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The Influence of Prostate Volume on the Ratio of Freeto Total Prostate Specific Antigen in Serum ofPatients with Prostate Carcinoma and BenignProstate Hyperplasia

BACKGROUND. Determining the ratio of free to total prostate specific antigen (f-Carsten Stephan, M.D.PSA to t-PSA, calculated as the percentage of f-PSA [f-PSA%]) in serum allows forMichael Lein, M.D.a clearer distinction between patients with prostate carcinoma (PCa) and patientsKlaus Jung, M.D.with benign prostate hyperplasia (BPH) than determining the level of t-PSA alone.Dietmar Schnorr, M.D.To find influencing factors on f-PSA%, the authors investigated prostate volume,Stefan A. Loening, M.D.TNM classification, and tumor stage.

METHODS. The authors measured f-PSA and t-PSA in 36 men with untreated PCaDepartment of Urology, University Hospital(tumor classification: T1, 2, 3pN0, M0), 44 patients with BPH, and 54 healthyCharite, Humboldt University Berlin, Berlin, Ger-controls. Prostate volume was determined by transrectal ultrasound.many.RESULTS. The median values of t-PSA and f-PSA% were 7.8 mg/L and 10.5% in PCapatients, 4.3 mg/L and 20.8% in patients with BPH, and 1.4 mg/L and 23.6% in the

control group. Patients with PCa had a significantly lower proportion of f-PSA than

BPH patients and healthy men. There was no correlation of f-PSA% to TNM stage

or tumor grade. In PCa patients a significant positive correlation (correlation coef-

ficient [r] 0.51, P 0.001) was found between f-PSA% and prostate volume,whereas there was no significant correlation in BPH patients (r 00.27, P 0.05).There was a significant difference in f-PSA% between PCa and BPH patients with

prostate volumes smaller than 40 cm3 (9.0% vs. 21.6%, P 0.01) but not betweenpatients in these 2 groups with prostate volumes exceeding 40 cm3 (15.1% vs.

18.2%, P 0.11).CONCLUSIONS. Determining the ratio of f-PSA to t-PSA to discriminate betweenPCa and BPH patients yields significant results only in men with a prostate volume

of less than 40 cm3. Cancer 1997; 79:1049. q 1997 American Cancer Society.

Supported in part by a grant from the Founda-tion of the Klee family (Michael Lein) and from KEYWORDS: prostate carcinoma, benign prostate hyperplasia, prostate volume,the Fonds der Chemischen Industrie (Klaus prostate specific antigen, ratio of free to total prostate specific antigen, diagnosticJung, project no. 400700). validity.

The authors thank Silke Klotzek for her valuable

Stechnical assistance. erum prostate specific antigen (PSA) exists in different molecularforms.15 PSA is predominantly bound to a1-antichymotrypsin(PSA-ACT) with approximately 7090% of total PSA (t-PSA). Further-This work includes parts of the doctoral thesis

of Carsten Stephan. more, serum PSA also binds in trace amounts to a1-antitrypsin anda2-macroglobulin, whereas a2-macroglobulin encapsules all epitopes

Address for reprints: Klaus Jung, Department of of PSA.6 Approximately 1030% of t-PSA is not bound to proteins andUrology, University Hospital Charite, Humboldt is called free PSA (f-PSA). Recent publications have reported on theUniversity Berlin, Schumannstrae 20/21,

use of molecular forms to distinguish between patients with prostate10098 Berlin, Germany.carcinoma (PCa) and patients with benign prostate hyperplasia(BPH).2,4,5 PCa patients have a lower ratio of f-PSA/t-PSA (f-PSA%)Received May 1, 1996; revision received August

15, 1996; accepted August 30, 1996. than BPH patients. Therefore, the determination of f-PSA and calcula-

q 1997 American Cancer Society

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Free/Total PSA Ratio and Prostate Volume/Stephan et al. 105

TABLE 1tion of the f-PSA/t-PSA ratio have been suggested asTotal PSA, Free PSA, and Free PSA% in Healthy Persons, Patientsa useful diagnostic tool to differentiate between PCawith Benign Prostate Hyperplasia, and Patientsand BPH patients.2,4,5,710 with Prostate Carcinoma

Reasons for lower f-PSA% values in patients withPCa compared with BPH patients have not been clari- Benign prostate Prostate

Controls hyperplasia carcinomafied until now. It was postulated that PCa cells, inMeasurement (n 54) (n 44) (n 36)contrast to prostate cells of BPH, synthesize increased

amounts of a1-antichymotrypsin to form PSA-ACT Total PSA (mg/L)a 1.4 (0.493.15) 4.3b (1.313.6) 7.8b,c (3.9516.4)complexes early in the PCa cells.11,12 There are only a Free PSA (mg/L)a 0.29 (0.170.53) 0.81b (0.381.85) 0.8b (0.411.7)few reports of other variables influencing f-PSA%.10,13 Free PSA%a 23.6 (1345.8) 20.8 (11.438.3) 10.5b,c (6.817.6)In the current study, prostate volume, tumor TNM

PSA: prostate specific antigen; PSA%: percentage of free prostate specific antigen.stage, and grade were analyzed as factors influencinga Values are given as median (and 1090 percentiles).t-PSA and f-PSA%. b Significantly different from controls by at least P 0.01 (MannWhitney U test).c Significantly different from patients with benign prostate hyperplasia by at least P 0.01 (Mann

MATERIAL AND METHODS Whitney U test).PatientsThe study included 134 men with total PSA values to23 mg/L. The control group was comprised of 54healthy men (median age, 54.3 years). Thirty-six pa- were incubated together with alkaline phosphatase-

conjugated monoclonal anti-PSA antibody and formedtients had an untreated PCa (median age, 66.1 years).Stage was assigned to each patient according to the a PSA-antibody sandwich complex. After removing the

unbound conjugate by centrifugal wash, the chemilu-TNM system14 and ultimately confirmed pathologi-cally (TNM stage: T1-3pN0M0; Grade G1-3). Forty-four minescent substrate, a phosphate ester of adamantyl

dioxetane, was added. In the presence of alkalinepatients had BPH (median age, 71 years). Thirty-twoBPH patients underwent a transurethral resection and phosphatase, that substrate was cleaved into unstable

intermediate emitting photons that were measured bythere was histologic proof whereas in 12 patients thediagnosis was made clinically. However, because there the luminometer of the analyzer. For determining f-

PSA, f-PSA was bound to the polystyrene bead duringwere no differences between the two groups of BPHpatients, they were considered as one group. the first incubation period and an alkaline phospha-

tase-labeled polyclonal goat anti-PSA antibody wasBlood samples were taken before diagnostic pro-cedures or 4 weeks (at the earliest) after digital exami- bound to that formed complex of f-PSA/anti-f-PSA an-

tibody in a second incubation cycle. The followingnation, prostatic biopsy, and transrectal ultrasound.No patients received any hormonal therapy before steps corresponded to those described for the determi-

nation of t-PSA.blood sampling. Blood sampling in BPH patients wasmade before transurethral resection. Blood sampleswere centrifuged at 16001 relative centrifugal force (g) Statistical Analysis

The percentage of free PSA (f-PSA%) was calculated asfor 10 minutes. The sera were frozen at 070 7C within2 hours after collection and were not thawed (and the ratio of f-PSA to t-PSA multiplied by 100. The au-

thors used the Mann-Whitney U test, variance analysisrefrozen) before testing.(ANOVA), and the rank correlation coefficient ac-cording to Spearman with the statistical package Stat-Methods

The size of the prostate was determined in all PCa and graphics, version 5.01 (Statistical Graphics Corp.,Rockville, MD). The diagnostic validity was evaluatedBPH patients by transrectal ultrasonography (COMBI-

SON 330; Fa. Kretz Technik, Zipf, Austria). by the receiver operation characteristic (ROC) curveanalysis.15 The GraphROC for Windows software wast-PSA and f-PSA measurements in serum were

performed with the IMMULITE PSA and Free PSA kits used for calculations of areas under the curves.16

(Diagnostic Products Corp., Los Angeles, CA; Cat. No.LKPS1 and LKPF1). The assays were solid-phase, two- RESULTS

Table 1 shows the results of t-PSA and f-PSA measure-site sequential chemiluminescent immunometric testsand were automatically handled on the IMMULITE ments and for f-PSA% calculation. Patients with PCa

had a lower proportion of f-PSA than BPH patientsAutomated Analyzer. The solid phase was a polysty-rene bead coated with a polyclonal antibody specific and healthy men. The PCa-free groups showed no dif-

ferences in f-PSA% values.for PSA or with a monoclonal anti-PSA antibody spe-cific only for f-PSA. For determining t-PSA, samples TNM stage and grade had no influence on the

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106 CANCER January 1, 1997 / Volume 79 / Number 1

and BPH patients, as the authors suggested in a previ-ous paper.17 The analysis of these two volume groupsresulted in two important findings (Table 2): 1) BPHpatients with prostate volumes 40 cm3 and40 cm3did not differ in f-PSA% values (P 0.46). Prostatevolume had no influence on f-PSA% in BPH patients;and 2) the f-PSA% values in PCa patients differed sig-nificantly in both volume groups (9% vs. 15.1%; P 0.002). This confirms the increase of f-PSA% with in-creasing prostate volume. Hence it follows that thereis a significant difference in f-PSA% (P 0.0001) inBPH and PCa patients with volumes 40 cm3. If theprostate volume exceeds 40 cm3, both groups do notdiffer significantly in f-PSA% (18.2% vs. 15.1%; P 0.11). It should be noted that the evaluation of thesubset of patients only with PSA values within therange of 410 mg/L resulted in nearly identical medianf-PSA% values as given for the total group in Table 2.Whereas BPH patients with a prostate volume 40cm3 (n 5) and 40 cm3 (n 13) had f-PSA% valuesof 20.9% and 18.1%, respectively, PCa patients (n FIGURE 1. Relationship between the free/total prostate specific antigen14; n 8) had values of 9.1% (n 14) and 15.4%ratio and prostate volume in patients with prostate carcinoma (s) and(n 8), respectively. Thus, the different effect of thebenign prostate hyperplasia (m). The vertical line separates patients withprostate volume in BPH and PCa patients on the f-prostate volume 40 cm3 from those with 40 cm3. The horizontal linePSA% values as described above does not depend oncorresponds to the cutoff value of 15% for free/total prostate specificthe total PSA value within the range of 023 mg/L.antigen ratio.

Only one PCa patient with a prostate volume of40 cm3 exceeded the value of 15% f-PSA% (Fig. 1).Of the BPH patients, only one patient was below thisratio of f-PSA/t-PSA. The t-PSA was not correlated to

the grade (correlation coefficient [r] 0.3; P 0.08) cutoff limit. Thus, values for sensitivity and specificitywere high (93.8% and 96.2%, respectively). Comparedbut to the TNM stage (r 0.43; P 0.05), whereas f-

PSA% had no correlation to either grading (r 0.04; with f-PSA% calculation alone, this leads to an increaseof efficiency to 95%.P 0.81) or TNM stage (r 0.09; P 0.58).

The authors were especially interested in the rela- Figure 2 includes the ROC curves of t-PSA and f-PSA% for all PCa and BPH patients (n 80) and thetionship of prostate volume to PSA. In BPH patients

the t-PSA showed a positive correlation to prostate f-PSA% curves for all PCa and BPH patients with pros-tate volumes 40 cm3 (n 42). The t-PSA curve forvolume (r 0.66; P 0.0001). In contrast to this corre-

lation, PCa patients showed no relationship between the patients with prostate volumes 40 cm3 is notindicated but used in calculations. The f-PSA% curveprostate volume and t-PSA (r 0.01; P 0.93). How-

ever, PCa patients showed a significant positive corre- of all 80 patients and the t-PSA curve of patients withvolumes 40 cm3 runs significantly above the t-PSAlation between f-PSA% and the prostate volume (r

0.51; P 0.001). Conversely, BPH patients showed no curve of all patients (P 0.05). The f-PSA% curve ofpatients with volumes 40 cm3 runs again signifi-relationship between f-PSA% and prostate volume (r

00.27; P 0.05). The contrast in the relationship cantly above the f-PSA% curve of all BPH and PCapatients (P 0.05). It follows that the diagnostic valid-of t-PSA and f-PSA% to prostate volume in PCa and

BPH patients was noteworthy. ity of f-PSA% as a diagnostic tool to discriminate be-tween PCa and BPH patients would be essentially im-To accurately distinguish the gland volume as a

factor influencing PSA, the prostates were subdivided proved if it is used in combination with prostate vol-ume (40 cm3 and 40 cm3).into glands 40 cm3 and enlarged glands with vol-

umes 40 cm3. The individual f-PSA% values withrespective prostate volume for BPH and PCa patients DISCUSSION

PSA is the most important serum parameter for earlyare shown in Figure 1. The f-PSA% cutoff was markedas 15% in this figure. This cutoff guaranteed a high detection of PCa.18 Increasing PSA concentrations are

also found in BPH, inflammatory prostatic disease, ordiagnostic efficiency in discriminating between PCa

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Free/Total PSA Ratio and Prostate Volume/Stephan et al. 107

TABLE 2Total PSA and Free PSA% in Dependence on Prostate Volume in Patients with Benign Prostate Hyperplasiaand Prostate Carcinoma

Benign prostate hyperplasia Prostate carcinoma

Vol 40 cm3 Vol 40 cm3 Vol 40 cm3 Vol 40 cm3Measurement (n 16) (n 28) (n 26) (n 10)

Total PSA (mg/L)a 2.4 (0.965.1) 6.2b (2.519.6) 7.6b (3.916.4) 7.9 (4.117.6)Free PSA%a 21.6 (15.235.7) 18.2 (9.241.3) 9b (6.314.2) 15.1c (8.422.5)

PSA: prostate specific antigen; PSA%: percentage of free prostate specific antigen.a Values are given as median (and 1090 percentiles).b Significantly different from patients with benign prostate hyperplasia and prostate volume 40 cm3 by at least P 0.01 (MannWhitney U test).c Significantly different from patients with prostate carcinoma and prostate volume 40 cm3 by at least P 0.01 (MannWhitney U test).

ables better discrimination of PCa and BPH. A numberof reports regarding t-PSA, f-PSA, and the ratio of bothhave demonstrated the possibility of improving dis-crimination between PCa and BPH.2,4,5,710 The currentinvestigation confirms these results but points out theinfluence of prostate volume as a further parameter.

In 1995 Hammerer et al.20 described a dependenceof PSA on the three individual glandular zones of theprostate. The correlation coefficients among serumPSA and the transition zone, peripheral zone, and cen-tral zone were 0.934, 0.546, and 0.368, respectively.Most BPH develops from the transition zone. Hyper-plasia of the transition zone therefore is responsiblefor an increase in the volume of the entire gland. Thecurrent study results confirm this correlation, becauset-PSA from BPH patients strongly correlated with pros-tate volume. Contrary to this, PCa patients show nocorrelation between these two parameters, but doshow the above mentioned significant correlation be-tween f-PSA% and prostate volume, whereas BPH pa-tients have no relationship between f-PSA% and vol-

FIGURE 2. Receiver operating characteristic curves for total prostate ume.specific antigen ( l ), free/total prostate specific antigen ratio (f- The most important result of this article is thePSA%) ( s ), and free/total prostate specific antigen ratio combined demonstration of the significant positive correlationwith prostatic volume 40 cm3 ( . ) for patients with prostate between prostate volume and calculated f-PSA% incarcinoma and benign prostate hyperplasia. The areas under the curves patients with PCa. If the volume increases, the f-PSA%for total prostate specific antigen, free/total prostate specific antigen ratio, also increases. PCa patients with an enlarged glandand the ratio combined with volume 40 cm3 were 0.708 (standard error often have BPH as well. This could lead to a decrease[SE]: 0.059), 0.862 (SE: 0.040), and 0.971 (SE: 0.024), respectively. in the influence of the PCa on f-PSA% in patients with

both conditions. An investigation by Stamey et al.21

regarding the influence of the PCa on f-PSA% showeda general increase of bound PSA (PSA-ACT/PSA) withcould be age-related or caused by rectal manipulation.increasing PCa volume. Patients with the largest PCaTherefore, various approaches including PSA velocity,volumes (1217 cm3) had the smallest f-PSA% values.PSA density, age-related PSA reference intervals, andThis confirms the influence of PCa volume on the rela-the ratio of free to total PSA have been suggested totion of PSA forms in the serum. However, the data ofimprove the diagnostic validity of PSA.19 The detection

and measurement of different PSA forms in serum en- Stamey et al.21 were based on prostates with only a

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108 CANCER January 1, 1997 / Volume 79 / Number 1

single peripheral carcinoma. In the current study, the creasing the sensitivity and specificity to approxi-mately 95% may lead to a more effective detection ofauthors did not measure the tumor volume and were

unable to further substantiate the results of Stamey et PCa.al.21 The authors have had experiences similar to thoseof other authors in that the irregular shape and espe-

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