Original Papers Tumor Biol 1990;11:289-294
© 1990 S. Karger AG, Basel 1010—4283//90/0116-0289S2.75/0
Clinical Usefulness of Prostate-Specific Antigen and Prostatic Acid Phosphatase in Patients with Prostatic Cancer X. Filellaa, R. Molina a, J. Jo*, B. Umbertb, J.L. Bedinia, A.M. Ballesta* Departments of “Clinical Biochemistry (Unit Cancer Research) and b Urology, Hospital Clinic i Provincial, Barcelona, Spain
Key Words. Prostatic cancer ■PSA • PAP Abstract. Serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels were measured in 70 patients with benign prostatic hypertrophy (BPH) and in 70 patients with prostatic cancer. PSA was increased above the cutoff level of 10 ng/ml in 13 % of patients with BPH and in 87% of patients with prostatic cancer. In contrast, abnormal PAP levels were found in 14 and 76% of patients, respectively. We concluded that, due to its high specificity, PSA is a useful marker in the management of patients with prostatic carci noma and that it surpasses PAP in this regard.
Cancer of the prostate is the second most common cancer and the third leading cause of death in the USA. If diagnosed early, 84% of patients are alive 5 years after treatment [1], In 1936, Gutman and Gutman [2] reported an increase in acid phosphatase levels in pa tients with metastatic prostatic carcinoma. Since Foti et al. [3] described a radioimmu noassay for prostatic acid phosphatase (PAP), numerous publications have evaluated the utility of PAP in prostatic cancer [4], Prostate-specific antigen (PSA) was iden tified in 1979 by Wang et al. [5]. It is a gly
coprotein with a molecular weight of 34,000 daltons. Immunorcactivc PSA is present in normal and neoplastic prostatic epithelial cells [6], Since its identification, PSA had been evaluated for its usefulness in the stag ing and monitoring of patients with prostatic cancer [7-10], In the present work, the serum levels of PSA and PAP were determined in patients with benign prostatic hypertrophy (BPH) or prostatic cancer. We compared the effi ciency of both tumor markers in the manage ment of patients with prostatic cancer.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Introduction
Patients and Methods Serum PSA and PAP concentrations were mea sured in 70 patients with BPH and in 70 patients with untreated prostatic cancer (12 with stage B, 18 with stage C and 40 with stage D). The diagnosis of pros tatic cancer was confirmed by histological examina tion, and tumor staging was performed by clinical examination, urography, computerized tomography and scintigraphy scans of the skeleton. Patients with prostatic cancer were classified according to the Whit more system [11], We have excluded from our series patients with recent (48 h) prostatic manipulation and bladder catheter installation. Venous blood was drawn by venipuncture, and the serum was stored at - 2 0 ° C until analyzed. PSA and PAP determinations were performed with immunoradiometric assays using commercially available kits (Tandem-R-PSA and Tandem-R-PAP, Hybritech, San Diego, Calif., USA). Although the 98th percentile of healthy subjects in our experience is 2 ng/ml, we used, according to sev eral reports [8, 12, 13], 10 ng/ml as the cutoff level for PSA. Usually, the cutoff level used for PAP is be tween 2.8 and 3.2 ng/ml [8, 10, 12, 13). Considering the high percentage of false positives in patients with BPH, we used a second cutoff level for PAP. We selected 4 ng/ml, corresponding to the 85th percentile of the values of PAP in patients with BPH. This cutoff level is located at the same specificity as that chosen for PSA. Results are expressed as sensitivity, specificity and efficiency. Sensitivity was calculated by dividing the number of patients with elevated tumor marker levels and prostatic cancer by the total number of patients with prostatic cancer. Specificity was calcu lated by dividing the number of patients with nonele vated tumor marker levels and BPH by the total num ber of patients with BPH. Finally, we considered effi ciency as the sum of the patients with elevated tumor marker levels and prostatic cancer and the patients with nonelevated tumor marker levels and BPH di vided by the total number of patients. Sensitivity, specificity and efficiency are expressed as percent ages. Statistical evaluation of the results was done using the x2 test with Yates’ correction (qualitative results) and the Mann-Whitney U test (quantitative results) because the determined values did not follow a nor mal distribution. Receiver operating characteristic
Filella/Molina/Jo/Umbert/Bedini/Ballesta
(ROC) curves were used in the comparison between PSA and PAP assays. The correlation coefficient was calculated by the least-squares method.
Results Table 1 lists the PSA levels in patients with BPH. Of these patients, 87% had PSA levels greater than 2 ng/ml, but only 13% had PSA levels greater than 10 ng/ml. In the same patients, the serum concentration of PAP was increased above 2.8 ng/ml in 30% and above 4 ng/ml in 14% (table 2). The serum PSA levels in patients with prostatic cancer are also indicated in table 1. The concentration of PSA was above the cutoff limit of 10 ng/ml in 87% of these patients. A significant difference (p < 0.001) was observed in serum levels of PSA be tween patients with prostatic cancer and pa tients with BPH. The serum PSA levels in patients with cancer increased progressively through stages B, C and D. High levels were found especially in patients with advanced disease, and a significant difference was ob served between patients with stage C and D (p < 0.05). We noted that the median PSA value in the group of patients with prostatic cancer was 9.6-fold the chosen cutoff level. Results regarding PAP in patients with prostatic cancer are indicated in table 2. PAP levels were elevated above 4 ng/ml in 76% of patients with prostatic cancer. We observed a significant difference (p < 0.001) in serum PAP levels between patients with prostatic cancer and patients with BPH. The highest PAP levels were found in the group of patients with advanced tumor and a sig nificant difference was observed between pa tients with stage C and D (p < 0.005). The median PAP value in patients with cancer was 5.5-fold the cutoff level.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
290
PSA and PAP in Prostatic Cancer
291
Table 1. Serum PSA levels in patients with BPH and prostatic cancer Group
BPH Prostatic Total Stage Stage Stage
Number % of patients with PSA of -------------------------------patients > 2 ng/ml > 10 ng/ml 70
87
13
70 12 18 40
94 92 94 95
87 67 89 92.5
Serum PSA level, ng/ml -------------------------------------------------mean SD median range 7.3
14.5
3
298,1 74.1 77.2 464.6
704.9 107.7 55.8 894.5
96 19 71 113
< 2 -8 9
10th/90th percentile
2/14
cancer B C D
< 2-4,274 < 2-390 < 2 -2 1 3 < 2 -4 ,2 7 4
3/600 2/152 4/173 16/2,000
Statistical significance: BPH vs. prostatic cancer, p < 0.01; stage B vs. stage C, n.s.; stage B vs. stage D, p < 0.01; stage C vs. stage D, p < 0.05.
Table 2. Serum PAP levels in patients with BPH and prostatic cancer Group
BPH Prostatic Total Stage Stage Stage
Number of patients
% of patients with PAP
Serum PAP level, ng/ml
> 2.8 ng/ml > 4 ng/ml
mean
70
30
14
2.5
1.6
2.3
70 12 18 40
84 75 78 90
76 50 61 90
151.0 8.6 24.3 250.7
572.8 10.2 34.3 741.9
22.0 4.0 14.0 54.0
SD
10th/90th percentile
median range < 1 -8 .2
1/5
cancer B C D
< 1-4,700 < 1-39 1.7-150 < 1-4,700
2.1/270 2.1/19 2/54 2.2/609
Table 3 shows the comparison of serum PSA and PAP levels in patients with pros tatic cancer. Both markers were elevated above cutoff levels (10 ng/ml for PSA and 4 ng/ml for PAP) in 74% of these patients. Nine patients (13%) had increased PSA lev els only, while 1 patient (1 %) had increased PAP levels only. Neither marker was ele vated in 11 % of these patients. Figure 1 presents the ROC curves for PSA and PAP comparing BPH and cancer
patients. Also, the specificity, sensitivity and efficiency at different cutoff levels are indi cated in table 4. Generally, at equal specific ity, a higher sensitivity, but without statisti cal significance, was observed for PSA. As well, we found in general a higher efficiency for PSA. We noted a correlation between PSA and PAP levels in patients with BPH (r = 0.420, p < 0.001) as well as in patients with pros tatic cancer (r = 0.426, p < 0.001).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Statistical significance: BPH vs. prostatic cancer, p < 0.001; stage B vs. stage C, n.s.; stage B vs. stage D, p < 0.001; stage C vs. stage D, p < 0.005.
Filella/Molina/Jo/Umbert/Bedini/Ballesta
292
Table 3. Comparison of serum PSA and PAP levels in patients with prostatic cancer Group
PSAVPAP*
PSAVPAP-
PSA/PAP*
PSA/PAP-
n
%
n
%
n
%
n
%
Stage B Stage C Stage D
7 11 34
58.3 61.1 85.0
1 5 3
8.3 27.7 7.5
0 0 1
0 0 2.5
4 2 2
33.3 11.1 5.0
Total
52
74.3
9
12.9
1
1.4
8
11.4
PSA*= > 10 ng/ml; PAP* = > 4 ng/ml.
Table 4. Specificity, sensitivity and efficiency of PSA and PAP at different cutoff levels
100 95 90 85 80 75 70 65
PSA
PAP
cutoff, ng/ml
sensitivity, % efficiency, %
cutoff, ng/ml
sensitivity, % efficiency, %
89 19 14 9 8 6 5 4.1
50 79 86 87 87 89 89 89
7.5 5.5 5 4.1 3.5 3.1 2.8 2.7
64 71 71 76 79 81 84 83
75 87 88 86 83.5 82 79.5 77
Discussion Initial studies have indicated that a high percentage of patients with BPH had ele vated PSA levels. Kuriyama et al. [7], using a cutoff level of 1.8 ng/ml, found abnormal values in 68% of the patients with BPH. Rock et al. [10], using a cutoff level of 2.8 ng/ml, found increased values in 60% of cases. Our data confirm that PSA is elevated in patients with BPH, with serum PSA levels greater than 2 ng/ml in 87% of these patients (table 1). A second cutoff limit of 10 ng/ml was proposed by several authors to increase
82 83 80.5 80.5 79.5 78 77 74
the specificity of the assay [8, 12, 13]. This cutoff limit is near the level giving a higher efficiency in our series (14 ng/ml; table 4). However, we chose 10 ng/ml as the cutoff limit to compare our results with other au thors. The use of this second cutoff limit for PSA increases markedly the specificity (13 vs. 87%), with little loss of sensitivity (94 vs. 87%). Other authors reported similar results using this decision level [8, 12, 13]. How ever, the concentrations of PSA in serum of patients with BPH appear to overlap those of patients with prostatic cancer (table 1). Con sequently, it is not sufficiently specific to use
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Specificity %
PSA and PAP in Prostatic Cancer
293
as a test for the early diagnosis of prostatic cancer. Selecting lOng/ml as the upper limit of the assay, PSA is a sensitive tumor marker in the evaluation of patients with prostatic can cer. Likewise, serum PSA levels are related to the clinical stage of disease with abnormal values in 67% of patients with stage B, 89% of patients with stage C and 92.5% of pa tients with stage D (table 1). Also, a signifi cant difference in serum levels was observed between patients with stage C and D (p < 0.05). Using a cutofflevel of 2.8 ng/ml, PAP was elevated in 84% of patients with prostatic cancer (table 2). However, 30% of patients with BPH had PAP levels higher than 2.8 ng/ml. As happened with PSA, using a second decision level of 4 ng/ml increased the specificity (70 vs. 86%) with little loss of sensitivity (84 vs. 76%). ROC curves were constructed to compare the diagnostic value of both tests at different cutoff levels. Figure 1 shows the ROC curves for PSA and PAP. In agreement with pre
vious reports [8, 9], we found that PSA has greater value in the evaluation of patients with prostatic cancer than PAP. At equal specificity, we observed, in general, a higher sensitivity and efficiency for PSA compared to PAP (table 4). However, we have not ob served a significant difference between the tests. It is interesting to note the parallel evo lution of the ROC curves of both PSA and PAP and the significant correlation between PSA and PAP in patients with BPH as well as in patients with prostatic cancer. In patients with prostatic cancer, we com pared the median values of PSA and PAP as related to the cutoff limit and found that the ratio was higher for PSA (9.6 vs. 5.5). This indicates that the increases in PSA are greater than those of PAP. These results and the higher sensitivity, specificity and effi ciency of PSA as compared to PAP suggest that PSA is a better tumor marker than PAP in patients with prostatic cancer and that the results are in agreement with those reported by other authors [9, 14, 15]. Siddall et al. [14] reported a better relationship between
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Fig. 1. ROC curves for PSA (•) and PAP (o).
serum PSA levels and clinical evolution than those obtained with serum PAP levels. The value of the combined use of PSA and PAP has been suggested by Kuriyama et al. [16]. Our results are in disagreement with this report for several reasons. First, we found in our series a correlation between serum PSA and PAP levels as shown by the ROC curves (fig. 1). Also, simultaneous eval uation of both tumor markers did not in crease the sensitivity. Abnormal serum PAP levels were found in only 1% of patients with normal PSA values. PSA and PAP are chem ically and immunologically different, but the production and access to blood of PSA and PAP in prostatic cancer are probably regu lated by similar mechanisms. We found PSA to be a useful tumor marker in the management of patients with prostatic cancer. Also, we conclude that PSA is more sensitive than PAP and that the simultaneous determination of both does not increase the efficiency obtained with PSA alone. However, since both PSA and PAP may be elevated in patients with BPH, nei ther assay is specific for prostatic cancer. References 1 Cancer Facts and Figures 1988. New York, Amer ican Cancer Society, 1988, p 12. 2 Gutman AB, Gutman EB: An ‘acid’ phosphatase occurring in the serum of patients with metasta sizing carcinoma of the prostate gland. J Clin Invest 1936;17:473-479. 3 Foti AG, Cooper JF, Herchman PD, et al: Detec tion of prostatic cancer by solid-phase radioim munoassay of serum prostatic acid phosphatase. N Engl J Med 1977;297:1357-1361. 4 Heller JE: Prostatic acid phosphatase: Its current clinical status. J Urol 1987;137:1091-1103. 5 Wang MC, Valenzuela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 1979;17:159-163.
Filella/Molina/Jo/Umbert/Bedini/Ballesta
6 Nadji M, Tabei SZ, Castro A, et al: Prostate-spe cific antigen: An immunohistological marker for prostatic neoplasms. Cancer 1981;48:1229-1232. 7 Kuriyama M, Wang MC, Papsidero LD, et al: Quantitation of prostate specific antigen by sensi tive enzyme immunoassay. Cancer Res 1980;40: 4658-4662. 8 Ercole CJ, Lange PH, Mathisen M, et al: Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with pros tatic cancer. J Urol 1987; 138:1181-1184. 9 Stamey TA, Yang N, Hay AR, et al: Prostate spe cific antigen as a serum marker for adenocarci noma of the prostate. N Engl J Med 1987;317: 909-916. 10 Rock RC, Chan DW, Bruzek D, et al: Evaluation of a monoclonal immunoradiometric assay for prostate-specific antigen. Clin Chem 1987;33: 2257-2261. 11 Whitmore WJ: The natural history of prostatic cancer. Cancer 1973;32:1104-1112. 12 Morote J, Ruibal A, Palou J: Evaluation of spe cific antigen and prostatic acid phosphatase spec ificity: Study of false values. Int J Biol Markers 1986;1:141-146. 13 Tizzani A, Casseta G, Piana P, et al: Serum pros tate-specific antigen determination in prostatic carcinoma. Int J Biol Markers 1987;2:184-186. 14 Siddall JK, Shetty SD, Cooper EH: Measurements of serum x-seminoprotein and prostate specific antigen evaluated for monitoring carcinoma of the prostate. Clin Chem 1986:32:2040-2043. 15 Kellokumpu-Lehtinen P, Nurmi M, Koskinen P, Irjala K: Prostate-specific antigen as a marker of adenocarcinoma of prostate. Urol Res 1989; 17: 245-249. 16 Kuriyama M, Wang MC, Lee CI, et al: Multiple marker evaluation in human prostate cancer with the use of tissue-specific antigens. J Natl Cancer Inst 1982;68:99-105.
Received: August 22, 1989 Accepted: April 9, 1990 Xavier Filella. PhD Department of Clinical Biochemistry Hospital Clinic i Provincial Villarroel, 170 E-08036 Barcelona (Spain)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
294
© 1990 S. Karger AG, Basel 1010—4283//90/0116-0289S2.75/0
Clinical Usefulness of Prostate-Specific Antigen and Prostatic Acid Phosphatase in Patients with Prostatic Cancer X. Filellaa, R. Molina a, J. Jo*, B. Umbertb, J.L. Bedinia, A.M. Ballesta* Departments of “Clinical Biochemistry (Unit Cancer Research) and b Urology, Hospital Clinic i Provincial, Barcelona, Spain
Key Words. Prostatic cancer ■PSA • PAP Abstract. Serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels were measured in 70 patients with benign prostatic hypertrophy (BPH) and in 70 patients with prostatic cancer. PSA was increased above the cutoff level of 10 ng/ml in 13 % of patients with BPH and in 87% of patients with prostatic cancer. In contrast, abnormal PAP levels were found in 14 and 76% of patients, respectively. We concluded that, due to its high specificity, PSA is a useful marker in the management of patients with prostatic carci noma and that it surpasses PAP in this regard.
Cancer of the prostate is the second most common cancer and the third leading cause of death in the USA. If diagnosed early, 84% of patients are alive 5 years after treatment [1], In 1936, Gutman and Gutman [2] reported an increase in acid phosphatase levels in pa tients with metastatic prostatic carcinoma. Since Foti et al. [3] described a radioimmu noassay for prostatic acid phosphatase (PAP), numerous publications have evaluated the utility of PAP in prostatic cancer [4], Prostate-specific antigen (PSA) was iden tified in 1979 by Wang et al. [5]. It is a gly
coprotein with a molecular weight of 34,000 daltons. Immunorcactivc PSA is present in normal and neoplastic prostatic epithelial cells [6], Since its identification, PSA had been evaluated for its usefulness in the stag ing and monitoring of patients with prostatic cancer [7-10], In the present work, the serum levels of PSA and PAP were determined in patients with benign prostatic hypertrophy (BPH) or prostatic cancer. We compared the effi ciency of both tumor markers in the manage ment of patients with prostatic cancer.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Introduction
Patients and Methods Serum PSA and PAP concentrations were mea sured in 70 patients with BPH and in 70 patients with untreated prostatic cancer (12 with stage B, 18 with stage C and 40 with stage D). The diagnosis of pros tatic cancer was confirmed by histological examina tion, and tumor staging was performed by clinical examination, urography, computerized tomography and scintigraphy scans of the skeleton. Patients with prostatic cancer were classified according to the Whit more system [11], We have excluded from our series patients with recent (48 h) prostatic manipulation and bladder catheter installation. Venous blood was drawn by venipuncture, and the serum was stored at - 2 0 ° C until analyzed. PSA and PAP determinations were performed with immunoradiometric assays using commercially available kits (Tandem-R-PSA and Tandem-R-PAP, Hybritech, San Diego, Calif., USA). Although the 98th percentile of healthy subjects in our experience is 2 ng/ml, we used, according to sev eral reports [8, 12, 13], 10 ng/ml as the cutoff level for PSA. Usually, the cutoff level used for PAP is be tween 2.8 and 3.2 ng/ml [8, 10, 12, 13). Considering the high percentage of false positives in patients with BPH, we used a second cutoff level for PAP. We selected 4 ng/ml, corresponding to the 85th percentile of the values of PAP in patients with BPH. This cutoff level is located at the same specificity as that chosen for PSA. Results are expressed as sensitivity, specificity and efficiency. Sensitivity was calculated by dividing the number of patients with elevated tumor marker levels and prostatic cancer by the total number of patients with prostatic cancer. Specificity was calcu lated by dividing the number of patients with nonele vated tumor marker levels and BPH by the total num ber of patients with BPH. Finally, we considered effi ciency as the sum of the patients with elevated tumor marker levels and prostatic cancer and the patients with nonelevated tumor marker levels and BPH di vided by the total number of patients. Sensitivity, specificity and efficiency are expressed as percent ages. Statistical evaluation of the results was done using the x2 test with Yates’ correction (qualitative results) and the Mann-Whitney U test (quantitative results) because the determined values did not follow a nor mal distribution. Receiver operating characteristic
Filella/Molina/Jo/Umbert/Bedini/Ballesta
(ROC) curves were used in the comparison between PSA and PAP assays. The correlation coefficient was calculated by the least-squares method.
Results Table 1 lists the PSA levels in patients with BPH. Of these patients, 87% had PSA levels greater than 2 ng/ml, but only 13% had PSA levels greater than 10 ng/ml. In the same patients, the serum concentration of PAP was increased above 2.8 ng/ml in 30% and above 4 ng/ml in 14% (table 2). The serum PSA levels in patients with prostatic cancer are also indicated in table 1. The concentration of PSA was above the cutoff limit of 10 ng/ml in 87% of these patients. A significant difference (p < 0.001) was observed in serum levels of PSA be tween patients with prostatic cancer and pa tients with BPH. The serum PSA levels in patients with cancer increased progressively through stages B, C and D. High levels were found especially in patients with advanced disease, and a significant difference was ob served between patients with stage C and D (p < 0.05). We noted that the median PSA value in the group of patients with prostatic cancer was 9.6-fold the chosen cutoff level. Results regarding PAP in patients with prostatic cancer are indicated in table 2. PAP levels were elevated above 4 ng/ml in 76% of patients with prostatic cancer. We observed a significant difference (p < 0.001) in serum PAP levels between patients with prostatic cancer and patients with BPH. The highest PAP levels were found in the group of patients with advanced tumor and a sig nificant difference was observed between pa tients with stage C and D (p < 0.005). The median PAP value in patients with cancer was 5.5-fold the cutoff level.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
290
PSA and PAP in Prostatic Cancer
291
Table 1. Serum PSA levels in patients with BPH and prostatic cancer Group
BPH Prostatic Total Stage Stage Stage
Number % of patients with PSA of -------------------------------patients > 2 ng/ml > 10 ng/ml 70
87
13
70 12 18 40
94 92 94 95
87 67 89 92.5
Serum PSA level, ng/ml -------------------------------------------------mean SD median range 7.3
14.5
3
298,1 74.1 77.2 464.6
704.9 107.7 55.8 894.5
96 19 71 113
< 2 -8 9
10th/90th percentile
2/14
cancer B C D
< 2-4,274 < 2-390 < 2 -2 1 3 < 2 -4 ,2 7 4
3/600 2/152 4/173 16/2,000
Statistical significance: BPH vs. prostatic cancer, p < 0.01; stage B vs. stage C, n.s.; stage B vs. stage D, p < 0.01; stage C vs. stage D, p < 0.05.
Table 2. Serum PAP levels in patients with BPH and prostatic cancer Group
BPH Prostatic Total Stage Stage Stage
Number of patients
% of patients with PAP
Serum PAP level, ng/ml
> 2.8 ng/ml > 4 ng/ml
mean
70
30
14
2.5
1.6
2.3
70 12 18 40
84 75 78 90
76 50 61 90
151.0 8.6 24.3 250.7
572.8 10.2 34.3 741.9
22.0 4.0 14.0 54.0
SD
10th/90th percentile
median range < 1 -8 .2
1/5
cancer B C D
< 1-4,700 < 1-39 1.7-150 < 1-4,700
2.1/270 2.1/19 2/54 2.2/609
Table 3 shows the comparison of serum PSA and PAP levels in patients with pros tatic cancer. Both markers were elevated above cutoff levels (10 ng/ml for PSA and 4 ng/ml for PAP) in 74% of these patients. Nine patients (13%) had increased PSA lev els only, while 1 patient (1 %) had increased PAP levels only. Neither marker was ele vated in 11 % of these patients. Figure 1 presents the ROC curves for PSA and PAP comparing BPH and cancer
patients. Also, the specificity, sensitivity and efficiency at different cutoff levels are indi cated in table 4. Generally, at equal specific ity, a higher sensitivity, but without statisti cal significance, was observed for PSA. As well, we found in general a higher efficiency for PSA. We noted a correlation between PSA and PAP levels in patients with BPH (r = 0.420, p < 0.001) as well as in patients with pros tatic cancer (r = 0.426, p < 0.001).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Statistical significance: BPH vs. prostatic cancer, p < 0.001; stage B vs. stage C, n.s.; stage B vs. stage D, p < 0.001; stage C vs. stage D, p < 0.005.
Filella/Molina/Jo/Umbert/Bedini/Ballesta
292
Table 3. Comparison of serum PSA and PAP levels in patients with prostatic cancer Group
PSAVPAP*
PSAVPAP-
PSA/PAP*
PSA/PAP-
n
%
n
%
n
%
n
%
Stage B Stage C Stage D
7 11 34
58.3 61.1 85.0
1 5 3
8.3 27.7 7.5
0 0 1
0 0 2.5
4 2 2
33.3 11.1 5.0
Total
52
74.3
9
12.9
1
1.4
8
11.4
PSA*= > 10 ng/ml; PAP* = > 4 ng/ml.
Table 4. Specificity, sensitivity and efficiency of PSA and PAP at different cutoff levels
100 95 90 85 80 75 70 65
PSA
PAP
cutoff, ng/ml
sensitivity, % efficiency, %
cutoff, ng/ml
sensitivity, % efficiency, %
89 19 14 9 8 6 5 4.1
50 79 86 87 87 89 89 89
7.5 5.5 5 4.1 3.5 3.1 2.8 2.7
64 71 71 76 79 81 84 83
75 87 88 86 83.5 82 79.5 77
Discussion Initial studies have indicated that a high percentage of patients with BPH had ele vated PSA levels. Kuriyama et al. [7], using a cutoff level of 1.8 ng/ml, found abnormal values in 68% of the patients with BPH. Rock et al. [10], using a cutoff level of 2.8 ng/ml, found increased values in 60% of cases. Our data confirm that PSA is elevated in patients with BPH, with serum PSA levels greater than 2 ng/ml in 87% of these patients (table 1). A second cutoff limit of 10 ng/ml was proposed by several authors to increase
82 83 80.5 80.5 79.5 78 77 74
the specificity of the assay [8, 12, 13]. This cutoff limit is near the level giving a higher efficiency in our series (14 ng/ml; table 4). However, we chose 10 ng/ml as the cutoff limit to compare our results with other au thors. The use of this second cutoff limit for PSA increases markedly the specificity (13 vs. 87%), with little loss of sensitivity (94 vs. 87%). Other authors reported similar results using this decision level [8, 12, 13]. How ever, the concentrations of PSA in serum of patients with BPH appear to overlap those of patients with prostatic cancer (table 1). Con sequently, it is not sufficiently specific to use
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Specificity %
PSA and PAP in Prostatic Cancer
293
as a test for the early diagnosis of prostatic cancer. Selecting lOng/ml as the upper limit of the assay, PSA is a sensitive tumor marker in the evaluation of patients with prostatic can cer. Likewise, serum PSA levels are related to the clinical stage of disease with abnormal values in 67% of patients with stage B, 89% of patients with stage C and 92.5% of pa tients with stage D (table 1). Also, a signifi cant difference in serum levels was observed between patients with stage C and D (p < 0.05). Using a cutofflevel of 2.8 ng/ml, PAP was elevated in 84% of patients with prostatic cancer (table 2). However, 30% of patients with BPH had PAP levels higher than 2.8 ng/ml. As happened with PSA, using a second decision level of 4 ng/ml increased the specificity (70 vs. 86%) with little loss of sensitivity (84 vs. 76%). ROC curves were constructed to compare the diagnostic value of both tests at different cutoff levels. Figure 1 shows the ROC curves for PSA and PAP. In agreement with pre
vious reports [8, 9], we found that PSA has greater value in the evaluation of patients with prostatic cancer than PAP. At equal specificity, we observed, in general, a higher sensitivity and efficiency for PSA compared to PAP (table 4). However, we have not ob served a significant difference between the tests. It is interesting to note the parallel evo lution of the ROC curves of both PSA and PAP and the significant correlation between PSA and PAP in patients with BPH as well as in patients with prostatic cancer. In patients with prostatic cancer, we com pared the median values of PSA and PAP as related to the cutoff limit and found that the ratio was higher for PSA (9.6 vs. 5.5). This indicates that the increases in PSA are greater than those of PAP. These results and the higher sensitivity, specificity and effi ciency of PSA as compared to PAP suggest that PSA is a better tumor marker than PAP in patients with prostatic cancer and that the results are in agreement with those reported by other authors [9, 14, 15]. Siddall et al. [14] reported a better relationship between
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
Fig. 1. ROC curves for PSA (•) and PAP (o).
serum PSA levels and clinical evolution than those obtained with serum PAP levels. The value of the combined use of PSA and PAP has been suggested by Kuriyama et al. [16]. Our results are in disagreement with this report for several reasons. First, we found in our series a correlation between serum PSA and PAP levels as shown by the ROC curves (fig. 1). Also, simultaneous eval uation of both tumor markers did not in crease the sensitivity. Abnormal serum PAP levels were found in only 1% of patients with normal PSA values. PSA and PAP are chem ically and immunologically different, but the production and access to blood of PSA and PAP in prostatic cancer are probably regu lated by similar mechanisms. We found PSA to be a useful tumor marker in the management of patients with prostatic cancer. Also, we conclude that PSA is more sensitive than PAP and that the simultaneous determination of both does not increase the efficiency obtained with PSA alone. However, since both PSA and PAP may be elevated in patients with BPH, nei ther assay is specific for prostatic cancer. References 1 Cancer Facts and Figures 1988. New York, Amer ican Cancer Society, 1988, p 12. 2 Gutman AB, Gutman EB: An ‘acid’ phosphatase occurring in the serum of patients with metasta sizing carcinoma of the prostate gland. J Clin Invest 1936;17:473-479. 3 Foti AG, Cooper JF, Herchman PD, et al: Detec tion of prostatic cancer by solid-phase radioim munoassay of serum prostatic acid phosphatase. N Engl J Med 1977;297:1357-1361. 4 Heller JE: Prostatic acid phosphatase: Its current clinical status. J Urol 1987;137:1091-1103. 5 Wang MC, Valenzuela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 1979;17:159-163.
Filella/Molina/Jo/Umbert/Bedini/Ballesta
6 Nadji M, Tabei SZ, Castro A, et al: Prostate-spe cific antigen: An immunohistological marker for prostatic neoplasms. Cancer 1981;48:1229-1232. 7 Kuriyama M, Wang MC, Papsidero LD, et al: Quantitation of prostate specific antigen by sensi tive enzyme immunoassay. Cancer Res 1980;40: 4658-4662. 8 Ercole CJ, Lange PH, Mathisen M, et al: Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with pros tatic cancer. J Urol 1987; 138:1181-1184. 9 Stamey TA, Yang N, Hay AR, et al: Prostate spe cific antigen as a serum marker for adenocarci noma of the prostate. N Engl J Med 1987;317: 909-916. 10 Rock RC, Chan DW, Bruzek D, et al: Evaluation of a monoclonal immunoradiometric assay for prostate-specific antigen. Clin Chem 1987;33: 2257-2261. 11 Whitmore WJ: The natural history of prostatic cancer. Cancer 1973;32:1104-1112. 12 Morote J, Ruibal A, Palou J: Evaluation of spe cific antigen and prostatic acid phosphatase spec ificity: Study of false values. Int J Biol Markers 1986;1:141-146. 13 Tizzani A, Casseta G, Piana P, et al: Serum pros tate-specific antigen determination in prostatic carcinoma. Int J Biol Markers 1987;2:184-186. 14 Siddall JK, Shetty SD, Cooper EH: Measurements of serum x-seminoprotein and prostate specific antigen evaluated for monitoring carcinoma of the prostate. Clin Chem 1986:32:2040-2043. 15 Kellokumpu-Lehtinen P, Nurmi M, Koskinen P, Irjala K: Prostate-specific antigen as a marker of adenocarcinoma of prostate. Urol Res 1989; 17: 245-249. 16 Kuriyama M, Wang MC, Lee CI, et al: Multiple marker evaluation in human prostate cancer with the use of tissue-specific antigens. J Natl Cancer Inst 1982;68:99-105.
Received: August 22, 1989 Accepted: April 9, 1990 Xavier Filella. PhD Department of Clinical Biochemistry Hospital Clinic i Provincial Villarroel, 170 E-08036 Barcelona (Spain)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 10:30:30 AM
294
