Introduction

The primary purpose of any screening exam is to detect the early stages of a pathological condition, enabling timely intervention and preventing unnecessary morbidity or mortality before clinical signs or symptoms develop. In prostate cancer screening, an elevated serum prostate-specific antigen (PSA) level is the most common initial laboratory finding, as the vast majority of men with early prostate cancer are asymptomatic. PSA is a highly sensitive but relatively nonspecific and imprecise screening tool, as both benign and malignant conditions elevate the serum marker.[1] The use of PSA screening has become controversial, with differing guidelines and recommendations regarding its application across various age groups. Despite the risks associated with serum PSA screening, including the potential for unnecessary biopsies and overdiagnosis, it remains the single most useful tool for the early detection of prostate cancer, offering patients the best chance for a cure. Although the use of PSA for prostate cancer screening is somewhat controversial, its effectiveness in determining the extent of malignancy, monitoring disease progression, identifying biochemical recurrences, and evaluating treatment response is unquestionable.

Etiology and Epidemiology

Prostate cancer is the second most commonly diagnosed solid cancer in adult males, following non-melanoma skin cancer, and is the second leading cause of male cancer-related deaths worldwide.[2] In the United States alone, approximately $10 billion is spent annually on prostate cancer treatment.[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 using serum PSA.[4] Data from the National Institutes of Health indicate a 44% reduction in prostate cancer-specific mortality as 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 United States decreased from 39/100,000 male individuals to 19/100,000 from 1992 to 2017, which is a 51% decrease. According to simulation models, a large portion of this decrease, 45% to 70%, is believed 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 annual screening in the optimal age range of 55 to 75 years reduced prostate cancer-specific mortality by 64% (95% confidence interval 50% to 78%, P<.001) and overall mortality by 24% (95% confidence interval 15% to 34%, P<.001).[6] As prostate cancer is slow-growing, it typically takes at least 10 years for a typical localized cancer to cause significant symptoms. According to the Social Security Administration Actuarial Tables, the average 75-year-old male in the United States has a life expectancy of just over 11 years. Therefore, after 75, the vast majority of men do not receive any benefit from identifying or treating their localized prostate cancers.

General Recommendations for Prostate-Specific Antigen Testing

Comparisons between screened and unscreened populations have repeatedly shown a 50% cancer-specific mortality decrease when PSA testing is widely used over time. Despite the controversies regarding overdiagnosis and overtreatment, most professional healthcare organizations, associations, and societies recommend PSA screening for prostate cancer. Groups such as 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 United States Preventive Services Task Force provide recommendations on who should be screened, at what age, and how frequently. Please see StatPearls' companion references, "Prostate Cancer Screening" and "Prostate Cancer," for more information.

Care should be taken to consider the patient's personal preferences, overall health, family history, and comorbidities. Patients 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. Please see StatPearls' companion reference, "Prostate Cancer," for more information.

• PSA testing should be performed only after a comprehensive discussion of the risks and benefits of prostate cancer screenings.
• A single baseline PSA level is suggested for all men aged 40 to 45.
• Annual testing is reasonable in higher-risk men starting at 45.
• A change of >0.75 ng/mL per year or >25% is considered suspicious.
• At least 2 separate elevated PSA tests are required to confirm the increase.
• Routine screening should be discontinued in men with a life expectancy of 10 years or less based on comorbidities or by the age of 75.
• Men who fall outside of guidelines but are fully informed and are requesting testing should have a PSA level performed.
• PSA screening is not recommended for men who do not benefit from testing or refuse treatment if cancer is detected.
• High-risk individuals include those men with the following:
  • African descent
  • Lynch syndrome
  • Family history of prostate cancer, especially if a first-degree relative was diagnosed before 65
  • Family history of multiple malignancies
  • PSA density of 0.15 or higher
  • Positive germline testing for BRCA1 and BRCA2

Pathophysiology

PSA 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.[7] A small portion of this active PSA 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.[8] 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. Please refer to "Free and Total PSA" in the Results section for more information.

PSA decreases seminal viscosity by chemically breaking down the proteins semenogelin and fibronectin, which are responsible for the initial gel-like consistency of normal semen. This reduced viscosity allows for easier sperm migration into the cervix and promotes overall fertility.[9] As men age, spermatozoa production is altered, with a resultant adverse effect on sperm count and quality, which impairs reproductive function.[10] PSA levels also increase with age, which is believed to be an evolutionary adaptation that confers genetic fitness and promotes fertility over other competing males. This adaptation 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. Prostate cancer cells do not produce more PSA than benign cells; in fact, they tend to manufacture less. However, malignant cells more easily allow PSA to pass through the cell wall into the surrounding extracellular fluid and eventually reach the bloodstream. This process occurs because these malignant prostate cells lack a basal layer that otherwise restricts the passage of PSA outside the cell. Very high Gleason score cancer cells that are highly undifferentiated may not produce PSA.

Specimen Requirements and Procedure

Serum prostate-specific antigen is still a somewhat controversial screening tool for healthy, asymptomatic males because elevated levels of serum PSA can be associated with various benign prostatic conditions. Infection, trauma, inflammation, and benign prostatic hyperplasia can elevate serum PSA levels, reducing the specificity of the biomarker for use in predicting prostate cancer. Studies show that up to 86% of individuals with benign prostatic hyperplasia may have elevated levels of serum PSA.[11] The decision to screen an asymptomatic male using serum PSA should involve shared decision-making. Such discussions involve 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 has remained totally asymptomatic and clinically inactive.

The United States Preventative Task Force recommends selectively offering serum PSA screening individually according to professional judgment and patient preference in males aged 55 to 69 (grade C).[12] 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 10 years. Current guidelines recommend against routine prostate cancer screening with serum PSA in healthy asymptomatic individuals aged 70 to 75.

Many professional associations and societies have developed their guidelines. In general, it is recommended that high-risk individuals begin annual PSA screenings for prostate cancer by age 45, such as those of African descent, those with a family history of prostate cancer or multiple cancers, those with Lynch syndrome, or those with known high-risk germline mutations such as BRCA2. For men at average risk, screenings should begin no later than 50 years, following a full discussion of the pros and cons of such testing. The testing should be continued until patients reach 70 to 75 years. Due to the very high variability of PSA testing results, 2 separate specimens are recommended before conducting further investigations in patients with abnormal PSA elevations. Some clinicians prescribe a 2- to 6-week course of antibiotics to reduce prostatic inflammation or low-grade prostatitis, which can elevate PSA levels, before repeating the test.[13][14] Please see StatPearls' companion reference, "Prostate Cancer Screening," for more information.

Diagnostic Tests

Serum PSA is far superior to digital rectal examination (DRE) and transrectal prostatic ultrasonography (TRUS) for detecting early prostate cancer.[15] When using a PSA value greater than 4 ng/mL, detection rates for prostate cancer achieve a specificity of 91%. In contrast, a digital rectal examination 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. However, with increased use of PSA testing, many individuals experienced adverse effects and unnecessary procedures because their PSA values were elevated secondary to benign conditions.[16] The risk of overdiagnosis, particularly overtreatment, can be minimized by carefully reviewing and discussing the viable options, benefits, and risks at each stage of the diagnostic process.

Overall, PSA sensitivity ranges from 9% to 33%, depending on age and the PSA cut-off values, indicating that up to 91% of individuals with elevated serum PSA levels do not have prostate cancer.[17] 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 experience a progression of their cancer that requires definitive therapy.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) can also be used to detect prostate cancer. However, it is expensive and time-consuming. Other noninvasive options should be explored before using MRI, as even T-1 and T-2 weighted imaging lack sufficient specificity or sensitivity to justify utilization as a screening tool. In addition, MRI can 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.[17]

Prostate-Specific Risk Stratification Bioassays

Prostate-specific risk stratification bioassays are designed to identify patients with elevated PSA levels who can safely avoid biopsies. These tests use either genomics or specific biochemical markers in the serum or urine to identify 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 United States, such as 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 ultimately test negative and can safely avoid a biopsy. MRI and bioassays prevent unnecessary, low-yield biopsies in selected, borderline, or questionable cases. Because of their cost and complexity, these tests are inappropriate for general screening.

Overdiagnosis, Overtreatment, and Unnecessary Biopsies

Overdiagnosis and overtreatment are often cited as reasons to discontinue PSA testing for prostate cancer.[18]

Overdiagnosis: Overdiagnosis is defined by the Institute for Quality and Efficiency in Healthcare as the diagnosis of a medical condition, disease, or disorder that has never 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. Overdiagnosis is not a misdiagnosis or a false alarm, and it is an inevitable part of all screening tests to some degree.[18][19] The only way to eliminate overdiagnosis is to avoid all screening tests, as it is impossible 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. The harmful effects of overdiagnosis can be minimized by carefully explaining, before PSA screening, that most men with an elevated PSA do not 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 such as PSA are never urgent; therefore, patients have ample time to review the available information on screening and carefully consider their options.[18][20]

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

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

Overtreatment: Overtreatment of indolent prostatic cancers can cause significant physical harm, a dramatic decrease in quality of life, and may ultimately not provide any survival benefit to the patient.[18] 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 received full definitive therapy. To be considered for definitive treatment, patients under active surveillance must show evidence of disease progression and meet eligibility criteria regarding life expectancy, age, and comorbidities. When fully implemented, this approach can effectively eliminate most cases of prostate cancer overtreatment.[18]

Unnecessary biopsies: Using pre-biopsy tools and procedures can minimize the risk of unnecessary biopsies. 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 can help reduce unnecessary biopsies. 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.

Some suggest that there is no such thing as an unnecessary biopsy, as all biopsies are performed to establish a definitive diagnosis, which is what a prostate biopsy accomplishes. Labeling any biopsy as unnecessary simply because it produces a negative result is misleading; 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 mitigation can be accomplished by following the established guidelines and recommendations related to low-grade, low-stage prostate cancers, optimally using MRI scans and risk stratification bioassays, fully implementing active surveillance protocols where appropriate, and avoiding screenings in patients who do not benefit from them—such as those who refuse biopsies and treatment, those with a life expectancy of lesser than 10 years, and asymptomatic patients older than 75.

Testing Procedures

With the increased use of PSA as a screening tool for prostate cancer and its subsequent overdiagnosis and overtreatment, several national societies have revised 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.[21] Total serum PSA exists in 3 isoforms of equal concentration—intact and free PSA, pro-PSA, and benign prostatic hyperplasia–associated PSA. All 3 isoforms have been studied as potential biomarkers for differentiating the causes of PSA elevation.

Benign prostatic hyperplasia–associated PSA is generally found in transitional zone tissue, indicating its expression by hyperplastic prostatic tissue. A proportional increase in benign prostatic hyperplasia–associated PSA is directly related to prostate volume and suggests benign prostatic hyperplasia.[22] Several studies have shown that pro-PSA, alone or preferably in combination with other markers, can serve as a valuable biomarker for more aggressive prostate cancer, as pro-PSA is associated with increasing Gleason scores.[23] Incorporating pro-PSA into a bioassay risk analysis profile has shown promise in predicting prostate cancer in individuals with mildly elevated PSA values.[24][25]

Interfering Factors

Screening with PSA has led to earlier detection of prostate cancer; however, morbidity increases for all patients with elevated PSA values, 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 ever require further intervention because of an aggressive form of prostate cancer.[17] There is no level of PSA that reliably guarantees that prostate cancer is present or absent.

5-Alpha reductase inhibitors (5-ARIs) reduce PSA levels by 50%, but this effect typically takes between 6 and 12 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 before starting 5-ARI medications, specifically due to the delayed effect on PSA levels and the time required for this reduction to become fully apparent. 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.[26] 

Besides 5-alpha reductase inhibitors, other medications such as statins, nonsteroidal anti-inflammatory drugs, acetaminophen, and thiazide have also been shown to lower PSA levels.[27][28][29][30] Obese men with high body mass index have larger intravascular volumes, so they tend to have lower PSA values solely due to this dilutional effect. Whether the normal PSA range should be adjusted for this dilution effect remains unclear.[31] 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 increased serum PSA levels and the likelihood of a prostate cancer diagnosis. However, determining the appropriate point for further evaluation can be unclear.[11] A 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.[32][33] This situation is a trade-off—a lower cutoff finds more cancers but requires more testing and biopsies, whereas a higher cutoff delays 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% of prostate cancers.[34] Using the same laboratory value (1.1 ng/mL) in Black men, 50% of cases in men aged 50 to 59, and 75% of cases in those aged 70 to 79, demonstrates laboratory values that necessitate further workup and subject untold individuals to unnecessary and uncomfortable biopsies.[35] By comparison, increasing the PSA cutoff value to 10 ng/mL reduces unnecessary medical evaluations for most indolent causes, but it is estimated that half of all cancers detected by PSA can no longer be organ-confined or localized, thereby negating any potential benefit of early detection.[36] 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 Prostate-Specific Antigen

Using 4 ng/mL as the single upper normal limit for serum PSA does not adequately account for the natural increase in serum PSA 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 men.[37] Therefore, the age-adjusted ranges are recommended when analyzing serum PSA values.[38]

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

• 40-49: ≤2.5 ng/mL
• 50-59: ≤3.5 ng/mL
• 60-69: ≤4.5 ng/mL
• 70-79:≤6.5 ng/mL [37]

Free and Total Prostate-Specific Antigen: Free PSA is a subset of intact PSA. A decrease in the ratio of this serum biomarker (free PSA/total PSA) may be used to improve the sensitivity of prostate cancer detection when initial total PSA values are between 4 and 10 ng/mL.[39][40] Some studies have included pro-PSA in their intact PSA assay, enhancing the predictive value beyond that of intact PSA alone.[41]

When the total PSA is between 4 and 10 ng/mL, free % PSA can be used.[37]

• 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%.

Please see StatPearls' companion reference, "Prostate Cancer Screening," for more information.

Prostate-Specific Antigen Density: The prostate volume in cubic centimeters can be calculated using the formula: (width cm × height cm × length cm) x 0.52. These values are measured using either an MRI or prostatic ultrasound. When the prostate volume is known, PSA density can be calculated by dividing the total PSA (ng/mL) by the prostate volume (cc). A PSA density of 0.15 or more is considered suspicious for cancer.[42]

Prostate-Specific Antigen 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. More significant increases are considered suspicious.[43] Calculating the PSA velocity requires 3 separate PSA determinations over at least 18 months.

Prostate-Specific Antigen Doubling Time: Aggressive, rapidly growing prostate cancers are more dangerous than slow-growing malignancies, which can be estimated using 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.[44] If the PSA doubling time is less than 3 months, the prostate cancer mortality rate is 20 times greater.[45] A higher Gleason score tends to lower the survival rate as well.

Prostate Biopsies

The decision to perform a biopsy should include at least 2 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. Results of an MRI or prostate cancer bio-assay examination, if available, should also be included. Performing a prostate biopsy can be a complicated decision. In general, biopsies should not be recommended in patients where there is an unacceptable risk, such as those who cannot safely stop anticoagulant therapy. In addition, biopsies are not appropriate for patients who do not accept treatment even if a dangerous cancer is found or for those whose life expectancy due to age or comorbidities is well below the minimum 10 years necessary to see a significant benefit from treatment. Patients should be fully informed of the risks and benefits of the biopsy and given sufficient time to decide on their choice. Please see StatPearls' companion reference, "Prostate Cancer Screening," for more information.

Prostate-Specific Antigen 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%) do not show any disease progression and can safely avoid the adverse effects and complications of definitive cancer therapy.

A repeat biopsy 6 to 18 months after the initial diagnosis is the standard of care for patients on active surveillance, given the high reported rate of pathological reclassification of up to 35% after the second confirmatory biopsy.[46][47][48] 

Prostate MRIs are recommended before the rebiopsy to optimize results and monitor the progress of any identifiable lesions.[49][50][51][52] For higher-risk patients on active surveillance—such as those with African ancestry, high PSA density (0.15 or more), a family history of prostate cancer, or positive for high-risk genomic biomarkers—both an MRI and a repeat biopsy are suggested. PSA monitoring for patients on active surveillance is generally performed every 6 months. A significant change is generally considered a PSA level greater than 0.75 ng/mL or more than 25% a year, a PSA doubling time of less than 3 years, or a total PSA greater than 10 ng/mL. A notable change in the MRI Prostate Imaging Reporting and Data System (PI-RADS) score (from PI-RADS 3 to PI-RADS 4 or 5) or marked enlargement of a known cancer nodule is also considered significant and prompts a rebiopsy.

For 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.[53][54][55][56] The suggested protocol was compared to an alternate regimen where repeat biopsies were performed after the initial confirmatory biopsy 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.[57] The use of finasteride or dutasteride, 5-alpha-reductase inhibitors, and enzalutamide, an androgen receptor inhibitor, has not been shown to significantly affect slowing PSA level increases or cancer progression in patients on active surveillance.[58][59]  

Prostate-Specific Antigen 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.[60][61]

Radical prostatectomy: Following a radical prostatectomy, all prostatic tissue should be removed. Therefore, any detectable PSA following the surgery indicates some remaining prostatic tissue, which is typically presumed to be cancerous.[62] This prostatic tissue could be either localized or metastatic disease. Generally, if the PSA is undetectable for 2 years or longer and then gradually begins to rise, a locally recurrent cancer in the prostatic bed is likely.[63][64] Conversely, if the PSA rises quickly and never becomes undetectable after surgery, metastatic disease is more likely.[63][65] Slowly rising PSA levels are sometimes caused by a small amount of residual prostate tissue left behind after surgery, which occurs 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 2 consecutive serum PSA levels greater than 0.2 ng/mL.[66]

Radiation therapy: After definitive radiation therapy, PSA levels typically decrease gradually, often taking up to 18 months to reach their lowest point (nadir).[67] The lower the final nadir achieved, the better the cancer-specific prognosis.[60][68] A biochemical recurrence after definitive radiation therapy is defined as 2 PSA levels >2 ng/mL above the nadir level.[69] The need for 2 levels is due to the phenomenon known as the PSA bounce, which typically occurs 12 to 18 months after initial radiation therapy.[70] There is no way to determine whether 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.[70] In a large retrospective study involving 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.[71] Prostate cancer-specific mortality was at 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.[71]

European Urological Association Risk Stratification for Progression After Biochemical Prostate-Specific Antigen 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.[72]

• 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

Positron Emission Tomography Scans for Post-Prostatectomy Biochemical Prostate-Specific Antigen Recurrence 

When the PSA level is greater than 0.2 ng/mL, prostatic positron emission tomography (PET) scanning can be performed to 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. In contrast, others suggest 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 levels are additional laboratory values that may suggest prostate cancer but are very nonspecific and typically indicate advanced disease, making them useless for screening or early detection. A digital rectal examination (DRE) should be performed on all individuals with abnormal PSA levels even though no specific finding reliably confirms either the presence or absence of prostate cancer. DRE is used to improve the overall sensitivity of the screening and could be an important factor in determining management if cancer is detected.

Overall, up to 14% of patients with prostate cancer have metastatic disease at the time of diagnosis. The finding of metastatic prostate cancer can be correlated with elevated PSA values. Serum PSA values greater than 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 greater than 100 ng/mL.[73] 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 less than 10 ng/mL rarely demonstrate metastatic disease or skeletal spread. For this reason, bone scans in prostate cancer are not generally recommended unless the PSA levels are greater than 20 ng/mL.[74] 

Enhancing Healthcare Team Outcomes

No PSA value guarantees the presence or absence of prostate cancer. Despite being 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 using the test likely continues to be controversial. Individuals aged 45 to 75 should be given the option for screening after discussing the risks and benefits, with particular consideration given to patient preference, age, comorbidities, and family history. Following the decision to screen, PSA values are instrumental in determining the next steps in treatment. Generally, low PSA values in asymptomatic individuals are reassuring, and significantly elevated PSA values are concerning for prostate cancer.

Some of the drawbacks of screening can be minimized through risk stratification strategies and recognizing the potential for overtreatment in low-risk diseases. All healthcare team members should be aware of the controversies involved and be prepared to assist the patient in decision-making. There is no controversy regarding the use of PSA testing in patients with known malignant diseases. In these cases, the team should encourage patients to be involved in their healthcare decisions, adhere to follow-up PSA tests according to clinician recommendations, and follow published guidelines to achieve optimal outcomes.