Prostate Cancer - PSA

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

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 prostate-specific antigen (PSA) – screening recommendations can be found in the Screening section

Laboratory Testing

  • Total PSA (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 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 (National Comprehensive Cancer Network [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
  • 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 (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

  • The American Urological Association (AUA), National Comprehensive Cancer Network (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-specific antigen (PSA) is used for prostate cancer screening starting at 50 years, except in cases of increased risk
  • Prostate-specific antigen (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

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
    • Median age – 66 years (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 prostate-specific antigen (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
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 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

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 

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

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

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 

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

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

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

Carroll PR, Parsons K, Andriole G, Bahnson RR, Castle EP, Catalona WJ, Dahl DM, Davis JW, Epstein JI, Etzioni RB, Farrington T, Hemstreet GP, Kawachi MH, Kim S, Lange PH, Loughlin KR, Lowrance W, Maroni P, Mohler J, Morgan TM, Moses KA, Nadler RB, Poch M, Scales C, Shaneyfelt TM, Smaldone MC, Sonn G, Sprenkle P, Vickers AJ, Wake R, Shead DA, Freedman-Cass DA. NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016. J Natl Compr Canc Netw. 2016; 14(5): 509-19. PubMed

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

Mulhem E, Fulbright N, Duncan N. Prostate Cancer Screening. Am Fam Physician. Leawood, KS [Published Oct 2015; Accessed: May 2017]

NCCN Clinical Practice Guidelines in Oncology, Prostate Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Mar 2017]

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: Jun 2012. College of American Pathologists (CAP). Northfield, IL [Revised Jun 2012; Accessed: Dec 2016]

Qaseem A, Barry MJ, Denberg TD, Owens DK, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians Ann Intern Med. 2013; 158(10): 761-9. PubMed

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 HJ, 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, 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

Colicchia M, Morlacco A, Cheville JC, Karnes J. Genomic tests to guide prostate cancer management following diagnosis. Expert Rev Mol Diagn. 2017; 17(4): 367-377. 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

Friedlander TW, Fong L. The end of the beginning: circulating tumor cells as a biomarker in castration-resistant prostate cancer. J Clin Oncol. 2014; 32(11): 1104-6. PubMed

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

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

Qaseem A, Barry MJ, Denberg TD, Owens DK, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians Ann Intern Med. 2013; 158(10): 761-9. 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

Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia S, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford D, Crowley JJ, Coltman CA. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004; 350(22): 2239-46. PubMed

Vaishampayan UN. Changing face of metastatic prostate cancer: the law of diminishing returns holds true. Curr Opin Oncol. 2017; 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: July 2017