Prostate Cancer - PSA

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

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 can be elevated in benign conditions
  • 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 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
    • 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 (National Comprehensive Cancer Network [NCCN], 2015)
  • 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
    • 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)
    • May reduce rate of rebiopsy (Wei, 2014)
    • 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

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

Genetic Testing

  • Genetic testing should be considered (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) 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

  • 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
  • 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)
    • 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

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

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

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

Serial measurements of PSA required

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

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

Limitations

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

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

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

PIN4 Prostate Triple Stain by Immunohistochemistry 2010045
Method: Immunohistochemistry

P504S (AMACR) by Immunohistochemistry 2004076
Method: Immunohistochemistry

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

Prostate Specific Antigen by Immunohistochemistry 2004112
Method: Immunohistochemistry

PTEN by Immunohistochemistry 2004115
Method: Immunohistochemistry

PTEN with Interpretation by Immunohistochemistry 2007031
Method: Immunohistochemistry

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

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

ERG by Immunohistochemistry 2012555
Method: Immunohistochemistry

Related Tests

Guidelines

Basch E, Oliver TK, Vickers A, Thompson I, Kantoff P, Parnes H, Loblaw A, Roth B, Williams J, Nam RK. Screening for prostate cancer with prostate-specific antigen testing: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol. 2012; 30(24): 3020-5. PubMed

Carter B, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KLynn, Holmberg L, Kantoff P, Konety BR, Murad MHassan, Penson DF, Zietman AL. Early detection of prostate cancer: AUA Guideline. J Urol. 2013; 190(2): 419-26. PubMed

Greene KL, Albertsen PC, Babaian RJ, Carter B, Gann PH, Han M, Kuban DAnn, Sartor O, Stanford JL, Zietman A, Carroll P. Prostate specific antigen best practice statement: 2009 update. J Urol. 2009; 182(5): 2232-41. PubMed

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. PubMed

Heidenreich A, Abrahamsson P, Artibani W, Catto J, Montorsi F, Van Poppel H, Wirth M, Mottet N, European Association of Urology. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol. 2013; 64(3): 347-54. PubMed

Lim LS, Sherin K, ACPM Prevention Practice Committee. Screening for prostate cancer in U.S. men ACPM position statement on preventive practice. Am J Prev Med. 2008; 34(2): 164-70. PubMed

Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int. 2014; 114(3): 323-5. PubMed

Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012; 157(2): 120-34. PubMed

NCCN Clinical Practice Guidelines in Oncology, Prostate Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jan 2016]

Parker C, Gillessen S, Heidenreich A, Horwich A, ESMO Guidelines Committee. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5: v69-77. PubMed

Prostate Cancer: Screening. U.S. Preventive Services Task Force. Rockville, MD [Accessed: Jun 2015]

Protocol for the Examination of Specimens from Patients with Carcinoma of the Prostate Gland. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Sturgeon CM, Duffy MJ, Stenman U, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJørgen, Rittenhouse H, Semjonow A, Shih I, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP, National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008; 54(12): e11-79. PubMed

Wolf AM D, Wender RC, Etzioni RB, Thompson IM, D'Amico AV, Volk RJ, Brooks DD, Dash C, Guessous I, Andrews K, DeSantis C, Smith RA, American Cancer Society Prostate Cancer Advisory Committee. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010; 60(2): 70-98. PubMed

General References

Berg CD. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: the prostate cancer screening results in context. Acta Oncol. 2011; 50 Suppl 1: 12-7. PubMed

Bjartell A, Montironi R, Berney DM, Egevad L. Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. Acta Oncol. 2011; 50 Suppl 1: 76-84. PubMed

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

Croswell JM, Kramer BS, Crawford D. Screening for prostate cancer with PSA testing: current status and future directions. Oncology (Williston Park). 2011; 25(6): 452-60, 463. PubMed

Djulbegovic M, Beyth RJ, Neuberger MM, Stoffs TL, Vieweg J, Djulbegovic B, Dahm P. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ. 2010; 341: c4543. PubMed

Doyen J, Alix-Panabières C, Hofman P, Parks SK, Chamorey E, Naman H, Hannoun-Lévi J. Circulating tumor cells in prostate cancer: a potential surrogate marker of survival. Crit Rev Oncol Hematol. 2012; 81(3): 241-56. PubMed

Duffy MJ. PSA in screening for prostate cancer: more good than harm or more harm than good? Adv Clin Chem. 2014; 66: 1-23. PubMed

Epstein JI, Egevad L, Humphrey PA, Montironi R, Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014; 38(8): e6-e19. PubMed

Hayes JH, Barry MJ. Screening for prostate cancer with the prostate-specific antigen test: a review of current evidence. JAMA. 2014; 311(11): 1143-9. PubMed

Heidenreich A, Abrahamsson P, Artibani W, Catto J, Montorsi F, Van Poppel H, Wirth M, Mottet N, European Association of Urology. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol. 2013; 64(3): 347-54. PubMed

Modular Analytics E170 package insert, Indianapolis, IN: Roche Diagnostics, 2005.

Noguez JH, Fantz CR. Pathology consultation on prostate-specific antigen testing. Am J Clin Pathol. 2014; 142(1): 7-15. PubMed

Roobol MJ, Haese A, Bjartell A. Tumour markers in prostate cancer III: biomarkers in urine. Acta Oncol. 2011; 50 Suppl 1: 85-9. PubMed

Shariat SF, Semjonow A, Lilja H, Savage C, Vickers AJ, Bjartell A. Tumor markers in prostate cancer I: blood-based markers. Acta Oncol. 2011; 50 Suppl 1: 61-75. PubMed

Sikaris K. Prostate cancer screening. Pathology. 2012; 44(2): 99-109. PubMed

Simmons MN, Berglund RK, Jones S. A practical guide to prostate cancer diagnosis and management. Cleve Clin J Med. 2011; 78(5): 321-31. PubMed

Wei JT, Feng Z, Partin AW, Brown E, Thompson I, Sokoll L, Chan DW, Lotan Y, Kibel AS, Busby E, Bidair M, Lin DW, Taneja SS, Viterbo R, Joon AY, Dahlgren J, Kagan J, Srivastava S, Sanda MG. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. 2014; 32(36): 4066-72. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Gunawardena K, Campbell D, Meikle W. Antiandrogen-like actions of an antioxidant on survivin, Bcl-2 and PSA in human prostate cancer cells. Cancer Detect Prev. 2005; 29(4): 389-95. PubMed

Gunawardena K, Campbell D, Meikle W. Combination therapy with vitamins C plus E inhibits survivin and human prostate cancer cell growth. Prostate. 2004; 59(3): 319-27. PubMed

Guseva NV, Rokhlin OW, Glover RA, Cohen MB. P53 and the proteasome regulate androgen receptor activity. Cancer Biol Ther. 2012; 13(7): 553-8. PubMed

Jackson BR, Roberts WL. Brief report: Free prostate-specific antigen test utilization. Consistency with guidelines. J Gen Intern Med. 2005; 20(9): 859-61. PubMed

Liu T, Willmore-Payne C, Layfield LJ, Holden JA. Lack of BRAF activating mutations in prostate adenocarcinoma: a study of 93 cases. Appl Immunohistochem Mol Morphol. 2009; 17(2): 121-5. PubMed

Patel JC, Maughan BL, Agarwal AM, Batten JA, Zhang TY, Agarwal N. Emerging molecularly targeted therapies in castration refractory prostate cancer. Prostate Cancer. 2013; 2013: 981684. PubMed

Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S A. 2009; 106(38): 16351-6. PubMed

Slev PR, La'ulu SL, Roberts WL. Intermethod differences in results for total PSA, free PSA, and percentage of free PSA. Am J Clin Pathol. 2008; 129(6): 952-8. PubMed

Medical Reviewers

Last Update: February 2016