Prostate-specific antigen (PSA) is a glycoprotein produced primarily by the epithelial cells that line the acini and ducts of the prostate gland. PSA is concentrated in prostatic tissue, and serum PSA levels are normally very low. Disruption of the normal prostatic architecture, such as by prostatic disease, allows greater amounts of PSA to enter the general circulation. Elevated serum PSA levels have become an important marker of prostate pathologieswhich include benign prostatic hyperplasia, prostatitis, and especially prostate cancer, the focus of this document. Prostatic intraepithelial neoplasia (PIN) does not appear to raise serum PSA levels.
Prostate cancer is the most common form of noncutaneous cancer in men in the United States, and the second leading cause of male cancer mortality, accounting for more than 30,000 deaths in 1999 (American Cancer Society). The natural history of this disease is remarkably heterogeneous and, at this time, is not clearly understood. Autopsy studies have shown that approximately one in three men over the age of 50 years has histologic evidence of prostate cancer, with up to 80% of these tumors being microscopic in size or clinically insignificant. Fortunately, only about 3% of men will die from this disease.[2-4]
Some studies have found that a large proportion of patients diagnosed with clinically localized prostate cancer who did not receive early aggressive treatment still had favorable clinical outcomes and normal life expectancies. Most of these studies included an older population of men as well as a larger proportion of men with low-grade tumors than in a series of men treated for prostate cancer. This disparity between the high prevalence rates for histologic prostate cancer and the relatively low lifetime risk of prostate cancer death highlights the difficulty in distinguishing cancers destined to cause significant illness and premature death from those that will not.
PSA testing is one of several measures that can be used to identify high-risk tumors (Figure 1). Other such measures include: Gleason score, clinical stage, and the patients estimated life expectancy.[5,6] Because of the biological variability of prostate cancer and the lack of a completed randomized, controlled trial that proves the benefit of early detection, the use of PSA for prostate cancer early detection remains controversial.
1. The goal of early prostate cancer detection.
The goal of early detection is to identify patients who have clinically significant prostate cancers, ie, cancers that are at an early stage when treatment is most likely to be effective. The risk of prostate cancer death can be substantial, especially in younger patients with moderate- or high-grade tumors. Studies have shown that long-term survival is considerably diminished in men diagnosed with prostate cancer that has already spread beyond the confines of the prostate to regional lymph nodes or more distant sites. In general, tumors in such cases are not curable, although patients may benefit from palliative therapies. Cure is defined in this document as lifetime freedom from the disease.
2. The proportion of clinically significant prostate cancer detected with PSA is unknown.
There is currently no universally accepted definition of what is clinically significant or insignificant prostate cancer. Ideally, such a determination would be made using only information obtained noninvasively, allowing an accurate decision to avoid aggressive therapy in certain patients. Previous studies have focused on measures such as cancer volume, pathologic stage, surgical margin status, and biopsy histologic grade.[8-12]
Tumor grade appears to be the strongest prognostic factor, although such assessments, even from multiple biopsy specimens, are subject to sampling errors.[8,9] The most common system currently in use is the Gleason grading system based on architectural criteria. The pathologist assigns a primary grade from 1 to 5, with 5 being the most aggressive, to the pattern occupying the greatest area of the specimen. A secondary grade is then assigned to the pattern occupying the second largest area. These two grades are added to determine the Gleason score, which ranges from 2 to 10. It is generally agreed that tumors with a Gleason score of 2 to 4 have lower biological aggressiveness, scores of 5 to 6 have an intermediate aggressiveness, and those with a Gleason score ³ 7 are biologically aggressive tumors.
Tumor volume exceeding 0.5 mL (a characteristic of roughly one-fifth of prostate cancers discovered during incidental autopsies) is considered by many experts to predict clinical significance. Tumors that exceed 0.5 to 1.9 mL of volume appear to produce sufficient amounts of serum PSA to exceed the normal range and begin to exhibit spread beyond the prostate (extraprostatic disease).[15-17] No currently available noninvasive imaging method(s) can reliably measure tumor volume.
Several studies have found that a very large proportion of cancers detected through PSA testing are likely to be clinically important, but that PSA testing is unlikely to detect many of the more prevalent small-volume histologic cancers.[7,19,20] Only a small proportion of prostate tumors detected by PSA and treated with radical prostatectomy are subsequently found to be clinically insignificant (ie, very small and low grade).[9,19-22]
Approximately one-third of cancers found through early detection efforts with PSA and treated surgically have evidence of extracapsular spread, poorly differentiated histology, large tumor volume, or distant metastasis.[9,19-21] Although these features do not always indicate a poor outcome or ultimate death from the disease, they correlate with a significantly greater chance of disease progression. Also of note, autopsy studies have found capsular penetration, lymph node spread, and poorly differentiated tumors in a limited number of patients with no clinical suspicion of prostate cancer.
Recent data suggest that combinations of preoperative data, including PSA level, clinical stage, and Gleason score from biopsy, can significantly enhance the ability to predict actual pathologic stage. The value of such combinations, however, for clinical decision-making with individual patients remains uncertain.
3. PSA testing detects more tumors than does DRE, and it detects them earlier. However, the most sensitive method for early detection of prostate cancer uses both DRE and PSA. Both tests should be employed in a program of early prostate cancer detection.
Prior to the use of PSA for early detection of prostate cancer, digital rectal examination (DRE) detected considerably fewer tumors. It is generally accepted that the dramatic increase (by 82% in men over age 65 years) in prostate cancer detection between 1986 and 1991 was due to the proliferation of PSA testing.[24,25] Of prostate cancers currently detected, about 75% have an abnormal PSA.
During the pre-PSA era (before about 1986-1987), as many as 35% of all patients with what was thought to be clinically confined prostate cancer were found to have positive lymph nodes, and two-thirds had pathologically advanced disease.[26,27] Currently, lymph node involvement is noted in less than 5% of patients, and there is evidence that serial PSA testing (eg, yearly testing) has led to a decrease in the number of patients with pathologically advanced disease.[23,28]
PSA testing thus detects more tumors than does DRE and detects them earlier. Although many of these tumors have aggressive characteristics, some may grow slowly enough that they pose no risk to the patient. As yet, there is no way to identify with certainty the tumor that has no risk of spreading and potentially causing premature death or morbidity.[21,29]
PSA is currently the best single test for early prostate cancer detection, but the combination of PSA and DRE is betterbecause DRE will detect some of the tumors in patients who have prostate cancer despite a normal PSA of less than 4.0 ng/mL.[4,30] Transrectal ultrasonography is not a useful test for early prostate cancer detection; it adds little to the combination of PSA and DRE.[4,30]
Evidence from three uncontrolled studies that allow a direct comparison of the yields of PSA and DRE suggests that combining both tests improves the overall rate of prostate cancer detection when compared with either test alone.[31-33] In these studies, volunteers were tested uniformly with both PSA and DRE. From 18% to 26% of patients had either an abnormal PSA or an abnormal DRE. Cancer was detected in 3.5% to 4.0% of patients. Although PSA identified a larger number of cancers than did DRE, PSA and DRE each detected cancers not identified by the other. Also of note, approximately 20% of prostate cancers with aggressive features are found in men whose PSA level is less than 4 ng/mL.
There is clearly strong evidence in favor of including both DRE and PSA in any program for early detection of prostate cancer. However, the value of serial determinations of PSA or DRE in patients with a normal initial examination is unknown. There is evidence, as mentioned previously, that serial PSA determinations lead to a decrease in detection of pathologically advanced disease.