Prostate Specific Antigen
- Article Author:
- Michael David
- Article Editor:
- Stephen Leslie
- Updated:
- 6/9/2020 3:09:53 PM
- For CME on this topic:
- Prostate Specific Antigen CME
- PubMed Link:
- Prostate Specific Antigen
Introduction
The primary reason for the utilization of any screening exam should be that the procedure detects the premature 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 laboratory abnormality, as the majority of men with early prostate cancer have no symptoms. However, prostate-specific antigen, otherwise known as PSA, is clinically imprecise as benign and malignant processes both, can elevate the serum marker.[1] Despite the risks and benefits of serum PSA screening, it is the most useful tool available for the detection of early prostate cancer, giving affected individuals the best chance for cure.
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] A figure that has been increasing over the past 20 years, proportionally to the increase in prostate cancer diagnosis, which is likely as a result of the aging population and improved detection utilizing serum prostate-specific antigen (PSA).[4] Despite the improvements in the detection of prostate cancer, overall mortality rates are not significantly lower.[5]
Pathophysiology
Prostate-specific antigen (PSA) is a serine protease enzyme produced by the columnar epithelium of prostatic tissue. Following production, it passes through the basal cell layer, endothelial cells, and capillary membranes to enter the systemic circulation.[6] Semenogelin and fibronectin proteins are responsible for the gel-like consistency of the seminal fluid. Locally, PSA prevents seminal coagulation by breaking down these proteins into smaller peptides and thereby, helping facilitate impregnation.[7] As men age, spermatozoa production is altered with a resultant adverse effect on sperm count and quality, which impairs reproductive function.[8] However, PSA production increases with age. This increase is thought to be an evolutionary adaptation that confers genetic fitness over other male counterparts. Thus, increasing the prevalence of conditions such as benign prostatic hyperplasia in the general population.
Specimen Requirements and Procedure
Serum prostate-specific antigen (PSA) is a controversial screening exam for healthy, asymptomatic males as elevated serum PSA is found in a litany of benign conditions. Infection, trauma, inflammation, and benign prostatic hyperplasia (BPH) can transiently elevate serum PSA levels, which reduce the specificity of the laboratory value for use in predicting prostate cancer. Research has demonstrated that 86% of the individuals with BPH have an elevated serum PSA.[9] The decision to screen an asymptomatic male utilizing serum PSA should involve shared decision making. This is simply a discussion regarding the benefits and risks, 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 asymptomatic. 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). The general health of the patient is an important factor in the decision to screen as guidelines recommend against screening individuals who have a life expectancy of fewer than 10 years. Current guidelines recommend against prostate screening with serum PSA in asymptomatic individuals over the age of 70 years.
Diagnostic Tests
Serum prostate-specific antigen (PSA) has been demonstrated to be superior to digital rectal examination (DRE) and transrectal prostatic ultrasonography for the detection of early prostate cancer.[10] When employing a value of greater than 4 ng/mL, serum PSA detection rates for prostate cancer approach, a specificity of 91%. By comparison, a digital rectal exam is far less specific, at 59%. Initially, the potential to detect early prostate cancer, with the intent to avoid progression of the disease and decrease mortality, was embraced by the urologic community. But with increased utilization of the PSA screening, there have been large numbers of individuals who experience increased morbidity and unnecessary procedures because their PSA value may have been elevated secondary to a benign condition.[11] Overall, PSA sensitivity varies between 9% to 33% depending on age, and PSA cut off values used.[12] Essentially, this means that as many as 91% of individuals with elevated PSA values do not have prostate cancer. Regarding the elevated PSA values that prove to be cancerous, the majority 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 active treatment. This means that the PSA screening will identify prostate cancer; however, the risk of mortality is not lessened. Magnetic resonance imaging (MRI) may be used in the detection of prostate cancer as well. However, it can be costly, and other options should be exhausted prior to utilization as even T-1 and T-2 weighted imaging lacks the specificity or sensitivity to justify utilization as a method of screening.[12]
Testing Procedures
With the increased utilization of prostate-specific antigen (PSA) 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 prostate cancer.[13] Total serum PSA exists in three isoforms of equal concentration: intact free PSA, pro-PSA, and BPH-associated PSA (BPSA). All three isoforms have been studied as a potential biomarker for the differentiation of 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.[14]
Multiple studies have demonstrated the benefit of utilizing pro-PSA as a biomarker for more aggressive prostate cancer, as pro-PSA is associated with increasing Gleason scores.[15] Also, pro-PSA has been incorporated into a Prostate Health Index (PHI),[16] which has shown promise in predicting prostate cancer in individuals with mildly elevated PSA values.[17]
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 PSA values are between 4 ng/mL to 10 ng/mL.[18][19] Some studies have included pro-PSA in their intact PSA assay, which convolutes the predictive value of intact PSA alone.[20]
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 serum values that are elevated due to prostate cancer, the majority of the 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.[12] Therefore, serum PSA levels are not specific for prostate cancer, much less aggressive prostate cancers that may require future intervention. Subsequently, there is no level of prostate-specific antigen that guarantees that prostate cancer is present or absent.
Results, Reporting, Critical Findings
A prostate-specific antigen [PSA] value of greater than or equal to 4.0 ng/mL is the consensus standard at which further evaluation for prostate cancer should occur. 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,[21] this value requires some individuals with prostate cancer to be missed during serum screening so that fewer individuals are subjected to unnecessary biopsy.[22] However, there is no PSA value that can guarantee the detection of prostate cancer. Values as low as 1.1 ng/mL, routinely overlook 17 percent of prostate cancers.[23] Utilizing the same laboratory value [1.1 ng/mL] in black males, fifty percent cases in ages 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 needless biopsy.[24] By comparison, increasing the PSA cutoff value to 10 ng/mL will reduce the unnecessary medical evaluation for the indolent causes of an abnormal laboratory value, but it is estimated that half of all cancers detected by this PSA value are no longer organ confined, thereby, negating any potential benefit of early detection.[25] However, it should be noted that there is a direct relationship with the likelihood of prostate cancer diagnosis and an increase in PSA value.[9]
Clinical Significance
Early prostate cancer is generally asymptomatic, and often, an elevated serum PSA level is the first indication of cancer. Anemia and elevated alkaline phosphatase are additional laboratory values that may suggest prostate cancer. However, these abnormal laboratory values suggest advanced disease, and therefore, are not useful for early detection. Digital rectal examination (DRE) should be performed on all individuals with an abnormal PSA screening. However, similar to serum PSA screening, there is no exam finding on DRE that confers the presence or absence of prostate cancer. Yet, it may be utilized to improve the sensitivity of the PSA and will be an important factor in deciding management.
The finding of metastatic prostate cancer can be correlated with elevated PSA values. Serum PSA values greater than or equal to 20 ng/mL has a positive predictive value of 65% for metastatic skeletal involvement. This number increases linearly with a positive predictive value for metastatic disease in 86% of values greater than or equal to 100 ng/mL.[26] It should not be assumed that an individual with serum PSA values greater than or equal to 100 ng/mL at the time of diagnosis has metastatic progression. By comparison, serum PSA values of less than or equal to 10 ng/mL rarely demonstrate metastatic disease. However, as many as 14% of prostate cancer diagnosis demonstrates metastatic disease at the time of diagnosis.
Quality control and Lab Safety
The decision to refer to urology will include the PSA value, history, examination, and patient preference. There is a direct correlation with age and serum PSA concentration, with a 3.2% increase per year, demonstrated in healthy 60-year-old males.[27] Therefore, when utilizing serum PSA values, it is important to adjust for age. The 95 percentile PSA value is commonly used for abnormal reference range, which are as follows:
- Males 40-49 years: more than 2.5 ng/mL
- Males 50-59 years: more than 3.5 ng/mL
- Males 60-69 years: more than 4.5 ng/mL
- Males 70-79 years: more than 5.5 ng/mL
Enhancing Healthcare Team Outcomes
There is no prostate-specific antigen value that guarantees the presence or absence of prostate cancer. However, it currently is the best manner in which to detect early, and often asymptomatic malignancy. Yet, the decision to screen healthy individuals will continue to be controversial while utilizing the test. Individuals between the ages of 55 and 69 years should be given the opportunity to be screened following a conversation regarding the risks and benefits of screening with particular consideration given to patient preference. 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. Although these assumptions are not definitive.
There is uncertainty, and controversy, regarding the best manner in which to handle an intermediate PSA value. The crux of the conundrum is that many individuals with benign conditions, leading to the minimally elevated PSA value, are subjected to unnecessary prostate biopsy in an effort to differentiate between a condition that is likely to be benign versus the less-likely chance of malignancy. Especially when considering that the majority of the malignancies discovered are indolent and are likely not to require medical management.