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
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.
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This document was developed by the PSA Best Practice Policy Task
Force, convened by the American Urological Association (AUA). Members
of this multidisciplinary task force include:
Ian Thompson, MD
Professor and Chair,
Division of Urology,
University of Texas Health Sciences
Center at San Antonio,
7703 Floyd Curl Drive,
San Antonio, Texas 78284
Peter Carroll, MD
Professor and Chair,
Department of Urology, University of California U-575, UCSF Medical Center, 533 Parnassus Avenue,
San Francisco, California 94143
Christopher Coley, MD
Chief of Medicine, Harvard University Health Services, 75 Mount Auburn Street,
Cambridge, Massachusetts 02138
Greg Sweat, MD
Instructor, Department of Family Medicine, Mayo Clinic, Rochester, Minnesota 55905
Chief of Urology, Walter Reed Army Medical Center, Washington, DC 20307-5001
Paul Schellhammer, MD
Department Head, Eastern Virginia Graduate School of Medicine, Norfolk, Virginia 23507
John Wasson, MD
Herman O. West Chair of Geriatrics, and Director for the Center for Aging, Dartmouth Medical School,
Department of Community and Family Medicine, Hanover, New Hampshire 03756