Japanese Journal of Clinical Oncology 31:506-509 (2001)
© 2001 Foundation for Promotion of Cancer Research
Significance of Prostate-specific Antigen–
1-Antichymotrypsin Complex for Diagnosis and Staging of Prostate Cancer
1Department of Urology, Kobe University School of Medicine, Kobe and 2 Department of Urology, Hyogo Perceptual Awaji Hospital, Sumoto, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective: To evaluate the clinical significance of measuring the prostate-specific antigen–
1-antichymotrypsin (PSA–ACT) for differentiating prostate cancer from benign prostate hypertrophy (BPH) and for the staging of prostate cancer. Methods: Before treatment, total PSA (tPSA) and PSA–ACT were measured in 120 patients with prostate cancer and in 150 patients with BPH using immunofluorometric techniques with different monoclonal antibodies against PSA and ACT. Furthermore, the tPSA and PSA–ACT densities of the whole prostate (PSAD and ACTD, respectively) were calculated.
Results: tPSA, PSAD, PSA–ACT and ACTD levels in patients with prostate cancer paralleled the clinical stage and were significantly higher than those in patients with BPH. Furthermore, these four values were significantly higher in patients with pathologically extraprostatic disease than those with organ-confined disease. Receiver operating characteristics analysis among patients with PSA values of 4.1–10 ng/ml revealed that the areas under the curve for tPSA and ACTD were similar to those for PSA–ACT and ACTD, respectively and that no significant differences in the differentiation between prostate cancer and BPH were observed among these parameters.
Conclusions: Measurement of PSA–ACT provides useful information for the clinical staging of prostate cancer and differential diagnosis between prostate cancer and BPH; however, compared with tPSA, PSA–ACT may not be significantly superior in the diagnosis and staging of prostate cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Serum prostate-specific antigen (PSA) has been demonstrated to be a useful marker for the diagnosis and staging of prostate cancer, but it appears to have limited value particularly in patients with intermediate PSA levels, since elevated serum PSA could be found in patients with benign prostatic disease, such as benign prostatic hypertrophy (BPH) and prostatitis (1). Therefore, in order to increase specificity in the diagnosis and staging of prostate cancer, the value of several PSA-related parameters have been evaluated, including PSA density (PSAD) (2), PSA velocity (3) and free-to-total PSA ratio (4). Despite promising results in previous studies, no method has been sufficiently reliable to allow clinical decision making in individual patients for either discriminating between benign and malignant prostate disease or predicting the extent of prostate cancer.
Recent studies have demonstrated that PSA in serum occurs in different molecular forms. The majority of PSA is complexed with serum protease inhibitors, that is, ~70–90% is bound to 1-antichymotrypsin (ACT), a smaller amount being complexed with 1-antitrypsin, 2-macrogloblin and C protein, whereas 10–30% of total PSA (tPSA) is not bound to serum proteins and is called free PSA (5). Moreover, several studies have shown that serum from patients with prostate cancer contains a higher proportion of PSA–ACT than that from patients with benign prostatic disease (5,6). Serum PSA–ACT therefore appears to be more closely associated with the progression of prostate cancer than serum PSA. However, to our knowledge, relatively few studies evaluating the value of measuring serum PSA–ACT for the diagnosis and staging of prostate cancer have been reported and their conclusions are not consistent (7–10).
In the present study, we retrospectively analyzed the clinical usefulness of measurement of the serum PSA–ACT level and its density for the staging of prostate cancer and also the differential diagnosis of prostate cancer among patients with intermediate serum PSA levels.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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A total of 120 patients with prostate cancer and 150 patients with BPH were enrolled in this study. Blood samples were collected before digital rectal examination (DRE) and transrectal ultrasound (TRUS) of prostate from patients who had not received any treatment for prostate cancer. After the blood had been allowed to clot for 60 min at room temperature, serum was separated by centrifugation at 2000 g for 15 min at 4°C, stored at –80°C within 1 h and then assessed during a 1–12-week period.
All patients were pathologically confirmed as having BPH or prostate cancer by systematic sextant transrectal biopsies of the prostate under the guidance of TRUS. Indications for prostate biopsies were a serum tPSA level >4.1 ng/ml and/or a suspicious DRE irrespective of TRUS findings. The clinical stage was classified according to the criteria advocated by the Japanese Urological Association and the Japanese Pathological Society (11), based on the findings of TRUS, DRE, pelvic computed tomography, magnetic resonance imaging and bone scan.
tPSA and PSA–ACT were measured using immunofluorometric assay systems (Tosoh, Tokyo, Japan and Dainippon Pharmaceutical, Osaka, Japan, respectively). PSAD and PSA–ACT density (ACTD) were calculated by dividing the serum tPSA and PSA–ACT values by the prostate volume, respectively. Prostate volume was determined by a single urologist (S.H.) based on the findings of TRUS as described previously (12). Briefly, the anteroposterior (AP) and transverse (TR) greatest dimensions were measured at their respective greatest dimensions and the superior–inferior (SI) greatest dimension was measured at the maximum length from the base to the apex of the prostate in the middle sagital plane. The prostate volume was calculated from the equation of a prolate ellipsoid: volume = 0.52 x TR x AP x SI.
Values from patients with and without prostate cancer were compared using the Mann–Whitney U-test. Receiver operating characteristic (ROC) curve analyses, which were plotted as graphical presentations of sensitivity against 100 minus the corresponding specificity, were performed and the area under the curve (AUC) was calculated as described previously (13). Probability values (P values) of <0.05 were considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The clinical stage of the 120 patients with prostate cancer was stage B in 48, C in 32 and D in 40. As shown in Table 1, tPSA, PSAD, PSA–ACT and ACTD levels paralleled the clinical stage of prostate cancer. In addition, Table 1 shows significant differences between patients with prostate cancer and BPH with respect to tPSA, PSAD, PSA–ACT and ACTD. Significant differences in tPSA, PSAD, PSA–ACT and ACTD values were also observed between patients even with stage B disease and BPH.
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Among 120 patients with prostate cancer, 42 underwent radical prostatectomy and pelvic lymphadenectomy. Pathological examination revealed that the disease was organ- and non-organ (extraprostatic extension) -confined in 20 and 22 patients, respectively. Table 2 shows the findings of PSA, PSAD, PSA–ACT and ACTD analyses in organ-confined versus extraprostatic diseases. In patients with organ-confined diseases, the mean levels of PSA, PSAD, PSA–ACT and ACTD were significantly lower than those in extraprostatic diseases; however, among them, none provided significant discriminative power compared with the other three variables.
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We then analyzed the ROC curves in patients with serum PSA values of 4.1–10 ng/ml to evaluate the clinical usefulness of tPSA, PSAD, PSA–ACT and ACTD for differentiation of prostate cancer and BPH. In the present series, there were 27 patients with prostate cancer and 93 patients with BPH with a PSA range of 4.1–10 ng/ml. Although the differences were not significant, the ROC curves for PSA–ACT and ACTD were superior to those for tPSA and PSAD, respectively, for the discrimination between prostate cancer and BPH (Fig. 1), that is, the AUCs were 0.711, 0.785, 0.736 and 0.792 for tPSA, PSAD, PSA–ACT and ACTD, respectively.
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The specificity of each assay within the range 80–95% sensitivity was calculated (Table 3). As determined by ROC analysis, PSA–ACT and ACTD provided better specificities than tPSA and PSAD, respectively; however, no significant difference in the specificities was observed among these assays.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Theoretically, the occurrence of the various PSA forms in serum allows for a better discrimination between prostate cancer and BPH (1,4), that is, the proportion of PSA complexed with ACT increases in patients with prostate cancer and there is a close association between tPSA and PSA–ACT (5,6). These findings suggest that serum PSA–ACT may be more closely associated with the progression of prostate cancer than serum PSA, and, therefore, could be more useful for staging and diagnosis of prostate cancer. However, only limited findings have been reported and they remain controversial (7–10). Thus, the value of PSA–ACT had not been established; therefore, in the present study, we evaluated the clinical significance of measurement of the PSA–ACT for the differentiation of prostate cancer from BPH and for the preoperative staging of prostate cancer.
We first demonstrated the significant elevation of PSA, PSAD, PSA–ACT and ACTD levels in patients with prostate cancer compared with those in patients with BPH. Furthermore, tPSA, PSAD, PSA–ACT and ACTD levels in patients with prostate cancer paralleled the clinical stage. We then verified the abilities of these four variables to differentiate extraprostatic disease from organ-confined disease. Although PSA–ACT and ACTD provided more precise information as potential markers for the biochemical staging than tPSA and PSAD, respectively, no significant difference in the usefulness of staging were observed among these variables.
All four values assessed in this series differed significantly between patients with BPH and prostate cancer, suggesting that they may be appropriate parameters to distinguish between these two groups. We therefore examined whether PSA–ACT and ACTD could diagnose prostate cancer more effectively than PSA and PSAD using ROC analysis in patients with serum PSA values of 4.1–10 ng/ml. The AUCs of PSA–ACT and ACTD were larger than those of tPSA and PSAD, respectively; however, no significant differences were found in the AUCs among these four assays. The specificities of these assays within the range 80–95% sensitivity showed similar results to the ROC analysis, that is, despite the provision of better specificity by PSA–ACT and ACTD than PSA and PSAD, respectively, no significant differences were observed among them. Therefore, it might be difficult to avoid unnecessary prostate biopsies in patients with intermediate serum PSA levels by the introduction of PSA–ACT assay.
As described above, several conflicting data regarding the value of PSA–ACT in the detection of prostate cancer have been reported (7–10). These discrepancies may possibly be explained as follows. 1) Each investigator employed different conditions for the preparation and storage of serum samples and also employed different immunofluorometric assay systems for the measurement of PSA–ACT. 2) The method of prostate biopsy was different for each institution, including whether the repeated biopsy was performed when histological results were negative. 3) The sum of free PSA plus PSA–ACT equals the tPSA in patients with benign prostatic disease but not with prostate cancer owing to the increased occurrence of minor forms of complexed PSA in serum obtained from prostate cancer patients. Moreover, the present results were different from those theoretically predicted according to the previously reported findings that serum PSA–ACT may be more closely associated with disease progression than serum PSA (5,6). Therefore, further studies involving a larger number of samples should be performed under identical conditions and using an identical assay system that can detect as many kinds of complexed PSA forms as possible.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Measurement of PSA–ACT and ACTD provides useful information for the clinical staging of prostate cancer and the differential diagnosis between prostate cancer and BPH. However, compared with tPSA and PSAD, PSA–ACT and ACTD have no additional value for the staging of prostate cancer or for the differentiation of BPH from prostate cancer.
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FOOTNOTES |
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+ For reprints and all correspondence: Isao Hara, Department of Urology, Kobe University School of Medicine, 7–5–1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
Abbreviations: PSA, prostate-specific antigen; ACT, 1-antichymotrypsin; tPSA, total PSA; PSAD, PSA density; ACTD, PSA–ACT density; DRE, digital rectal examination; TRUS, transrectal ultrasound; AP, anteroposterior; TR, transverse; SI, superior–inferior; ROC, receiver operating characteristic; AUC, area under the curve; BPH, benign prostatic hypertrophy
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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1 Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery-what we have learned and where we are going. J Urol 1999;162:293–306.[Web of Science][Medline]
2 Benson MC, Whang IS, Olsson CA, McMahon DJ, Cooner WH. The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen. J Urol 1992;147:815–6.[Web of Science][Medline]
3 Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. J Am Med Assoc 1992;267:2215–20.
4 Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol 1997;158:2162–7.[Web of Science][Medline]
5 Stenman UA, Leinonen J, Alfthan H, Ranniko S, Tuhkanen K, Alfthan O. A complex between prostate-specific antigen and 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 1991;51:222–6.
6 Lilja H, Cockett AT, Abrahamsson PA. Prostate specific antigen predominantly forms a complex with 1-antichymotrypsin in blood. Cancer 1992;37:230–4.
7 Bjork T, Piironen T, Pettersson K, Lovgren T, Stenman UH, Oesterling JE, et al. Comparison of analysis of the different prostate-specific antigen forms in serum for detection of clinically localized prostate cancer. Urology 1996;48:882–8.[Web of Science][Medline]
8 Kuriyama M, Ueno K, Uno H, Kawada Y, Akimoto S, Noda M, et al. Clinical evaluation of serum prostate-specific antigen-alpha1-antichymotrypsin complex values in diagnosis cancer: a cooperative study. Int J Urol 1998;5:48–54.[Medline]
9 Jung K, Brux B, Lein M, Knabich A, Sinha P, Rudolph B, et al. Determination of alpha1-antichymotrypsin–PSA complex in serum does not improve the differentiation between benign prostatic hyperplasia and prostate cancer compared with total PSA and percent free PSA. Urology 1999;53:1160–8.[Web of Science][Medline]
10 Okegawa T, Noda H, Nutahara K, Higashihara E. Comparison of two investigative assays for the complexed prostate-specific antigen in total prostate specific antigen between 4.1 and 10.0 ng/mL. Urology 2000;55:700–4.[Web of Science][Medline]
11 Japanese Urological Association, The Japanese Pathological Society. General Rules for Clinical and Pathological Studies on Prostatic Cancer, 2nd ed. Tokyo: Kanehara 1992 (in Japanese).
12 Gohji K, Nomi M, Egawa S, Morisue K, Takenaka A, Okamoto M, et al. Detection of prostate carcinoma using prostate specific antigen, its density and the density of the transition zone in Japanese men with intermediate serum prostate specific antigen concentrations. Cancer 1997;79:1969–76.[Web of Science][Medline]
13 Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29–36.
Received April 26, 2001; accepted June 25, 2001.
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