Introduction
Background
Prostate-specific antigen (PSA) is a protein produced by normal prostate cells. This enzyme participates in the dissolution of the seminal fluid coagulum and plays an important role in fertility. The highest amounts of PSA are found in the seminal fluid; some PSA escapes the prostate and can be found in the serum. This serum component has been used to track the response to therapy in men with prostate cancer.
PSA evaluation was never intended to serve as a diagnostic test for prostate cancer but is useful in helping to identify men in whom a prostate biopsy would be appropriate. The PSA level tends to rise in men with benign prostatic hyperplasia (BPH) and is a good marker for prostate volume. PSA levels are usually elevated in men with acute bacterial prostatitis. The most valuable measurement of PSA is its change over time rather than the actual serum level. No identifiable PSA level guarantees normalcy; in addition, no specific level indicates that a biopsy should be performed. Instead, PSA velocity or doubling time has been shown to be a more accurate and reliable predictor for recommending a prostate biopsy and treating patients with this disease.
PSA levels have been used in screening large populations of men for prostate cancer and have been shown to be useful. Studies are still underway to determine definitively if PSA screening actually makes any real difference in the detection and survival of men with this disease, but most urologists would testify that they see far fewer patients with advanced prostate cancer since the PSA era began.
The test has dramatically changed the way that men are evaluated and treated for prostate cancer. Prior to the PSA evaluation era, nearly 70% of men diagnosed with prostate cancer already had extraprostatic or metastatic disease, and an abnormality in the prostate had to be palpably evident before a biopsy was performed. Since the advent of PSA evaluation, fewer than 3% of men have metastases at the time of diagnosis and 75% of men have nonpalpable cancer. In this latter group, the cancer was detected based on biopsy performed because of a rapidly rising or markedly elevated PSA level.
Since the test was introduced into clinical practice in 1986, the early diagnosis and management of prostate cancer has been revolutionized and much has been learned about the strengths and weaknesses of this assay. PSA testing not only helps in the early diagnosis but also assists in assessing the response to therapy, determining tumor progression, and, in its most controversial role, screening for prostate cancer.
Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.1
For excellent patient education resources, visit eMedicine's Prostate Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.
History
In the 1960s, Ablin et al reported on novel proteins found in seminal fluid. In 1971, in the Japanese Journal of Legal Medicine, Hara et al identified what they considered a protein unique to semen. They were attempting to find a substance in seminal fluid that would aid in the investigation of rape cases. The protein Hara et al isolated from human seminal plasma was named gamma seminoprotein.
In 1973, Li and Beling isolated and purified this protein. In 1978, Sensabaugh characterized it as a semen-specific protein; he referred to it as p30 because of its molecular weight. In 1985, Graves et al published a paper in the New England Journal of Medicine on the postcoital investigation of rape using this new protein.
Perhaps the most important contribution in the development of this test was the report by Wang and his associates at Roswell Park. In 1979, they published a paper in Investigative Urology in which they described their isolation of a tissue-specific antigen from the prostate using gel electrophoresis and called it PSA. Further study by Wang et al demonstrated that this protein was immunologically identical to that discovered by Hara and Sensabaugh.
In 1980, Papsidero and Wang et al developed a serologic test allowing PSA to be measured in the serum. In 1985, Graves et al published a paper on the postcoital investigation of rape cases using the presence of this new protein.
In 1987, Stamey and associates at Stanford University published the first definitive clinical study investigating the utility of PSA in prostate cancer. Since then, extensive investigation into the various uses for this protein has occurred.
PSA immunoassays
Before the second PSA Standardization Conference held at Stanford in 1994, 2 predominant assays were available, the Yang, which used a polyclonal antibody, and the Hybritech, which used a monoclonal antibody. Differences existed in the purification techniques for PSA. As a result, these and other newly developed assays delivered results that could not be compared, rendering patient treatment difficult and the interpretation of research data nearly impossible.
Riehmann et al reported interlaboratory variations of as much as 55% in patients without prostate cancer. At this conference, an agreement was made to use the purification method of Sensabaugh and Blake, which became the international standard. However, standardization issues persist, and interpretation of the data remains confusing.
When 2 different assays are used to measure the same serum sample, discrepancies can occur due to differences in assay calibration, assay kinetics, or different detection standardization of PSA in the serum. Although correlation coefficients between assays may be high, biases can occur, with one assay reporting a PSA result that is 20-30% lower than the other. Results obtained in one assay cannot be extrapolated to another assay. This variability is of importance in clinical situations, such as screening, and when assay results are used to calculate prostate-specific antigen density (PSAD), prostate-specific antigen velocity (PSA-V), and age-specific reference ranges.
Assay variability also is important when the PSA is in the low (0.1-4) or intermediate (4-10) range. At these levels, the clinician is attempting to make a decision about the need for a biopsy and the recurrence of cancer following surgery or radiation therapy, as well as evaluating results in patients with BPH and prostatitis. This variability leads to repetitive PSA testing in each patient to confirm or disprove a result that is elevated or markedly different from previous results. The same variability for an initial PSA is less relevant when the PSA is high (>10) because a biopsy is performed regardless.
The processing and storage of samples represent other potential problems for interpreting PSA results. Blood samples should be centrifuged, and the serum should be separated and frozen within 2-3 hours. Specimens frozen at less than -70°C can be stored for at least a month. Reliability of the protein is believed to be maintained when the specimen is frozen at less than -20°C for several weeks.
The performance of a marker for the detection of cancer is evaluated frequently by a Receiver Operating Characteristic (ROC) curve. This measures sensitivity and specificity simultaneously and permits a comparison of assays. Marker performance improves as sensitivity and specificity approach 100%. The area under the test curve is used as a quantitative measurement of the accuracy of the test. The closer the curve approaches the upper corner of the graph, the better the performance of the test.
Since the introduction of the first assay, numerous commercial assays have become available. The first-generation assays have lower limits of PSA detection of 0.2 ng/mL. The second-generation assays have detection limits of lower than 0.1 ng/mL. The third-generation ultrasensitive assays can detect PSAs at levels as low as 0.003 ng/mL. Currently, these low levels are primarily of interest in detecting recurrent cancer following radical prostatectomy. PSA doubling times have been shown to be an important indicator in deciding the need for a biopsy and in monitoring patients with prostate cancer. When PSA levels are less than 0.5 ng/mL, doubling times lose their accuracy.
In most clinical situations, little difference exists between the data obtained with any assay as long as the same assay method is being used consistently. Wymenga et al (2000) compared a first-generation (IMx) and a second-generation (IMMULITE) assay in men with BPH and prostate cancer. For most of the men, these assays were equivalent. Although these assays showed strong concordance and limited variability, the results from a single individual may be of clinical importance. The discrepancy between the values is magnified when used to evaluate age-specific reference ranges and to calculate PSAD and PSA-V.
The interpretation of PSA results requires clinical evaluation and patient education. Patients are increasingly aware of the PSA test since media frequently report which PSA tests are considered worthless and which should be performed regularly. Patients often compare their results with each other and appreciate the physician's opinion in the interpretation of the results.
Race
The incidence of prostate cancer is higher in black men than in white men. Reports have indicated that PSA levels are higher in black men, even when controlling for age, clinical stage, and Gleason grade. Moul et al (1999) have suggested that that these higher levels are related to the larger tumor volumes found in these men (1.3-2.5 times greater). Morgan et al (1996) evaluated 411 black men who had prostate cancer and noted that 40% of cases would have been missed using the traditional age-specific reference ranges.
Age
The standard PSA reference range is 0-4 ng/mL. PSA levels tend to increase with age; this increase is related to prostate volume. Most PSA is made in the transition zone (TZ) of the prostate, and this region of the prostate increases in volume in men with BPH.
Oesterling et al (1993) proposed using a different cutoff based on age. Accordingly, a man younger than 50 years should have a PSA level of less than 2.5 ng/mL. A man older than 70 years might have a PSA level of 6.5 ng/mL, and this finding is considered within the reference range.
Although a PSA level cutoff of 4 ng/mL has been the traditional threshold at which a prostate biopsy has been recommended, 30% of the cancers detected occur in men whose PSA level is less than 4 ng/mL.
The use of these age-specific ranges poses certain problems. With lower PSA ranges established, more men with prostate cancer are detected. Most cancer is detected in older men, ie, men with larger prostates and higher PSA levels. If the goal of testing is to identify the greatest number of cancers, all older men should be tested. If the intent is to diagnose the same percentage of cancer in each age group, the age-adjusted reference range could be used.
Brawer et al (1993) studied the age-adjusted PSA values compared to the standard of 0-4 ng/mL as a part of a prostate cancer screening program. They found that the number of men older than 50 years exceeding the age-adjusted threshold is enhanced slightly, but the cancer detection rate was reduced significantly. Comparing their data to the US Life Table actuarial values, they observed that a significant increase in population longevity would occur if the value of 4.0 ng/mL were used as the cutoff.
Aus et al (1992) reported the results of a Swedish screening study in which men with a PSA of 3.0 ng/mL or higher had a combination of DRE, transrectal ultrasonography, and sextant biopsies. PSA levels of 3-4 ng/mL were found in 243 of these men. Cancer was found in 32 (13.2%), which represented 23% of the cancers detected.
Most clinicians use the standard 4.0 ng/mL as the cutoff for cancer detection regardless of age, but, if cancer detection in men aged 50 years or younger is considered clinically advisable, then a cutoff of 2.5 ng/mL for this group is appropriate.
Characteristics of Prostate-Specific Antigen
PSA is a 33-kd protein consisting of a single-chain glycoprotein of 237 amino acid residues, 4 carbohydrate side chains, and multiple disulfide bonds. PSA is homologous with the proteases of the kallikrein family. PSA may be referred to as human glandular kallikrein-3 (hK-3) to distinguish PSA from human glandular kallikrein-2 (hK-2), another prostate cancer marker with which it shares 80% homology. Human glandular kallikrein-1 (hK-1) is a kallikrein that is found primarily in pancreas and renal tissue but shows 73% and 84% homology with PSA.
Because of the structural similarities between these kallikreins, concern exists that both the polyclonal and monoclonal assays may have cross-reactivity, which would result in discrepancies in PSA measurements. Using recombinant production of PSA and hK-2, Lovgren et al (1995) demonstrated that very few monoclonal anti-PSA immunoglobulin Gs (IgGs) cross-react with hK-2. Epitopes have been identified that are unique to PSA without cross-reactivity to hK-2. This has led to the development of ultrasensitive immunoassays that are specific for PSA and hK-2, as well as assays that are fully cross-reactive with both proteins.
PSA is a neutral serine protease with biochemical attributes that are similar to the proteases involved in blood clotting. The role of proteases in the coagulation process has been studied extensively and applies to all serine proteases, including PSA. PSA splits the seminal vesicle proteins seminogelin I and II, resulting in liquefaction of the seminal coagulum.
The complete gene encoding PSA has been sequenced and localized to chromosome 19. PSA is found primarily in prostate epithelial cells and in the seminal fluid.
The exact mechanism by which PSA gains access to the serum is unknown, but a possible mechanism has been suggested. The lumen of the prostate gland contains the highest concentration of PSA in the body. A number of barriers exist between the glandular lumen and the capillaries. These include the basement membrane of the glands, the prostatic stroma, and the capillary endothelial cell. Diseases such as infection, inflammation, and cancer may produce a breakdown in these barriers, allowing more PSA to enter the circulation.
PSA levels can rise dramatically with a prostate infection, but they return to the reference range after the infection has healed. A vigorous prostate massage also can produce a brief elevation of PSA. Low concentrations of PSA have been identified in urethral glands, endometrium, normal breast tissue, breast milk, salivary gland tissue, and in the urine of males and females. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.
Serine proteases are bound mostly to various serum proteins. A small percent of serum PSA exists in the free form, but the majority is bound to either alpha2-macroglobulin (AMG) or alpha1-antichymotrypsin (ACT). These are the 2 major serine protease inhibitors in the blood, and they comprise 10% of the total serum proteins. The ejaculate primarily contains free prostate-specific antigen (fPSA) in a concentration of 1 million ng/mL. When serum PSA is bound to ACT, 2 epitopes are left unmasked and can be detected with immunoassays. The complex formed with AMG is enveloped by this proteinase inhibitor so that no epitopes are left exposed for detection.
The half-life and metabolic clearance rate have been determined from studies of patients undergoing radical prostatectomy. Stamey et al (1987) found the half-life to be 2.2 days plus or minus 0.8, while Oesterling et al (1993) calculated the half-life and determined it to be 3.2 days plus or minus 0.1. Because of its relatively long half-life, a minimum of 2-3 weeks is required for the serum PSA to reach its nadir following radical prostatectomy, when it should be undetectable. The majority of PSA is produced by the glands in the TZ of the prostate. This portion of the prostate is associated with BPH. The peripheral zone (PZ), where 80% of prostate cancers originate, produces very little PSA.
By measuring PSA before and after transurethral resection of the prostate, Stamey et al (1987) were able to calculate the amount of PSA produced per gram of benign prostatic tissue. Comparing the weights of resected tissue and the change in serum PSA, the PSA in ng/mL/g of hyperplastic tissue was 0.31 plus or minus 0.25. The polyclonal Yang assay was used for this study. The Hybritech monoclonal assay produced a measurement of 0.5 ng/mL plus or minus 0.4. Lee et al (1992) calculated that serum PSA was elevated in 0.12 ng/mL/g of benign prostatic tissue using the monoclonal assay. No diurnal variation exists, and PSA measurements in the same individual tend to remain unchanged when obtained at daily, weekly, and monthly intervals. Carter et al (1992) found that PSA levels measured from serum samples frozen for more than 25 years remained stable.
Factors influencing PSA measurement
For clinical purposes, PSA is considered prostate organ specific but not prostate cancer specific. A major limitation of PSA as a prostate cancer marker is the overlap in values between BPH and prostate cancer. Normal hyperplastic and neoplastic epithelial cells make PSA, but the PSA produced by cancer cells is 10 times higher per gram of tissue than that produced by normal or hyperplastic tissue.
The interpretation of PSA may vary according to the amount of BPH tissue and the epithelial-stromal ratio. Most PSA is produced in the hyperplastic transitional zone (TZ) of the prostate. A relatively small amount of PSA is produced in the PZ, where 80% of prostate cancers originate. Cancers developing in the TZ tend to produce large amounts of PSA.
The PSA produced by cancer cells may vary according to the grade of the cancer. High-grade cancer cells tend to lose their ability to shed tumor markers. A Gleason grade 5 prostate cancer produces less PSA than a grade 3 cancer. Some patients with advanced prostate cancer may have low or undetectable PSA levels.
PSA levels can be altered by pharmacologic therapies, prostatic diseases other than cancer, and urologic manipulations. 5-alpha reductase inhibitors such as finasteride (Proscar) and dutasteride (Avodart) decrease PSA levels by 50% in most men with BPH after a 6-month course of therapy, after which the level remains stable. However, this change varies and can range from an 80% decrease to a 20% increase. The new PSA level establishes a revised baseline for comparative PSA measurements, or the PSA can be doubled to allow comparison with pre-medication levels. The mean percent of fPSA is not affected significantly by 5-alpha reductase therapy. The alpha1-adrenergic antagonists do not appear to alter PSA levels.
An increase in PSA levels has been reported following ejaculation. In 67% of the men older than 50 years who were tested, a 41% mean increase (0.8 ng/mL) in PSA occurred 1 hour after ejaculation.
PSA levels have been demonstrated to be elevated in acute prostatitis, subclinical or chronic prostatitis, and urinary retention. Nadler et al (1995) reported that serum PSA levels higher than 4.0 in 148 men with subclinical prostatitis could be attributed to their disease because all had negative findings from biopsies repeated on multiple occasions.
No significant change occurs in the PSA level following a DRE, but a short-term 2-fold increase can occur if a vigorous prostate massage is performed. Cystoscopy, urethral catheterization, and transrectal prostate ultrasonography do not tend to elevate the PSA. Performing a prostate needle biopsy increases PSA by a median of 7.9 ng/mL or 6.5 times baseline values within 5 minutes following the biopsy, and this level persists for 24 hours.
The time for PSA to return to the baseline level depends on the precipitating event and the half-life of 2.2-3.2 days. Two to four weeks may need to elapse before the PSA returns to its original level following a biopsy. If an infection occurs as a result of the biopsy, return to baseline levels may take longer. Following ejaculation, PSA levels have been reported to return to their original levels within 48 hours, while fPSA returns to baseline at 6 hours because of its shorter half-life of 2 hours.
Following relief of urinary retention, PSA levels decrease 50% in 24-48 hours. Acute prostatitis not only produces large increases in PSA, but also the return to baseline depends on the resolution of the infection, which may require 6-8 weeks or longer. PSA levels have been used to determine the duration of antimicrobial therapy in men with acute bacterial prostatitis.
Other physiological activities of PSA
Sutkowski and associates (1999) suggested that PSA may regulate the volume of stromal tissue in men with BPH. PSA cleaves insulinlike growth factor–binding protein-3 (IGFBP3), which decreases its affinity for insulinlike growth factor (IGF-1), which is an epithelial cell mitogen. Dissociation of the IGF-1–IGFBP3 complex makes IGF-1 available to bind to its receptor and to stimulate cell proliferation.
Using a tissue culture model, these investigators demonstrated a concentration-dependent proliferative response of BPH-derived stromal cells to IGF-1. IGFBP3 inhibited this response in a concentration-dependent manner. IGFBP3 alone had no effect on stromal cell proliferation. When stromal cells were incubated with PSA alone or with a combination of PSA, IGF-1, and IGFBP3, an increase in stromal cell numbers was demonstrated and was dependent on PSA concentration. Zinc, an endogenous inhibitor of PSA enzymatic activity, attenuated the stimulatory effect of PSA at intraprostatic physiologic concentrations.
Fortier et al (1999) evaluated the antiangiogenic properties of PSA. Based on the observation that patients with breast cancer who had higher levels of PSA had a better prognosis than those with low levels, they hypothesized that PSA may have antiangiogenic properties. To test this concept, they evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion. They treated bovine and human endothelial cells with purified human PSA and then stimulated them with fibroblast growth factor-2 (FGF-2) and vascular endothelial cell growth factor (VEGF). In another experiment to evaluate the ability of PSA to inhibit lung metastases of melanoma cells, these investigators administered B16BL6 melanoma cells intravenously to mice and then administered PSA for 11 consecutive days.
The results of these experiments demonstrated that PSA inhibited endothelial cell proliferation, migration, and invasion by 50% or more. PSA inhibited endothelial cell responses to both FGF-2 and VEGF. In the mouse model, a 40% reduction in the mean number of lung tumor nodules occurred compared to saline-treated controls. The authors conclude that PSA, in addition to its other physiologic functions, also may act as an endogenous antiangiogenic protein. This finding may explain the slow progression of cancer in some patients, and the authors postulate that strategies that inhibit PSA production may be counterproductive.
Other Prostate Cancer Markers
In the circulation, PSA forms complexes with other protease inhibitors. Most of the PSA is bound to ACT. Free or unbound PSA accounts for only a small amount of PSA in the circulation, although it is the major form found in the ejaculate.
PSA also forms another complex with AMG. This complex is difficult to measure because it has no exposed epitopes to which an antibody can attach. For this reason, adding enzymatically active PSA to serum in vitro does not allow ready identification of this complex, and commercial assays are not available currently. The insignificant levels of this complex indicate that the PSA-AMG complex is unlikely to have a biologic role in the serum.
Free PSA
PSA represents a major indicator for the diagnosis and management of prostate cancer. However, within the range of 4-10 ng/mL, in which 75% of men do not have cancer, the PSA lacks specificity. At this range, 4 men require a biopsy to identify 1 man with cancer.
Stenman et al studied this problem and reported in 1991 that men with prostate cancer had more complexed prostate-specific antigen (cPSA) than fPSA, in contrast to men with BPH. After the development of an immunoassay, investigators demonstrated that the ratio of free-to-total prostate-specific antigen (f/tPSA) was lower in men with prostate cancer. In the PSA range of 4-10, total prostate-specific antigen (tPSA) segregates adequately between men with or without cancer. The f/tPSA is more discriminatory.
A 7-institution study investigated 63 men with BPH, 30 men with prostate cancer (prostate size >40 cm3), and 20 men with small prostates. All of the PSA levels were 4-10 ng/mL. The median f/tPSA proportion was 0.188 (in BPH), 0.159 (in prostate cancer [prostate size >40 cm3]), and 0.092 (in small prostates). This implies that prostate size is an important variable in selecting a cutoff value for fPSA. For men whose prostates are smaller than 40 cm3, a percent fPSA of 0.137 or lower is used to detect 90% of the cancers, and 76% of the negative biopsy findings can be eliminated. For men with prostates larger than 40 cm3, a cutoff of 0.205 allows detection of 90% of the cancers, and 38% of the negative biopsy findings can be eliminated. If the patient has a normal-sized prostate on DRE, a value of 0.234 is necessary to detect 90% of the cancers, sparing 31.3% of the patients an unnecessary biopsy.
Brawer et al compared the specificity of tPSA and f/tPSA at various sensitivities. At a sensitivity of 80% and a tPSA of 4.11, the specificity was 35.6% compared to 46.2% for f/tPSA with a cutoff point of 19%. At a sensitivity of 90% with a cutoff for tPSA of 3.4, the specificity was 25.3%, while the f/tPSA at a cutoff point of 24% was 26.2%. In a large population of men with PSA levels of 4-10 ng/mL and a cutoff point of 25% or less, 95% of the cancers would be detected, and 20% of the patients would be spared a biopsy. fPSA is most useful in men with persistently elevated PSA levels who have had a previous biopsy with negative findings. As the percent of fPSA declines, the probability of a cancer being present increases. Conversely, higher fPSA percent indicates a lower probability that cancer exists. Even with this added information, the decision to perform a biopsy on any given patient is based on good judgment.
No conclusive data demonstrate the value of fPSA in the staging of prostate cancer, although several studies have indicated that a correlation may exist. In the Baltimore Longitudinal Study of Aging in a small number of men who developed prostate cancer, the f/tPSA significantly segregated those who developed cancer from those who did not up to 15 years before the diagnosis. Twelve men with stage T3 or T4 disease with Gleason scores of 7 or higher or who had positive margins following radical prostatectomy had lower f/tPSA levels than 8 men with less aggressive cancers. tPSA was elevated only 5 years before diagnosis.
Human glandular kallikrein-2
hK-2 is a serine protease that is approximately 80% homologous in primary structure to PSA (hK-3). hK-2 is responsible for the conversion of the inactive pro-PSA zymogen to the enzymatically active PSA in vitro. This conversion is a prerequisite for the formation of PSA-ACT and other complexes. hK-2 is expressed in higher levels as prostate cancer cells become more anaplastic compared to PSA, which tends to diminish. PSA and hK-2 occur in high concentrations in prostatic and seminal fluid but exist in small concentrations in the blood.
The Goteborg screening study evaluated 604 men with tPSA higher than 3. These men had DREs, transrectal ultrasonography, and sextant prostate biopsies. Cancer was identified in 144 men (23.8%). Significantly higher levels of hK-2 and tPSA were found in those with cancer, while the f/tPSA was lower. The optimum equation predicting the presence of cancer was as follows:
hK-2 X tPSA / fPSA
The ROC was 0.81. At a sensitivity of 75%, the specificity of tPSA was 47%, tPSA/fPSA was 63%, and hK-2 X fPSA / tPSA was 74%. At any higher sensitivity, the tPSA consistently had decreasing specificity, while the other 2 equations produced similar results.
Men with localized cancer who were treated with radical prostatectomy had lower hK-2 levels if the cancer was organ confined compared to men with extraprostatic extension. tPSA levels in this same cohort were not different.
Prostate-specific membrane antigen
In 1987, Horoszewicz et al first reported on this antigenic marker to prostate epithelial cells, which can be found in the serum. Prostate-specific membrane antigen (PSMA) is a 100-kd type II membrane protein that is expressed in all types of prostatic tissue, including normal epithelial cells, BPH, prostatic intraepithelial neoplasia, and cancer. The gene for PSMA has been fully sequenced and cloned and encodes for a glycoprotein consisting of 3 domains: an intracellular domain, a transmembrane region, and a large 707–amino acid extracellular sequence making up the bulk of the molecule.
The genetic location of PSMA is on the short arm of chromosome 11. Two variations have been identified and characterized, but their individual roles have not been elucidated. Nonprostate expression of PSMA has been identified in a portion of the proximal tubule cells of the kidney, the salivary glands, and in the small bowel, particularly the duodenum, which has high folate hydrolase activity that is essential for absorbing ingested folates. Reactivity of anti-PSMA monoclonal antibodies has been demonstrated to the endothelium of malignant tissue endothelium but not to normal endothelium. A wide variety of carcinomas express PSMA consistently and strongly in their tumor-associated neovasculature; however, similar expression has not been found in prostate cancer neovasculature.
PSMA is a protein that can be distinguished from PSA. It is a selective marker for prostate epithelial cells and is expressed to a greater extent than PSA in higher-grade cancers. Bostwick et al (1998) found that 70% of benign epithelium expresses this marker antigen, 78% of prostate intraepithelial neoplastic cells also express this marker, and 80% of invasive cancer cells demonstrate the antigen.
The development of immunoassays and Western blot–based assays for PSMA has permitted an increasing number of studies. PSMA levels seem to correlate with stage and tumor volume. Following radical prostatectomy, PSMA levels become undetectable and rise when the tumor recurs. PSMA primers used in a reverse transcriptase–polymerase chain reaction (RT-PCR) have been used to detect circulating prostate cancer cells. This method detects as few as 1 tumor cell in 10 million lymphocytes. The use of this method for clinical decision-making has been limited. With this technology, cancer cells can be identified in the circulation and in the bone marrow of patients with all stages of prostate cancer. This indicates that cancer cells begin leaving the prostate early in the development of the disease, but most of these cells do not survive, and their identification does not correlate with patient prognosis or survival.
Ferrari and colleagues (1997) demonstrated an increase in the ability to detect micrometastases in lymph nodes removed during radical prostatectomy using the PSMA RT-PCR technology compared to standard histologic techniques. They obtained lymph nodes from 33 patients who were having a radical prostatectomy with Gleason scores of 7 or higher and serum PSA levels of 10 or higher. Routine pathology examinations identified cancer cells in 4 (12%) of these patients. PSA and/or PSMA expression was positive in 27 (82%) of the patients. The 4 patients with positive lymph node findings also had positive results for both PSA and PSMA. Among the 29 patients with no histologic evidence of disease, 23 (79%) tested positive with RT-PCR. In these 23 patients, PSMA was detected more frequently than PSA, although only PSA was found in 2 patients.
Although this demonstrates that prostate cancer cells or fragments of these cells can be found in pelvic lymph nodes, the status of these cells and their viability cannot be ascertained. This is another indication of the early egress of cancer cells from the prostate, but this observation does not necessarily correlate with patient prognosis and survival.
PSMA serves as the basis for the ProstaScint scan. This is an imaging study used to detect metastatic cancer. Its primary use has been to identify prostate cancer cells in lymph nodes and in the prostate base.
PSMA is being evaluated as a means for therapy. When PSMA is used as an immunotherapeutic agent, dendritic cells are primed with PSMA and infused into the patient. This is intended to produce a specific immune response to prostate cells. Using PSMA as a guide to identify and target prostate cells, radioactive isotopes and cytotoxic agents can be delivered to these cells.
Cell cycle inhibitor p27
The cell cycle inhibitor, p27, is a putative tumor suppressor gene. Loss of p27 is associated with a poor prognosis in patients with breast, colorectal, and prostate carcinoma. In men treated with radical prostatectomy, loss of p27 expression correlates with an increased probability of cancer recurrence and a decrease in survival rates. Decreased p27 expression also is associated with high-grade cancer cells, positive surgical margins, seminal vesicle invasion, and lymph node metastases.
Serum insulinlike growth factor
IGF-1, its binding protein, insulinlike growth factor-binding protein (IGFBP), and its receptor, insulinlike growth factor receptor (IGFR), have been implicated in the development of prostate cancer. PSA cleaves IGF-1 from its binding protein, allowing this potent growth factor to act on prostate epithelial cells.
Plasma concentrations of IGF-1 have been associated with an increased risk of developing prostate cancer. In the Physicians' Health Study, 152 cases of prostate cancer were matched with 152 controls from the population of 14,916 physicians. Serum samples assayed for IGF-1 at the outset of the study found a positive association with the subsequent development of prostate cancer. Men in the highest quartile for IGF-1 had a relative risk of 2.4 (95% confidence interval [CI], 1.2-4.7) compared to men in the lowest quartile. The predominant IGF-1 binding protein, IGFBP-3, has growth inhibitory properties diminishing the effect of IGF-1. After correcting for IGFBP-3 levels, the risk of developing prostate cancer was 4.5 times greater for the highest quartile compared to the lowest quartile.
The clinical usefulness of this assay has yet to be demonstrated because alternative explanations for these findings may exist. Prostate size and a large overlap in actual values limit the utility of the test but do provide additional information regarding the biology of this disease.
Detection of Prostate Cancer Using Prostate-Specific Antigen
The introduction of PSA into clinical practice has greatly increased the detection of localized prostate cancer and, by doing so, has decreased the diagnosis of regional and metastatic disease. PSA has had such a profound clinical effect that questions have arisen regarding the significance of the cancers that are being detected. A number of studies consistently have shown that clinically insignificant cancers are detected in fewer than 20% of men using a PSA cutoff of 4.0 ng/mL, but nearly one half of all the cancers detected because of an elevated PSA level are localized, and these patients are candidates for potentially curative therapy.
Detection of prostate cancer using a combination of PSA and DRE has been evaluated by a number of investigators. In men with prostate cancer whose PSA level was less than 4 ng/mL, normal DRE findings were present in 4-9%, while DRE findings were positive in 10-20%. When the PSA level was greater than 4 ng/mL, negative DRE results were found in 12-32% of patients, while positive DRE results were present in 42-72% of patients.
Clinical stage T1c is defined as prostate cancer detected using a biopsy because of an elevated PSA level and normal DRE findings. This is the most prevalent stage of cancer diagnosed currently. The detection of T1c tumors has increased the probability of the cancer being organ confined at the time of radical prostatectomy to 60%. Adding the DRE to the patient evaluation still demonstrated that 60% of the tumors were organ confined. This adds support to the contention that cancers detected because of PSA testing are likely to be clinically significant.
PSA testing with a cutoff of 4.0 ng/mL has a sensitivity of 67.5-80%. This implies that 20-30% of cancers are missed when only the PSA level is obtained. The sensitivity can be improved by lowering the cutoff or by monitoring PSA values so that a rising PSA level of more than 20-25% per year or an increase of 0.75 ng/mL in a year would trigger performance of a biopsy regardless of the PSA value.
The specificity of PSA at levels greater than 4.0 ng/mL is 60-70%. Specificity can be improved by using age-adjusted values, PSA-V, and determinations of f/tPSA ratios. Another method is to adjust the PSA according to the size of the prostate or volume determinations of the TZ, which produces most of the PSA, and the PZ, which produces less PSA but a majority of the cancers.
Schroder et al (2001) reported on the results of the European Randomized Study of Screening for Prostate Cancer. They sought to develop a strategy for the early detection of prostate cancer using a PSA cutoff of 3.0 ng/mL or greater as the only indication for a biopsy and excluding the DRE as a part of this study. This protocol was compared to one in which a PSA of 4.0 ng/mL or greater or the presence of a positive DRE was the indication for a biopsy. They identified 430 men with prostate cancer of the 8612 men who were screened according to those who had a PSA level of 4.0 ng/mL or greater or those with positive findings on DRE. Tumor characteristics obtained from radical prostatectomy specimens in these men formed the basis for comparison with the other protocol using a cutoff of 3.0 ng/mL and no DRE.
The detection rate (ie, proportion of cancer in those screened) was 5.0 for the PSA cutoff of 4.0 ng/mL and 4.7 for the 7943 men with PSA levels of 3.0 ng/mL. The positive predictive value in both protocols for men whose PSA level was 3.0-3.9 ng/mL was 18.0% and 6.4%, respectively.
Prostate cancer detected with the new strategy (ie, PSA 3.0 ng/mL) had a similar distribution of Gleason scores but a larger proportion of organ-confined disease. Tumor volumes were smallest in patients whose PSA levels were less than 2.9 ng/mL. Minimal disease was present in 50% of these patients, compared to 28% of those whose PSA levels were 3.0-3.9 ng/mL. Lowering the biopsy indication to a PSA of 3.0 ng/mL without a DRE raised the positive predictive value from 18.2% to 24.3%. The number of biopsies required to detect one patient with cancer changed from 5.2 to 3.4. The characteristics of the cancers detected with this strategy had minimal variation from protocols combining PSA, DRE, and transrectal ultrasound.
Babaijan et al studied the incidence of prostate cancer in a screening population of men with a PSA of 2.5-4.0 ng/mL. Of the 268 men who participated in this screening, 151 agreed to have prostate biopsies. Cancer was identified in 37 (24.5%) of these men. Based on the biopsy data, Babaijan et al concluded that the cancer was clinically significant in 67.6% of the detected cancers.
The level of PSA correlates with the detection rate of prostate cancer. Men older than 50 years have a 20-30% possibility of having prostate cancer if their PSA level is greater than 4.0 ng/mL. If the PSA level is 2.5-4.0 ng/mL, a biopsy is likely to detect cancer in 27% of men. For PSA levels greater than 10 ng/mL, the possibility of positive biopsy findings increases to 42-64%. Even at PSA levels of 4-10 ng/mL, Partin et al (1994) found that one half of the patients treated with radical prostatectomy had extraprostatic extension. When the PSA level is greater than 10 ng/mL, the risk of extraprostatic cancer is increased greatly. In the same study, Partin et al noted that 80% of men with PSA levels greater than 20.0 had extraprostatic disease.
Frequency of PSA testing
The goal of early detection of prostate cancer is the identification of patients who have clinically significant cancers at a time when treatment is most likely to be effective. The risk of death from prostate cancer is significant in those with moderate-to-high–grade tumors. This is especially true in younger men. Long-term survival is compromised when the cancer has spread beyond the confines of the prostate, into the regional lymph nodes, and to distant sites.
No generally accepted definition exists of a clinically significant or insignificant cancer. Stage, grade, tumor volume, and PSA testing are used to address this issue.
A large proportion of cancers detected because of PSA testing are clinically significant, and clinically insignificant cancers are unlikely to be detected by PSA screening. Only a small proportion of prostate cancers detected by PSA testing and treated with radical prostatectomy are low-volume (<0.2 cm3) and low-grade (Gleason grade 1-2). Nearly one third of cancers identified because of PSA screening and treated with radical prostatectomy have evidence of capsular penetration, high Gleason grades (4-5), large tumor volumes, or distant metastases. These prognostic risk factors do not always correlate with survival, but they do increase the possibility of tumor recurrence and progression.
Although PSA testing detects more cancers than DRE, a combination of the 2 methods is better. DRE detects more cancers for the PSA cutoff of 4.0 ng/mL, but this may not occur if the cutoff is lowered to 3.0 ng/mL.
PSA screening is recommended annually for all men aged 50 years and older who have an anticipated lifespan of 10 or more years according to guidelines established by the American Urological Association and the American Cancer Society. For men with a family history of prostate cancer or for black men, PSA testing should begin at age 40 years.
Carter et al (1997) evaluated the frequency of PSA testing without compromising prostate cancer detection in men with a low PSA value and normal DRE findings. Using data from the Baltimore Longitudinal Study of Aging, they determined that 95% of men with PSA levels of 4.0 ng/mL or less had potentially curable disease. A Gleason grade of 3 or less and a tumor volume of 0.5 cm3 or less was found in 69% of men studied. In men with pretreatment PSA levels of 4-5 ng/mL, 89% of the cancers were potentially curable and only one third were considered small tumors. Carter et al concluded that potentially curable prostate cancer is not compromised when measuring PSA every other year in men with PSA levels of 2 ng/mL or less, as long as the DRE findings are normal.
Smith et al reported a 4% PSA conversion from a baseline PSA of less than 2 ng/mL to a level of more than 4 ng/mL when patients were observed semiannually for 4 years.
In men with normal DRE findings, PSA screening may be performed annually for those with a stable PSA level greater than 2.5 ng/mL, while PSA screening in those with PSA levels less than 2.5 ng/mL can be performed biannually.
Using the same Baltimore Longitudinal Study of Aging database, Carter et al (1997) further evaluated the association of baseline PSA, age, and prostate cancer detection. They conducted a prospective study of men aged 60-65 years who had serial PSA testing. These men were observed until they either were diagnosed with prostate cancer or reached age 75 years. The time of cancer detection was defined as the date on which a PSA level above 4.0 was detected. All of those diagnosed with cancer had PSA levels greater than 4.0 ng/mL, and 14 of 15 patients with cancer that would have been detected by a PSA conversion among the 65-year-old cohort had PSA levels of 1.1 ng/mL or more.
The authors postulated that if PSA testing were discontinued in men aged 65 years whose PSA level was 0.5 ng/mL or less, 100% (95% CI, 78-100%) of the cancers would be detected by age 75 years. If PSA testing were discontinued in men aged 65 years whose PSA was 1.0 ng/mL or less, 94% (95% CI, 70-100%) of the cancers would be detected by age 75 years.
PSA density
In 1992, Benson et al introduced the concept of PSAD to correlate PSA and prostate volume. This was based on the knowledge that most PSA is produced in the TZ of the prostate; cancer cells produce more PSA per unit volume than benign cells. PSAD is defined as the total serum PSA divided by prostate volume, as determined by transrectal ultrasound measurement. Theoretically, PSAD could help distinguish between prostate cancer and BPH in men whose PSA levels are 4-10 ng/mL. The value of PSAD is limited because of its dependency on the individual performing the prostate volume measurement. In addition, the BPH volume does not always correlate with serum PSA values because of the variation that exists between individuals in their epithelial-to-stromal ratios. PSA is made only by the epithelial cells, which produces a lower PSA level even though the total volume of the prostate is high.
Seaman et al (1994) reported that the value of PSAD could improve the detection rate of cancer at a cutoff of 0.15. In a large multicenter trial, Catalona et al (1998) reported that nearly 50% of cancers would be missed using the cutoff of 0.15. Brawer et al studied 107 men with PSA levels in the 4-10 ng/mL range and found no statistical difference between those with positive and negative biopsy findings using the 0.15 cutoff.
PSA transition zone density
Kalish introduced prostate-specific antigen density of the transition zone (PSA-TZ) as a refinement of the original PSAD. This refinement is predicated on 2 assumptions, as follows: (1) measuring TZ volume by transrectal ultrasonography is more accurate than measuring the entire prostate volume because of the difficulty in measuring the true border of the apex in the longitudinal view, and (2) most of the PSA entering the circulation arises from the TZ.
Zisman et al (2000) have offered a new index using the PZ fraction of PSA to predict the presence of prostate cancer in men with PSA levels of 4-10 ng/mL. They point out that the PZ contributes little to the amount of tPSA. The PZ fraction can be calculated using the following formula:
tPSA X (total prostate volume - TZ volume) / total prostate volume
PZ volume is measured by subtracting the TZ volume from the entire prostate volume while neglecting the central zone. They compared the positive and negative predictive values using tPSA, PSAD, PSA-TZ, and prostate-specific antigen peripheral zone density (PSA-PZ). The efficacy of PSA and PSA-TZ was similar, at 60%. PSA-PZ was 70% and PSAD was 80%. The negative predictive values were superior to the positive predictive values. The negative predictive value for PSA and PSAD ranged from 78-83% and 78-88%, respectively. The negative predictive value of PSA-TZ and PSA-PZ ranged from 87-92% and 81-100%, respectively. Using ROC curves, both PSA-TZ and PSA-PZ were significantly larger than PSA and PSAD. When patients with negative DRE findings were studied using the ROC curve, the area under the PSA-PZ curve was larger than that of the PSA-TZ curve.
PSA velocity
In 1992, Carter et al introduced the concept of PSA-V in an effort to improve the ability of PSA to detect prostate cancer. PSA-V is used to monitor the change in PSA over time using longitudinal measurements. Greater changes in PSA-V were detected in men with cancer compared to those without cancer 5 years before the diagnosis was made. Additional studies have shown that this difference can be detected up to 9 years before prostate cancer diagnosis.
PSA-V is calculated using the following equation:
i/2 ([PSA2 - PSA1 / time 1 in years] + [PSA3 - PSA2 / time 2 in years])
PSA1 = First PSA measurement
PSA2 = Second PSA measurement
PSA3 = Third PSA measurement
At least 3 PSA measurements are needed during a 2-year period or at least 12-18 months apart to obtain maximal benefit from the results.
A PSA-V of 0.75 ng/mL or greater per year was suggestive of cancer (72% sensitivity, 95% specificity). A PSA-V of 0.75 ng/mL or greater correlated with the diagnosis of cancer in 72% of the patients, and only 5% had no cancer. The limitations of PSA-V testing include that it is difficult to calculate, that PSA is not cancer specific, and that PSA varies significantly with time and with different assays. Nevertheless, a PSA-V greater than 0.75 ng/mL per year is useful in some situations in helping to decide the need for initial or repeat biopsy.
Age-specific reference ranges
The standard PSA reference range of 0.0-4.0 ng/mL does not account for age-related volume changes in the prostate that are related to the development of BPH. Oesterling et al (1993) presented the concept that age-related reference ranges would improve cancer detection rates in younger men and would increase the specificity of PSA testing in older men. Using reference ranges of 0-2.5 for men aged 40-49 years, 0-3.5 for men aged 50-59 years, 0-4.5 for men aged 60-69 years, and 0-6.5 for men aged 70-79 years, they reported an overall specificity of 95%.
A different reference range was used for black men. With a PSA range of 0-2 for men aged 40-49 years, specificity was 93%. A PSA range of 0-4 produced a specificity of 88% for men aged 50-59 years, a PSA range of 0-4.5 produced a specificity of 81% for men aged 60-69 years, and a PSA range of 0-5.5 produced a specificity of 78% for men aged 70-79 years.
Using these reference ranges, Partin et al (1994) detected 74 additional cancers in men aged 60 years younger in a study of 4600 men with clinically localized prostate cancer. Pathology results were favorable in men undergoing radical prostatectomy; 80% of these men had organ-confined disease with a Gleason score of 7 or less. Using the same ranges for men older than 60 years, less than 3% of the cancers missed were nonpalpable, of which 95% had favorable histology results. The potential detection of prostate cancer increased 18% in younger men and decreased 22% in older men.
Reissigl et al (1997) studied the effect of biopsy rates and prostate cancer detection using age-specific ranges and a PSA cutoff of 4 ng/mL. The data came from an Austrian screening study of more than 21,000 men aged 45-75 years. They reported an 8% increase in cancer diagnosis of organ-confined disease in men younger than 59 years. In men older than 60 years who had normal DRE findings, 21% fewer biopsies were performed, while 4% of organ-confined cancers were missed. Controversy exists regarding the advantage of age-specific PSA reference ranges compared to the standard PSA cutoff of 4.0 ng/mL.
In an early detection study of 6600 men, Catalona and coworkers (1994) reported that the standard PSA cutoff was optimal for all age groups.
Littrip et al concluded that the standard reference range remains the most effective and least costly means for screening. These investigators argue that a lower PSA cutoff in younger men could result in additional unnecessary biopsies and greater health care costs; whereas raising the cutoff level for older men could result in fewer cancers being detected.
The use of age-specific reference ranges in clinical practice results in the diagnosis of more cancers in men younger than 60 years at the expense of more negative findings on biopsy. However, early potentially curable cancers should be diagnosed in this age group. An increasing number of men in the fifth and sixth decades of life are being diagnosed with significant cancers as a result of using age-specific reference ranges in addition to PSAD and PSA-V. No easy answer is available to decide when biopsies may be avoidable and when they are necessary. Clinical judgment and experience dictate the answer to this dilemma until a perfect test is developed, and that is unlikely.
The influence of race on age-specific reference ranges has been studied. Reports indicate that PSA levels are higher in black men compared to white men, even when controlled for age, clinical stage, and Gleason grade. Moul et al (1999) have suggested that higher PSA values in black men are due partly to larger tumor volumes when compared to white men. In a study of 411 black men with prostate cancer, Morgan et al (1996) reported that 40% of these cancers would have been missed using the standard PSA values.
The Use of Prostate-Specific Antigen To Monitor Therapy
The ultrasensitive PSA assays have increased the lead time for identifying biochemical recurrence following definitive local therapy. These assays can measure PSA levels as low as 0.001 ng/mL. Ellis et al (1997) reported a 10-fold increased sensitivity in 24 patients who had a radical prostatectomy. The patients had a previously undetectable PSA using the conventional assays. Using multivariate analysis, Yu et al (1997) demonstrated a significant advantage in the ability to detect early relapse using ultrasensitive PSA measurement compared to tumor volume and positive surgical margins.
PSA after radical prostatectomy
Serial PSA measurements provide the most effective means of detecting early recurrence following radical prostatectomy. After surgery, most men have a rapid decline in their PSA levels, which are expected to be undetectable within a month. The failure to achieve this level is indicative of residual cancer. A PSA level elevation following a period during which it was undetectable connotes the presence of prostate cells somewhere in the body. This may be from residual normal glandular elements remaining in the bladder wall or at the apex of the prostate, but, generally, a detectable and rising PSA level indicates the presence of cancer cells.
The preoperative PSA level and the time interval between surgery and the detection of PSA using standard assays can be used to predict disease-free survival and the pattern of recurrence. Pound et al analyzed data from 1623 men who had a radical prostatectomy. Their clinical course was followed for 5 years plus or minus 3. The 5-year actuarial recurrence-free rate for men whose initial PSA levels were greater than 20 ng/mL was 54%. For men whose PSA levels were 10.1-20 ng/mL or 4.1-10 ng/mL, the rates were 72% and 82%, respectively. The timing of PSA detection was predictive of local versus distant disease recurrence. During the first year after surgery, 7% of patients with detectable PSA had a local recurrence, but 93% of patients had distant metastases with or without local recurrence. After the second year, the rates were 61% and 39%, respectively.
Patel et al (1997) reported that PSA doubling time was a better predictor of time to clinical recurrence than preoperative PSA, stage, and pathological Gleason score. A PSA doubling time of 6 months or less after surgery indicated metastatic disease. They reported that 80% of 77 patients with detectable PSA postoperatively and a doubling time longer than 6 months remained clinically disease-free, compared to 64% with a PSA doubling time shorter than 6 months. Pound and associates (1999) used a doubling time of 10 months to derive similar conclusions. They cautioned against treating patients with long PSA doubling times too early because most of these men lived for many years before evidence of clinical disease was detected.
PSA-V and pathology stage have been studied to determine treatment failure and the need for additional intervention. A detectable PSA level in a patient with micrometastatic lymph node disease, a Gleason score greater than 7, and/or seminal vesicle invasion indicates distant metastatic disease.
Partin et al (1994) used multivariate analysis to study PSA-V, Gleason score, and pathologic stage to predict local recurrence and distant metastases. In patients whose PSA became detectable a year or more following surgery, a PSA-V less than 0.75 correlated with local recurrence in 94% of patients, while a velocity greater than 0.75 predicted distant disease in more than 50% of patients. A detectable PSA within the first 2 postoperative years is indicative of distant metastases and correlates with other risk factors such as stage and grade. This is important in determining which patients might benefit from local radiation therapy following prostatectomy.
PSA to monitor response to radiation therapy
A consensus has not been reached on an acceptable PSA level following radiation therapy. PSA levels decline slowly, and a nadir may not be reached for a median of 17 months. In some patients, a transient rise in the PSA level may occur at 12 months following completion of therapy, and this usually decreases during the subsequent year.
Two methods generally are used to assess the patient prognosis. In the first method, a nadir of 0.5 ng/mL correlates with a biochemical-free survival of 5 years. The American Society for Therapeutic Radiology and Oncology (ASTRO) recommends another method, in which a biochemical recurrence is defined as 3 consecutive rises above the nadir with measurements obtained at 3- to 6-month intervals.
Pattern of PSA rise after local therapy
A pattern of PSA rise after local therapy distinguishes between local and distant recurrence. Distant disease can be predicted if the PSA does not become undetectable following radical prostatectomy, begins to rise within 12 months, or has a doubling time of 6 months. The same characteristics apply to radiation therapy and cryotherapy, although the time to nadir is prolonged. Patients whose PSA level becomes detectable 24 months or more after radical prostatectomy likely have local recurrence. Patients with PSA doubling times of 12 months or more following surgery, radiation therapy, or cryotherapy are likely to have local recurrence.
Factors Influencing Prostate-Specific Antigen Levels
The serum PSA level can be altered by various medications, noncancerous prostatic disease, and urologic manipulations. Finasteride and dutasteride, 5-alpha reductase inhibitors that are commonly prescribed for the treatment of BPH, can produce a decrease in total prostate levels by 50% within 6 months of therapy. This alteration fluctuates widely, ranging from -81% to +20%. After 3-4 months of therapy, another PSA measurement can be obtained to establish a new baseline.
Alpha1-adrenergic antagonists, which are frequently used to treat the symptoms of BPH, do not alter PSA levels.
Herbal products such as saw palmetto do not affect PSA levels.
fPSA levels are unaffected by finasteride or dutasteride. PSAD (ie, tPSA divided by prostate volume) is affected by 5-alpha reductase medications because the major PSA-producing region of the prostate is reduced in volume.
Any medications that alter testosterone levels can affect the serum PSA. The use of luteinizing hormone-releasing hormone (LHRH) agonists and antagonists to stop production of testosterone by the testicles is a cornerstone in the treatment of prostate cancer. This manipulation produces a profound reduction in PSA levels, usually making them undetectable. Raising testosterone levels may increase PSA levels, but not to the same degree as reducing testosterone production.
Problems With Prostate-Specific Antigen Testing
The advent of PSA testing has revolutionized the diagnosis of prostate cancer and has provided a powerful tool to assess the effects of therapy. Although PSA cannot be used to diagnose prostate cancer and is not a specific prostate cancer marker, the benefits of PSA testing outweigh its drawbacks.
The lack of standardization between assays and laboratories is a major problem. Efforts are underway to correct this situation, but inconsistency between assays may make comparisons difficult.
Another problem involves the handling and processing of the blood samples in physicians' offices or in the laboratories. The blood sample should be centrifuged and the serum should be separated within 2-3 hours. If the assay is not performed within the next 2-3 hours, the serum should be frozen. Once frozen at -20°C or -70°C, the enzyme remains stable for at least a month.
The next problem involves the decision to perform a biopsy in patients with PSA levels in the range of 4-10 ng/mL. In clinical practice, the test often is repeated after a 2- to 4-week course of antibiotics such as doxycycline or a fluoroquinolone, and, if confirmed, a biopsy is performed. The intention is to use the antibiotics to treat any prostatitis present. Prostate cancer would, of course, not be affected by standard antibiotics. The fPSA, PSAD, and other manipulations do not replace clinical judgment.
Screening large populations of men for prostate cancer remains controversial; most clinicians do not screen all of their male patients but make a decision as to which men should be tested based on age, symptoms, family history, expected longevity, general medical condition, physical examination findings, and, often, the patient's request for the test. Urologists obtain PSA measurements for most of their male patients in the appropriate age group because they believe they have an obligation to detect any prostate cancer at the earliest possible stage of its development.
Medical/Legal Pitfalls
The leading cause of malpractice claims against urologists is the failure to diagnose prostate cancer in a timely manner. Primary care physicians and internists also are increasingly being held liable for failure to obtain PSA testing for their patients and for failure to refer those with elevated PSA levels to a urologist.
Confusion remains regarding the reference range for PSA levels. Typically, the reference range has been considered to be 0-4 ng/mL, but this is considered by many to be too high for men in the fifth and sixth decades of life and too low for men older than 75 years. If the reference range is set lower (some advocate a reference range of 0-3 ng/mL), more biopsies are performed and more prostate cancer is detected; however, whether this is clinically significant disease is unknown. Any cancer is a significant finding for men in the fifth to seventh decades of life, but whether diagnosis of prostate cancer in every man older than 70 years is necessary is undetermined. This is a difficult decision and one for which the clinical data are limited. This type of medical decision requires clinical judgment. Certainly, rapidly rising PSA levels should be investigated thoroughly.
Physicians have an obligation to discuss the positives and negatives of PSA testing with their patients. Ample information is available about PSA testing from the American Cancer Society, the American Urological Association, and on the Internet to assist physicians and patients. Men should have periodic PSA testing, and, if a strong family history of prostate cancer exists, the testing should be performed at 6-month intervals. Serially observing PSA levels and performing biopsies on patients whose PSA levels rise more than 20-25% or 0.75 ng/mL in a year represents typical practice. All patients with PSA levels consistently greater than 4.0 should be referred to a urologist for evaluation and a determination of the need for a biopsy.
Keywords
PSA, prostate cancer, digital rectal examination, DRE, prostate acid phosphatase, prostate-specific antigen test, PSA test, ultrasound-guided prostate biopsy, gamma seminoprotein, prostate-specific antigen density, PSAD, prostate-specific antigen velocity, PSA-V, benign prostatic hyperplasia, BPH, prostatitis, human glandular kallikrein-3, hK-3, prostate-specific membrane antigen, PSMA, free prostate-specific antigen, fPSA, complexed prostate-specific antigen, cPSA, total prostate-specific antigen, tPSA, free-to-total prostate-specific antigen ratio, f/tPSA
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References
[Best Evidence] U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. Aug 5 2008;149(3):185-91. [Medline].
Aus G, Skude G. Effect of ultrasound guided core biopsy of prostate on serum concentration of prostate specific antigen and acid phosphatase activity. Scand J Urol Nephrol. 1992;26(1):21-3. [Medline].
Becker C, Piironen T, Pettersson K, et al. Clinical value of human glandular kallikrein 2 and free and total prostate-specific antigen in serum from a population of men with prostate-specific antigen levels 3.0 ng/mL or greater. Urology. May 2000;55(5):694-9. [Medline].
Benson MC, Whang IS, Olsson CA, et al. The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen. J Urol. Mar 1992;147(3 Pt 2):817-21. [Medline].
Benson MC, Whang IS, Pantuck A, et al. Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol. Mar 1992;147(3 Pt 2):815-6. [Medline].
Bostwick DG, Pacelli A, Blute M. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. Jun 1 1998;82(11):2256-61. [Medline].
Brawer MK. Prostate-specific antigen: current status. CA Cancer J Clin. Sep-Oct 1999;49(5):264-81. [Medline].
Brawer MK, Aramburu EA, Chen GL, et al. The inability of prostate specific antigen index to enhance the predictive the value of prostate specific antigen in the diagnosis of prostatic carcinoma. J Urol. Aug 1993;150(2 Pt 1):369-73. [Medline].
Carroll P, Coley C, McLeod D, et al. Prostate-specific antigen best practice policy--part II: prostate cancer staging and post-treatment follow-up. Urology. Feb 2001;57(2):225-9. [Medline].
Carter HB, Epstein JI, Chan DW. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA. May 14 1997;277(18):1456-60. [Medline].
Carter HB, Pearson JD, Metter EJ. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. Apr 22-29 1992;267(16):2215-20. [Medline].
Catalona WJ, Hudson MA, Scardino PT. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol. Dec 1994;152(6 Pt 1):2037-42. [Medline].
Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. May 20 1998;279(19):1542-7. [Medline].
Chen YT, Luderer AA, Thiel RP, et al. Using proportions of free to total prostate-specific antigen, age, and total prostate-specific antigen to predict the probability of prostate cancer. Urology. Apr 1996;47(4):518-24. [Medline].
Chybowski FM, Bergstralh EJ, Oesterling JE. The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study. J Urol. Jul 1992;148(1):83-6. [Medline].
D''Amico AV, Whittington R, Malkowicz SB. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol. Jan 1999;17(1):168-72. [Medline].
Dalton DL. Elevated serum prostate-specific antigen due to acute bacterial prostatitis. Urology. Jun 1989;33(6):465. [Medline].
Eastham JA, Riedel E, Scardino PT. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA. May 28 2003;289(20):2695-700. [Medline].
Ellis WJ, Vessella RL, Noteboom JL. Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay. Urology. Oct 1997;50(4):573-9. [Medline].
Ercole CJ, Lange PH, Mathisen M, et al. Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J Urol. Nov 1987;138(5):1181-4. [Medline].
Ferrari AC, Stone NN, Eyler JN, et al. Prospective analysis of prostate-specific markers in pelvic lymph nodes of patients with high-risk prostate cancer. J Natl Cancer Inst. Oct 15 1997;89(20):1498-504. [Medline].
Fortier AH, Nelson BJ, Grella DK, Holaday JW. Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst. Oct 6 1999;91(19):1635-40. [Medline].
Gormley GJ, Ng J, Cook T, et al. Effect of finasteride on prostate-specific antigen density. Urology. Jan 1994;43(1):53-8; discussion 58-9. [Medline].
Guess HA, Heyse JF, Gormley GJ. The effect of finasteride on prostate-specific antigen in men with benign prostatic hyperplasia. Prostate. 1993;22(1):31-7. [Medline].
Haese A, Becker C, Noldus J, et al. Human glandular kallikrein 2: a potential serum marker for predicting the organ confined versus non-organ confined growth of prostate cancer. J Urol. May 2000;163(5):1491-7. [Medline].
Hara M, Inorre T, Fukuyama T. Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma. Jpn J Legal Med. 1971;25:322-324.
Hara M, Inoue T, Koyanagi Y. Preparation and immunoelectrophoretic assessment of antisera to human seminal plasma. Jpn J Legal Med. 1966;20:356.
Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology. Aug 1997;50(2):239-43. [Medline].
Higashihara E, Nutahara K, Kojima M, et al. Significance of serum free prostate specific antigen in the screening of prostate cancer. J Urol. Dec 1996;156(6):1964-8. [Medline].
Irani J, Levillain P, Goujon JM, et al. Inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. J Urol. Apr 1997;157(4):1301-3. [Medline].
Kirkali Z, Kirkali G, Esen A. Effect of ejaculation on prostate-specific antigen levels in normal men. Eur Urol. 1995;27(4):292-4. [Medline].
Lee F, Littrup PJ. The role of digital rectal examination, transrectal ultrasound, and prostate specific antigen for the detection of confined and clinically relevant prostate cancer. J Cell Biochem Suppl. 1992;16H:69-73. [Medline].
Li TS, Beling CG. Isolation and characterization of two specific antigens of human seminal plasma. Fertil Steril. Feb 1973;24(2):134-44. [Medline].
Lilja H, Haese A, Bjork T, et al. Significance and metabolism of complexed and noncomplexed prostate specific antigen forms, and human glandular kallikrein 2 in clinically localized prostate cancer before and after radical prostatectomy. J Urol. Dec 1999;162(6):2029-34; discussion 2034-5. [Medline].
Lovgren J, Piironen T, Overmo C. Production of recombinant PSA and HK2 and analysis of their immunologic cross-reactivity. Biochem Biophys Res Commun. Aug 24 1995;213(3):888-95. [Medline].
Luderer AA, Chen YT, Soriano TF, et al. Measurement of the proportion of free to total prostate-specific antigen improves diagnostic performance of prostate-specific antigen in the diagnostic gray zone of total prostate-specific antigen. Urology. Aug 1995;46(2):187-94. [Medline].
Morgan TO, Jacobsen SJ, McCarthy WF. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med. Aug 1 1996;335(5):304-10. [Medline].
Moul JW, Connelly RR, Mooneyhan RM. Racial differences in tumor volume and prostate specific antigen among radical prostatectomy patients. J Urol. Aug 1999;162(2):394-7. [Medline].
Nadler RB, Humphrey PA, Smith DS, et al. Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. J Urol. Aug 1995;154(2 Pt 1):407-13. [Medline].
Neal DE Jr, Clejan S, Sarma D. Prostate specific antigen and prostatitis. I. Effect of prostatitis on serum PSA in the human and nonhuman primate. Prostate. 1992;20(2):105-11. [Medline].
Nixon RG, Brawer MK. Refinements in serum prostate-specific antigen testing for the diagnosis of prostate cancer. In: Hendry WF, Kirby AS, eds. Recent Advances in Urology. 7th ed. London, England:. Churchill Livingstone;1998.
Oesterling JE, Rice DC, Glenski WJ. Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on serum prostate-specific antigen concentration. Urology. Sep 1993;42(3):276-82. [Medline].
Ohori M, Dunn JK, Scardino PT. Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer?. Urology. Nov 1995;46(5):666-71. [Medline].
Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology. May 1994;43(5):649-59. [Medline].
Patel A, Dorey F, Franklin J. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol. Oct 1997;158(4):1441-5. [Medline].
Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery--what we have learned and where we are going. J Urol. Aug 1999;162(2):293-306. [Medline].
Pound CR, Partin AW, Eisenberger MA. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. May 5 1999;281(17):1591-7. [Medline].
Recker F, Kwiatkowski MK, Piironen T. The importance of human glandular kallikrein and its correlation with different prostate specific antigen serum forms in the detection of prostate carcinoma. Cancer. Dec 15 1998;83(12):2540-7. [Medline].
Reissigl A, Bartsch G. Prostate-specific antigen as a screening test. The Austrian experience. Urol Clin North Am. May 1997;24(2):315-21. [Medline].
Schellhammer PF, Wright GL Jr. Biomolecular and clinical characteristics of PSA and other candidate prostate tumor markers. Urol Clin North Am. Nov 1993;20(4):597-606. [Medline].
Schroder FH, Roobol-Bouts M, Vis AN. Prostate-specific antigen-based early detection of prostate cancer-- validation of screening without rectal examination. Urology. Jan 2001;57(1):83-90. [Medline].
Seaman EK, Whang IS, Cooner W. Predictive value of prostate-specific antigen density for the presence of micrometastatic carcinoma of the prostate. Urology. May 1994;43(5):645-8. [Medline].
Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. Oct 8 1987;317(15):909-16. [Medline].
Stenman UH, Leinonen J, Alfthan H. A complex between prostate-specific antigen and alpha 1- antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res. Jan 1 1991;51(1):222-6. [Medline].
Sutkowski DM, Goode RL, Baniel J, et al. Growth regulation of prostatic stromal cells by prostate-specific antigen. J Natl Cancer Inst. Oct 6 1999;91(19):1663-9. [Medline].
Tchetgen MB, Song JT, Strawderman M, et al. Ejaculation increases the serum prostate-specific antigen concentration. Urology. Apr 1996;47(4):511-6. [Medline].
Vessella RL, Lange PH. Issues in the assessment of PSA immunoassays. Urol Clin North Am. Nov 1993;20(4):607-19. [Medline].
Wang MC, Valenzuela LA, Murphy GP. Purification of a human prostate specific antigen. Invest Urol. Sep 1979;17(2):159-63. [Medline].
Wymenga LF, Groenier K, Visser-van Brummen P. Reliability analysis of first and second generation PSA assays. Can J Urol. Aug 2000;7(4):1070-6. [Medline].
Yu H, Diamandis EP, Wong PY. Detection of prostate cancer relapse with prostate specific antigen monitoring at levels of 0.001 to 0.1 microG./L. J Urol. Mar 1997;157(3):913-8. [Medline].
Zisman A, Leibovici D, Kleinmann J. Predicting CAP in patients with intermediate PSA using modified PSA indices. Can J Urol. Dec 2000;7(6):1144-8. [Medline].
Further Reading
Keywords
PSA, prostate cancer, digital rectal examination, DRE, prostate acid phosphatase, prostate-specific antigen test, PSA test, ultrasound-guided prostate biopsy, gamma seminoprotein, prostate-specific antigen density, PSAD, prostate-specific antigen velocity, PSA-V, benign prostatic hyperplasia, BPH, prostatitis, human glandular kallikrein-3, hK-3, prostate-specific membrane antigen, PSMA, free prostate-specific antigen, fPSA, complexed prostate-specific antigen, cPSA, total prostate-specific antigen, tPSA, free-to-total prostate-specific antigen ratio, f/tPSA
