Diseases

Once prostate cancer is diagnosed by the presence of cancer cells on prostate biopsy and assigned a cancer grade (Gleason score), PSA is used in combination with the grade of the prostate cancer to determine further medical studies needed for cancer staging. Staging (otherwise viewed as the extent of spread of the cancer within the body, or "Where in the body are the cancer cells?") determines if the cancer is localized (confined to the organ) or metastatic (has spread to other parts of the body). Staging therefore drives the best management and appropriate treatment for the cancer. As mentioned earlier, serum PSA levels correlate with the risk of prostate cancer extension outside of the prostate including seminal vesicle invasion as well as metastasis to the pelvic lymph nodes.The proportion of men with cancer confined to the prostate is about 80% when the PSA level at diagnosis is less than 4.0 ng/mL; about 70% when the PSA level is between 4.0 and 10.0 ng/mL; and about 50% when the PSA level is greater than 10.0 ng/mL. This is why patients with serum PSA levels of less than 10.0 ng/mL are most likely to respond well to local therapy such as prostatectomy (surgical removal of the prostate) or external beam radiation (radiation therapy). The need for additional medical tests such as a bone scan and CT scan to assess the extent of the prostate cancer will depend on the prostate biopsy results and PSA. Bone scans, used to determine if the prostate cancer has spread to the bones, are recommended if there is high grade prostate cancer present, extensive disease on the biopsy, and PSA > 10-20 ng/mL. CT scan is used to assess for pelvic lymph node enlargement suggestive of prostate cancer metastases to the lymph nodes and is recommended for individuals with high grade prostate cancer and PSA > 10 ng/mL. Over the past few decades, several predictive tools (otherwise called nomograms) have included the PSA in their parameters to predict posttreatment outcomes. These nomograms include the Partin and Kattan nomograms from Memorial Sloan Kettering. For instance, the Kattan nomogram is an online predictive tool that is available to the public (https://www.mskcc.org/nomograms/prostate).

A periodic PSA determination is used to detect disease recurrence after treatment. Serum PSA should decrease and remain at undetectable levels after a radical prostatectomy (complete removal of the prostate and seminal vesicles). An increase in the PSA over time after radical prostatectomy is suggestive of recurrent prostate cancer. Similarly, failure of the PSA to decrease to an undetectable level after radical prostatectomy may indicate residual prostate cancer. Similarly, serum PSA should fall to a low level (nadir) following radiation therapy, high intensity focused ultrasound, and cryotherapy and remain at or near this level over time.

Clinically localized prostate cancer (prostate cancer confirmed to the prostate gland) generally does not usually cause any symptoms. In general, most men with organ-confined (early, localized) prostate cancers have PSA values that are typically less than 20 ng/mL. Once PSA values are greater than 20 ng/mL, the risk for metastatic (distant spread) disease increases significantly. Men with early prostate cancer usually feel perfectly well and have no urinary symptoms related to the prostate cancer. Although prostate cancer is diagnosed by the presence of prostate cancer cells in a prostate biopsy specimen, elevated PSA remains the most common indication for prostate biopsy. An abnormal prostate on digital rectal examination is also an indication for prostate biopsy, and thus prostate cancer screening should not be solely PSA-based.It is the hope that the ability to identify changes like increases in PSA or abnormalities on rectal examination will allow for early detection of prostate cancer and allow for close monitoring (active surveillance) or definitive treatment to prevent the development of metastatic disease and prostate cancer-related deaths. However, given the sensitivity of PSA testing, the trade-off of evaluating those individuals with an elevated PSA is the possibility of an unnecessary prostate biopsy and associated risks (infection, blood in the urine/ejaculate) and anxiety. In addition, current prostate cancer screening is limited by its ability to identify individuals with high-risk prostate cancer, prior to prostate biopsy.Limitations with PSA testing have led to a search for alternative biomarkers. More recently, other novel biomarkers and tests (PCA3, 4K, PHI, as well as prostate MRI imaging) have emerged as additional adjuncts to patient counseling. Unfortunately, none can confirm the presence of prostate cancer. Nor can these tests, including PSA, allow one to predict prior to biopsy if an individual has an aggressive form of prostate cancer.Although not perfectly specific as a biomarker, the level of PSA has been demonstrated to be an independent variable to predict the presence of prostate cancer. In fact, the higher the level, the more likely prostate cancer is present. An abnormality in results will usually require additional testing. However, definitive diagnosis of prostate cancer depends on the presence of cancer cells obtained either from prostate biopsy or surgical specimens.In general, PSA levels greater than 4 ng/mL are usually considered suspicious. As levels increase above 10.0 ng/mL, the probability of cancer increases dramatically. However, not all men with prostate cancer have elevated PSA levels. It is known that a small but significant number of people with prostate cancer can present with a PSA level of less than 4.0 ng/mL. This is why health care professionals may use lower thresholds to decide when to do a biopsy, depending on the presence of risk factors (for example, family history of prostate cancer, ethnicity) and other factors such as PSA density and PSA velocity.For an average man over the age of 50 with a normal digital rectal exam, the average probability of having prostate cancer detectable by prostate biopsy according to his PSA level is as follows:Probability of Prostate Cancer Detectable by Biopsy According to PSA LevelPSA Level (ng/mL)0 to 2.02.0 to 4.04.0 to 10.0greater than 10.0Prostate Cancer on Biopsy (%)10%25%17% to 32%43% to 65%Since the likelihood of having prostate cancer increases proportionately with PSA level, there is no threshold below which a man can be reassured that prostate cancer is not present.In order to improve the specificity of the PSA test in the early detection of prostate cancer, several modifications of the serum PSA value have been described including the ratio of free/total PSA and the measurement of PSA change over time.

PSA is measured by a simple blood test that does not require fasting or special preparation. Since the amount of PSA in the blood is very low, detection of it requires a very sensitive type of technology (monoclonal antibody technique). The PSA protein can exist in the blood by itself (known as free PSA) or be bound with other substances (known as bound or complexed PSA). PSA is mostly bound to three substances: alpha-2-macroglobulin, alpha 1-antichymotrypsin (ACT), and albumin. Total PSA is the sum of the free and the bound forms. The total PSA is what is measured with the standard PSA test. More recently, a precursor of PSA, proenzyme PSA ([-2] proenzyme PSA), has been identified, which may be helpful in determining prostate cancer risk in men with a PSA under 10 and a normal digital rectal examination. The prostate health index (PHI) is a new approved test that measures the total PSA, free PSA, and [-2] proenzyme PSA. The National Comprehensive Cancer Network guidelines include use of PHI as a secondary test option for men making decisions about an initial or repeat biopsy. The 4K score test is another test that incorporates PSA. The 4K score uses a prediction model based on clinical variables (age, prior biopsy, digital rectal examination results) and laboratory measurements of total PSA, free PSA, intact PSA, and a related protein known as hK2 (human kallikrein-related peptidase 2).

Ultimately, the decision to use PSA for the early detection of prostate cancer should be individualized. Men should be informed of the known risks and the potential benefits of early screening. Not all men are appropriate candidates for screening efforts. For instance, screening in men with less than a 10-year life expectancy, either due to age or other illness, is discouraged as there will be most likely no benefit for them.If prostate cancer is detected on prostate biopsy, all treatment options should be discussed. The benefits and risks of the many treatment options should be reviewed and discussed with men found to have prostate cancer. The AUA recommends that this discussion include active surveillance in men with low-risk prostate cancer. The goal of active surveillance is to allow men to maintain their quality of life when the disease is slow-growing or inactive but still allow them to be cured of prostate cancer when the disease appears to become more aggressive or is growing. Other novel biomarkers, such as PCA3 (see below), may assist the clinician in these decisions.

The use of age-specific PSA ranges for the detection of prostate cancer is helpful to avoid unnecessary investigations in older men with larger prostate glands. Median PSA value for men aged 40 to 49 years is 0.7 ng/mL and for men 50 to 59 years is 0.9 ng/mL. Not all studies have agreed that this is better than simply using a level of 4.0 ng/mL as the highest normal value. Nevertheless, due to the age-related growth of the prostate, the concept of adjusting the cutoff values based on age has helped reduce unnecessary prostate biopsies in older men to improve early prostate cancer detection. Below are the suggested age-adjusted values based on age and race.PSA levels chartAge-Specific Reference Ranges for Serum PSAAge Range (Years)Asian AmericansAfrican AmericansCaucasians40 to 490 to 2.0 ng/mL0 to 2.0 ng/mL0 to 2.5 ng/mL50 to 590 to 3.0 ng/mL0 to 4.0 ng/mL0 to 3.5 ng/mL60 to 690 to 4.0 ng/mL0 to 4.5 ng/mL0 to 4.5 ng/mL70 to 790 to 5.0 ng/mL0 to 5.5 ng/mL0 to 6.5 ng/mL

The "normal" PSA serum concentration remains a debate, however, for most laboratory readings, it should be less than 4.0 ng/mL. The prostate gland generally increases in size and produces more PSA with increasing age, so it is normal to have lower levels in young men and higher levels in older men. Due to these normal changes in PSA with age, the concept of age-adjusted PSA normals have been described and recommended. What is considered to be a normal PSA level also depends on ethnicity and family history of prostate cancer. Once an initial PSA has been obtained, the change in the PSA over time, the PSA velocity, plays a role in clinical decision making. It is felt that the PSA velocity over a year should be less than 0.75 ng/mL. For example, a man 50 to 59 years of age with a PSA level that is 0.5 ng/mL one year and increases to 2.5 ng/mL the following year, may be viewed as having a normal PSA level, but the rate of change in his PSA (PSA velocity) would be worrisome for an underlying prostate cancer. Lastly, as the size of the prostate gland may affect the PSA level, PSA density (PSA level divided by prostate volume) can also be a helpful number. A PSA density of 0.18 or less appears to be an optimal number.

The level of PSA is a continuous parameter; the higher the value, the higher the probability of having prostate cancer. On the other hand, men may have prostate cancer despite low levels of PSA. In a U.S. prevention study, 6.6% of the men whose PSA level was less than 0.5 ng/mL had prostate cancer. Thus, although age and ethnicity-based normal reference ranges exist, they have limitations. Furthermore, PSA does not allow one to predict the likelihood of clinically significant prostate cancer (meaning cancer that is likely to be aggressive and require treatment) being present, thus subjecting men to potentially unnecessary biopsy and treatment and the morbidity associated with these.

Medications commonly taken to treat benign enlargement of the prostate (BPH) such as finasteride (Proscar), dutasteride (Avodart), and a combination of dutasteride and tamsulosin (Jalyn) can decrease the PSA by about 50% within six to 12 months of starting their use. Another medication used to treat fungal infections, ketoconazole, can also lower PSA levels. Lastly, herbal supplements such as saw palmetto and those containing phytoestrogens, which are plant-derived chemicals with estrogen-like effects, can also lower the PSA level. It is important to tell your health care provider all the medications, both prescription and nonprescription, as well as any herbal preparations or health supplements that you are taking.

It is believed that elevation of PSA in the blood is due to its release into the circulation (bloodstream) because of a breakdown (disruption) of the prostate cellular architecture (structure). However, the reasons are not fully known. An elevated PSA level can occur in the setting of different prostate diseases/conditions including prostate cancer but also as a result of noncancerous causes. It is important to note that PSA is not specific to prostate cancer but to prostatic tissue, and therefore PSA elevations may indicate the presence of any kind of prostate disease. Common benign causes of PSA elevation include benign prostatic hyperplasia or BPH (an age-related, natural enlargement of the prostate, secondary to a noncancerous growth of prostate glandular cells), prostatitis (inflammation or infection of the prostate), and urinary tract infection. In fact, PSA elevation can also occur with prostate manipulation such as ejaculation, prostate examination (digital rectal examination), medical instrumentation (cystoscopy), urinary retention or Foley catheter placement, and prostate biopsy. It is also thought that vigorous exercise that may affect the prostate, such as bicycle riding, can increase the PSA. It is for these reasons that patients should abstain from sex one to two days prior to PSA testing. Some physicians may recommend repeating a PSA test to ensure that the elevation is not related to these noncancerous causes.

Prostate-specific antigen (PSA) is a substance produced only by certain cells within the male prostate gland. Biochemically, it belongs to the protease family of kallikrein and is also known as human kallikrein 3 (hK3). PSA is released by the prostate into the semen where it acts to liquefy the semen following ejaculation. Most of the PSA produced by the prostate gland is carried out of the body in semen, but a very small amount escapes into the bloodstream, so PSA is normally found in low amounts (nanograms per milliliter or ng/mL) in the blood. PSA has also been found in some breast tissue in women, although these amounts of PSA are very low.If the PSA level is high for your age or is steadily increasing (with or without an abnormal physical exam), further investigation, namely a prostate biopsy, may be recommended. The health care provider should consider other health risk factors of prostate cancer such as family history, prostate volume, the presence of benign prostatic hyperplasia (BPH), urinary symptoms, rectal exam findings, ethnicity, and medications that you are taking before recommending the biopsy. At this time, prostate biopsy for pathology review is the only way to determine if prostate cancer or other abnormal cells are present in the prostate.

Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE. During this examination a doctor inserts a finger into the rectum to feel the prostate for lumps, size, shape, tenderness, and hardness. A suspect DRE is an absolute indication for prostate biopsy, regardless of the PSA level. In about 18% of patients with abnormal DRE, prostate cancer will be detected regardless of the PSA level.

Although prostate cancer cells do not produce more PSA than benign prostate tissue, the PSA produced from cancerous cells appears to escape an enzymatic processing that cleaves the bond between PSA and the protein that binds to it. Therefore, men with prostate cancer have a greater fraction of complexed, or bound, serum PSA and a lower amount of unbound (free) PSA compared with men without prostate cancer. Therefore, the free/total PSA ratio (percent free PSA) can be additionally used in clinical practice to discriminate between PSA elevation secondary to benign prostatic disease and prostate cancers. This is particularly useful for patients with a total PSA level between 4.0 and 10.0 ng/mL and a negative normal rectal exam to help the health care provider to decide if a biopsy is necessary. In one study, prostate cancer was found in 56% of men with a free/total PSA less than 0.10 (10%) but in only 8% of men with free/total PSA greater than 0.25 (25%). Nevertheless, the concept of free PSA must be used with caution as several factors may influence the free/total PSA ratio such as temperature and prostate size. Furthermore, the free PSA measurement is not clinically useful for patients with total serum PSA values less than 10.0 ng/mL or in the follow-up of patients with known prostate cancer.More recently, a chemical precursor of PSA has been identified, [-2] proenzyme PSA. Preliminary studies show some promise that the level of this chemical, [-2] proenzyme PSA, may help differentiate between prostate cancer and benign enlargement of the prostate (BPH) in men with a normal rectal examination and a PSA between 2.5 and 10 ng/mL.

A newly discovered biomarker is known as PCA3 (prostate cancer antigen 3). PCA3 may help to discriminate between cancer-related versus nonspecific PSA elevations. PCA3 was initially identified by comparing prostate cancer tissue with nonmalignant normal prostatic tissue. PCA3 is a type of genetic material known as noncoding RNA that is found at high levels in prostate cancerous tissue. But unlike PSA, it is only present at a low level in benign prostatic tissue. Hence PCA3 can be considered a prostate cancer specific marker.While PSA is detected in the blood, PCA3 is measured in the urine obtained after prostatic massage. The main advantages of PCA3 over PSA testing are its higher sensitivity and specificity. In particular, PCA3 may be useful for identifying prostate cancer in men who initially had negative biopsies despite an elevated PSA. This is why the use of a PCA3 test may help reduce the number of potentially unnecessary biopsies generated by nonspecific positive PSA screening tests. PCA3 scores that are over 35 are considered higher risk and would then warrant investigation by a prostate biopsy. The 2013 AUA guidelines on early detection of prostate cancer recognize that PCA3 plays a role as a secondary screening test (after PSA screening) and can be used as an adjunct for informing decisions about the need for biopsy or repeat biopsy.

Change in PSA levels over time can be used to assess both cancer risk and aggressiveness of the particular tumor. Most urologists use these PSA metrics to help drive patient counseling and care. PSA velocity is defined as the rate (speed) of change in PSA over time. PSA doubling time is the time it takes the PSA value to increase by 100% (or double). Although these two measures do not appear to be useful in determining who is at risk for prostate cancer, they do appear to be useful in monitoring some individuals with prostate cancer.

The 4kscore test measures free and total PSA, human kallikrein 2 (hk2), and intact PSA and considers age, digital rectal examination results, and prior biopsy status. The test result reports the percent likelihood of finding high-grade prostate cancer on a prostate biopsy result. This test is not approved by the FDA, rather it is regulated as a laboratory-developed test. No cutoff threshold has been established for this test. Currently, the NCCN recommendations are that this test can be considered in patients prior to biopsy and for those with a prior negative prostate biopsy who are thought to be at higher risk for a high grade prostate cancer.

One of the limitations of the PSA test is that PSA is not specific to prostate cancer and that it can be affected by several common conditions such as benign enlargement of the prostate, inflammation, and infection of the prostate. Furthermore, there is some variability in PSA results when using different testing equipment. One study showed that 25% (one in four) men who had an initial PSA result between 4 ng/mL and 10 ng/mL had a normal test result when it was repeated.Limitations of PSA testing include a high false-positive rate (a test that incorrectly indicates that a particular condition is present). In fact, only about 25% of men who have an elevated PSA between 4 ng/mL and 10 ng/mL will have prostate cancer identified on prostate biopsy and 75% will not. If one uses a lower cutoff of 3.1 ng/mL, PSA had a sensitivity (the proportion of men who test positive for the condition among those that have the condition) of 32% and specificity (the proportion of negatives that are correctly identified as negative) of 87% for identifying prostate cancer.Another concern in addition to the low specificity in detecting the presence of prostate cancer is the inability of the test to discriminate between a more aggressive, high-risk, prostate cancer from one that is less likely to cause harm, or a low-risk prostate cancer. This is thought to lead to overtreatment in up to 50% of men with prostate cancer.

The PSA blood test is frequently covered by insurance, especially for men who are 50 years of age and older. PSA blood tests costs $20-$50. However, if it is obtained in the doctor's office during a visit to the doctor there may be an additional charge of $25-$100 for the office visit. There are PSA blood tests available for home use. The home blood test comes with a lancet to prick your finger and squeeze out a sample of blood, a kit to collect the blood, a bandage, and an address or prepaid mailer to return to the laboratory. Not all of the advertised home blood tests are approved by the U.S. Food and Drug Administration (FDA). You can access the FDA web site to make sure you are using an approved test.

The goal of measuring PSA in men with no symptoms of cancer as a screening test for prostate cancer is to reduce the mortality caused by this cancer. Although the advent of prostate cancer screening is associated with decreased prostate cancer deaths, concerns exist regarding risks of overtreatment and the associated risks of such treatments.A substantial number of the cancers detected by PSA screening are early stage and low-risk, and these patients will likely never die from this disease. PSA screening, due to its low specificity, does not allow differentiating between low-risk and high-risk prostate cancer. Hence PSA systematic screening is inevitably associated with over-diagnosis and potentially overtreatment. Therefore, not only do these patients not benefit from early detection but they also carry the burden of a cancer diagnosis. In addition, a subset of these patients may suffer the side effects of an unnecessary treatment.One large European trial (ERSPC) found that PSA screening significantly reduces the mortality (death rate) of prostate cancer but is also associated with a high risk of over-diagnosis. The cumulative incidence of prostate cancer was 8.2% in the PSA screening group and 4.8% in the control group. Patients in the screening group were 20% less likely to die from prostate cancer compared with the control group. The absolute risk difference between the two groups was 0.71 deaths per 1,000 men. This means that to prevent one death from prostate cancer, 1,410 men would need to be screened with PSA testing and 48 additional cases of prostate cancer would need to be treated.Another trial (PLCO) conducted in the United States recently concluded that there is no evidence of an improvement in death rate from prostate cancer with annual PSA screening compared with usual medical care. After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control groups were 3.7 and 3.4 deaths per 10,000 person-years, respectively, meaning that there was no significant difference between the two groups.Based on the results of the PLCO trial, the U.S. Preventive Service Task Force (USPSTF) initially advised against PSA screening in their draft recommendation issued in 2011. More recently, the USPSTF issued a draft of revised recommendations that await finalization. This draft statement reports that the decision about whether to be screened for prostate cancer should be an individualized one. That USPSTF recommended individualized decision-making about screening for prostate cancer after discussion with the physician so that each man has the opportunity to understand the potential benefits and harms of screening and to incorporate his values and preferences into his decision.Several urological associations, including the American Urological Association (AUA), Canadian Urological Association (CUA), and European Urological Association (EAU), still value the benefit of PSA screening and recommend physician-patient discussions about screening on an individual basis. The American Urological Association guidelines currently do not recommend routine prostate cancer screening in men between the ages of 40 and 54 years who are felt to be at average risk. For men less than 55 years of age at higher risk (for example, family history of prostate cancer, African-American race), decisions regarding prostate cancer screening should be individualized. The guidelines panel recommends shared decision-making for men 55-69 years of age who are considering prostate cancer screening. Furthermore, the panel notes that to reduce the harms of screening a routine screening interval of two years or more may be preferred over annual screening in those men who shared in clinical decision-making and decided on screening. Lastly, routine PSA screening was not recommended in men 70 years of age and older or any male with less than a 10- to 15-year life expectancy.The American Cancer Society recommends that asymptomatic men (with no symptoms) who have at least a 10-year life expectancy have an opportunity to make an informed decision with their health care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at 50 years of age. Men in higher risk groups should receive this information before 50 years of age.The National Comprehensive Cancer Network (NCCN) guidelines for early detection of prostate cancer noted that most panel members favored informed prostate cancer screening, in men with 10 or more year life expectancy, beginning at age 45 years of age. The panel recommended testing at one- to two-year intervals for men with a PSA of > 1.0 ng/ml and every two to four years for those with PSA