/STRU^NI RAD
UDK 616.05-006.04-097:577.1
Urinary Prostate Specific Antigen: is the Clinical Use
Likely?
..............................
Pejcic T, Hadzi-Djokic J, Acimovic M, Topuzovic C,
Milkovic B, Janjic A.
Institute for Urology and Nephrology, Clinical Centre of
Serbia, Belgrade
rezime
Prostate specific antigen (PSA) blood test represents the standard procedure in prostate cancer
(CaP) diagnosis and follow-up. However, determination of PSA in the urine, where PSA is present
in much higher concentrations than in the blood,
still remains in the field of research.Objectives:To
determine urinary concentrations of PSA (uPSA)
in different groups of patients (pts.), and to estimate is
it possible to differentiate benign and malignant prostate diseases and to follow-up the results of treatment.
Methods: Between january 2001. and November 2003.,
urinary concentrations of PSA were determined at
142 pts. divided in seven groups: 1. young and healthy
volunteers, 2. "BPH-24": pts. with benign prostatic
hyperplasia (BPH) who collected the sample of 24hour voided urine, 3. "BPH-I": pts. with BPH who
collected the first portion of first urinary voiding, 4.
"TRUS-CaP": pts. with CaP which gave the first portion of urine just prior to transrectal ultrasoundguided prostate biopsy (TRUS- biopsy), 5. "TRUSnon-CaP": pts. who gave first portion of urine prior to
TRUS-biopsy, but biopsy did not prove the presence of
CaP, 6. "RRP": pts. who underwent radical retropubic prostatectomy (RRP), 7. "AAT": pts. who underwent androgen deprivation therapy.Results:Average
uPSA value in the group of young and healthy volunteers, was 13.8+19.6 ng/ml, in "BPH-24": 38.0+ 44.4
ng/ml, in "BPH-I": 140.8+140.9 ng/ml, in "TRUSCaP": 234.8+277.7 ng/ml, in TRUS-non-CaP: 113.1
+148.5 ng/ml, and in the group "RRP": 4.4+4.7 ng/ml.
There was no statistically significant difference of average uPSA values between "BPH-I" and "TRUSCaP" groups. The significant difference was found between the group of young volunteers and "BPH-I". In
"TRUS-CaP" group, there was strong correlation between tumour size and aggressivenes and uPSA concentration. Finally, PSA and uPSA decline during androgen deprivation therapy, strongly correlated (up to
r=0.95). Conclusions:Determination of uPSA cannot
differentiate BPH and CaP. However, in the group of
pts. with proven localized CaP, uPSA can provide additional information concerning T-staging. Moreover,
simultaneous monitoring of PSA and uPSA response
on hormonal therapy, can provide an early recognition
of androgen-indiferent CaP (AIPCA) and hormoneresistent CaP (HRPCA).
Key words: urinary prostate specific antigen, tumor
volume antiandrogen therapy
INTRODUCTION
P
rostate specific antigen (PSA) is the proteolitical enzyme which physiological function is liquefaction of
seminal coagulum, the process that allows the progressive
motility of spermatozoa. The PSA concentration in seminal plasma is 0.3- 3.0 mg/ml, which makes PSA one of
the most abundant proteins synthetised in the prostate.
The determination of PSA concentrations in blood is one
of the most important tools in prostate diseases detection
and follow-up. On the other hand, PSA measurement in
urine took place in the sporadic clinical researches.
1.1. PSA in the prostate
The concentration of PSA in the prostate is similar in
normal, hyperplastic and malignant tissue and counts
0.01- 0.08 mg/ml tissue.1,2,3,4 That means that prostate of
20g contains 0.2- 1.6mg PSA.
Major form of PSA in the prostatic tissue is free PSA,
that makes more than 98% of total PSA. 4 There is no apparent physiological function of PSA in the prostatic tissue: after the synthesis in the cytosol, PSA molecules are
preserved in secretory granules (SG). Prostatic secretory
epithelial cells empty the contents of SG into the acinar
and ductal lumina. The amount of the synthesis depend on
androgens and sexual stimulation, which is under parasympathetical control. From prostatic ducts, PSA molecules arrive in the prostatic urethra, from where are been
washed during the micturition. Different to this "basal
70
T. Pejcic et al.
PSA leakage", massive acinar and ductal emptying take
place during the ejaculation. Central and transition zone
ducts enter the prostatic urethra in the sharp angle, lateral
to the verumontanum. Peripheral zone ducts enter the urethra perpendicullary, along the distance between verumontanum and distal urethral sphincter. These differencies play an important role in the drainage of seminal fluid
into the urethra.
1.2. PSA in the periurethral glands and "minor prostatic
glands"
The use of new fixative in the pathology, glutaraldehid,
enabled the identification of prostatic secretory granules
(SG) in epithelial cells out of the prostate. Prostatic SG
were identified in all periurethral glands in penile urethra,
and occasionally, in the urinary bladder, in more than
50% cases of cystitis cystica and glandularis. These "minor prostatic glands" 5 are made of prostatic cells, or
mixed prostatic and mucinous epithelium. Minor prostatic
glands are responsible for urethral PSA production after
radical prostatectomy and cystoprostatectomy.
ACI Vol. LII
TABLE 1
THE NUMBER OF PATIENTS IN VARIOUS GROUPS
No
Group
No of pts
Average age
1
zdravi
17
33.8
2
BHP-24
22
71.7
3
BHP-1
24
70.2
4
TRUS-CaP
27
69.1
5
TRUS-non-Cap
18
66.2
6
RRP
14
67.5
7
AAT
20
74.4
TOTAL
/
142
/
Average uPSA (ng/ml)
1.3. PSA in seminal plasma
The concentration of PSA in seminal plasma is 0.2-3
mg/ml; PSA concentration in expressate, after prostatic
massage, is 1-2mg/ml.6,7,8
The ratio between free and total PSA (f/T) is 0.76-0.81,
and is similar in healthy men, and the patients with CaP. 9
High concentration of active PSA forms is the result of
low concentrations of extracellular protease inhibitors in
seminal plasma, like protein-C-inhibitor (PCI), which has
only 5-10% molar concentration of PSA.10
250
200
150
100
50
0
RRP
1.4. Urinary PSA determination in clinical use
In one of the first reports about uPSA, in 1992., DeVere
White found average uPSA concentration in the group of
BPH patients, of 216 ng/ml. Moreover, he found elevated
concentrations of uPSA in 77% patients after RRP, and
concluded that the majority of patients after RRP has residual prostatic tissue.11
However, next year, from Stanford University came the
evidence that PSA in the urine originates from periurethral glands, but not from residual prostatic tissue.12 In this
issue, the authors found average uPSA in the group with
localized CaP, of 915.1ng/ml in the first urinary stream,
and 245.9 ng/ml in the middle stream. In the group with
RRP, average uPSA was 21.4 ng/mL in the first stream,
and 1.8 ng/mL in the middle stream. Similar uPSA levels
were found in patients without CaP, after cystoprostatectomy with bladder substitution: 15.5 ng/ml and 1.2 ng/ml.
Similar results were presented by Taka-yama.13
Breul14 found higher uPSA concentrations in BPH, than
in CaP group, using Tandem-E test: 748.78+246.3 ng/ml,
versus 214.57+121.2 ng/ml. The serum/urinary PSA ratio
was 177 +28.17, verus 15.76+5.47.
Irani15 collected the 24 hour urinary samples and expressed uPSA concentration in micrograms / mMol of urinary creatinine; he also found higher uPSA concentration
in BPH, than in CaP group: 30.7+4.7 microg. / mMol
creat., versus 4.6+1.6 microg. / mMol creat. In the group
Young
BPH-24
T-non-CaP
BPH-I
TRUS-CaP
FIGURE 1
AVERAGE uPSA VALUES IN DIFFERENT GROUPS
Average uPSA + 2 SD
800
700
600
500
400
300
200
100
0
RRP
Young
BPH-24
T-non-CaP
BPH-I
TRUS-CaP
FIGURE 2
AVERAGE uPSA +2SD
of patients with serum PSA in "grey zone" (4-10 ng/ml)
he found average uPSA of 18.5 microg. / mMol creat. In
BPH patients, and 5.2 microg. / mMol creat. In CaP patients.16 These results differed significantly. In the recent
issue17, the same author found significantly different
Br. 4
Prostate specific antigen in the urine: is the clinical
use likely?
71
TABEL 22
AVERAGE uPSA values
No
Group
uPSA(ng/ml)
PSA(ng/ml)
Prostate volume (ml)
1
Young/healthy
13.8+19.6
-
-
2
BHP-24
38.0+44.4
1.9+1.1
37.8+19.3
3
BHP-I
140.8+140.9
1.7+0.8
32.8+21.5
4
TRUS-CaP
234.8+277.7
40.3+118.6
35.5+11.4
5
TRUS-non-CaP
113.1+148.5
8.9+4.1
42.7+15.6
6
RRP
4.4+4.7
0.14+0.2
30.3+18.6
TABLE 3
STATISTICAL DIFFERENCIES BETWEEN AVERAGE uPSA values
t001
temp
Statistical
difference
1.684
2.423
3.609
+
BPH-24
1.684
2.423
3.245
+
Young
RRP
1.701
1.791
2.467
+
TRUS-CaP
TRUS-non0CaP
1.684
1.689
2.423
+
TRUS-CaP
BPH-I
1.46
1.684
2.423
O
BPH-I
TRUS-non-CaP
0.602
1.684
2.423
O
Group I
Group II
BPH-I
young
BPH-I
temp
t0.05
uPSA / PSA ratio in BPH and CaP group, in 12-hour collected urine: 4.2 versus 1.2. All patients had "grey zone"
PSA.
Hillenbrand18 found similar results and concluded that
uPSA increased total specificity of PSA in the screening
of CaP.
However, authors from Johns Hopkins Institute reported
different results, with no statistical differencies in total,
free, and ACT- bound uPSA between BPH and CaP
group.19
The concentration of PSA could be measured in the prostatic expressate, as well. Kim20 found different PSA concentration in expressate from BPH and CaP patients: 1.42
mg/ml and 2.25 mg/ml, respectively. Some authors found
elevated PSA in expressate in the group of patients with
residual disease, after RRP.21,22
Very interesting fact is that female-to-male transsexuals
could maintain PSA synthesis after testosterone substitution. The glands of Skene, or "female prostate" are responsible for urinary PSA concentrations, which are comparable with that of young and healthy males.23,24,25,26
METHODS
1. Between january 2001. and November 2003., urinary
concentrations of PSA were determined at 142 patients divided in seven groups: 1. young and healthy volunteers,
2. "BPH-24" group: patients with benign prostatic hyperplasia (BPH) who collected the sample of 24-hour
voided urine,
temp
3. "BPH-I" group: patients with BPH who collected the
first portion of first urinary voiding,
4. "TRUS-CaP" group: patients with CaP which gave
the first portion of urine just prior to transrectal ultrasound- guided prostate biopsy (TRUS- biopsy),
5. "TRUS-non-CaP" group: patients who gave first portion of urine prior to TRUS-biopsy, but biopsy did not
prove the presence of CaP,
6. "RRP" group: patients who underwent radical
retropubic prostatectomy (RRP),
7. "AAT" group: patients who underwent anti-androgen,
or androgen deprivation therapy.(Table 1).
All patients were diagnosed and controlled in the Institute for Urology and Nephrology, Clinical Centre of Serbia, in Belgrade. Control group consisted of young and
healthy volunteers. Patients with BPH had minimal voiding problems, or received medical therapy for BPH; all
patients had PSA 4.0 ng/ml and no suspect lesions on
TRUS and digitorectal examination (DRE). In "TRUSCaP" and TRUS-non-CaP" groups, TRUS- guided biopsy
was performed due to PSA 4.0 ng/ml, and/or suspect
findings on TRUS/ DRE. These patients gave first 70-80
ml of fresh urine just prior to biopsy. Urine was kept on –
4 C. Ultrasound examinations and TRUS- biopsies were
performed on Toshiba- Tosbee machine, with transrectal
probe IVE-506S. Prostate volume was calculated on usual
manner: a x b x c x pi/6. Biopsy was performed with needles of 160mm/16G, using Gallini biopsy gun. Pathohystological preparations were performed in Institute for
Pathology, Clinical Centre of Serbia, Belgrade. All PSA
72
T. Pejcic et al.
concentrations in serum and urine were determined using
IRMA-PSA test, produced in Institute for Nuclear Energy
Application (INEP), Zemun, Belgrade.
RESULTS
ACI Vol. LII
uPSA / number of positive cores correlation
7
1200
6
1000
5
3.1. Average uPSA concentrations
Average uPSA in control group was 13.8 19.6 ng/ml, in
"BPH-24", 38.0 44.4 ng/ml, in "BPH-I", 140.8 140.9
ng/ml, in "TRUS-CaP", 234.8 277.7 ng/ml, in "TRUSnon-CaP", 113.1 148.5 ng/ml, and in "RRP", 4.4 4.7
ng/ml. (Table 2,3)(Fig 1,2)
3.2. Average uPSA Density (uPSAD)
800
4
No +
400
2
uPSA
3.3. Correlations
3.3.1. Correlation between uPSA and prostate volume
There was a correlation between uPSA and prostate volume in the group TRUS-CaP, but not in other groups.
(Table 6).
3.3.2. Correlation between uPSA level and the tumour
size and aggressiveness
There was a correlation in group "TRUS-CaP", between
uPSA level and tumour size and aggressiveness. Tumour
size was estimated according to number of cancer-positive
cores and the percentage of infiltration of the matherial.
Tumour aggressiveness was estimated according to tumour grade and Gleason score.(Table 7, Fig 3).
200
1
0
0
1
Table 4. Average uPSA Density (uPSAD).
Average uPSAD differed statistically between groups
"TRUS-non-CaP" and "TRUS-CaP" (p > 0.05 ).
600
3
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
FIGURE 3
THE CORELATION BETWEEN uPSA LEVEL AND THE NUMBER OF CANCER POSITIVE BIOPSY CORES (NO+NUMBER
OF CANCER POSITIVE BIOPSY CORES)
1. PSA and uPSA during AAT
1000
100
PSA
10
uPSA
1
2004 2004 2004 2004 2004 2004 2004 2004 2004 2004 2005 2005 2005 2005 2005 2005 2005 2005
juni jul avg avg sep sep okt okt nov dec jan feb apr maj jun avg sep okt
0
CA
300
CA
150
CA
150
CA
150
CA
150
CA
150
CA
150
CA
150
CA
150
CA
150
CA
150
0
0
CA
150
CA
100
Ca
100
CA
100
0.1
3.3.3. The correlation between PSA and uPSA during
antiandrogen therapy
There is a graduate decline in PSA concentration during
antiandrogen therapy, followed by uPSA decline. In some
cases the correlation is very strong, up to 0.95 (p 0.01).
In other cases, PSA decline does not follow uPSA decline,
pointing out different response on therapy. (Fig. 4,5).
DISCUSSION
Prostate specific antigen is today one of the most frequently used tumour markers in medicine. Together with
its use in early cancer detection, i.e. screening of male
population older than 50 years, PSA has a major role in
preoperative staging, the choice of the therapy, and the
monitoring of the therapy.
PSA molecules enter the systemic circulation through
the rim capillaries around the acini. However, the physiological pathway of PSA is through the prostatic ducts
and urethra, from where the PSA molecules are expelled
within seminal fluid in the process of ejaculation. Between the ejaculations, prostatic fluid rich in PSA molecules, leaks through the ducts into prostatic urethra, in
which is collected untill first micturition.
So, the concentration of PSA in the urine is much higher
than in serum, but more liable to different influences.
Generally, urinary PSA concentration depend on synthesis
FIGURE 2
EXAMPLE OF PSA AND uPSA MONITORING DURING INTERMITTENT MONOHROMONAL ANTIANDROGEN THERAPY. TRENDLINES CONVERGE (CA=CYPROTERONE
ACETETATE, 0=INTERRUPTION OF THERAPY)
2. PSA and uPSA during AAT
10000
1000
PSA
100
uPSA
10
1
2004
okt
2005
mar
2005
apr
2005
maj
2005
jun
2005
jul
2005
avg
2005
okt
FIGURE 3
EXAMPLE OF PSA AND uPSA MONITORING DURING INTERMITTENT MONOHORMONAL ANTIANDROGEN THERAPY. TRENDLINES DIVERGE
in prostatic epithelial cells and the drainage through the
ductal system. The strenght of the synthesis depend on an-
Br. 4
Prostate specific antigen in the urine: is the clinical
use likely?
TABLE 4
AVERAGE uPSA DENSITY (uPSAD) AVERAGE uPSA
DENSITY (uPSAD)
/
TRUS-non-Cap
BPH-I
TRUS-CaP
X
3.05
4,94
6.08
SD
3,88
4.54
6.59
TABLE 5
CORRELATION BETWEEN uPSA LEVEL AND
PROSTATE VOLUME
/
rtab(0.05)
r
r2
Correlation
BPH-I
0.404
0.092
0.008
0
T-non-CaP
0.468
-0.138
0.019
0
TRUS-CaP
0.381
0.445
0.198
TABLE 6
CORRELATION BETWEEN uPSA LEVEL AND THE
TUMOUR SIZE AND AGGRESSIVENESS IN THE
GROUP TRUS-Cap
UPSA
rtab(0.05)
rtemp
rtab(0.01)
r2
N0+
0.381
-0.431
0.487
0.19
Infiltr %
0.381
-0.448
0.487
0.20
GS
0.381
-0.407
0.487
0.16
Grade
0.381
-0.420
0.487
0.18
drogen level and sexual stimulation. On the other hand,
drainage of transition and peripheral zones differs, and it
could be obstructed due to presence of postinflamatory
scars, simpexions, calcifications, hyperplastic nodes, or
tumours.
In surprisingly small number of issues about urinary
PSA, the differencies were found between the first and
middle urinary stream, what could be explained by washing-out of the urethra. Some authors found higher uPSA
levels in BPH, than in CaP, and the greater urinary-to-serum PSA ratio in BPH than in CaP, which could be explained with tumourous obstruction of the drainage ducts.
However, other authors did not find the uPSA differencies
in BPH and CaP. Moreover, they presented unstable levels of uPSA in single patient, so uPSA never gained
greater polularity and was never accepted in clinical practice.
In our work, we determined average uPSA level in the
group of patients without prostates, i.e. patients who underwent radical retropubic prostatectomy (RRP), without
evidence of residual disease, which was 4.4+4.7 ng/ml
and presented urethral PSA production. In the group of
young men, average uPSA was 13.8 +19.6 ng/ml, statistically higher than in men without prostates. Patients with
BPH that collected 24 hour urine, had lower uPSA levels
than patients who gave first urinary stream for analysis,
73
due to PSA instability on room temperature due to bacterial action. Groups with BPH, CaP, and group "TRUSnon-CaP", in which the chronic prostatitis was common
pathological finding, had similar uPSA levels which did
not differ statistically. This is not completelly clear, but,
most probably, other factors influenced the results by
compromising ductal drainage. In the "TRUS-CaP" group
we found a correlation between tumour size and aggressiveness. The correlation was negative, i.e. with the increase of tumour size and dedifferentiation, uPSA levels
were lower. This phenomenon is, most probably, the consequence of tumorous ductal obstruction.
In the group "AAT", there was extremely high correlation between PSA and uPSA levels during androgen deprivation, in various stages of the disease. As it can be postulated that uPSA reflects the function of the normal prostatic cells, that drain its content in the system of normal
ducts, and serum PSA shows the activity of malignant
cells, simultaneous monitoring of uPSA and PSA shows
the degree of the malignant cells androgen dependance.
So, strong correlation between uPSA and PSA respond
means that maligant cell clones are still androgen-sensitive, bad correlation depicts the begining of androgen indifference i.e. the moment for the modulation of therapy.
CONCLUSION
It is not possible to differentiate BPH and CaP only with
urinary PSA, due to numerous factors that take place in
benign and malignant prostate diseases. However, in the
group of patients with CaP, uPSA levels have correlation
with size and aggressiveness of the tumour and can provide additional information for T- staging, i.e. determination of local stage of the disease: very low uPSA means
great tumour volume and local spread.
Finally, simultaneous monitoring of uPSA and PSA
during androgen deprivation, enables early recognising of
androgen-indifferent, and further on, hormone- resistent
prostate cancer, and prompt change of therapy.
SUMMARY
Iako se daleko ve}e koli~ine PSA mogu na}i u urinu
nego u serumu ispitanika, odrejdivanje PSA u urinu
(uPSA) do danas nije na{lo klini~ku primenu. Cilj ovog
istra‘ivanja bio je da se odredi nivo uPSA kod razli~itih
grupa ispitanika i da se vidi da li je na osno-vu njega
mogu}e razlikovati razli~ite bolesti prostate i pratiti rezultate le~enja. Nivo PSA u urinu odredjen je kod 142 ispitanika, medju kojima su se nalazili zdravi ispitanici,
bolesnici sa benignom hiperplazijom prostate 9BHP) kao i
bolesnici sa karcinomom prostate (CaP) u razli~itim klini~kim stadijumima. Prose~na vrednost uPSA kod mladih
ljudi bila je 13,8 ng/ml, kod bolesnika sa BPH 140.8
ng/ml a kod bolesnika sa CaP 234,8 ng/ml. U grupi CaP je
na osnovu klini~kog materijala nadjena korelacija izmedju
veli~ine i agresiv-nosti tumora i nivoa uPSA. Najzad,
kontinuirano pra}enje nivoa uPSA u toku antiandrogene
terapije predstavlja kontrolu za kretanje PSA u serumu i
pru‘a korisne informacije u vezi androgene senzitivnosti
tumora.
74
T. Pejcic et al.
Klju~ne re~i: prostata specifi~ni antigen, veli~ina
tumora, antiandrogena terapija
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