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Editorial |
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287
a Address correspondence to this author at: Department of Pathology, The Johns Hopkins Medical Institutions, 600 N. Wolfe St., Meyer B-121, Baltimore, MD 21287. Fax 410-955-0767; e-mail dchan{at}pathlan.path.jhu.edu
In the quarter-century since its discovery (1), prostate-specific antigen (PSA) has been recognized as the most effective tumor marker for prostate cancer and has unquestionably played an important role in the diagnosis and clinical management of this disease. Prostate cancer remains the leading cancer site in men, with 179 300 new cancer cases estimated by the American Cancer Society for 1999, a slight decrease from the 1998 estimate of 184 500 cases(2). In addition to decreasing cancer cases, deaths from prostate cancer and cancer in general are declining, and prostate cancer survival rates are increasing (2). The incidence of prostate cancer has changed dramatically in the PSA era following the introduction of the first generation of PSA assays in the mid-1980s. Prostate cancer incidence increased 84% between 1987 and 1992 and then declined 46% between 1992 and 1994. This pattern has been attributed, in part, to increased cancer detection as a result of PSA testing with subsequent earlier diagnoses (3). Early detection of cancer affords a greater chance of detecting cancers at an early stage, when cancer is confined to the prostate and curative treatment is possible.
Although PSA is considered an effective tumor marker and is for all
intents and purposes organ specific, it is not cancer specific. There
is considerable overlap in PSA concentrations in men with prostate
cancer and men with benign prostate diseases, particularly in the range
of 4–10 µg/L. This range has thus been termed the diagnostic gray
zone. Several approaches have been proposed and investigated to improve
the diagnostic accuracy of PSA, including age-specific reference
ranges, PSA density, PSA velocity, neural network-derived indexes, and
the molecular forms of PSA (4). Use of the molecular forms,
primarily focusing on free PSA and PSA bound to
1-antichymotrypsin (ACT), has shown the most
promise. In an article in a previous issue of Clinical
Chemistry (5) and one in the present issue(6), Zhang and co-workers from the laboratory of Dr.
Ulf-Håkan Stenman describe the formation of PSA complexes with
2-macroglobulin (A2M) and
1-protease inhibitor (API); these articles are
significant for their contributions in furthering the attempt to
improve the clinical utility of PSA as well as the understanding of the
biology of PSA.
PSA, synthesized in the ductal epithelium of the prostate, is a member of the human kallikrein gene family and functions as a serine protease. PSA has been observed to form complexes with ACT, A2M, API, and protein C inhibitor in vitro (7), with the majority of PSA in serum complexed to ACT and A2M. In the early 1990s, Lilja et al.(8) and Stenman et al. (9) discovered that in serum, the majority of PSA (80–90%) is bound to protease inhibitors, whereas a small proportion (10–20%) is in the free form. It was also discovered that men with prostate cancer and men without cancer may differ in the proportions of free PSA and PSA-ACT, with a higher percentage of PSA bound to ACT in men with cancer (9).
Current total-PSA assays measure free PSA and available PSA complexes, primarily PSA-ACT. PSA-A2M is not immunoreactive because of the encapsulation of PSA by the A2M molecule. A second generation of assays for some of the molecular forms of PSA has been developed, based on the discoveries of Lilja et al. (8) and Stenman et al.(9). The development of assays for PSA-ACT has lagged behind that of assays for free PSA because of initial problems with nonspecific binding resulting from complexes between ACT and cathepsin G, the physiologic binding partner for ACT (10). Recently, however, an automated assay that measures all available PSA complexes (cPSA) was introduced by Bayer for the Immuno 1 analyzer. With the exception of PSA-ACT, little has been known about the concentrations of other circulating PSA complexes in prostate cancer and benign prostatic hyperplasia (BPH) until the recent work of Zhang and co-workers(5)(6), published in this journal.
Although the binding of PSA and A2M has been studied in vitro, attempts to quantify PSA-A2M in serum with A2M antibody-based assays have been hampered by nonspecific binding of A2M (5)(11). Measurement of PSA-A2M is also difficult because of the need to denature the A2M molecule to expose PSA epitopes. Sodium dodecyl sulfate has been investigated as a denaturing agent(12)(13), whereas high pH was used by Zhang et al. (5). In the assay described by Zhang et al.(5), serum PSA-A2M was measured using a PSA immunoassay after immunoadsorption of circulating immunoreactive PSA and denaturation of the remaining PSA-A2M complexes. Although the assay correlated with total-PSA concentrations in patient specimens, it underestimated PSA-A2M. Despite assay limitations, Zhang et al. were able show an increased median ratio of A2M-PSA to total PSA in BPH patients (19.5%) compared with prostate cancer patients (14.5%) when total-PSA concentrations were between 4 and 10 µg/L. This is in contrast to the behavior of PSA-ACT and may be explained by the mechanism of complex formation, observed in in vitro experiments, and by clearance (5). In the 4–10 µg/L diagnostic gray zone, the area under the ROC curve was greater for the percentage of PSA-A2M compared with total PSA. Unfortunately, the percentage of free PSA was not measured for comparison.
Zhang et al. (6) have also characterized PSA-API serum complexes with the development of a time-resolved immunofluorometric assay. Using this assay, they were able to quantify the proportion of PSA-API present in the sera of patients with prostate cancer or BPH and determined that although the majority of patients with detectable concentrations had <5% circulating PSA-API, a significant percentage of total PSA was attributable to PSA-API in 18% of patients with prostate cancer and 36% of patients with BPH. They additionally identified that free PSA, PSA-ACT, and PSA-API account for essentially all immunoreactive PSA. Differences among commercial assays for total PSA have been attributed primarily to antibody specificity and recognition of the free and ACT-complexed forms of PSA. The total-PSA immunofluorometric assay used in this study was deemed to be equimolar with respect to reactivity toward PSA-API and free PSA. It remains to be determined what role, if any, PSA-API will have in explaining discrepancies noted between other commercial PSA assays. As pointed out by the authors, it is clear that PSA-API does need to be considered in the standardization of current PSA assays and that the 90% PSA-ACT-10% free PSA standard (14) proposed to reduce intermethod differences is affected by PSA-API.
Zhang et al. (6) determined that the sum of free PSA, PSA-ACT, and PSA-API concentrations approximated the total PSA concentration and thus accounted for most, if not all, of the immunoreactive PSA in serum. In contrast to PSA-ACT, both PSA-A2M and PSA-API appear to constitute a higher percentage of total PSA in BPH than in cancer. Knowledge of these previously missing puzzle pieces may add to the discriminatory power of some of the other PSA molecular forms, either individually or in combination. In contrast, the specificity of PSA-ACT alone for the detection of prostate cancer may also be diminished in assays measuring all immunoreactive complexes. However, the percentage of free PSA and the percentage of complexed PSA have been reported to be equivalent in clinical utility(15). A new assay recently has been developed that combines a precipitating reagent to remove PSA-ACT from serum specimens and a total-PSA assay to measure the remaining free PSA and PSA complexes (Scantibodies Laboratory). The implications of this approach remain to be determined. Further studies are therefore needed to define the role of these newly characterized PSA forms in benign and malignant prostate diseases.
Despite the ability of the percentage of free PSA (16) and other molecular PSA forms to increase the specificity of total PSA in the diagnostic gray zone of 4–10 µg/L, there is a range of free PSA from 10% to 25% that can constitute an additional diagnostic gray zone. Of other markers similar or related to PSA, human kallikrein 2 (hK2) (17) seems to be the most promising to perhaps improve the differentiation of prostate cancer and BPH in the diagnostic gray zone for total PSA between 4 and 10 µg/L and the diagnostic gray zone for the percentage of free PSA between 10% and 25% by using a ratio of total hK2 to free PSA. The percentage of free PSA and the hK2:free PSA ratio have also been shown to increase the specificity of cancer detection for PSA concentrations between 2 and 4 µg/L(18).
Although PSA has been used successfully as a tumor marker for the early detection of prostate cancer (in conjunction with digital rectal examination), for monitoring of treatment, and for detecting recurrence following definitive treatment, there is still a considerable amount that is unknown about the biology of PSA as well as considerable potential to improve on the clinical utility of this tumor marker. The two articles in Clinical Chemistry by Zhang and co-workers (5)(6) characterizing PSA-A2M and PSA-API illustrate these facts and have made a significant contribution to the growing knowledge about PSA.
References
2-macroglobulin. Clin Chem 1998;44:2471-2479.
1-protease inhibitor in serum. Clin Chem 1999;45:814-821.
1-antichymotrypsin. Clin Chem 1991;37:1618-1625.
2-macroglobulin. Clin Chem 1996;42:545-550.
The following articles in journals at HighWire Press have cited this article:
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  B. R. Grzeda, T. Le Bui, C. N. Warner, T. L. Pirucki, L. M. Dewey, M. Babich, and J. A. Maggiore Measurement of Prostate-specific Antigen by Use of a Novel Blood Collection and Analytical System Clin. Chem., August 1, 2002; 48(8): 1272 - 1278. [Abstract] [Full Text] [PDF]
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 K. R. Swanson, L. D. True, D. W. Lin, K. R. Buhler, R. Vessella, and J. D. Murray A Quantitative Model for the Dynamics of Serum Prostate-Specific Antigen as a Marker for Cancerous Growth : An Explanation for a Medical Anomaly Am. J. Pathol., June 1, 2001; 158(6): 2195 - 2199. [Abstract] [Full Text] [PDF]
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D. W. Chan and L. J. Sokoll WHO First International Standards for Prostate-specific Antigen: The Beginning of the End for Assay Discrepancies? Clin. Chem., September 1, 2000; 46(9): 1291 - 1292. [Full Text] [PDF]
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