Blackwell Publishing AsiaMelbourne, AustraliaIJUInternational Journal of Urology0919-81722006 Blackwell Publishing Asia Pty LtdJuly 2006137915919Original ArticleUrinalysis and prostate

cancer detection
T Kato
et al.

International Journal of Urology (2006) 13, 915–919

Original Article

Clinical significance of urinary white blood cell count and serum

C-reactive protein level for detection of non-palpable prostate
cancer

TOMONORI KATO, HIROYOSHI SUZUKI, AKIRA KOMIYA, TAKASHI IMAMOTO, YUKIO NAYA,
TOYOFUSA TOBE AND TOMOHIKO ICHIKAWA
Department of Urology, Chiba University, Graduate School of Medicine, Chiba, Japan

Aim: The clinical significance of the urinary white blood cell (U-WBC) count and serum C-reactive protein (CRP) level was
evaluated in an effort to improve the efficiency of prostate biopsies.
Methods: We enrolled 228 consecutive patients with serum prostate-specific antigen (PSA) ranging from 3.0 to 20.0 ng/mL,
normal digital rectal examination findings, and who underwent prostate biopsies between January 2001 and August 2004. Of
these, 157 patients had histologically confirmed benign prostatic disease and the remaining 71 patients had prostate cancer. Patients
with a pretreatment U-WBC count ≤3 or >3/high power field were defined as non-pyuria and pyuria, respectively. The patients
were also separated into two groups based on the serum CRP level prior to biopsy. Several clinical factors were compared among
these subgroups.
Results: Inflammation was histologically detected at rates of 58.1% and 34.1% in the pyuria and non-pyuria groups, respectively
(P = 0.0014). The rates of cancer detection were significantly lower in the pyuria, than in the non-pyuria group (P = 0.0384). The
cancer detection rates did not significantly differ according to serum CRP levels prior to biopsy.
Conclusion: The U-WBC count appears to be a reliable indicator of minute prostatic inflammation. The serum PSA level was
elevated in patients with asymptomatic prostatitis. Counting U-WBC is a simple, convenient and non-invasive method that should
be valuable part of routine urological examinations.

Key words non-palpable prostate cancer, prostate biopsy, retrospective study, serum C-reactive protein, urinary white blood
cell count.

Introduction be avoided. Several PSA factors such as the free-to-total

PSA ratio, PSA density (PSAD) and PSA velocity have
Widespread serum prostate-specific antigen (PSA) screen-
been examined in an attempt to improve the efficiency of
ing has led to an increase in the rate of early prostate cancer
prostate biopsies.6,7 We evaluated the clinical significance
(PCa) detection, especially of non-palpable PCa. On the
of the serum C-reactive protein (CRP) level and the urinary
other hand, several reports have cautioned against an
white blood cell (U-WBC) count to clarify whether pros-
increase in unnecessary biopsies.1,2 Levels of serum PSA
tatic inflammation affects rates of cancer detection in pros-
increase not only in patients with PCa but also in those
tate biopsy specimens.
with various benign conditions of the prostate, including
inflammation.3,4
The most universally applied indications for prostate Methods
biopsy include irregular findings upon digital rectal exam-
ination (DRE) and/or PSA >4.0 ng/mL. Biopsies are indis- Patients
pensable when the DRE indicates a possibility of PCa. We enrolled 228 consecutive patients with serum PSA
However, biopsies of non-palpable conditions depend only values ranging from 3.0 to 20.0 ng/mL, whose DRE results
on the PSA value, which can often generate false positive were normal and who underwent prostate biopsies between
results due to being elevated by inflammation.5 Neverthe- January 2001 and August 2004 at Chiba University Hos-
less, unnecessary biopsies for non-palpable cases should pital. Patients with clinical evidence of prostatitis, macro-
scopic pyuria or systemic inflammatory diseases that might
affect serum CRP levels were excluded from the study.
Correspondence: Hiroyoshi Suzuki MD PhD, Department of We separated patients with U-WBC counts ≤3 or >3/
Urology, Chiba University, Graduate School of Medicine, 1- high power field (h.p.f.) into non-pyuria and pyuria groups,
8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. respectively. We also divided the patients into positive and
Email: hirosuzu@faculty.chiba-u.jp negative CRP groups depending upon serum CRP levels
Received 23 July 2005; accepted 18 January 2006. of ≥0.3 and <0.3 mg/dL, respectively.
916 T Kato et al.

Serum free-to-total prostate-specific antigen
assays
A single blood sample drawn before DRE was immediately
separated by centrifugation and refrigerated. Free and total
PSA values were measured using an Architect PSA kit
(Abbott, Chicago, IL, USA) according to the manufac-
turer’s instructions.
Serum C-reactive protein and urinary white
blood cell count determinations
Blood and urine samples were obtained 1–3 weeks before
biopsy, before DRE or at least more than 1 week after
DRE. Pretreatment serum CRP levels were measured using
a Latex CRP immunodetection kit (CRP-Latex ‘Seiken’,
Tokyo, Japan). The cut-off value was 0.3 mg/dL with 93%
specificity. Urine was examined using a centrifugal auto-
matic analyser (Model no. 6800; Hitachi, Tokyo, Japan)
and a light microscope.
Transrectal ultrasonography guided
systematic biopsy
Transrectal ultrasonography (TRUS) of the prostate was
performed using a scanner with a 7 MHz transducer. The
prostate was scanned in the transverse and sagittal planes
with the patient in the lithotomy position. Prostate volume
was determined using the formula for a prostate ellipsoid
(width × length × height × 0.523). The PSAD was calcu-
lated by dividing total PSA by prostate volume. Random
systematic biopsies were performed using an automatic
biopsy gun and an 18-gauge needle under TRUS guidance.
Biopsies essentially comprised six peripheral and two tran-
sitional zones. Additional biopsies were obtained if ultra-
sound revealed suspicious areas. Chronic inflammation of
the prostate was defined as infiltration of prostatic biopsy
specimens by inflammatory cells, lymphocytes, plasma
cells and/or histiocytes.8
Statistical analysis
The data represent means ± SD. Variables of the different
groups were compared by the Mann–Whitney U-test and
Student’s t-test using Stat-View (SAS institute, Cary, NC,
USA). A value of P < 0.05 was considered statistically
significant.
Results
Patient characteristics
Table 1 lists the characteristics of all 228 patients enrolled
in this study. Histology revealed benign prostatic disease
(BPD) in 157 of the 228 (68.9%) patients and PCa in the
remaining 71 (31.1%). Four and 21 of the 71 PCa and 157
BPD patients, respectively, had undergone previous pros-
tate biopsies. Inflammation was histologically evident in
biopsy specimens from 94 of the 228 (41.2%) patients.
Prostate cancer versus benign prostatic
hyperplasia
Table 1 compares the clinical parameters between the PCa
and BPD groups. The mean ages of the patients with PCa
and BPD were 68.6 ± 6.9 years and 66.5 ± 7.3 years,
respectively (P = 0.0447). Total PSA levels and the free-
to-total PSA ratios did not significantly differ between
these two groups. The mean prostate volumes were signif-
icantly larger in the BPD than in the PCa group (P =
0.0003) and the PSAD values were significantly higher in
the PCa than in the BPD group (P = 0.0008). Inflammation
was more frequently determined histologically in the BPD
(53.5%) than in the PCa group (14.1%; P < 0.0001).
Pyuria versus non-pyuria
Table 2 shows the distribution of the U-WBC count in this
series of 228 patients. Among them, 62 (27.2%) were
placed in the pyuria group, and the remaining 164 (71.9%)
were placed in the non-pyuria group. The U-WBC count
was not measured in two patients. Table 3 compares the
clinical parameters as well as the detection rates of cancer
and of histological inflammation between the two groups.
Age, free-to-total PSA ratios and PSAD values did not
significantly differ between the two groups. The total PSA
level and the prostate volume was significantly higher in
the pyuria, than in the non-pyuria group (P = 0.006;
P = 0.046). The serum CRP levels were also significantly

Table 1 Characteristics of enrolled patients†

BPD (n = 157) PCa (n = 71) P-value‡ Total (n = 228)

Age (years) 66.5 ± 7.3 (42–80) 68.6 ± 6.9 (49–88) 0.0447 67.2 ± 7.2 (42–88)
Total PSA (ng/mL) 8.57 ± 3.65 (3.06–19.65) 9.14 ± 4.43 (3.51–20.00) 0.3045 8.75 ± 3.91 (3.06–20.00)
Free-to-total PSA 19.4 ± 8.3 (3.1–43.3) 17.2 ± 10.0 (5.4–57.3) 0.1471 18.8 ± 8.9 (3.1–57.3)
ratio (%)
Prostate volume (mL) 45.5 ± 21.4 (14.6–139.0) 33.7 ± 16.6 (12.5–101.5) 0.0003 42.2 ± 20.8 (12.5–139.0)
PSAD 0.223 ± 0.131 (0.033–0.878) 0.307 ± 0.207 (0.075–1.344) 0.0008 0.247 ± 0.160 (0.033–1.344)
CRP (mg/dL) 0.128 ± 0.190 (0.0–1.4) 0.153 ± 0.281 (0.0–1.8) 0.4490 0.136 ± 0.222 (0.0–1.8)
Histological 53.5% (84/157) 14.1% (10/71) <0.0001 41.2% (94/228)
inflammation
detection rate

†Mean ± SD range; ‡BPD versus PCa. BPD, benign prostatic disease; CRP, C-reactive protein; PCa, prostate cancer; PSA,
prostate-specific antigen; PSAD, PSA density.
 Urinalysis and prostate cancer detection 917

Table 2 Distribution of U-WBC count and serum CRP level

PCa BPD Histological inflammation detection rate Total

U-WBC count (/h.p.f.)

<1 41 74 33.0% (38/115) 115
1–3 17 32 36.7% (18/49) 49
4–5 7 25 56.3% (18/32) 32
6–10 4 10 42.9% (6/14) 14
11–20 2 6 75.0% (6/8) 8
21–30 0 1 100.0% (1/1) 1
31–50 0 3 66.7% (2/3) 3
51–100 0 4 75.0% (3/4) 4
Not measured 0 2 100.0% (2/2) 2
CRP (mg/dL)
0.0 27 45 45.8% (33/72) 72
0.1 25 76 38.6% (39/101) 101
0.2 8 11 36.8% (7/19) 19
0.3 4 9 53.8% (7/13) 13
0.4 1 3 50.0% (2/4) 4
0.5 0 2 50.0% (1/2) 2
0.6–1.0 3 3 33.3% (2/6) 6
1.1–1.5 1 2 66.7% (2/3) 3
1.8 1 0 0.0% (0/1) 1
Not measured 1 6 14.3% (1/7) 7
Total 71 157 41.2% (94/228) 228

BPD, benign prostatic disease; CRP, C-reactive protein; h.p.f., high power field; PCa, prostate cancer; U-WBC, urinary white
blood cell.

Table 3 Clinical parameters and detection rate of PCa incidence and histological inflammation in pyuria and non-pyuria groups†‡

Non-pyuria group (n = 164) Pyuria group (n = 62) P-value

Age (years) 67.2 ± 7.2 (42–86) 67.3 ± 7.3 (49–88) 0.949

Total PSA (ng/mL) 8.33 ± 3.80 (3.06–20.00) 9.87 ± 4.03 (3.63–19.65) 0.006
Free-to total PSA ratio (%) 18.1 ± 8.2 (3.1–39.6) 20.2 ± 10.3 (6.0–57.3) 0.168
Prostate volume (mL) 40.3 ± 18.4 (12.5–101.5) 46.9 ± 25.8 (15.5–139.0) 0.046
PSAD 0.248 ± 0.176 (0.066–1.344) 0.248 ± 0.113 (0.033–0.560) 0.925
CRP (mg/dL) 0.103 ± 0.173 (0.0–1.8) 0.221 ± 0.303 (0.0–1.4) 0.0003
Cancer detection rate 35.4% (58/164) 21.0% (13/62) 0.038
Histological inflammation detection rate 34.1% (56/164) 58.1% (36/62) 0.0014

†Mean ± SD range; ‡non-pyuria, U-WBC ≤ 3/h.p.f.; pyuria, U-WBC > 3/h.p.f.; U-WBC was not measured in two patients.
CRP, C-reactive protein; h.p.f., high power field; PCa, prostate cancer; PSA, prostate specific antigen; PSAD, PSA density; U-
WBC, urinary white blood cell.

higher in the pyuria, than in the non-pyuria group (P =
0.0003). The rate of cancer detection was significantly
higher in the non-pyuria group (35.4% vs 21.0%,
P = 0.038), whereas that of histological inflammation was
higher in the pyuria group (58.1% vs 34.1%, P = 0.0014).
Positive- versus negative-C-reactive protein
In addition to the distribution of the U-WBC count, Table 2
shows the distribution of pretreatment serum CRP levels
in this series of patients. Among them, 29 (12.7%) were
placed in the positive-CRP group, and the remaining 192
(84.2%) were placed in the negative-CRP group. The
serum CRP levels were not measured in seven patients.
Table 4 compares the clinical parameters, as well as the
rates of cancer detection and of histological inflammation
between the serum CRP-positive (n = 29) and negative
(n = 192) groups. Age, total PSA, free-to-total PSA ratio,
prostate volume and PSAD values, as well as rates of
cancer detection and histological inflammation, did not
significantly differ between the two groups.
Discussion
Wang et al. originally isolated the serine protease PSA
from prostate epithelial cells in 1979.9 Thereafter, PSA
measurement became the most valuable criterion upon
which to base a diagnosis of PCa and to treat such patients.
However, discriminating between PCa and BPD is difficult,
918 T Kato et al.

Table 4 Clinical parameters, detection rate of PCa incidence and histological inflammation in positive- and negative-CRP
groups†‡

Negative-CRP group (n = 192) Positive-CRP group (n = 29) P-value

Age (years) 67.0 ± 7.2 (42–86) 67.8 ± 7.9 (52–88) 0.598

Total PSA (ng/mL) 8.80 ± 4.06 (3.20–20.00) 9.09 ± 2.80 (4.60–14.20) 0.717
Free-to total PSA ratio (%) 18.7 ± 9.2 (3.1–57.3) 17.8 ± 5.7 (9.0–28.3) 0.660
Prostate volume (mL) 41.8 ± 20.5 (12.5–139.0) 44.5 ± 24.1 (18.7–97.3) 0.570
PSAD 0.249 ± 0.163 (0.033–1.344) 0.254 ± 0.153 (0.094–0.546) 0.895
Cancer detection rate 31.3% (60/192) 34.4% (10/29) 0.831
Histological inflammation detection rate 41.1% (79/192) 48.3% (14/29) 0.546

†Mean ± SD range; ‡Negative, serum CRP < 0.3 mg/dL; positive, serum CRP = 0.3 mg/dL; Serum CRP was not measured in
seven patients. CRP, C-reactive protein; PCa, prostate cancer; PSA, prostate specific antigen; PSAD, PSA density.

particularly in patients with intermediate PSA levels. Since
both normal and malignant prostate glands express PSA
protein, it is not specific to PCa. Several PSA-related fac-
tors such as the free-to-total PSA ratio, PSAD and PSA
velocity, have been examined in an attempt to improve the
efficiency of prostate biopsies.6,7 Serum markers, such as
p53 antibody and insulin-like growth factor 1 (IGF-1),
have also been examined to improve positive predictive
value.10,11 Furthermore, advances in PCa visualization such
as magnetic resonance spectroscopic imaging, dynamic
contrast-enhanced magnetic resonance imaging, positron
emission tomography and transrectal power Doppler imag-
ing have improved the positive predictive value.12,13
Because prostate biopsy can be a painful procedure with
potentially significant morbidity, a valid management goal
must therefore be to minimize the rate of negative biopsies.
Serum PSA levels are increased not only in patients
with PCa, but also in those with non-malignant conditions
such as benign prostatic hyperplasia, prostatic manipula-
tion, and even asymptomatic and chronic prostatitis.3,4
Morote et al. retrospectively studied 284 patients with
no evidence of cancer in sextant ultrasound-guided biop-
sies. Benign tissue without inflammation was found in
23.2% of the patients, 68.3% had chronic prostatitis and
8.4% had acute prostatitis, suggesting that prostatic inflam-
mation is frequent in specimens of BPD.5 We histologically
detected inflammation in 53.5% of our BPD patients, and
in 14.1% of our PCa patients.
Asymptomatic prostatitis defined as the presence of
inflammatory cells in expressed prostatic secretions or in
histological prostate biopsy specimens, is classified as
National Institute of Health (NIH) category IV prostatitis.8
Our study included non-palpable cases without clinical
evidence of prostatitis and patients with NIH-IV prostatitis.
The pyuria group with a U-WBC count of over 3/h.p.f.
had significantly elevated serum PSA levels (P = 0.006).
However, the rate of cancer detection was significantly
lower than in the non-pyuria group (P = 0.038). Despite
the absence of clinical prostatitis symptoms, inflammation
was histologically frequent in the pyuria group (P =
0.0014). Prostate hyperplasia is frequently associated with
NIH-IV prostatitis.14,15
Our results failed to establish the clinical usefulness of
serum CRP levels in PCa screening. Serum CRP level was
higher in patients with pyuria than those without. Inflam-
mation may contribute to both elevated PSA and CRP. On
the other hand, there were no differences in rates of inflam-
mation and cancer detection between CRP positive and
negative group. The U-WBC count would more directly
indicate the presence of prostatic inflammation than serum
CRP level, and serum CRP level would have minor asso-
ciation with elevated PSA. Our results indicated that the
U-WBC count is a reliable method of detecting minute
prostatic inflammation. Thus, an inflammatory index such
as U-WBC in the clinical setting might be useful to distin-
guish non-palpable PCa from BPD.
Karazanashvili et al. investigated the possibilities of
improving the accuracy of PCa screening among 61
patients with a PSA value of 4–10 ng/mL, non-suspicious
results of DRE and inflammation in expressed prostate
secretion.16 They examined the PSA value change after
antibacterial treatment as diagnostic method. Pca detection
rate was low (6%) among the patient with decreased PSA
values, and prostate inflammation was observed in 100%
of cases. Contrary to this, PCa detection rate was high
(83%) among the patients with unchanged or even
increased PSA values, while only 17% of these patients
presented with prostate inflammation. They suggested that
chronic prostatitis is an important cause of elevated PSA
and assessment of PSA value change after antibacterial
treatment can improve PCa screening accuracy.
In men referred with raised PSA levels and without
abnormal findings on DRE, the incidence of coexisting
asymptomatic prostatitis might be quite high. Patients with
pyuria should be administered with antibiotics or antiphl-
ogistics before undergoing biopsy collection. Repeated
PSA measurements would also be effective. Counting U-
WBC is rapid, simple, convenient and non-invasive and
therefore should be of significant value for routine urolog-
ical examinations.
Acknowledgments
Supported by grants-in-aid for scientific research from the
Ministry of Education, Science, Technology and Culture,
Japan (14207061, 16591582 and 16689026), and the Pub-
lic Trust Haraguchi Memorial Cancer Research Fund
(2003).

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