Prostate-specific antigen ( PSA ), also known as gamma-seminoprotein or kallikrein-3 ( KLK3 ), is a glycoprotein enzyme that is encoded in humans by the KLK3 genes. PSA is a member of the related kallikrein peptidase family and secreted by epithelial cells of the prostate gland. PSA is produced for ejaculation, where it dilutes the semen in the seminal coagulum and allows the sperm to swim freely. It is also believed to play a role in dissolving cervical mucus, allowing the entry of sperm into the uterus.
PSA is present in small amounts in male serum with healthy prostate, but it is often increased in the presence of prostate cancer or other prostate disorders. PSA is not a unique indicator of prostate cancer, but it can also detect prostatitis or benign prostatic hyperplasia.
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Screening
The clinical practice guidelines for prostate cancer screening are varied and controversial due to uncertainty, whether the benefits of screening are ultimately greater than the risk of overdiagnosis and over treatment. In the United States, the US Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men aged 50 and older. Patients need to be informed about the risks and benefits of the PSA test before performing the test (see below). A PSA level of between 4 and 10 ng/mL (nanograms per milliliter) is considered suspicious and consideration should be given to confirming abnormal PSA with retest. If indicated, prostate biopsy is performed to obtain tissue samples for histopathological analysis. In the UK, the National Health Service (2018) does not mandate, or suggests for PSA testing, but allows patients to decide on the advice of their physician.
In 2018 the UK National Health Service did not offer a general PSA screening, for the same reason.
While PSA testing can help 1000 in 1,000,000 avoid deaths from prostate cancer, 4000 to 5,000 in 1,000,000 will die from prostate cancer after 10 years even with screening. This means that PSA screening can reduce the mortality of prostate cancer by 25%. Expected dangers including anxiety for 100 - 120 receive false positives, biopsy pain, and other complications of biopsy for false positive tests. Of those found to have prostate cancer, frequent overtreatment is common because most cases of prostate cancer are not expected to cause any symptoms. Therefore, many will experience treatment side effects, such as for every 1000 men screened, 29 will experience erectile dysfunction, 18 will suffer from urinary incontinence, 2 will experience serious cardiovascular events, 1 will have pulmonary embolism or deep venous thrombosis, and 1 perioperative death. Because the estimated danger relative to the risk of death is perceived by the patient as minimal, men who are found to have prostate cancer usually (up to 90% of cases) choose to receive treatment.
Risk stratification and staging
Men with prostate cancer can be characterized as low, medium, or high risk to have/develop metastatic or dying disease due to prostate cancer. The PSA level is one of three variables in which risk stratification is based; the other is the level of prostate cancer (Gleason assessment system) and the stage of cancer based on physical examination and imaging. D'Amico The criteria for each risk category are as follows:
- Low risk: PSA & lt; 10, Gleason score <= 6, AND clinical stage <= T2a
- Intermediate-risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c
- High risk: PSA & gt; 20, Gleason score> = 8, OR clinical stage> = T3
Given the relative simplicity of the 1998 D'Amico criterion (above), other predictive models of risk stratification based on mathematical probability constructs exist or have been proposed to allow for better matching of treatment decisions with disease features. Studies are being conducted into the incorporation of multiparametric MRI imaging results into nomograms that depend on PSA, grade Gleason and tumor stage.
Post-treatment monitoring
The PSA level is monitored periodically (eg, every 6-36 months) after treatment for prostate cancer - more often in patients with high-risk disease, more rarely in patients with low-risk illness. If surgical therapy (ie, radical prostatectomy) successfully removes all prostate tissue (and prostate cancer), PSA becomes undetectable within a few weeks. A subsequent increase in PSA levels above 0.2 ng/mL L is generally regarded as evidence of recurrent prostate cancer after radical prostatectomy; less commonly, it might just show the rest of the prostate tissue benign.
After radiation therapy from all types of prostate cancer, some PSA levels may be detected, even when the treatment eventually proves successful. This makes it more difficult to interpret the relationship between PSA levels and the relapse/persistence of prostate cancer after radiation therapy. PSA levels may continue to decline for several years after radiation therapy. The lowest level is called the nadir point of the PSA. A subsequent increase in PSA levels of 2.0 ng/mL over the nadir is the current definition of prostate cancer received after radiation therapy.
If recurrent prostate cancer is detected by elevated PSA levels after curative treatment, this is referred to as "biochemical recurrence". The likelihood of developing recurrent prostate cancer after curative treatment is related to the preoperative variables described in the previous section (PSA level and stage/stage of cancer). Low risk cancers are the most likely to reoccur, but they are also the most likely to have required care in the first place.
Histology
PSA is produced in prostate epithelial cells, and may be demonstrated in biopsy samples or other histologic specimens using immunohistochemistry. Disorders of this epithelium, for example in inflammation or benign prostate hyperplasia, may cause some diffusion of the antigen into the tissue around the epithelium, and is a cause of elevated PSA levels under these conditions.
More significantly, PSA remains present in prostate cells after they become malignant. Prostate cancer cells generally have variable or weak staining for PSA, due to their normal functional impairment. Thus, individual prostate cancer cells produce less PSA than healthy cells; elevated serum levels in prostate cancer patients are caused by an increase in the number of cells so much, not their individual activity. However, in most cases of prostate cancer, cells remain positive for antigens, which can therefore be used to identify metastases. Because some high-level prostate cancers may be completely negative for PSA, however, histologic analysis to identify such cases typically uses PSA in combination with other antibodies, such as PSAP and CD57.
Identify forensic semen
The PSA was first identified by researchers seeking to find a substance in semen that would assist in the investigation of rape cases. PSA is now used to indicate the presence of semen in forensic serology. Adult male semen has PSA levels far beyond those found in other tissues; therefore, the high PSA levels found in the sample are indicators that semen may exist. Because PSA is a biomarker expressed independently of spermatozoa, it remains useful in identifying semen from male vasectomy and azoospermia.
PSA can also be found at low levels in other body fluids, such as urine and breast milk, thereby setting a high interpretation threshold to exclude false positive results and definitively state that semen is present. While traditional tests such as crossover electrophoresis have a low enough sensitivity to detect only the seminal PSA, newer diagnostic tests developed from clinical prostate cancer screening methods have lowered the detection threshold by up to 4 ng/mL. This antigen level has been shown to be present in peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk. No research has been done to assess the level of PSA in tissues and the secretions of pre-pubescent children. Therefore, the presence of PSA from the high sensitivity test (4 ng/mL) can not conclusively identify the presence of semen, so it must be considered with the interpretation of the results.
Maps Prostate-specific antigen
Action mechanism
The physiological function of KLK3 is the dissolution of coagulum, a sperm-catching gel composed of semenogelin and fibronectin. Its proteolytic action is effective in liquefying the coagulum so that sperm can be released. PSA activities are well managed. In the prostate it is present as a proactive form that is activated through the action of KLK2, another peptidase associated with kallikrein. In the prostate, zinc ion concentrations are ten times higher than other body fluids. The zinc ion has a strong inhibitory effect on PSA activity and on KLK2, so the PSA is completely inactive. Further regulation is achieved through the variation of pH. Although its activity increases with higher pH, zinc inhibition effects also increase. The semen pH is slightly alkaline and the concentration of zinc is high. In ejaculation, semen is exposed to the pH of vaginal acid, due to the presence of lactic acid. In fertile pairs, the final vaginal pH after the coitus approaches the level of 6-7, which coincides well with the decrease in zinc inhibition of PSA. At this pH level, reduced PSA activity is resisted by a decrease in zinc inhibition. Thus, the coagulum is slowly liquefied, releasing sperm in a regular manner.
Biochemistry
Prostate-specific antigen (PSA, also known as kallikrein III, seminin, semenogelase, -seminoprotein and P-30 antigen) is a 34-kD glycoprotein produced almost exclusively by the prostate gland. This is a serine protease enzyme (EC 3.4.21.77), a gene located on the 19th chromosome (19q13) in humans.
History
The discovery of prostate-specific antigen (PSA) has been controversial; as PSA is present in the prostate tissue and semen, it is found independently and given a different name, thus adding to the controversy.
Flocks were the first to experiment with antigens in the prostate and 10 years later Ablin reported the presence of a deposition antigen in the prostate.
In 1971, Mitsuwo Hara characterized a unique protein in semen, gamma-seminoprotein. Li and Beling, in 1973, isolated protein, E1, from human semen in an attempt to find new methods to achieve fertility control.
In 1978, Sensabaugh identified the specific protein cement p30, but proved that it was similar to E1 protein, and that the prostate was the source. In 1979, Wang purified the tissue-specific antigen of the prostate ('prostate antigen').
PSA was first measured quantitatively in blood by Papsidero in 1980, and Stamey did initial work on the clinical use of PSA as a marker of prostate cancer.
Serum level
PSA usually exists in the blood at very low levels. Reference range less than 4 ng/mL for the first commercial PSA test, Hybritech Tandem-R PSA test was released in February 1986, based on a study that found 99% of 472 apparently healthy men had a total PSA level under 4 ng/mL - Normal upper limit is much smaller than 4 ng/mL.
Increased levels of PSA may indicate prostate cancer. However, prostate cancer can also be present in the absence of total PSA levels, where the test results will be a false negative.
Obesity has been reported to reduce serum PSA levels. Partially delayed early detection may explain worse outcomes in obese men with early prostate cancer. After treatment, a higher BMI also correlates with a higher risk of recurrence.
PSA levels can also be increased with prostatitis, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation, producing false-positive results. Anal rectal examination (DRE) has been shown in several studies to result in increased PSA. However, the effect was not clinically significant, as DRE led to the most substantial increase in patients with PSA levels that had risen above 4.0 ng/mL.
The "normal" reference range for prostate-specific antigen increases with age, as does the general range of cancer:
PSA speed
Despite previous findings, recent research has shown that elevated PSA levels (eg 0.35 ng/mL/year, 'PSA velocity') are not more specific markers for prostate cancer than serum PSA levels.
However, the rate of increase in PSA may have a value in the prognosis of prostate cancer. Men with prostate cancer whose PSA levels increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer had a higher risk of death from prostate cancer despite undergoing radical prostatectomy. The PSA speed (PSAV) found in the 2008 study is more useful than PSA DT (PSA DT) multiplier time to help identify people with life-threatening illness prior to starting treatment.
Men known to be at risk for prostate cancer, and who decide to plan their PSA value as a function of time (ie, year), may choose to use semi-log plots. The exponential growth in the PSA value appears as a straight line on the semi-log plot, so that the new PSA value significantly above the straight line signifies the switch to the new growth rate and significantly higher, that is, the more PSA speed high.
Free PSA
Most PSA in the blood is bound to a serum protein. Small numbers are not protein-bound and are called 'free PSA'. In men with prostate cancer, the ratio of free PSA (not bound) to total PSA decreased. The risk of cancer increases if the ratio of free to total is less than 25%. (See chart on the right.) The lower the ratio, the greater the probability of prostate cancer. Measuring the ratio of free PSA to total seems very promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL. However, both total and free PSA increased immediately after ejaculation, returning slowly to baseline in 24 hours.
Inactive PSA
The PSA test in 1994 failed to distinguish between prostate cancer and benign prostate hyperplasia (BPH) and commercial testing tools for PSA did not provide true PSA values. Thus with the introduction of free total PSA ratio, the reliability of the test has increased and measuring the enzyme activity can increase the total free PSA ratio and further increase the diagnostic value of the test. Proteolytically active PSA has been shown to have an anti-angiogenic effect and certain inactive subforma may be associated with prostate cancer, as demonstrated by MAb 5D3D11, an antibody capable of detecting abundant forms represented in serum from cancer patients. The presence of an inactive proenzyme form of PSA is another potential indicator of the disease.
Complex PSA
PSA is present in serum in free form (unbound) and in complexes with alpha 1-antichymotrypsin; research has been done to see if complexity of PSA measurements is a more specific and sensitive biomarker for prostate cancer than any other approach.
PSA in liquids and other biological tissues
It is now clear that the term prostate-specific antigen is a misnomer: it is an antigen but not specific to the prostate. Although present in large amounts in the prostate and semen tissues, it has been detected in liquids and other body tissues.
In women, PSA is found in female ejaculation at concentrations approximately equal to those found in men's semen. In addition to semen and female ejaculation, the greatest concentration of PSA in biological fluids is detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral gland, endometrium, normal breast tissue and salivary gland tissue. PSA is also found in female serum with breast, lung, or uterine cancers and in some patients with kidney cancer.
The tissue samples can be stained for the presence of PSA to determine the origin of malignant cells that have metastasized.
Interactions
Prostate-specific antigen has been shown to interact with protein C inhibitors.
See also
- The tumor marker
References
Further reading
External links
- MEROPS online database for peptidase and its inhibitors: S01.162
- American Cancer Society: A Complete Guide: Prostate Cancer Can Prostate Cancer Be Found Early?
- National Cancer Institute: Prostate-Specific Antigen (PSA) Test: Questions and Answers
- Prostate-Specific Antigen in US National Library of Medicine's Medical Subject Headings (MeSH)
- Prostate UK Help us stop life-threatening prostate disease
- PSA in the Online Test Lab
- Total testing procedure of PSA ELISA
Source of the article : Wikipedia
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