed in prostate cancer but not in benign hypertrophy
PCA3 is a prostate-specific noncoding messenger RNA (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

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 proPSA (also referred to as p2PSA)
- Multicenter study determined PHI may increase sensitivity of cancer detection for men with indeterminate serum PSA
- PHI could be useful in determination of need for biopsy in a person who has had no or negative prior biopsy
- Optimal cutoff of the test appears to be 24, which should lead to 36% of biopsies avoided with ~2.5% trade-off of high-grade cancers missed (NCCN Prostate Cancer Early Detection guideline, 2018)

Laboratory developed tests – not FDA approved
- Prostate-specific kallikrein (4Kscore) (NCCN Prostate Cancer Early Detection guideline, 2018)
  - Combination score of total PSA, free PSA, intact PSA, and human kallikrein 2 (hK2)
  - Stratifies risk of aggressive prostate cancer in patients with elevated PSA in whom 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 (NCCN Prostate Cancer Early Detection guideline, 2018)
- ConfirmMDx (NCCN Prostate Cancer Early Detection guideline, 2018) (not available at ARUP Laboratories)
  - 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 Prostate Cancer Early Detection guideline, 2018)

Histology

Definitive diagnosis requires biopsy and pathologist examination
Biopsy results determine subsequent monitoring, evaluation, and treatment recommendations (NCCN Prostate Cancer Early Detection guideline, 2018)
Useful immunohistochemical stains may include p504S, p63, and 34βE12
- For detailed descriptions, refer to ARUP’s Immunohistochemistry Stain Offerings

Genetic Testing

Consider genetic testing in the following (ACMG, 2015)
- Aggressive prostate cancer (Gleason score >7) diagnosed at any age and ≥2 close relatives with breast, ovarian, and/or pancreatic cancer
- ≥2 cases of prostate cancer at ≤55 years in close relatives
- ≥3 first-degree relatives with prostate cancer
Consider testing (germline and somatic) for BRCA1, BRCA2, ATM, PALB2, FANCA mutations in patients with regional or metastatic disease; if positive, refer to genetic counseling (NCCN Prostate Cancer guideline, 2018)

Prognosis

Future risk of cancer
- Baseline PSA above median for age at 40-49 years indicates a higher risk for prostate cancer/aggressive prostate cancer (NCCN Prostate Cancer Early Detection guideline, 2018)
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 ng/mL/cc)
  - 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), American Cancer Society (ACS), and the U.S. Preventive Services Task Force (USPSTF) recommend shared decision-making, with discussion of age, life expectancy, and risk factors, to determine when to start screening with PSA – refer to table below for specific guidelines
Current evidence supports a slight mortality benefit in screening men 55 to 69 years, which may offset the harms of screening (USPSTF, 2018)

Societal Recommendations for Early Detection of Prostate Cancer Using PSA Testing
Society	Age and Risk Categories	Screening Recommendation	Frequency of Screening
USPSTF, 2018	55-69, not high risk	Shared decision-making regarding screening, recognizing there is a small mortality benefit to screening that may balance risks; decision should be individual one	Not defined due to lack of data, but mortality benefit in studies with 2-yr interval data
	≥70 and older	Screening not recommended due to lack of mortality benefit (including for men expected to live 10-15 more yrs)	n/a
	African American men <55 yrs	Insufficient evidence to recommend screening
	Men with family history of prostate cancer <55 yrs	Insufficient evidence to recommend screening
AUA (2013, reaffirmed 2015)	<40 yrs, ≥70 yrs, or life expectancy <10-15 yrs	Screening not recommended due to lack of mortality benefit	n/a
	40-54 yrs, with average risk	Routine screening not recommended	n/a
	40-54 yrs, with higher risk	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is recommended
	55-69 yrs	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values
	≥70 yrs, in excellent health	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values
ACS (2016)	≥50 yrs, average risk, life expectancy ≥10 yrs	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	Biannually if PSA <2.5 ng/mL; annually if PSA ≥2.5 ng/mL
	≥45 yrs and high risk (African American, men with first-degree relative diagnosed with prostate cancer at an early age)	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values
	≥40 yrs with multiple family members diagnosed at an early age	Shared decision-making, including discussion of risks/benefits of screening and patient preferences
	<40 yrs, or <10-yr life expectancy	Insufficient evidence to recommend routine population screening with PSA	n/a
ASCO (2012)	<10 yr life expectancy	Screening not recommended because harms seem to outweigh potential benefits	n/a
ASCO (2012)	≥10 yr life expectancy	Shared decision-making, including discussion of risks/benefits of screening and patient preference, with understanding that there is insufficient data to support a mortality benefit in this population	n/a

Monitoring

PSA concentrations – recommended for monitoring disease progression, active surveillance
- Recommended frequency varies by organization; refer to Screening section for more information
- 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 – >164,000 in 2018 (ACS, 2018)
Age – risk rises steeply with age
- <50 years – low risk
- ≥65 years – 75% of cases
- Median age at diagnosis – 66 years (SEER, 2018)
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

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 DRE

Use to monitor patients for recurrence of cancer

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 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

Alternative to PCA3 testing in indeterminate PSA cases

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

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

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 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-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 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