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Prostate-Specific Antigen (PSA)  

It is normal for men to have low levels of PSA in their blood; however, prostate cancer or benign (not cancerous) conditions can increase PSA levels. As men age, both benign prostate conditions and prostate cancer become more frequent. The most common benign prostate conditions are prostatitis (inflammation of the prostate) and benign prostatic hyperplasia (BPH = enlargement of the prostate).

There is no evidence that prostatitis or BPH cause cancer, but it is possible for a man to have one or both of these conditions and to develop prostate cancer as well.

PSA is only present in men. PSA is present in all normal prostate tissue. The normal prostate cell holds onto most of the PSA. Very little leaks into the bloodstream. The small amount that leaks out is what is measured by the blood test. Prostate cancer cells actually have less PSA in each cell. However, the cancer cell tends to leak more PSA into the bloodstream. Knowing this fact, experts developed a range of expected values in patients with a normal prostate gland. The PSA value should be less than 4.0. This number reflects the belief that most men, roughly 95%, with normal prostate glands have a PSA value of 4.0 or less. (See below for age-specific normal values.) Almost any condition that affects the prostate can make the PSA rise.

The American Cancer Society and the American Urological Association recommend that men over age 50 have a yearly PSA. They should also have a rectal examination of the prostate. High-risk groups should begin screening at age 40 to 45. Men with a family history of the disease and African Americans fall into this category.

When evaluating PSA results, the doctor must also take into account the results of the rectal exam, the patient's age, previous PSA results, and prostatic size. For example, findings on a rectal exam must be looked into even if the PSA result is normal. Recent studies have suggested that the 4.0 level may be too high for younger men and too low for older men. Many researchers now use the following levels rather than the 4.0 used in the past. However, more time is needed to assure that these levels are more accurate.

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If the rectal exam is normal then the following recommendations are suggested: PSA of 4 or less. If the PSA level has been measured for the first time and is less than 4, repeat testing is recommended on a yearly basis. (This number may be dependent on age. See above for normal values.) PSA between 4 and 10.

If the PSA level is greater than 4 but less than 10, a diagnostic ultrasound of the prostate is recommended. If the ultrasound shows no suspicious areas, the prostate can be monitored through regular testing and exams.

Another option is to take random biopsies from various parts of the prostate. If observation alone is used, the PSA should be repeated in 4 to 6 months and no later than a year. If the ultrasound shows a suspicious area, then biopsy of the area needs to be performed. This can be done at the time of the ultrasound. The patient will need to take antibiotics ahead of time. 

If the PSA is greater than 10, diagnostic ultrasound of the prostate with biopsies is the recommended course. If the ultrasound shows no suspicious areas, then random biopsies of the prostate are taken. If the ultrasound shows suspicious areas, then biopsies of the areas along with random biopsies need to be done. If previous PSA values are available, test results will be evaluated differently. The PSA level almost always rises if cancer is growing. Any PSA level that is rising is suspicious. However, a high PSA level may not mean that cancer is present. For example, a male with a stable PSA of 8 over a three-year period is probably at less risk than a male with a PSA of 2, 4, and 6 over the same time frame. This is because the second patient's rising levels suggest growth. This makes it suspicious for cancer. If the first patient had a negative biopsy when the first high PSA value occurred, there may be no need to repeat the biopsies. If the PSA level jumped to 10 or 15 for no apparent reason, then repeat ultrasound and biopsies would be called for. Recent studies suggest that either a 20% rise or a measurable rise of 0.75 in PSA in one year should prompt a closer look. Ultrasound and biopsy may be needed.

PSA levels alone do not give doctors enough information to distinguish between benign prostate conditions and cancer but it is the first screening step for any man over 50. Your physician will take the result of the PSA test into account when deciding whether to check further for signs of prostate cancer.

The U.S. Food and Drug Administration (FDA) has approved the PSA test along with a digital rectal exam DRE to help detect prostate cancer in men age 50 and older. During a DRE, a doctor inserts a gloved finger into the rectum and feels the prostate gland through the rectal wall to check for bumps or abnormal areas. Together, these tests can help doctors detect prostate cancer in men who have no symptoms of the disease.

The FDA has also approved the PSA test to monitor patients with a history of prostate cancer to see if the cancer has come back (recurred). An elevated PSA level in a patient with a history of prostate cancer does not always mean the cancer has come back. A man should discuss an elevated PSA level with his doctor. The doctor may recommend repeating the PSA test or performing other tests to check for evidence of recurrence.

It is important to note that a man who is receiving hormone therapy for prostate cancer may have a low PSA reading during, or immediately after, treatment. The low level may not be a true measure of PSA activity in the man’s body. Men receiving hormone therapy should talk with their doctor, who may advise them to wait a few months after hormone treatment before having a PSA test.

For whom might a PSA screening test be recommended?

Doctors’ recommendations for screening vary. Some encourage yearly screening for men over age 50, and some advise men who are at a higher risk for prostate cancer to begin screening at age 40 or 45. Others caution against routine screening, while still others counsel men about the risks and benefits on an individual basis and encourage men to make personal decisions about screening.
Several risk factors increase a man’s chances of developing prostate cancer. These factors may be taken into consideration when a doctor recommends screening. Age is the most common risk factor, with nearly 70 percent of prostate cancer cases occurring in men age 65 and older. Other risk factors for prostate cancer include family history, race, and possibly diet. Men who have a father or brother with prostate cancer have a greater chance of developing prostate cancer. African American men have the highest rate of prostate cancer, while Asian and Native American men have the lowest rates. In addition, there is some evidence that a diet higher in fat, especially animal fat, may increase the risk of prostate cancer.

PSA test results report the level of PSA detected in the blood. The test results are usually reported as nanograms of PSA per milliliter (ng/ml) of blood. In the past, most doctors considered PSA values below 4.0 ng/ml as normal. However, recent research found prostate cancer in men with PSA levels below 4.0 ng/ml.  Many doctors are now using the following ranges, with some variation:

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There is no specific normal or abnormal PSA level. However, the higher a man’s PSA level, the more likely it is that cancer is present. But because various factors can cause PSA levels to fluctuate, one abnormal PSA test does not necessarily indicate a need for other diagnostic tests. When PSA levels continue to rise over time, other tests may be needed.

There are many possible reasons for an elevated PSA level, including prostate cancer, benign prostate enlargement, inflammation, infection, age, and race.

If no other symptoms suggest cancer, the doctor may recommend repeating DRE (Digital Rectal Exam) and PSA tests regularly to watch for any changes. If a man’s PSA levels have been increasing or if a suspicious lump is detected during the DRE, the doctor may recommend other tests to determine if there is cancer or another problem in the prostate. A urine test may be used to detect a urinary tract infection or blood in the urine. The doctor may recommend imaging tests, such as ultrasound (a test in which high-frequency sound waves are used to obtain images of the kidneys and bladder), x-rays, or cystoscopy (a procedure in which a doctor looks into the urethra and bladder through a thin, lighted tube). Medicine or surgery may be recommended if the problem is BPH or an infection.

If cancer is suspected, a biopsy is needed to determine if cancer is present in the prostate. During a biopsy, samples of prostate tissue are removed, usually with a needle, and viewed under a microscope. The doctor may use ultrasound to view the prostate during the biopsy, but ultrasound cannot be used alone to tell if cancer is present.

Detection does not always mean saving lives: Even though the PSA test can detect small tumors, finding a small tumor does not necessarily reduce a man’s chance of dying from prostate cancer. PSA testing may identify very slow-growing tumors that are unlikely to threaten a man’s life. Also, PSA testing may not help a man with a fast-growing or aggressive cancer that has already spread to other parts of his body before being detected.
 
False positive test results (also called false positives) occur when the PSA level is elevated but no cancer is actually present. False positives may lead to additional medical procedures that have potential risks and significant financial costs and can create anxiety for the patient and his family. Most men with an elevated PSA test turn out not to have cancer; only 25 to 30 percent of men who have a biopsy due to elevated PSA levels actually have prostate cancer.

False negative test results (also called false negatives) occur when the PSA level is in the normal range even though prostate cancer is actually present. Most prostate cancers are slow-growing and may exist for decades before they are large enough to cause symptoms. Subsequent PSA tests may indicate a problem before the disease progresses significantly.

Using the PSA test to screen men for prostate cancer is controversial because it is not yet known if this test actually saves lives. Moreover, it is not clear if the benefits of PSA screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example, the PSA test may detect small cancers that would never become life threatening. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation.

The procedure used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake prostate cancer screening.
 
The benefits of screening for prostate cancer are still being studied. The National Cancer Institute (NCI) is currently conducting the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO trial, to determine if certain screening tests reduce the number of deaths from these cancers. The DRE and PSA are being studied to determine whether yearly screening to detect prostate cancer will decrease a man’s chance of dying from prostate cancer. Full results from this study are expected in several years. Scientists also are researching ways to distinguish between cancerous and benign conditions, and between slow-growing cancers and fast-growing, potentially lethal cancers. Some of the methods being studied are:

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PSA velocity:
PSA velocity is based on changes in PSA levels over time. A sharp rise in the PSA level raises the suspicion of cancer.

Age-adjusted PSA:
Age is an important factor in increasing PSA levels. For this reason, some doctors use age-adjusted PSA levels to determine when diagnostic tests are needed. When age-adjusted PSA levels are used, a different PSA level is defined as normal for each 10-year age group. Doctors who use this method generally suggest that men younger than age 50 should have a PSA level below 2.4 ng/ml, while a PSA level up to 6.5 ng/ml would be considered normal for men in their 70s. Doctors do not agree about the accuracy and usefulness of age-adjusted PSA levels.

PSA density:
PSA density considers the relationship of the PSA level to the size of the prostate. In other words, an elevated PSA might not arouse suspicion if a man has a very enlarged prostate. The use of PSA density to interpret PSA results is controversial because cancer might be overlooked in a man with an enlarged prostate.

Free versus complexed (attached) PSA:
PSA circulates in the blood in two forms: free or attached to a protein molecule. With benign prostate conditions, there is more free PSA, while cancer produces more of the attached form. Researchers are exploring different ways to measure PSA and to compare these measurements to determine if cancer is present.

Alteration of PSA cutoff level:
Some researchers have suggested lowering the cutoff levels that determine if a PSA measurement is normal or elevated. For example, a number of studies have used cutoff levels of 2.5 or 3.0 ng/ml (rather than 4.0 ng/ml). In such studies, PSA measurements above 2.5 or 3.0 ng/ml are considered elevated. Researchers hope that using these lower cutoff levels will increase the chance of detecting prostate cancer; however, this method may also increase overdiagnosis and false positive test results and lead to unnecessary medical procedures.

Protein patterns:
Scientists are also studying a test that can rapidly analyze the patterns of various proteins in the blood. Researchers hope that this technique can determine if a biopsy is necessary when a person has a slightly elevated PSA level or an abnormal DRE.
 

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Prostate-Specific Antigen (PSA), Complexed

Other PSA tests that measure just the free or complexed portion are also available.

The relative proportions of free and complexed PSA are thought to be different in prostate cancer when compared with other prostatic diseases. Men with cancer are thought to have a smaller proportion of free PSA and more complexed PSA than men with other benign prostatic diseases such as benign prostatic hyperplasia (BPH) or prostatitis, which can also lead to abnormal total PSA test results.

Free or complexed PSA tests are provided by some laboratories usually in addition to the total PSA test. They have often been used as reflex tests following a raised total PSA test result. The results are then expressed as the percentage of free PSA compared with the total amount of PSA detected. Any results below a cut-off are thought to be suggestive of prostate cancer. These free or complexed PSA tests are designed to be used when the total PSA test result is marginally raised, and not in cases where the total PSA test result is very high and suggestive of advanced prostate cancer.

The introduction of free PSA (fPSA) testing has introduced a greater level of specificity in identifying early prostate cancer. In 1998, the FDA approved fPSA testing as a diagnostic aid for men with total PSA values between 4.0-10.0 ng/mL. This has often been the diagnostic gray zone for total PSA testing and fPSA may aid in the stratification. In general, “At any percent free PSA level, one could be a lot more reassured in the man with the small prostate…if somebody has a really low percent free PSA, 10 or 12, no matter how big or how small their prostate is, then you worry. And if a patient has a really high free PSA, say 30%, no matter how big or small his prostate is, you can feel reassured,” (William Catalona, M.D., Urologist at Barnes Hosptial, Washington University, St. Louis).

But fPSA levels between 10-25% are another gray zone as the table illustrates. Additional testing on the horizon includes complexed PSA and human glandular kallikrein (hK2) to fPSA ratio.

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Prostate-Specific Antigen (PSA), Free/Total Ratio

In the PSA range of 4-10, total prostate-specific antigen (tPSA) segregates adequately between men with or without cancer. The f/tPSA is more discriminatory.

A 7-institution study investigated 63 men with BPH, 30 men with prostate cancer (prostate size >40 cm3), and 20 men with small prostates. All of the PSA levels were 4-10 ng/mL. The median f/tPSA proportion was 0.188 (in BPH), 0.159 (in prostate cancer [prostate size >40 cm3]), and 0.092 (in small prostates).

This implies that prostate size is an important variable in selecting a cutoff value for fPSA.

For men whose prostates are smaller than 40 cm3, a percent fPSA of 0.137 or lower is used to detect 90% of the cancers, and 76% of the negative biopsy findings can be eliminated.

For men with prostates larger than 40 cm3, a cutoff of 0.205 allows detection of 90% of the cancers, and 38% of the negative biopsy findings can be eliminated.

If the patient has a normal-sized prostate on DRE, a value of 0.234 is necessary to detect 90% of the cancers, sparing 31.3% of the patients an unnecessary biopsy.
 

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Prostatic Acid Phosphatase (PAP)

Acid phosphatase is an enzyme found throughout the body, but primarily in the prostate gland. Like all enzymes, it is needed to trigger specific chemical reactions. Acid phosphatase testing is done to diagnose whether prostate cancer has spread to other parts of the body (metastasized), and to check the effectiveness of treatment. The test has been largely supplanted by the prostate specific antigen test (PSA).

The male prostate gland has 100 times more acid phosphatase than any other body tissue. When prostate cancer spreads to other parts of the body, acid phosphatase levels rise, particularly if the cancer spreads to the bone. One-half to three-fourths of persons who have metastasized prostate cancer have high acid phosphatase levels. Levels fall after the tumor is removed or reduced through treatment.

Tissues other than prostate have small amounts of acid phosphatase, including bone, liver, spleen, kidney, and red blood cells and platelets. Damage to these tissues causes a moderate increase in acid phosphatase levels.

Acid phosphatase is very concentrated in semen. Rape investigations will often include testing for the presence of acid phosphatase in vaginal fluid.

Laboratory testing measures the amount of acid phosphatase in a person's blood, and can determine from what tissue the enzyme is coming. For example, it is important to know if the increased acid phosphatase is from the prostate or red blood cells. Acid phosphatase from the prostate, called prostatic acid phosphatase (PAP), is the most medically significant type of acid phosphatase.

Subtle differences between prostatic acid phosphatase and acid phosphatases from other tissues cause them to react differently in the laboratory when mixed with certain chemicals. Laboratory test methods based on these differences reveal how much of a person's total acid phosphatase is derived from the prostate.

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