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.  The disease ranges from indolent malignancies, which may not need treatment, to more aggressive forms that should be treated.  Current recommendations aim to guide clinicians and patients toward a balanced and individualized approach to screening to avoid unnecessary treatment while enabling early detection of aggressive prostate cancers.   Such an approach to screening is especially important because of the harms associated with screening, such as false-positive results and consequent additional tests or biopsies, psychological distress, overdiagnosis, overtreatment, and adverse effects of treatment.  Laboratory testing involves serum prostate-specific antigen (PSA) testing, PSA derivatives, and other biomarkers. Digital rectal examination (DRE) is not recommended for use as a standalone test but should be considered in conjunction with PSA results in men who have chosen to undergo screening for early detection of prostate cancer.  Percent free PSA, PSA velocity, and PCA3, and calculations such as the Prostate Health Index (PHI), are useful for risk stratification.

Quick Answers for Clinicians

What are current recommendations on prostate-specific antigen (PSA) screening?

The U.S. Preventive Services Task Force (USPSTF) recommended against routine prostate-specific antigen (PSA) screening in 2012; however, the 2018 USPSTF guideline states that PSA screening in men 55-69 years of age may have limited benefit for some men and recommends individualized decision-making with regard to screening.  A number of other organizations offer similar recommendations. (See Societal Recommendations for Prostate Cancer Screening table below.)

Can prostate-specific antigen (PSA) results using different assays and laboratories be directly compared?

Clinicians should be aware that prostate-specific antigen (PSA) testing has not been harmonized ; ie, the assay and its performance may vary between laboratories, which may lead to significant variation in results.  Clinical guidelines for PSA testing may have been developed without a complete understanding of this variation.  Thus, results require careful interpretation because variation in results may lead to inappropriate clinical decision-making and potentially adverse effects on patient care.  Repeat PSA testing should be performed using the same assay and laboratory to maximize consistency.

What factors affect prostate-specific antigen (PSA) results?

Infection, ejaculation, trauma, recent procedures, benign conditions, and certain medications  all can affect prostate-specific antigen (PSA) lab test results.  See Prostate-Specific Antigen section below for additional information.

How do laboratory tests contribute to diagnosis?

Prostate-specific antigen (PSA) and other biomarker tests can help guide decisions about which patients should consider biopsy, but definitive diagnosis is based on biopsy and pathologist examination.

Which testing algorithms are related to this topic?

Indications for Testing

Laboratory testing for prostate cancer is appropriate in a variety of circumstances, such as for  :

  • Screening in men who elect to undergo testing for early detection of prostate cancer
  • Risk stratification to aid in decisions about necessity or frequency of testing
  • Follow-up in men with a previously elevated PSA or suspicious DRE result
  • Monitoring in men undergoing active surveillance for indolent cancer
  • Monitoring for recurrence following treatment for prostate cancer

Laboratory Testing

A variety of laboratory and risk calculation tests are used to determine which men should consider undergoing biopsy; some of these same tests are used for prognostic assessment and for monitoring after diagnosis.

Screening

Prostate-Specific Antigen

PSA is a glycoprotein found mainly in the seminal plasma but also in the circulation, and is not specific to cancer.  Recent procedures (eg, urethral, biopsy) can result in increased serum PSA levels, as can infection, ejaculation, or trauma.  PSA also can be elevated in men with benign conditions, such as prostatitis and benign prostatic hyperplasia (BPH),  and PSA levels can be affected (decreased) by treatment with 5-alpha reductase inhibitors.  In addition, normal PSA values do not rule out prostate cancer; some men have a normal PSA result but a suspicious DRE.  Despite these limitations, evidence from clinical trials still supports serum PSA testing for the timely detection of prostate cancer and to guide clinical decisions concerning biopsy.  A number of organizations recommend shared decision-making, which includes discussion of age, life expectancy, and risk factors, such as family history and race, to determine when to start screening with PSA. Results of a DRE (if performed) should be considered along with the PSA result.  Refer to table below for specific recommendations.

Societal Recommendations for Prostate Cancer Screening
Society Age and Risk Category Screening Recommendation Screening Frequency
NCCN (2019) ≥45-75 yrs Informed testing 1- to 2-yr intervals if PSA is ≥1.0 ng/mLa

2- to 4-yr intervals if PSA is <1.0 ng/mL

≥40 yrs with higher risk (African-American men or men with known or suspected cancer susceptibility gene) Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values 1-yr intervals
≥60 yrs with PSA <1.0 ng/mL Risk of metastases and death as a result of prostate cancer is low; this population can consider discontinuing screening n/a
>75 yrs Screening recommended only in healthy men with little or no comorbidity; widespread screening not recommended; men with PSA <3.0 ng/mL can consider discontinuing screening 4-yr interval appropriate in older men with lower PSA result; clinical judgment should be used
USPSTF, 2018 55-69 yrs, not high risk Shared decision-making regarding screening, recognizing there is a small mortality benefit of screening that may balance risks; decision should be an individual one Not defined due to lack of data, but mortality benefit appears to be associated with every-2-yr screening
≥70 yrs Screening is 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 support a separate screening recommendation specific to this population, but clinicians are advised to inform men of risk for prostate cancer and benefits/harms of screening to aid in personal decision-making
Men <55 yrs with family history of prostate cancer
AUA (2013, reviewed and confirmed 2018) <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
40-54 yrs, with higher risk (eg, positive family history, African American) Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values 2-yr interval is recommended
55-69 yrs
≥70 yrs, in excellent health
ACS (2016) ≥50 yrs, average risk, life expectancy ≥10 yrs Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values 2-yr interval is suggested if PSA is <2.5 ng/mL

1-yr interval is suggested if PSA is ≥2.5 ng/mL

≥45 yrs and high risk (African American, men with first-degree relative diagnosed at an early age)
≥40 yrs at very high risk (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 screening with PSA n/a
ASCO (2012) ≤10 yr life expectancy Screening not recommended because harms seem to outweigh potential benefits n/a
>10 yr life expectancy Shared decision-making, including discussion of risks/benefits of screening and patient preferences
aIn the event of PSA >3 ng/mL and/or suspicious DRE, work up for benign disease and repeat testing; if PSA is ≥3 ng/mL on repeat testing, consider further testing (%fPSA, PHI, 4Kscore).

AUA, American Urological Association; ACS, American Cancer Society; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network; %fPSA, percent free PSA

Sources: NCCN, 2019 ; USPSTF, 2018 ; Carter, AUA, 2013 ; ACS, 2016 ; Basch, ASCO, 2012 

Prostate-Specific Antigen Interpretation

A PSA above the median for one’s age group is associated with higher risk for prostate cancer development and with more aggressive cancer.  The higher the PSA result is above the median, the higher the individual’s risk.  NCCN recommends that patients with a steady and marked increase in PSA be encouraged to have a biopsy.  PSA levels of 4-10 ng/mL often prompt additional testing (cancer is discovered in approximately 30-35% of men with serum PSA results in this range), but NCCN now recommends that any man with a PSA >3 ng/mL be evaluated with repeat PSA testing as well as a DRE. 

For additional information concerning follow-up based on PSA test results, refer to the Prostate Cancer Early Detection Screening Algorithm.

Other Biomarker and Risk Calculation Tests

Various biomarker tests, including those based on PSA derivatives, can be used to further assess the probability of prostate cancer before proceeding with biopsy, and can therefore help select patients who should consider biopsy. Biomarker assays are also useful to assess whether biopsy should be repeated in men who have had a negative biopsy.  Caution should be used in interpreting biomarker test results.

In men who have not yet undergone biopsy but have a PSA of >3 ng/mL, NCCN recommends the following three tests be considered :

In men with a negative biopsy result but a higher risk for prostate cancer (eg, because of race, family history), NCCN suggests the following five tests be considered :

Percent Free Prostate-Specific Antigen

The percentage of total PSA that is unbound or free (%fPSA) is clinically informative because serum fPSA is markedly reduced in men with prostate cancer.  This testing is considered useful for patients with a normal DRE but total PSA results of 4-10 ng/mL ; the ratio of free to total PSA helps to distinguish between cancerous and benign conditions.  The risk is age dependent: The older the patient and the lower the %fPSA result, the higher the risk for prostate cancer. Evidence indicates that a %fPSA result of <25% detects 95% of prostate cancer cases. 

Refer to the ARUP Laboratory Test Directory for additional information about prostate cancer probability based on %fPSA.

Prostate-Specific Antigen Velocity

PSA velocity (PSAV) is the rate of change in PSA levels over time, and is based on three or more PSA test results obtained over a period of 18 months or longer. PSAV results should be interpreted with caution because of the high biologic variability associated with individual PSA measurements. Some studies have correlated risk of death from prostate cancer with PSAV ≥0.35 ng/mL/year.  NCCN recommends that PSAV be considered along with other criteria such as age, race, family history, and comorbidity when considering whether to proceed with biopsy in men with low PSA levels; PSAV is not considered helpful in the context of high PSA levels (≥10 ng/mL). 

Prostate-Specific Antigen Density

PSA density (PSAD) is determined by measuring the volume of the prostate using transrectal ultrasound; it is calculated by dividing the PSA level (in ng/mL) by the prostate volume (in cc). PSAD can help differentiate between prostate cancer and benign conditions, particularly BPH, because lower PSAD values suggest BPH.  However, precise measurement of PSA and prostate volume can be challenging. PSAD offers limited benefit compared with other tests but may be useful in patients with previous prostate volume measurements. 

PCA3

PCA3 is a noncoding RNA specific to prostate tissue and is overexpressed in men with prostate cancer. Laboratory testing for PCA3 quantifies this overexpression in urine samples collected after DRE.  PCA3 measurements are particularly helpful in determining which men may need a repeat biopsy; men with a PCA3 score of ≥25 are more likely to have prostate cancer detected on a repeat biopsy.  PCA3 testing can be used in conjunction with other criteria to help determine the necessity of a repeat biopsy in men ≥50 years of age  for whom a urologist would recommend a repeat biopsy based on current standard of care.

Refer to the ARUP Laboratory Test Directory for additional information about PCA3 test result interpretation.

Complexed Prostate-Specific Antigen

PSA exists in both free and complexed forms, one of which is the alpha-1-antichymotrypsin complexed form (cPSA). Clinical trial evidence indicates that the ratio of cPSA to total PSA may be informative in the same way that the %fPSA is informative.  Use of cPSA has been approved for use along with DRE to detect prostate cancer in men ≥50 years of age. 

Prostate Health Index

The PHI is based on a calculation that involves total PSA, fPSA, and a subcategory of free PSA called proPSA (also referred to as p2PSA). The PHI has increased sensitivity for prostate cancer detection compared with the fPSA-total PSA ratio; the PHI also correlates with cancer grade and is useful for distinguishing high-grade cancers (Gleason score ≥7) from low-grade cancers.  PHI may aid in distinguishing prostate cancer from benign prostatic conditions and in detecting prostate cancer in men ≥50 years of age with total PSA values of 4-10 ng/mL and with DRE findings that are not suspicious for cancer.

Refer to the ARUP Laboratory Test Directory for additional information about prostate cancer probability based on the PHI.

4Kscore​

The 4Kscore is based on a variety of characteristics, including fPSA, total PSA, human kallikrein 2, intact PSA (a type of fPSA), age, DRE results, and results of a prior biopsy. The resulting score is the probability, expressed as a percent, that a high-grade cancer (Gleason score ≥7) will be detected on biopsy.  The 4Kscore test can be considered before biopsy and in men with a previous negative biopsy result who may be at increased risk for clinically relevant prostate cancer. 

ConfirmMDx

ConfirmMDx is used to assess prostate cancer risk in men who are considering a repeat biopsy.  The FDA has not approved the test, a multiplex epigenetic assay that measures hypermethylation of GSTP1, APC, and RASSF1 promoter regions in tissue samples.  ConfirmMDx can be considered before a repeat biopsy to help determine which men are at greater risk for a cancer diagnosis and to reduce unnecessary biopsies. 

Familial Risk Testing

Gene variants related to familial prostate cancer continue to be investigated, but the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors recommend referral to genetic counseling in the following circumstances :

  • Two or more cases of prostate cancer diagnosed by 55 years of age in close relatives
  • Three or more first-degree relatives with prostate cancer
  • Aggressive prostate cancer (Gleason score >7) in the patient or in a first-degree relative, and two or more breast, ovarian, and/or pancreatic cancer cases in close relatives

Testing for hereditary cancers has increased in recent years, and panels are available that include genes associated with the risk of prostate cancer (eg, BRCA1, BRCA2, ATM, MLH1, MSH2, MSH6, HOXB13, CHEK2, NBN, PALB2, RAD51D, and TP53).

NCCN recommends that individuals who meet risk criteria for certain hereditary cancer syndromes be referred to a cancer genetics professional, and that the risk associated with such syndromes be included in discussions with men about prostate cancer screening. 

Diagnosis

Definitive diagnosis of prostate cancer requires biopsy and pathologist examination. Biopsy results inform subsequent evaluation, monitoring, and treatment recommendations. 

Prognosis

Prostate cancer is categorized as low, medium, or high risk for disease progression and mortality based on PSA level, clinical stage, and tumor grade.  Various characteristics suggest aggressive tumor behavior; these include higher PSAD (>0.10-0.15 ng/mL/cc), higher PSAV (>2 ng/mL/year), and a higher Gleason score.  

Genetic and Genomic Testing

Certain gene variants have been found to play a role in outcomes such as metastasis and castration resistance.  NCCN recommends that testing for variants (germline and somatic) in BRCA1, BRCA2, ATM, PALB2, and FANCA genes be considered in patients with regional or metastatic disease if testing was not already performed; patients with positive results should be referred for genetic counseling.  Germline genetic testing and genetic counseling should also be considered for all men with high-risk clinically localized prostate cancer.  Such testing may help guide decisions about the use of targeted treatments and/or clinical trial enrollment.

Individuals diagnosed with low risk or “favorable intermediate” risk disease may also choose to pursue testing with tumor-based molecular assays, such as Oncotype DX (not performed at ARUP Laboratories), for prognostic information, such as the risk of death if cancer is managed conservatively, or the risk of biochemical progression following specific treatment types. 

Monitoring

PSA concentrations should be measured periodically to evaluate patients for disease progression during active surveillance, and PSA results should be considered in light of other clinical and radiologic evidence; an increase in PSA alone does not confirm disease progression.  PSA testing every 6 months and DRE every 12 months is recommended during surveillance, unless more frequent monitoring is clinically indicated.  Active surveillance may require periodic biopsies as well.  

After radical prostatectomy, PSA will generally decrease to an undetectable level. Radiation therapy should also result in a low PSA concentration. A subsequent increase in PSA of ≥2 ng/mL above the PSA nadir is considered biochemical recurrence (BCR), which may precede local recurrence or metastasis by 7-8 years. 

ARUP Lab Tests

Screening

Primary Screening Tests

Preferred initial screening test for prostate cancer; use in conjunction with DRE

Use to monitor patients for cancer recurrence

Results from different assay methods or kits cannot be used interchangeably

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

May help in distinguishing cancer from benign conditions

Preferred initial screening test for prostate cancer; use in conjunction with DRE

May be used to monitor patients for cancer recurrence

Secondary Screening Tests

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 negative DRE

Alternative to PCA3 testing in indeterminate PSA cases

Results from different assay methods or kits cannot be used interchangeably

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

Aid in the decision to repeat biopsy in 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

Not for use in men with atypical small acinar proliferation on most recent biopsy

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

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

Beckman Coulter phi is indicated for use as an aid in distinguishing prostate cancer from benign prostatic conditions, for prostate cancer detection in men ≥50 years of age with total PSA ≥4.0 to ≤10.0 ng/mL, and DRE findings that are not suspicious for cancer

Use to stratify risk of aggressive prostate cancer in patients 40-80 yrs with elevated PSA in whom biopsy is being considered

Do not use if prostate cancer was previously diagnosed, DRE was performed within last 4 days, any procedure or therapy was used to treat symptomatic BPH within past 6 months, any invasive urologic procedure associated with a secondary PSA evaluation was performed within past 6 months, or 5-ARI therapy was administered within past 6 months

Components: Total PSA, free PSA, %FPSA, intact PSA, and hK2

Monitoring

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

Results from different assay methods or kits cannot be used interchangeably

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

Allow at least 7 days following administration of a doxorubicin dose before testing

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, ARUP Laboratories
Contributor

References

  1. 25394175

    Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70–87. Reaffirmed with Addendum: Genetics in Medicine (2019) 21:2844.

    PubMed
  2. 28825054

    Abida W

    Armenia J

    Gopalan A

    Brennan R

    Walsh M

    Barron D

    Danila D

    Rathkopf D

    Morris M

    Slovin S

    McLaughlin B

    Curtis K

    Hyman DM

    Durack JC

    Solomon SB

    Arcila ME

    Zehir A

    Syed A

    Gao JJ

    Chakravarty D

    Vargas HAlberto

    Robson ME

    Joseph V

    Offit K

    Donoghue MTA

    Abeshouse AA

    Kundra R

    Heins ZJ

    Penson AV

    Harris C

    Taylor BS

    Ladanyi M

    Mandelker D

    Zhang L

    Reuter VE

    Kantoff PW

    Solit DB

    Berger MF

    Sawyers CL

    Schultz N

    Scher HI

    JCO Precis Oncol

    2017
    2017
    PubMed
Additional Resources
  • 23638486

    Bradley LA
    Palomaki G
    Gutman S
    et al

    Bradley LA, Palomaki G, Gutman S, Samson DJ, Aronson N. PCA3 Testing for the Diagnosis and Management of Prostate Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Apr. PubMed

    Generic
  • Resources from the ARUP Institute for Clinical and Experimental Pathology®