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.^[1] It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.^[2]

Biochemically it is a serine protease (EC 3.4.21.77) enzyme, the gene of which is located on the nineteenth chromosome (19q13). ^[3]

Discovery

The discovery of prostate-specific antigen (PSA) is beset with controversy; as PSA is present in prostatic tissue and semen, it was independently discovered and given different names, thus adding to the controversy. The chronology of the discovery of PSA is reviewedby Rao et al. In 1960, Flocks was the first to experiment with antigens in the prostate and 10 years later Ablin reported the presence of precipitation antigens in the prostate. In 1971, Hara characterized a unique protein in the semen fluid, gamma-seminoprotein. Li and Beling, in 1973, isolated a protein, E1, from human semen in an attempt to find a novel method to achieve fertility control. In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source. In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen'). PSA was first measured quantitatively in the blood by Papsidero in 1980, and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.^[4]

Clinical significance

Serum PSA

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA ^[5]

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.^[6] 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.^[7] Obesity has been reported to reduce serum PSA levels.^[8] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.^[9]

PSA levels can be also increased by prostate infection, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,^[10][11] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies^[12] 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,^[13] recent research suggests that the rate of increase of PSA (the PSA velocity) is not a more specific marker for prostate cancer.^[14] 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.^[15]

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.^[16] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.^[10]

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.^[17]

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.^[18]

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.^[19]

Prostate cancer screening

Main article: 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).^[20] Recent reports indicate that refraining from ejaculation 24 hours or more prior to testing will improve test accuracy.^[10]

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.^[21] PSA is now used to indicate the presence of semen in forensic serology^[22]. 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.^[23]

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.^[17] 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.^[24] 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.^[17] 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.

See also

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

References

Further reading

External links

• American Cancer Society: Detailed Guide: Prostate Cancer Can Prostate Cancer Be Found Early?
• National Cancer Institute: The Prostate-Specific Antigen (PSA) Test: Questions and Answers
• MeSH Prostate-Specific+Antigen
• Prostate-Specific+Antigen at eMedicine Dictionary