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Clinical Chemistry 48: 1251-1256, 2002;
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(Clinical Chemistry. 2002;48:1251-1256.)
© 2002 American Association for Clinical Chemistry, Inc.

The Proportion of Prostate-specific Antigen (PSA) Complexed to {alpha}1-Antichymotrypsin Improves the Discrimination between Prostate Cancer and Benign Prostatic Hyperplasia in Men with a Total PSA of 10 to 30 µg/L

Manuel Martínez1, Francisco España2a, Montserrat Royo2, José M. Alapont1, Silvia Navarro2, Amparo Estellés2, Justo Aznar3, César D. Vera1 and Juan F. Jiménez-Cruz1

1 Department of Urology,
2 Research Center, and
3 Department of Clinical Pathology, La Fe University Hospital, 46009 Valencia, Spain.

aAddress correspondence to this author at: Hospital Universitario La Fe, Centro de Investigación, Avda. Campanar 21, 46009 Valencia, Spain. Fax 34-96-3868718; e-mail espanya_fra{at}gva.es.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The aim of this study was to assess the diagnostic accuracy of the proportion of prostate-specific antigen (PSA) complexed to {alpha}1-antichymotrypsin (PSA-{alpha}1ACT:PSA ratio) in the differential diagnosis of prostate cancer (CaP) and benign prostatic hyperplasia (BPH) in men with total PSA of 10–30 µg/L.

Methods: We used our immunoassays (ELISAs) for total PSA and PSA-{alpha}1ACT complex to study 146 men. In 123, total PSA was between 10 and 20 µg/L; 66 of these had CaP and 57 BPH. In 23 men, total PSA was between 20 and 30 µg/L; 14 of these had CaP and 9 BPH. We calculated the area under the ROC curves (AUC) for total PSA, PSA-{alpha}1ACT complex, and PSA-{alpha}1ACT:PSA ratio, and determined the cutoff points that gave sensitivities approaching 100%.

Results: In the total PSA range between 10 and 20 µg/L, the AUC was significantly higher for the PSA-{alpha}1ACT:PSA ratio (0.850) than for total PSA (0.507) and PSA-{alpha}1ACT complex (0.710; P <0.0001). A cutoff ratio of 0.62 would have permitted diagnosis of all 66 patients with CaP (100% sensitivity) and avoided 19% of unnecessary biopsies (11 of 57 patients). In the total PSA range between 20 and 30 µg/L, the AUC for the PSA-{alpha}1ACT:PSA ratio (0.980; 95% confidence interval, 0.82–0.99) was greater than the AUC for total PSA (0.750; 95% confidence interval, 0.51–0.89; P = 0.042). In this range, a cutoff point of 0.64 would have permitted the correct diagnosis of all 14 patients with CaP and 6 of the 9 with BPH.

Conclusions: The diagnostic accuracy of the PSA-{alpha}1ACT:PSA ratio persists at high total PSA concentrations, increasing the specificity of total PSA. Prospective studies with large numbers of patients are needed to assess whether the ratio of PSA-{alpha}1ACT to total PSA is a useful tool to avoid unnecessary prostatic biopsy in patients with a total PSA >10 µg/L.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The diagnostic accuracy of circulating prostate-specific antigen (PSA)1 for prostate cancer (CaP) is limited because increases are not specific for CaP. Benign conditions of the prostate influence its serum concentration; some patients with benign prostatic hyperplasia (BPH) have increased PSA (1), and many patients with clinically localized CaP do not have increased serum PSA (2). Attempts to improve the diagnostic accuracy of the PSA test include PSA density (3)(4), PSA velocity (5), and age-specific reference intervals (6), none of which has gained wide acceptance.

Active PSA forms complexes in vitro and in vivo with {alpha}1-antichymotrypsin ({alpha}1ACT), {alpha}2-macroglobulin, protein C inhibitor, {alpha}1-protease inhibitor, and inter-{alpha}1-trypsin inhibitor (7)(8)(9)(10)(11)(12)(13). Measurement of the proportion of PSA complexed to {alpha}1ACT may increase the diagnostic accuracy of PSA testing for early CaP and avoid unnecessary biopsy (7)(8)(14). Christensson et al. (15) reported better discrimination using the free-to-total PSA ratio instead of the proportion of PSA complexed to {alpha}1ACT. Theoretically, however, the measurement of PSA-{alpha}1ACT complex rather than free PSA has potential advantages. The major form of PSA circulating in men with CaP is PSA-{alpha}1ACT. Samples with a low total PSA concentration will have minimal amounts of PSA remaining in the free form; thus, free PSA will be more difficult to measure than complexed PSA. Furthermore, in our hands, PSA-{alpha}1ACT complex preparations are quite stable, and the imprecision of our assay for PSA-{alpha}1ACT (16) is even lower than reported for the free PSA assay (17). A cutoff of 0.80 for the PSA-{alpha}1ACT:PSA ratio, rather than a total PSA value of 4 µg/L, increased specificity from 38% to 79% without significantly decreasing sensitivity (82%) in men with total PSA <15 µg/L (14). Moreover, the PSA-{alpha}1ACT:PSA ratio in patients with BPH does not vary with age (18), which simplifies its clinical application. In addition, we have reported that neither physiologic changes in total PSA and PSA-{alpha}1ACT complex nor the treatment of BPH change the diagnostic efficacy of the PSA-{alpha}1ACT:PSA ratio (19).

It is accepted that the use of the free-to-total PSA ratio or the PSA-{alpha}1ACT:PSA ratio should be restricted to patients with a total PSA within determined limits (reflex range) (20). Although these limits are variable, patients with total PSA between 4 and 10 µg/L benefit most from the use of these ratios. This is a logical consequence of the predictive value of total PSA for CaP: CaP is unlikely at PSA <3 µg/L, but highly likely at PSA >10 µg/L (21). Nonetheless, previous results suggested that both the PSA-{alpha}1ACT:PSA ratio and the free-to-total PSA ratio add diagnostic information even at high PSA concentrations (9)(22). These preliminary reports and the optimal results obtained previously by our group, using the PSA-{alpha}1ACT:PSA ratio for the detection of CaP in total PSA ranges of 4–10 µg/L (14)(16) and <4 µg/L (23), prompted us to evaluate the usefulness of this ratio in patients with high total PSA. In the present study, we analyze a group of patients with total PSA concentrations between 10 and 30 µg/L. The objective was to increase specificity while maintaining sensitivities near 100%.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Between January 1995 and May 1998, blood specimens were obtained from 655 consecutive biopsied patients (Caucasian men) before any treatment. All patients had been referred to a urologist for prostatic evaluation in our hospital. A total of 146 patients in whom total PSA was 10–30 µg/L (123 with total PSA between 10 and 20 µg/L, and 23 with total PSA between 20 and 30 µg/L) were included in the study. All patients underwent an ultrasonography-guided needle sextant biopsy, including all suspicious lesions detected by echography. Patients diagnosed with BPH underwent at least two biopsies. On the basis of the histologic analysis, patients were classified as having BPH (n = 66) or CaP (n = 80). The size of the prostate was determined in all CaP and BPH patients by transrectal ultrasonography.

Of the 80 patients with CaP, 69 had a clinically localized tumor, 8 showed clinical signs of extracapsular extension, 2 had bone metastases, and 1 showed affected lymphatic nodules. In 21 patients (26%), tumors were well differentiated (Gleason score, 2–4); in 51 patients (64%), they were moderately differentiated (Gleason score, 5–7); and in 8 patients (10%), tumors were poorly differentiated (Gleason score, 8–10).

All blood samples were obtained between 0800 and 0900 before any manipulation that could alter PSA concentrations. The procedures followed were approved by our institution’s Institutional Review Board and were in accordance with the Helsinki Declaration of 1975. All patients gave informed consent. Blood samples were collected by venipuncture in tubes containing 0.13 mol/L sodium citrate (1 part citrate and 9 parts blood by volume) and were stored at 24 ± 2 °C for 2–3 h. Each sample was centrifuged at 1500g for 30 min, and the plasma was frozen in aliquots stored at -80 °C for not more than 6 months and thawed immediately before analysis. Each aliquot was thawed only once.

We measured total PSA and PSA-{alpha}1ACT complex in plasma samples, using our ELISAs (14)(16). Each test was performed without knowledge of the results of the others. The detection limit of the total PSA assay, defined as the PSA concentration that provided an ELISA signal equal to that of the assay buffer plus 3 SD, was 0.2 µg/L, and the CVs were 4.5–7.4% for intraseries and 6.3–10% for interseries determinations. The detection limit of the PSA-{alpha}1ACT assay was 0.1 µg/L complexed PSA, and the CVs were 6.8–9.3% for intraseries and 8.7–13% for interseries determinations.

All statistical calculations [Student t-test, Mann–Whitney mean nonparametric U-test, and area under the ROC curve (AUC)] were performed using a computer program for medical statistics (MedCalc software). Unless specified, the values represent the mean ± SD. P <0.05 was considered statistically significant.

We followed the guidelines for publication on studies of diagnostic accuracy of medical tests (24).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We included in the study all 146 patients with a total PSA of 10–30 µg/L. Of the 123 patients with a PSA between 10 and 20 µg/L, 66 had CaP and 57 had BPH. Of the 23 patients with a PSA between 20 and 30 µg/L, 14 had CaP and 9 had BPH. Analysis of the clinical characteristics of the patients (Table 1 ) indicated no significant differences in age and total PSA between patients with BPH and those with CaP. Prostate volume was significantly greater in BPH than in CaP patients, whereas the concentration of PSA-{alpha}1ACT complex and the PSA-{alpha}1ACT:PSA ratio were significantly higher in patients with CaP than in those with BPH.


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  		Table 1. Clinical characteristics of 66 patients with BPH and 80 with CaP (total PSA between 10 and 30 µg/L).

We used ROC curves to assess the performances of the tests. Results for men with total PSA between 10 and 20 µg/L are shown in Fig. 1 , and Table 2 shows the sensitivity, specificity, and AUC for several cutoff points of each test. The AUC was significantly larger (P <0.0001) for the PSA-{alpha}1ACT:PSA ratio and for PSA-{alpha}1ACT complex than for total PSA. A cutoff point of 0.62 would have permitted detection of all 66 patients with CaP and avoided 19% of negative biopsies (11 of 57).



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  		Figure 1. ROC curves for total PSA (T), PSA-{alpha}1ACT (C), and the PSA-{alpha}1ACT:PSA ratio (C/T) in men with total PSA between 10 and 20 µg/L.

Arrows show the locations of selected cutpoints indicated in Table 2Up .


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  		Table 2. Sensitivity, specificity, and AUC for total PSA, PSA-{alpha}1ACT, and complexed-to-total PSA ratio (C/T) for men with total PSA between 10 and 20 µg/L.

In the subset of patients with a total PSA between 20 and 30 µg/L, the AUC for the PSA-{alpha}1ACT:PSA ratio (0.980) was even greater than in the subset of patients with a PSA between 10 and 20 µg/L (Table 3 ) and significantly greater than for total PSA (0.750; P = 0.042). Although the number of patients in this group was small, a cutoff point of 0.64 would have permitted detection of all 14 patients with CaP and avoided 6 of the 9 negative biopsies.


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[in this window]
[in a new window]
  		Table 3. Sensitivity, specificity, and AUC for total PSA, PSA-{alpha}1ACT, and complexed-to-total PSA ratio for men with total PSA between 20 and 30 µg/L.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results show that a cutoff of 0.62 for the PSA-{alpha}1ACT:PSA ratio identified all cases of CaP in the group of men with total PSA between 10 and 20 µg/L and could have prevented biopsies in 11 of the 57 patients with BPH. The diagnostic accuracy was even higher in patients with total PSA between 20 and 30 µg/L. Although the number of patients in this total PSA range is small, the results suggest that the use of a cutoff of 0.64 would have permitted correct diagnosis of the 14 patients with CaP and avoided 6 unnecessary biopsies.

To our knowledge, there is only one report in the literature evaluating the diagnostic accuracy and potential utility of the proportion of PSA complexed to {alpha}1ACT in the differentiation between CaP and BPH at high total PSA (9). In this study, the proportion of PSA complexed to {alpha}1ACT was higher in CaP than in BPH patients, even in the range of total PSA between 10 and 20 µg/L. However, because the report by Christensson et al. (15) showed better discrimination between CaP and BPH with the free-to-total PSA ratio rather than the PSA-{alpha}1ACT:PSA ratio, most laboratories followed their recommendations, and for a few years, the free-to-total PSA ratio was the only marker used. In general, all groups agreed that, compared with total PSA, the free-to-total PSA ratio increases specificity while retaining sensitivity, avoiding a significant number of unnecessary biopsies (25)(26)(27)(28)(29)(30)(31)(32). Nevertheless, there are some discrepancies in these studies: e.g., the cutoff point used for the free-to-total PSA ratio in these studies varied between 0.15 and 0.25 and the proportion of unnecessary biopsies that would have been avoided in the different series ranged between 13% and 65%. Some authors have even questioned the clinical utility of the free-to-total PSA ratio (27)(28). These differences have been attributed to differences in study design and the use of different assays. Nevertheless, most authors concur that measurement of the free-to-total PSA ratio should be restricted to patients with a narrow total PSA interval, the reflex range (20), the range with the highest diagnostic efficacy. The lower limit of this range varies between 2 and 4 µg/L, whereas the higher limit ranges from 10 to 20 µg/L, although the most accepted reflex range is 4–10 µg/L. This is a logical consequence of the predictive value of total PSA concentrations because the probability of CaP is low for total PSA concentrations <3–4 µg/L and very high (>50%) for concentrations >10 µg/L (21). Nevertheless, Virtanen et al. (22) showed that the free-to-total PSA ratio might also be used to evaluate the need for a biopsy in the total PSA range between 10 and 30 µg/L.

From a theoretical point of view, measuring the PSA-{alpha}1ACT complex, rather than free PSA, has a potential advantage in test samples with low total PSA. In such samples, only a minimal fraction of PSA is in the free form, with most circulating PSA bound in the PSA-{alpha}1ACT complex. Furthermore, in our hands, the PSA-{alpha}1ACT complex is quite stable, and the CVs of our assay for PSA-{alpha}1ACT (16) are even lower than those usually reported for the free PSA assay. Finally, the use of plasma rather than serum seems to improve the utility of the PSA-{alpha}1ACT:PSA ratio in the early detection of CaP (16).

Our assay for PSA-{alpha}1ACT complex is methodologically different from that recently described and commercialized. Our assay is a sandwich ELISA that specifically measures the complex between PSA and its major plasma inhibitor, {alpha}1ACT, using anti-PSA as the capture antibody and labeled anti-{alpha}1ACT as detection antibody. The commercial assay (33) uses a preliminary step to mask all free PSA in the sample and then measures the PSA complexed to any plasma inhibitor, including {alpha}1ACT and {alpha}1-protease inhibitor. The first reports on the commercial assay showed contradictory results. Brawer et al. (34) claimed that the complexed PSA alone (as measured with the commercial assay) showed a diagnostic efficacy similar to that obtained with the free-to-total PSA ratio, and an even higher efficacy in the total PSA range between 4 and 10 µg/L. However, Stamey and Yemoto (35) found that the commercial complex assay alone did not improve the efficacy of the free-to-total PSA ratio and that it was necessary to use the complexed-to-total PSA ratio to find improvement. The discrepancies may be attributed to differences in the series of patients with respect to prostate volume. In any case, with the commercial complexed PSA assay, the use of either the complexed PSA alone (34) or the complexed-to-total PSA ratio (35) was equivalent to, but did not improve on, the efficacy of the free-to-total PSA ratio. According to a previous report (16), our PSA-{alpha}1ACT:PSA ratio showed better diagnostic accuracy than the free-to-total PSA assay, especially in plasma samples. However, it will be necessary to perform further studies to directly compare both complexed PSA assays. It has been reported that PSA-{alpha}1-protease inhibitor complex, which is detected with the commercial assay but not with our assay for PSA-{alpha}1ACT, decreases in CaP, whereas PSA-{alpha}1ACT increases (36). This fact may give a theoretical advantage to our PSA-{alpha}1ACT complex assay over the commercial complexed PSA assay (36).

It is possible that some of the patients with total PSA >10 µg/L might have undiagnosed CaP. In fact, repeat biopsies increase (15–20%) the detection rate of CaP (37). In the present study, this bias was reduced by the fact that all patients had undergone at least two prostatic biopsies, including the transition zone in the second biopsy.

Prospective studies with larger numbers of participants are necessary to determine whether the PSA-{alpha}1ACT:PSA ratio is useful to avoid prostatic biopsies in men with total PSA >10 µg/L or whether it may be used as a criterion for rebiopsy. Nevertheless, our results suggest that in men with total PSA between 10 and 30 µg/L, it is possible to establish a reasonably low cutoff point for the PSA-{alpha}1ACT:PSA ratio, e.g., 0.7, to avoid rebiopsies in these patients. Only when total PSA or the ratio increases would a rebiopsy be indicated.


   Acknowledgments
 
This work was supported in part by Research Grants 99/1035 and 01/1148 from the Fondo de Investigación Sanitaria (Madrid, Spain).


   Footnotes
 
1 Nonstandard abbreviations: PSA, prostate-specific antigen; CaP, prostate cancer; BPH, benign prostatic hyperplasia; {alpha}1ACT, {alpha}1-antichymotrypsin; and AUC, area under the ROC curve.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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