Introduction

The primary reason for the utilization of any screening exam should be that the procedure detects the early stages of a pathologic condition and allows for early intervention, thereby preventing unnecessary morbidity or mortality before any clinical signs or symptoms of the disease. For the detection of prostate cancer, an elevated serum prostate-specific antigen is the most common initial laboratory abnormality, as the vast majority of men with early prostate cancer have no symptoms.

Prostate-specific antigen, otherwise known as PSA, is a very sensitive but relatively non-specific and imprecise screening tool as both benign and malignant processes will elevate the serum marker.[1] It has also become very controversial, with varying guidelines and recommendations on how it should be used and for which age groups. Despite the risks of serum PSA screening and the potential for some "unnecessary" biopsies as well as overdiagnosis, it remains the single most useful tool available for the early detection of prostate cancer, giving affected individuals the best chance for a cure.

While the use of PSA for prostate cancer screening is somewhat controversial, there is no question regarding its usefulness in helping determine the extent of the malignancy, tracking its progress, identifying biochemical recurrences, and determining treatment response.

Etiology and Epidemiology

Cancer of the prostate is the second most diagnosed solid cancer in adult males, surpassed only by non-melanoma skin cancer. It is the second leading cause of male cancer death worldwide.[2] In the United States alone, 10 billion dollars is spent annually treating prostate cancer.[3] This figure has been increasing over the past 20 years, proportionately to the increase in prostate cancer diagnosis, likely due to the aging population and improved detection utilizing serum prostate-specific antigen (PSA).[4]

Data from the NIH indicates a 44% drop in prostate cancer-specific mortality since PSA testing became widely available in the early 1990s. The Surveillance, Epidemiology, and End Result Program (SEER) Cancer Statistics Review 1975 to 2017 from the National Cancer Institute indicates that prostate cancer mortality rates in the US decreased from 39/100,000 male individuals to 19/100,000 from 1992 to 2017, a 51% decrease. According to simulation models, a large portion of this decrease, 45% to 70%, is thought to be due to PSA testing, as screening significantly decreased the incidence of metastatic disease.[5]  

A large 2018 Kaiser Permanente study of over 400,000 patients found that yearly screening in the optimal age range of 55 to 75 years reduced prostate cancer-specific mortality by 64% (95% confidence interval 50-78%, P <.001) and overall mortality by 24% (95% confidence interval 15%-34%, P <.001).[6]

Since prostate cancer is slow growing, it typically takes at least ten years for a typical localized cancer to cause significant symptoms. At age 75, the Social Security Administration Actuarial Tables indicate that the average US male will live slightly over 11 years. Therefore, after age 75, the vast majority of men would not receive any benefit from identifying or treating their localized prostate cancers.

General Recommendations for PSA Testing

Comparisons of screened and unscreened populations have repeatedly shown a 50% cancer-specific mortality decrease when PSA testing is widely used over time.[7] This is why, despite the controversies regarding overdiagnosis and overtreatment, the overwhelming majority of professional healthcare organizations, associations, and societies recommend PSA screening for prostate cancer. An in-depth review of the various guidelines on PSA testing from various groups (The American Academy of Family Physicians, The American Cancer Society, The American Urological Society, The Canadian Task Force on Preventive Healthcare, The European Association of Urology, and The US Preventive Services Task Force, among others) can be found in our companion StatPearls reference article on "Prostate Cancer Screening."[8]

Care should be taken to consider the patient's personal opinions and desires as well as their overall health, family history, and comorbidities. They should be fully informed of the risks and benefits of prostate cancer screening. Clinicians should endeavor to avoid the overtreatment of low-grade, low-stage prostate cancers, which can be accomplished by following the American Urological Association and the National Comprehensive Cancer Network (NCCN) Guidelines on treating localized prostate cancer.[7]

• PSA testing should only be done after a detailed, comprehensive explanation of the risks and benefits of prostate cancer screenings.
• A single baseline PSA level is suggested for all men aged 40 to 45.
• Yearly testing is reasonable in higher-risk men starting at age 45.
• A change of >0.75 ng/mL per year or >25% is considered suspicious.
• At least two separate elevated PSA tests are needed to confirm the increase.
• Routine screening should be stopped in men with ten years or less of life expectancy (based on comorbidities) or by age 75.
• Men who fall outside of guidelines but are fully informed and are requesting testing should have a PSA level performed.
• Patients who would not benefit from testing or refuse treatment if cancer were found should probably not be screened.
• High-risk individuals would include those men with the following:
  • African descent
  • Lynch Syndrome
  • Family history of prostate cancer (especially if a first-degree relative and cancer were found <age 65)
  • Family history of multiple malignancies.
  • PSA density of 0.15 or more
  • Positive germline testing for BRCA1, BRCA2 

Pathophysiology

Prostate-specific antigen is a serine protease enzyme produced by the columnar epithelium of prostatic tissue. The proenzymatic intracellular form of PSA is pro-PSA.

Following cellular production, pro-PSA passes through the basal and endothelial cell layers before entering the prostatic ducts, where it is converted to active PSA, finally penetrating the capillary membranes to enter the systemic circulation.[9] A small portion of this active PSA then undergoes proteolysis, becoming inactive or "free" PSA when it enters the bloodstream and remains unbound. Active PSA that reaches the bloodstream rapidly becomes bound to circulating protease inhibitors.[10] The age-adjusted percent free to protein-bound PSA ratio is a useful indicator of cancer as the free PSA/total PSA ratio tends to decrease in malignancy. (See Free and Total PSA under "Results" below.)

PSA decreases seminal viscosity by chemically breaking down the proteins (semenogelin and fibronectin) responsible for the initial gel-like consistency of normal semen. This decreased viscosity allows for easier sperm migration into the cervix and promotes overall fertility.[11]

As men age, spermatozoa production is altered, with a resultant adverse effect on sperm count and quality, which impairs reproductive function.[12] 

PSA levels also increase with age. This increase is thought to be an evolutionary adaptation that confers genetic fitness and promotes fertility over other competing males. This may partly explain the increasing prevalence of conditions such as benign prostatic hyperplasia in the general population and the need for age-specific normal ranges for serum PSA levels. (See below.)

Prostate cancer cells do not produce more PSA than benign cells; in fact, they tend to manufacture less. However, malignant cells will more easily allow PSA to pass through the cell wall into the surrounding extracellular fluid and eventually reach the bloodstream. This is because malignant prostate cells lack a basal layer that would otherwise restrict the passage of PSA outside the cell. Very high Gleason score cancer cells that are highly undifferentiated may not produce a significant amount of PSA. 

Specimen Requirements and Procedure

Serum prostate-specific antigen is still a somewhat controversial screening exam for healthy, asymptomatic males, as elevated serum PSA is found in a litany of benign prostatic conditions. Infection, trauma, inflammation, and benign prostatic hyperplasia (BPH) can elevate serum PSA levels, which reduces the specificity of the biomarker for use in predicting prostate cancer. Research has demonstrated that up to 86% of individuals with BPH may have an elevated serum PSA.[13] 

The decision to screen an asymptomatic male utilizing serum PSA should involve shared decision-making. This is simply a discussion regarding the risks and benefits, such as a falsely elevated PSA value that may lead to an unnecessary biopsy of a benign condition or the discovery of indolent prostate cancer that can lead to the treatment of a condition that would have remained totally asymptomatic and clinically inactive.

The United States Preventative Task Force recommends selectively offering serum PSA screening on an individual basis according to professional judgment and patient preference in males between the ages of 55 and 69 (grade C).[14] The patient's general health is an important factor in the decision to screen, as guidelines recommend against screening individuals with a life expectancy of fewer than ten years. Current guidelines recommend against routine prostate cancer screening with serum PSA in healthy asymptomatic individuals over 70 to 75 years old.

Many professional associations and societies have developed their own guidelines. These are well summarized in our companion StatPearls reference article on "Prostate Cancer Screening."[8] In general, it is recommended that annual PSA screenings for prostate cancer be started by age 45 in high-risk individuals (patients of African descent or ethnicity, a family history of either prostate cancer or multiple cancers, Lynch syndrome, or known high-risk germline mutations such as BRCA 2) and no later than age 50 for men at average risk after a full discussion of the pros and cons of such testing. The testing should be continued until age 70 to 75.[8]

Due to the very high variability of PSA testing results, two separate specimens are recommended before conducting further investigations in patients with abnormal PSA elevations. Some physicians will give patients two to six weeks of antibiotics before repeating the PSA level if the initial test is elevated. This is intended to reduce prostatic inflammation or low-grade prostatitis that might elevate the PSA level.[15][16]

Diagnostic Tests

Serum prostate-specific antigen has been demonstrated to be far superior to digital rectal examination (DRE) and transrectal prostatic ultrasonography (TRUS) for detecting early prostate cancer.[17] When employing a value greater than 4 ng/mL, serum PSA detection rates for prostate cancer approach a specificity of 91%. A digital rectal exam is far less specific, at only 59%.

Initially, the urologic and medical community heartily embraced the potential of PSA screenings to detect early prostate cancer, with the intent to avoid any disease progression and decrease mortality. But with increased utilization of PSA testing, many individuals experienced side effects and "unnecessary" procedures because their PSA values were elevated secondary to benign conditions.[18] The risk of overdiagnosis and particularly overtreatment, can be minimized by a careful review and discussion of the viable options, benefits, and risks at each stage of the diagnostic process.

Overall, PSA sensitivity varies between 9% to 33% depending on age and the PSA cut-off values used. This suggests that up to 91% of individuals with elevated serum PSA levels do not have prostate cancer.[19] In clinical practice, the actual risk of prostate cancer in men with an elevated PSA is roughly 30%.

Most malignancies found due to elevated PSA levels are low-risk prostate cancers that are often managed by monitoring with active surveillance. Only about 25% of men managed by active surveillance will experience a progression of their cancer that requires definitive therapy.

Magnetic resonance imaging (MRI) can also be used to detect prostate cancer. However, it is costly and time-consuming, and other non-invasive options should be exhausted before its use, as even T-1 and T-2 weighted imaging lack sufficient specificity or sensitivity to justify utilization as a screening tool. It will also miss about 25% of clinically significant malignancies. MRI prostate scans have been useful in identifying suspicious nodules when a decision has already been made to consider a biopsy.[19]

Prostate-specific risk stratification bioassays are designed to determine which patients with elevated PSA levels can safely avoid biopsies. These tests use either genomics or specific biochemical markers in the serum or urine to identify those individuals with elevated PSA levels with a low likelihood of clinically significant (Gleason grade 4) cancer. All of the currently available commercial products in the US (like the Prostate Health Index (PHI), 4K Score, PCA3, SelectMDx, and EPI Exosome testing) have at least a 90% negative predictive value indicating that there is less than a 10% chance of finding significant cancer if the test is negative. Between 25% and 30% of all patients having one of these prostatic bioassays will ultimately test negative and can safely avoid a biopsy.

MRI and prostatic bioassay risk stratification testing are used in selected, borderline, or questionable cases to avoid unnecessary, low-yield biopsies. Because of their cost and complexity, these tests are not appropriate for general screening.

Overdiagnosis, Overtreatment, and "Unnecessary" Biopsies

Overdiagnosis and overtreatment have been touted as reasons to discontinue PSA testing for prostate cancer.[20]

Overdiagnosis is defined by the "Institute for Quality and Efficiency in Healthcare" as the diagnosis of a medical condition, disease, or disorder that would never have caused the patient an earlier death or any symptoms or clinical problems. Overdiagnosis is considered harmful if it leads to unnecessary treatments or causes the patient undue psychological stress or anxiety. It is not a misdiagnosis or a "false alarm," and it is an inevitable part of all screening tests to some degree.[20][21] 

The only way to eliminate overdiagnosis is to avoid all screening tests, as it is not possible to accurately predict the course or outcome of every disease discovered through screening nor foresee all other related and unrelated medical events that might occur to the patient in the future. The harmful effects of overdiagnosis can be minimized by carefully explaining, before PSA screening, that most men with an elevated PSA don't have cancer and that the vast majority of prostate cancers discovered by PSA testing never need treatment or cause the patient any harm. Screening tests like PSA are never urgent, so there is plenty of time for patients to review the available information on screening and carefully consider their options.[20][22]

For many patients, the choice boils down to one of the following:

• Conduct regular screening tests even if that risks possible overdiagnosis of indolent cancers that might result in procedures or treatments that can cause psychological or physical harm.
• Avoiding screening tests will eliminate overdiagnosis and potentially uncomfortable treatments. However, it also means that a potentially serious cancer would only be discovered at a later stage when curative treatment is no longer effective or available.

Overtreatment of indolent prostatic cancers can cause significant physical harm, dramatically decrease quality of life, and may ultimately not provide any survival benefit to the patient.[20] The introduction of active surveillance protocols for low-risk-low-stage prostate cancer effectively eliminated overtreatment for 70% to 75% of such patients who previously would have received full definitive therapy. To be considered for definitive treatment, active surveillance patients would need evidence of disease progression while being monitored and meet eligibility criteria regarding life expectancy, age, and comorbidities. If fully implemented, such a plan would effectively eliminate most cases of prostate cancer overtreatment.[20]

"Unnecessary" biopsies can be minimized by the optimal use of pre-biopsy tools and procedures. Prostate biopsies can be uncomfortable and lead to prolonged bleeding and infections, but they are also the only way to definitively diagnose prostate cancer which is a potentially lethal but curable disease if caught early. Using age-adjusted PSA normal ranges and limiting PSA screenings only to those likely to benefit from treatment will help. The increasing use of MRI scans and risk stratification bioassays can eliminate 25% to 30% or more of low-yield biopsies by better identifying patients unlikely to have clinically significant (Gleason grade 4) disease.

It has been suggested that there is no such thing as an "unnecessary" biopsy, as all biopsies are done to establish a definitive diagnosis which is what a prostate biopsy accomplishes. It is disingenuous to suggest that any biopsy is "unnecessary" just because the result is negative; otherwise, all biopsies with negative results could also be considered "unnecessary." The negative effects of overdiagnosis can be substantially mitigated by carefully avoiding the treatment of indolent cancers. This can be accomplished by following the established guidelines and recommendations related to low-grade, low-stage prostate cancers, optimally utilizing MRI scans and risk stratification bioassays, fully implementing active surveillance protocols where appropriate, and avoiding screenings in patients who would not benefit from them, such as those who would refuse biopsies and treatment, individuals with a life expectancy of fewer than ten years, and asymptomatic patients over the age of 75.

Testing Procedures

With the increased utilization of prostate-specific antigen as a screening for prostate cancer, and its subsequent overdiagnosis and overtreatment, several national societies have modified their guidelines regarding the use of serum PSA screening. This modification has led to an effort to differentiate between clinically significant prostate cancer versus indolent disease.[23] 

Total serum PSA exists in three isoforms of equal concentration: intact and free PSA, pro-PSA, and BPH-associated PSA (BPSA). All three isoforms have been studied as potential biomarkers for differentiating the causes of PSA elevation.

BPSA is generally limited to transitional zone tissue, and this biomarker would, therefore, be expressed by hyperplastic prostatic tissue. A proportional increase in its presence is directly related to prostate volume and suggests BPH.[24]

Several studies have demonstrated the benefit of utilizing pro-PSA, alone or preferably in combination, as a biomarker for more aggressive prostate cancer, as pro-PSA is associated with increasing Gleason scores.[25] Incorporating pro-PSA into a bioassay risk analysis profile has shown promise in predicting prostate cancer in individuals with mildly elevated PSA values.[26][27]

Interfering Factors

Screening with PSA has led to earlier detection of prostate cancer; however, morbidity increases for all patients with an elevated lab value, as a majority of the patients have a benign condition as the etiology of the elevated serum PSA. When evaluating the elevated serum values due to prostate cancer, most prostate cancers are indolent and never progress to a point in which intervention is required. As few as 2% of all elevated serum PSA values above 3 ng/mL will ever require further intervention because of an aggressive form of prostate cancer.[19] There is no level of prostate-specific antigen that reliably guarantees that prostate cancer is present or absent.

It is well known that 5-alpha reductase inhibitors (5-ARIs) will reduce PSA levels by 50%, but this effect typically takes between six and twelve months. PSA levels in men on long-term 5-ARI medications should be doubled for screening purposes. Conversely, patients should be screened for prostate cancer prior to being started on 5-ARI medications specifically because of this delayed PSA reduction effect and how long it takes to become fully expressed. There is no significant change in prostate cancer incidence or progression in men on 5-ARI medications compared to similar male cohorts without the drugs.[28] 

Besides 5-alpha reductase inhibitors, statins, NSAIDs, acetaminophen, and thiazide have all been shown to lower PSA levels.[29][30][31][32]

Obese men with high BMI will have larger intravascular volumes, so they tend to have lower PSA values solely due to this dilutional effect. It remains unclear if the normal PSA range should be adjusted for this effect.[33] 

Technical errors and inaccurate measurements of prostatic volume can lead to erroneous PSA density determinations. The use of different laboratory tests for PSA can cause some variation in the results. Prostatitis, a digital rectal examination, hard bowel movement, urologic instrumentation, and recent ejaculation can all increase PSA levels.

Results, Reporting, and Critical Findings

There is a direct relationship between an increased serum PSA level and the likelihood of a prostate cancer diagnosis. However, it isn't always clear at which point further evaluation is warranted.[13] A prostate-specific antigen [PSA] value of greater than or equal to 4.0 ng/mL is the consensus standard for further prostate cancer evaluation. This value has been shown to maximize specificity at the expense of sensitivity for prostate cancer detection. Although prostate cancer has been routinely found in individuals with PSA values above 4.0 ng/mL, this value requires some individuals with prostate cancer to be missed so that fewer individuals are subjected to unnecessary biopsies.[34][35] It is a trade-off. A lower cutoff would find more cancers but requires more testing and biopsies. A higher cutoff would delay the detection of some potentially dangerous cancers. 

No PSA value can guarantee the detection of prostate cancer. Values as low as 1.1 ng/mL routinely overlook up to 17 percent of prostate cancers.[36] Utilizing the same laboratory value [1.1 ng/mL] in Black males, fifty percent of cases in men aged 50 to 59 years, and 75 percent of cases in ages 70 to 79 years, would demonstrate laboratory values that would necessitate further workup and subject untold individuals to unnecessary and uncomfortable biopsies.[37] By comparison, increasing the PSA cutoff value to 10 ng/mL would reduce unnecessary medical evaluations for most indolent causes, but it is estimated that half of all cancers detected by PSA would no longer be organ-confined or localized, thereby negating any potential benefit of early detection.[38]

The single general consensus standard normal upper limit for PSA is considered to be no more than 4 ng/mL. (PSA is measured either in ng/mL or mcg/L. These units are equivalent, so 1 ng/mL = 1 mcg/L.)

Age-Adjusted PSA

Using 4 ng/mL as the single upper normal limit for serum PSA does not adequately account for the natural increase in serum prostate-specific antigen that is expected to occur with age. There is a direct correlation between age and serum PSA concentration, with an expected  3.2% increase per year demonstrated in healthy 60-year-old males.[39] Therefore, when analyzing serum PSA values, it is recommended to use the age-adjusted ranges.[40]

The 95th percentile PSA value is commonly used for the age-adjusted normal reference ranges, which are as follows:

• Males 40-49 years: no more than 2.5 ng/mL
• Males 50-59 years: no more than 3.5 ng/mL
• Males 60-69 years: no more than 4.5 ng/mL
• Males 70-79 years: no more than 6.5 ng/mL[39]

Free and Total PSA: Free PSA is a subset of intact PSA. A decrease in the ratio of this serum biomarker [free PSA/total PSA] may be utilized to improve the sensitivity of prostate cancer detection when initial total PSA values are between 4 ng/mL to 10 ng/mL.[41][42] Some studies have included pro-PSA in their intact PSA assay, which is an improvement over the predictive value of intact PSA alone.[43]

When the total PSA is between 4 and 10 ng/mL, free % PSA can be used.[8][39]

• The higher the free % PSA, the lower the risk of cancer.
• The actual cancer risk varies according to age.
• If the free % PSA is <10%, the cancer risk is 50%.
• If the free % PSA is >25%, the cancer risk is <10%.

PSA Density: The volume of the prostate in cubic centimeters can be calculated by the formula: (width cm x height cm x length cm) x 0.52. These values are measured by either an MRI or prostatic ultrasound. When the volume of the prostate is known, a PSA density calculation can be done by dividing the total PSA in ng/mL by the prostate volume in cc's. A PSA density of 0.15 or more is considered suspicious for cancer.[44]

PSA Velocity: A slow increase in PSA level is expected over time, but a more rapid rise could indicate malignancy. Generally, a yearly increase in PSA of no more than 0.75 ng/mL higher per year and no more than 25% is considered acceptable. Greater increases are considered suspicious.[45] Calculating the PSA velocity requires three separate PSA determinations over at least 18 months.

PSA  Doubling Time: Aggressive, rapidly growing prostate cancers are more dangerous than slow-growing malignancies. This can be estimated by the PSA doubling time in patients with known prostate cancer. A PSA doubling time of 2 years or longer is generally considered reasonably acceptable. As the PSA doubling time becomes shorter, the 5-year prostate cancer mortality rate increases. A PSA doubling time longer than 12 months is associated with a 5-year prostate cancer-specific death rate of 10% compared to those with a doubling time of 1 year or less who have a 50% mortality.[46] If the PSA doubling time is <3 months, the prostate cancer mortality rate is 20 times greater.[47] A higher Gleason score tends to lower the survival rate as well.

Prostate Biopsies

The decision to perform a biopsy should include at least two elevated PSA values and take into consideration the patient's age, comorbidities, medical history, family history, high-risk factors, physical examination, urinary symptoms, reasonable life expectancy, and personal preference after a thorough review of the risks and benefits. It should also include the results of an MRI or prostate cancer bio-assay examination, if available.

Performing a prostate biopsy can be a complicated decision. In general, biopsies should not be recommended in patients where there is an unacceptable risk (i.e., unable to stop anticoagulant therapy safely), where treatment would not be accepted even if a dangerous cancer were found, or where the life expectancy due to age or comorbidities is well below the minimum ten years necessary to see a significant benefit from treatment. Patients should be fully informed of the risks and benefits of the biopsy as well as given sufficient time to decide on their choice. 

An in-depth review of the pros and cons of prostate cancer screening and the role of prostate MRIs, prostatic cancer risk stratification bioassays, and PSA testing can be found in our companion StatPearls reference article on "Prostate Cancer Screening."[8]

PSA Use in Active Surveillance of Prostate Cancer

Active surveillance for prostate cancer is based on the finding that low-grade, low-stage prostate cancer is relatively indolent, causing most patients no clinical harm. Low-risk (Gleason 3+3=6) and selected low intermediate-risk (Gleason 3=4+7) patients are generally considered candidates for active surveillance. Most of these patients (about 25%) will not show any disease progression and can safely avoid the side effects and complications of definitive cancer therapy. A repeat biopsy 6 to 18 months after the initial diagnosis remains the standard of care for patients on active surveillance. This is due to the high reported rate of pathological reclassification of up to 35% after the second confirmatory biopsy.[48][49][50] 

Prostate MRIs are recommended prior to the rebiopsy to optimize the results and to track the progress of any identifiable lesions.[51][52][53][54] It is suggested that an MRI and a repeat biopsy be performed on higher-risk patients on active surveillance. (Higher risk would include those with African ancestry, high PSA density (0.15 or more), a family history of prostate cancer, or positive for high-risk genomic biomarkers.

Recommended PSA monitoring for patients on active surveillance is generally every six months. A significant change would generally be considered a PSA level >0.75 ng/mL or >25% a year, a PSA doubling time of <3 years, or a total PSA >10 ng/mL. A notable change in the MRI PIRADS score (from PIRADS 3 to PIRADS 4 or 5) or marked enlargement of a known cancer nodule would also be considered significant and prompt a rebiopsy.

In men with stable PSA levels and digital rectal examinations, follow-up prostate biopsies after the initial "confirmatory" rebiopsy should generally be considered every 2 to 4 years, and MRI scans should be repeated every 1 to 2 years, depending on risk factors and comorbidities. MRI alone is not reliable enough to completely supplant prostate biopsies.[55][56][57][58] 

The suggested protocol was compared to an alternate regimen where, after the initial "confirmatory" biopsy, repeat biopsies were performed only when significant changes in the MRI scan or PSA level were detected. This regimen eliminated many prostate biopsies compared to a scheduled protocol but missed too many clinically significant cancers.[59]

The use of finasteride or dutasteride (5-alpha-reductase inhibitors) and enzalutamide (an androgen receptor inhibitor) have not been shown to significantly affect slowing PSA level increases or cancer progression in patients on active surveillance.[60][61]  

PSA After Definitive Prostate Cancer Therapy

Overall, a recurrence rate after definitive therapy (either radical surgery or radiation) is expected in 25% to 40% of patients who undergo definitive curative treatment.[62][63]

Following a radical prostatectomy, all prostatic tissue should have been removed. Therefore, any detectable PSA following the surgery indicates some remaining prostatic tissue, usually presumed to be cancerous.[64] This may be localized or represent metastatic disease. In general, if the PSA is undetectable for two years or longer and then starts to rise gradually, a locally recurrent cancer in the prostatic bed is likely.[65][66] If the PSA rises quickly and never becomes undetectable after surgery, metastatic disease is more likely.[65][67] 

Slowly rising PSA levels are sometimes caused by a small amount of residual prostate tissue left behind after surgery. This can occur in 5% to 15% of all radical prostatectomy patients and does not necessarily indicate residual cancer. Adjunctive therapy should be considered if the PSA level reaches 0.4 ng/mL or more.

The American Urological Association (AUA) guidelines on localized prostate cancer define a post-radical prostatectomy biochemical recurrence as two consecutive serum PSA levels >0.2 ng/mL.[68]

After definitive radiation therapy, PSA levels tend to fall relatively slowly. It may take 18 months for these levels to reach a nadir.[69] The lower the final nadir achieved, the better the cancer-specific prognosis.[62][70] 

A biochemical recurrence after definitive radiation therapy is defined as 2 PSA levels>2 ng/mL above the nadir level.[71] The need for two levels is due to the phenomenon known as the "PSA bounce." This will typically occur at 12 to 18 months after initial radiation therapy.[72] There is no way to determine if this represents a true recurrence except by following the PSA levels and finding the PSA increase to be only transient. The clinical significance of the "PSA bounce" remains unclear.[72]

In a large retrospective study of 2694 men, all treated with external beam radiation therapy for localized prostate cancer, those who demonstrated a biochemical recurrence developed metastases at a median of 5.4 years.[73] Prostate cancer-specific mortality was 10.5 years. Negative prognostic factors included a higher initial Gleason score, a more advanced initial cancer staging, a shorter time interval from initial treatment to biochemical failure, and a faster PSA doubling time.[73]

European Urological Association Risk Stratification for Progression After Biochemical PSA Recurrence

Biochemical recurrence after definitive therapy for localized prostate cancer is a significant, independent risk factor for metastatic disease, cancer-specific mortality, and overall mortality. The European Urological Association has suggested the following high and low-risk stratification categories for both post-radical prostatectomy surgery and radiation therapy patients.[74]

• Low-risk
  • After radical prostatectomy: PSA doubling time >12 months and Gleason score <8
  • After radiation therapy: Interval to biochemical failure >18 months and Gleason score <8
• High-risk
  • After radical prostatectomy: PSA doubling time <12 months and Gleason score >7
  • After radiation therapy: Interval to biochemical failure and Gleason score >7

PET Scans For Post-Prostatectomy Biochemical PSA Recurrence 

When the PSA level is >0.2 ng/mL, prostatic PET scanning can be performed. This will help differentiate localized recurrences in the prostatic bed after radical prostatectomies that might benefit from pelvic irradiation from those with disseminated disease where systemic treatment is preferred. Some experts recommend PET scans for all post-radical prostatectomy patients with a biochemical recurrence and suitable PSA levels, while others recommend a more selective approach using a risk stratification model.  

Clinical Significance

Early prostate cancer is generally asymptomatic, and an elevated serum PSA level is often the first indication of malignancy. Anemia and elevated alkaline phosphatase are additional laboratory values that may suggest prostate cancer but are very nonspecific and suggest advanced disease, which makes them useless for screening or early detection. A digital rectal examination (DRE) should be performed on all individuals with an abnormal PSA screening even though no specific finding reliably confirms either the presence or absence of prostate cancer. It is utilized to improve the overall sensitivity of the screening and could be an important factor in deciding on management if cancer is discovered.  

Overall, up to 14% of prostate cancer patients demonstrate metastatic disease at the time of diagnosis. The finding of metastatic prostate cancer can be correlated with elevated PSA values. Serum PSA values >20 ng/mL have a positive predictive value of 65% for metastatic disease and skeletal involvement. This number increases linearly with a positive predictive value for metastatic disease of 86% for PSA levels >100 ng/mL.[75] However, it should not be assumed that an individual with serum PSA values >100 ng/mL at the time of diagnosis has metastatic disease. By comparison, serum PSA values <10 ng/mL rarely demonstrate metastatic disease or skeletal spread. This is why bone scans in prostate cancer are not generally recommended unless the PSA level is >20 ng/mL.[76] 

Enhancing Healthcare Team Outcomes

No prostate-specific antigen value guarantees the presence or absence of prostate cancer. While controversial, nonspecific, and imperfect, PSA testing is currently still the best and most sensitive early indicator of an asymptomatic prostatic malignancy. The decision to screen healthy individuals utilizing the test will likely continue to be controversial. Individuals between the ages of 45 and 75 years should be given the opportunity to be tested following a conversation regarding the risks and benefits of screening, with particular consideration given to patient preference, age, comorbidities, and family history. Following the decision to screen, PSA values will be instrumental in determining the next steps in treatment. It is generally accepted that low PSA values in asymptomatic individuals are reassuring, and significantly elevated PSA values are concerning for prostate cancer. Some of the negative aspects of screening can be minimized by risk stratification strategies and a recognition that it is easy to recommend overtreatment of low-risk disease. All healthcare team members should be aware of the controversies involved and be prepared to assist the patient in the decision-making process.

There is no controversy regarding the utility of PSA testing in patients with known malignant disease. The entire team should encourage patients to be involved in their healthcare decisions and to obtain follow-up PSA tests according to physician recommendations and published guidelines; this will ensure optimal outcomes. [Level 5]