Prostate specific antigen

Prostate specific antigen (PSA) is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of normal men, and is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is the most effective test currently available for the early detection of prostate cancer. Rising levels of PSA over time are associated with both localized and metastatic prostate cancer (CaP).

Biochemistry

Prostate specific antigen (PSA), also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the semen and allows sperm to swim freely. [cite journal | title = Biology of Prostate-Specific Antigen | last = Steven P. Balk, Yoo-Joung Ko, Glenn J. Bubley | journal = Journal of Clinical Oncology | volume = 28 | issue = 2 | date = 2003 | pages = 383–91 | accessdate = 2006-09-17 |format = Abstract | url =http://www.jco.org/cgi/content/full/21/2/383 | pmid = 12525533 | doi = 10.1200/JCO.2003.02.083] It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm. [cite book | title=American Society of Andrology Handbook | chapter=Chapter 8: What is the prostate and what is its function? | chapterurl=http://www.andrologysociety.com/resources/handbook/ch.8.asp | accessdate=2006-09-17]

Biochemically it is a serine protease (EC number|3.4.21.77) enzyme, the gene of which is located on the nineteenth chromosome (19q13). [cite journal | title = Biology of Prostate-Specific Antigen | author = Lilja H. | journal = Urology | volume = 62 | issue = (5 Suppl 1) | year = 2003 | month=Nov | pages = 27–33 | accessdate = 2006-09-17 | pmid = 14607215 | doi = 10.1016/S0090-4295(03)00775-1]

Clinical significance

erum PSA

PSA is normally present in the blood at very low levels. The reference range of 0-4.0 ng/mL for the first commercial PSA test, the Hybritech Tandem-R PSA test released in February 1986, was based on a study that found 99% of 472 apparently healthy men had a total PSA level below 4 ng/mL—the upper limit of normal is much less than 4 ng/mL. cite journal |author=Kolota, Gina |month=May 30, |year=2004 |title=It Was Medical Gospel, but It Wasn't True |journal=The New York Times |pages=p. 4.7 |url=http://query.nytimes.com/gst/fullpage.html?res=9F05E5DD1E3EF933A05756C0A9629C8B63
cite journal |author=Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA Jr |month= May 27, |year=2004 |title=Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter |journal=N Engl J Med |volume=350 |issue=22 |pages=2239–46 |pmid=15163773
cite journal |author=Carter HB |month= May 27, |year=2004 |title=Prostate cancers in men with low PSA levels--must we find them? |journal=N Engl J Med |volume=350 |issue=22 |pages=2292–4 |pmid=15163780 |doi=10.1056/NEJMe048003
cite book |author=Mytrle JF, Klimley PG, Ivor L, Bruni JF |year=1986 |chapter=Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer |title=Advances in Cancer Diagnostics |location=San Diego |publisher=Hybritech Inc
cite book |author=Mytrle JF, Ivor L |year=1989 |chapter=Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem®-R/Tandem®-E PSA) |editors=Catalona WJ, Coffey DS, Karr JP (eds.) |title=Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16-19, 1988 at Prout's Neck, Maine, U.S.A. |location=New York |publisher=Elsevier |isbn=0-444-01514-0 |pages=pp. 161-71
cite book |author=Mytrle JF |year=1989 |chapter=Normal Levels of Prostate-Specific Antigen (PSA) |editors=Catalona WJ, Coffey DS, Karr JP (eds.) |title=Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16-19, 1988 at Prout's Neck, Maine, U.S.A. |location=New York |publisher=Elsevier |isbn=0-444-01514-0 |pages=pp. 183-9
cite journal |author=Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL |month= April 25, |year=1991 |title=Measurement of prostate-specific antigen in serum as a screening test for prostate cancer |journal=N Engl J Med |volume=324 |issue=17 |pages=1156–61 |pmid=1707140
cite journal |author=Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, et al. |month= May |year=1994 |title=Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men |journal=J Urol |volume=151 |issue=5 |pages=1283–90 |pmid=7512659] Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative. [cite journal | author = Thompson I, Pauler D, Goodman P, Tangen C, Lucia M, Parnes H, Minasian L, Ford L, Lippman S, Crawford E, Crowley J, Coltman C | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = N Engl J Med | volume = 350 | issue = 22 | pages = 2239–46 | year = 2004 | pmid = 15163773] Obesity has been reported to reduce serum PSA levels. [cite journal | author = Bañez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L, Rodriguez C, Wang Y, Terris MK, Aronson WJ, Presti JC Jr, Kane CJ, Amling CL, Moul JW, Freedland SJ. | title = Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer | journal = JAMA | volume = 350 | issue = 19 | pages = 2275–80 | year = 2004 | pmid = 18029831 | accessdate = 2008-04-27] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer. [cite journal | last = Robert Dreicer | title = Why Do Obese Men Have Lower PSA Concentrations? | journal = Journal Watch | publisher = New England Journal of Medicine | date = 2007-11-20 | url = http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1 | accessdate = 2008-04-27 ]

PSA levels can be also increased by prostate infection, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,cite journal | last = Herschman JD, Smith DS, Catalona WJ | title = Effect of ejaculation on serum total and free prostate-specific antigen concentrations | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9255295&dopt=Citation | journal = Urology | volume = 50 (2) | pages = 239–43 | year = 1997 | doi = 10.1016/S0090-4295(97)00209-4 ] [cite journal |author=Nadler RB; Humphrey PA; Smith DS; Catalona WJ; Ratliff TL |title=Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels |journal=Journal of Urology |volume=154 |issue=2 Pt 1 |pages=407–13 |year=1995 | url = http://www.medscape.com/medline/abstract/7541857?src=emed_ckb_ref_0 |accessdate = 2008-05-11 |doi=10.1016/S0022-5347(01)67064-2] producing a false positive result. Digital rectal examination (DRE) has been shown in several studiescite journal |author=Crawford ED, Schutz MJ, Clejan S, Drago J, Resnick MI, Chodak GW, Gomella LG, Austenfeld M, Stone NN, Miles BJ, et al |year=1992 |title=The effect of digital rectal examination on prostate-specific antigen levels |journal=JAMA |volume=267 |issue=16 |pages=2227–8 |pmid=1372943 |doi=10.1001/jama.267.16.2227
cite journal |author=Chybowski FM, Bergstralh EJ, Oesterling JE |year=1992 |title=The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study |journal=J Urol |volume=148 |issue=1 |pages=83–6 |pmid=1377290
cite journal |author=Collins GN, Martin PJ, Wynn-Davies A, Brooman PJ, O'Reilly PH |year=1997 |title=The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study |journal=J Urol |volume=157 |issue=5 |pages=1744–7 |pmid=9112518 |doi=10.1016/S0022-5347(01)64849-3
cite journal |author=Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U |year=2005 |title=Effect of prostatic massage on serum complexed prostate-specific antigen levels |journal=Urology |volume=66 |issue=6 |pages=1234–8 |pmid=16360449 |doi=10.1016/j.urology.2005.06.077] to produce an increase in PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL.

Despite earlier findings, [{cite journal | author = Carter H, Pearson J, Metter E, Brant L, Chan D, Andres R, Fozard J, Walsh P | title = Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease | journal = JAMA | volume = 267 | issue = 16 | pages = 2215–20 | year = 1992 | pmid = 1372942 | doi = 10.1001/jama.267.16.2215] recent research suggests that the rate of increase of PSA (the PSA velocity) is not a more specific marker for prostate cancer. [cite journal | author= H. Ballentine Carter | title = Assessing Risk: Does This Patient Have Prostate Cancer? | journal = Journal of the National Cancer Institute | volume = 98 | issue = 8 | pages = 506–7 | date = 2006 | url = http://jncicancerspectrum.oxfordjournals.org/cgi/content/full/jnci;98/8/506 | format = Editorial | accessdate = 2006-09-14 | pmid = 16622114 | doi = 10.1093/jnci/djj155 ] However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy. [cite journal | author = D'Amico A, Chen M, Roehl K, Catalona W | title = Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy | journal = N Engl J Med | volume = 351 | issue = 2 | pages = 125–35 | year = 2004 | pmid = 15247353 | doi = 10.1056/NEJMoa032975]

Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called free PSA. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph at right.) The lower the ratio the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL. [cite journal | author = Catalona W, Smith D, Ornstein D | title = Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements | journal = JAMA | volume = 277 | issue = 18 | pages = 1452–5 | year = 1997 | pmid = 9145717 | doi = 10.1001/jama.277.18.1452] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.

Other biologic fluids & tissues

It is now clear that the term prostate specific antigen is a misnomer. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.cite paper | author = Dale L. Laux, M.S. & Sarah E. Custis | title = Forensic Detection of Semen III. Detection of PSA Using Membrane Based Tests: Sensitivity Issues with Regards to the Presence of PSA in Other Body Fluids | publisher = Midwestern Association of Forensic Scientists | url = http://mafs.net/pdf/forensicdetectionsemen3.pdf | format = PDF | accessdate = 2008-05-11 ]

Other than semen, the greatest concentrations of PSA in biological fluids are detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral glands, endometrium, normal breast tissue and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer. [Citation |last=Stanley A Brosman |title= eMedicine: Prostate-Specific Antigen |publisher= WebMD |url= http://www.emedicine.com/med/TOPIC3465.HTM#section~CharacteristicsofProstateSpecificAntigen|accessdate=2008-05-11]

Tissue samples can be stained for the presence of PSA in order to determine the origin of maligant cells that have metastasized.cite journal |author=Chuang AY, Demarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI |title=Immunohistochemical Differentiation of High-grade Prostate Carcinoma From Urothelial Carcinoma |journal= The American Journal of Surgical Pathology|volume=31 |issue=8 |pages=1246–1255 |year=2007 |pmid=17667550 |doi=10.1097/PAS.0b013e31802f5d33]

Prostate cancer screening

The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older. PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and should be followed by rectal ultrasound imaging and, if indicated, prostate biopsy. PSA is false positive-prone (7 out of 10 men in this category will still not have prostate cancer) and false negative-prone (2.5 out of 10 men with prostate cancer have no elevation in PSA). [cite journal | author = Thompson I, Pauler D, Goodman P, Tangen C, Lucia M, Parnes H, Minasian L, Ford L, Lippman S, Crawford E, Crowley J, Coltman C | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = N Engl J Med | volume = 350 | issue = 22 | pages = 2239–46 | year = 2004 | pmid = 15163773] Recent reports indicate that refraining from ejaculation 24 hours or more prior to testing will improve test accuracy.

Forensic identification of semen

PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases. [Citation |last=Hara M, Inorre T, Fukuyama T. |title=Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma |journal= Jpn J Legal Med. |year=1971 |volume=25 |pages=322–324 |accessdate=2008-05-11] PSA is now used to indicate the presence of semen in forensic serology [Citation | last = Bill O. Gartside, Kevin J. Brewer & Carmella L. Strong | title = Estimation of Prostate-Specific Antigen (PSA) Extraction Efficiency from Forensic Samples Using the Seratecâ PSA Semiquant Semiquantitative Membrane Test | newspaper = Forensic Science Communications | volume = 5 | issue = 2 | date = April 2003| url =http://www.fbi.gov/hq/lab/fsc/backissu/april2003/gartside.htm | accessdate = 2008-05-11 ] . The semen of adult males has PSA levels far in excess of those found in other tissues, therefore, a high level of PSA found in a sample is an indicator that semen may be present. Because PSA is a biomarker that is expressed independently of spermatazoa, it remains useful in identifying semen from vasectomized and azoospermic males.cite paper | author = M. Hochmeister, O. Rudin, U.V.Borer, A. Kratzer, Ch. Gehrig and R. Dirnhofer | title = Evaluation of Prostate-Specific Antigen (PSA) Membrane Tests for the Forensic Identification of Semen | publisher = Eighth International Symposium on Human Identification | date = 1997 | url = http://www.promega.com/geneticidproc/ussymp8proc/33.html | accessdate = 2008-05-11 ] It is important to note that PSA can also be found at low levels in other body fluids, such as urine and breast milk, thus setting a high minimum threshold of interpretation to rule out false positive results is necessary to conclusively state that semen is present. While traditional tests such as crossover electrophoresis have a sufficiently low sensitivity to only detect seminal PSA, newer diagnostics tests developed from clinical prostate cancer screening methods have lowered the threshold of detection down to 4ng/mL. [Citation |last=Manfred N. Hochmeister, Bruce Budowle, Oskar Rudin, Christian Gehrig, Urs Borer, Michael Thali, and Richard Dirnhofer |title=Evaluation of Prostate-Specific Antigen (PSA) Membrane Test Assays for the Forensic Identification of Seminal Fluid |journal= Journal of Forensic Science |year=1999 |volume=44 |pages=1057–60 |url= http://projects.nfstc.org/workshops/resources/articles/Evaluation%20of%20prostate-specific%20antigen%20(PSA)%20membrane%20test%20assays%20for%20the%20forensic%20identification%20of%20seminal%20fluid.pdf |accessdate=2008-05-11] This level of antigen has been shown to be present in the peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk. No studies have been performed to assess the PSA levels in the tissues and secretions of pre-pubescent children. Therefore, the presence of PSA from a high sensitivity (4ng/mL) test cannot conclusively identify the presence of semen, so care must be taken with the interpretation of such results.

ee also

* False positive/False negative
* Prostate cancer
* Prostate cancer screening
* Tumor markers

References

Further reading

*cite journal |author=De Angelis G, Rittenhouse HG, Mikolajczyk SD, Blair Shamel L, Semjonow A |title=Twenty Years of PSA: From Prostate Antigen to Tumor Marker |journal=Reviews in urology |volume=9 |issue=3 |pages=113–23 |year=2007 |pmid=17934568 |doi=PBB_Further_reading
citations =
*cite journal | author=Henttu P, Vihko P |title=Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate |journal=Ann. Med. |volume=26 |issue= 3 |pages= 157–64 |year= 1994 |pmid= 7521173 |doi=
*cite journal | author=Diamandis EP, Yousef GM, Luo LY, "et al." |title=The new human kallikrein gene family: implications in carcinogenesis |journal=Trends Endocrinol. Metab. |volume=11 |issue= 2 |pages= 54–60 |year= 2001 |pmid= 10675891 |doi=
*cite journal | author=Lilja H |title=Biology of prostate-specific antigen |journal=Urology |volume=62 |issue= 5 Suppl 1 |pages= 27–33 |year= 2003 |pmid= 14607215| doi=10.1016/S0090-4295(03)00775-1

External links

* American Cancer Society: Detailed Guide: Prostate Cancer [http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_prostate_cancer_be_found_early_36.asp Can Prostate Cancer Be Found Early?]
* National Cancer Institute: [http://www.cancer.gov/cancertopics/factsheet/Detection/PSA The Prostate-Specific Antigen (PSA) Test: Questions and Answers]
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