1. health and fitness
2. disease
3. cancer

0022-5347/05/1736-1926/0
THE JOURNAL OF UROLOGY®
Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 173, 1926 –1929, June 2005
Printed in U.S.A.
DOI: 10.1097/01.ju.0000158444.56199.03
PROSTATE CANCER DETECTION IN MEN WITH PROSTATE SPECIFIC
ANTIGEN 4 TO 10 NG/ML USING A COMBINED APPROACH OF
CONTRAST ENHANCED COLOR DOPPLER TARGETED AND
SYSTEMATIC BIOPSY
ALEXANDRE PELZER,* JASMIN BEKTIC, ANDREAS P. BERGER, LEO PALLWEIN,
ETHAN J. HALPERN, WOLFGANG HORNINGER, GEORG BARTSCH AND FERDINAND FRAUSCHER
From the Departments of Urology (AP, JB, APB, WH, GB) and Radiology (LP, FF), Innsbruck Medical University, Innsbruck, Austria,
and Department of Radiology, Thomas Jefferson University, Jefferson Prostate Diagnostic Center (EJH), Philadelphia, Pennsylvania
ABSTRACT
Purpose: Transrectal gray scale ultrasound guided biopsy is the standard method for diagnosing prostate cancer (PC). Improved cancer detection with ultrasound contrast agents is related to
better detection of tumor vascularity. We evaluated the impact of a combined approach of
contrast enhanced, color Doppler targeted biopsy (CECD) and systematic biopsy (SB) for the PC
detection rate in men with prostate specific antigen (PSA) 4.0 to 10 ng/ml.
Materials and Methods: We examined 380 screening volunteers with a total PSA of 4.0 to 10
ng/ml (percent free PSA less than 18). CECD was always performed before SB. Another investigator blinded to contrast enhanced findings performed 10 SBs. The cancer detection rate for the
CECD, SB and combined approaches was assessed.
Results: PC was detected in 143 of 380 patients (37.6%, mean total PSA 6.2 ng/ml). The PC
detection rate for CECD and for SB was 27.4% and 27.6%, respectively. The overall cancer detection rate with the 2 methods combined was 37.6%. For targeted biopsy cores the
detection rate was significantly better than for SB cores (32.6% vs 17.9%, p ⬍0.01). CECD in a
patient with cancer was 3.1-fold more likely to detect PC than SB.
Conclusions: CECD allows for the detection of lesions that cannot be found on gray scale
ultrasound or SB. CECD allows for assessment of neovascularity associated with PC. However,
the combined use of CECD and SB allows for maximal detection of PC with a detection rate of
37.6% in our patients with PSA 4 to 10 ng/ml.
KEY WORDS: prostate; prostatic neoplasms; prostate-specific antigen; biopsy; ultrasonography, Doppler, color
Transrectal gray scale ultrasound (US) guided biopsy is
the standard method for diagnosing prostate cancer (PC) in
patients with increased total prostate specific antigen (tPSA)
and/or abnormal digital rectal examination. Various biopsy
strategies have been devised to increase the diagnostic yield
of prostate biopsy, including sampling visually abnormal areas, more lateral placement of biopsies, anterior biopsies and
an increasing number of cores, ranging from 5 region sampling to saturation biopsies with up to 45 cores.1⫺4 Color
Doppler imaging is another tool that may be used to improve
biopsy performance. Especially when combined with a contrast enhancing agent, Doppler US is a reliable, sensitive and
noninvasive method to show tumor blood flow and, therefore,
it has an important role in diagnostic US. Increased microvascularity accompanies cancer growth. Neovascularity may
be detectable by color Doppler imaging due to abnormal blood
flow patterns in larger feeding vessels.5, 6 Others have noted
the improved positive predictive value of color Doppler imaging for detecting PC but most agree that color Doppler
targeted biopsy does not detect many cancers identified by
systematic gray scale US guided biopsy.7, 8 Thus, gray scale
US guided biopsy remains the standard of care. More recently US contrast agents have been used to improve cancer
detection.9 Improved cancer detection with US contrast
agents is related to the better detection of slow flow and flow
in small vessels, that is tumor vascularity, through an increased signal-to-noise ratio compared with the conventional
color Doppler technique.10 We evaluated the impact of contrast enhanced, color Doppler targeted biopsy (CECD) combined with systematic biopsy (SB) to compare the cancer
detection rate of the 2 techniques and evaluate the overall
cancer detection rate in this population.
MATERIALS AND METHODS
We examined 380 consecutive asymptomatic screening
male volunteers with tPSA 4.0 to 10 ng/ml (free-to-total PSA
less than 18%). Table 1 lists study population characteristics.
Digital rectal examination was not part of the screening
process in this study, although it was done directly before
biopsy. Patient age was 41 to 77 years (average 60.7). Study
exclusion criteria were clinical prostatitis within 1 month of
biopsy, active urinary tract infection or contraindications to
the US contrast agent SonoVue®.
The night before biopsy all participants began a 5-day
Submitted for publication August 9, 2004.
* Correspondence: Department of Urology, Innsbruck Medical
University, Anichstrasse 35, A-6020 Innsbruck, Austria (telephone:
⫹43 512 504 24810; FAX: ⫹43 512 504 28365; e-mail:
alexandre.pelzer@uibk.ac.at).
1926
TABLE 1. Screening population characteristics
Mean (range)
No. pts
PSA (ng/ml)
%fPSA
Complete PSA (ng/ml)
Prostate vol (ml)
* In 280 patients.
380
6.2 (4–10)
12.83 (4–18)
4.7 (0.79–25)*
35.54 (11–175)
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PROSTATE CANCER DETECTION USING COMBINED APPROACH
Detection rate of combined methods was above 95% CI of CECD and SB, for which detection rate was 27.4% and 27.6%, respectively
course of a fluoroquinolone antibiotic or appropriate alternative antibiotic if there was a fluoroquinolone allergy. A
cleansing enema was administered on the morning of biopsy.
Patients were instructed not to ingest aspirin or nonsteroidal
anti-inflammatory agents for at least 5 days before biopsy.
CECD and the SB were performed using a needle guidance
device with the patient in the lithotomy position.
Five targeted biopsy cores were obtained during intravenous injection of the US contrast agent SonoVue®, which
amplifies the color Doppler signal up to 25 dB.11 The contrast
agent was prepared in standard fashion and administered to
a maximum dose of 4.8 ml. Color Doppler system presets
were optimized based on experience to detect contrast enhanced flow. Contrast enhanced imaging was always performed before systematic biopsies to avoid biopsy induced
hyperemia on the contrast enhanced imaging study. CECD
were performed into a maximum of 2 hypervascular areas in
the peripheral zone (PZ) only. No targeted biopsies were
performed in the transitional zone (TZ). This biopsy approach
was done using a 9 MHz end fire probe, which enables a
single plane approach.
Subsequently another investigator blinded to contrast enhanced findings performed 10 SBs in standard spatial distribution. This biopsy was guided by gray scale US using an
endorectal probe unit fitted with a biplane probe operating at
a gray scale frequency of 7.5 MHz. Biopsies were obtained
without regard to prostate US appearance. Two biopsy cores
per side were obtained from the apex area, including 1 medial
and 1 lateral. Another biopsy core was obtained on each side
from the lateral aspect of the mid prostate, 1 was obtained on
each side from the posterolateral area at the base, most likely
in the central zone, and a final biopsy core was obtained from
each side of the TZ. TZ biopsies were anterior biopsies in the
mid prostate.12 Biopsies were obtained transrectally using
an 18 gauge biopsy needle. Each biopsy core was reviewed by
a pathologist and reported as cancer with an assigned
Gleason score, or as prostatic intraepithelial neoplasia, inflammation or benign prostatic tissue.
For statistical analyses the Mann-Whitney U test was
used. All statistical calculations were performed using SPSS
10.0 software (SPSS, Chicago, Illinois) with p ⬍0.05 considered as statistically significant.
The cancer detection rates of the 2 techniques were compared. We further evaluated the overall cancer detection
rate.
PC was detected in 143 of the 380 patients (37.6%) with a
mean tPSA of 6.2 ng/ml (range 4.0 to 10). PC was detected in
104 of the 380 patients (27.4%) during CECD and in 105
(27.6%) during SB (see figure, table 2). Based on cancers
detected by biopsy using either technique the sensitivity for
cancer detection was 73.4% (105 of 143 cases) for targeted
biopsy and 72% (104 of 143 cases) for SB (see figure, table 2).
The overall cancer detection rate with the 2 methods combined was 37.6% (143 patients) with a mean tPSA of 6.2
ng/ml. The detection rate of the combined methods was above
the 95% CI limit of CECD and SB (see figure). Based on the
cancer detection per core performed by CECD (32.6% or 233
of 715 cores) the detection rate was significantly better for
CECD than for SB (17.9% or 257 of 1,430 cores, p ⬍0.01, table
3). CECD in a patient with PC was 3.1-fold more likely to
detect PC than SB.
Mean patient age at CECD and at SB detected PC was
64.13 and 63.69 years, mean PSA was 6.1 and 5.9 ng/ml, and
mean Gleason score was 5.9 and 6.07, respectively. Gleason
score in all 143 patients diagnosed by contrast enhanced
imaging and gray scale US was between 4 and 9. In contrast
to CECD (2 cases), the systematic approach detected more
cases with a Gleason score of 4 and 5 (7). Table 4 shows the
distribution of Gleason scores in all 143 patients with cancer.
Analysis by patient demonstrated no statistically significant
difference in the overall cancer detection rate in the CECD
and SB arms of our study (27.4% vs 27.6%).
TABLE 2. Cancer detection rate of CECD vs SB
SB
Neg
Pos
Pos
Total No.
237
39
38
66
275
105
Totals
276
104
380
PC was detected in 104 patients (27%) during CECD and in 105 (27.6%)
during SB.
TABLE 3. Detection rate by number of cores
No. Cores
Contrast
Enhanced
RESULTS
Table 1 lists screening population characteristics. Mean
patient age was 60.69 years (range 41 to 77), mean tPSA was
6.2 ng/ml, the mean free-to-total PSA ratio was 12.83%
(range 4% to 18%) and mean prostate volume was 35.5 ml
(range 11 to 175).
No. CECD
Neg
Pos
Neg
233
482
Gray Scale
257
1,173
Totals (%)
715 (32.60)
1,430 (17.90)
CECD in patient with PC was 3.1-fold more likely to detect PC than SB (p
⬍0.01).
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PROSTATE CANCER DETECTION USING COMBINED APPROACH
TABLE 4. Gleason score distribution
Gleason
Score
4
5
6
7
8
9
No. Gray
Scale
3
4
25
5
1
No. Contrast
Enhanced
2
0
31
5
1
No. Gray Scale ⫹
Contrast Enhanced
2
27
34
2
1
Totals (%)
38 (10.0)
39 (10.2)
66 (17.0)
In contrast to CECD targeted biopsy (2 patients), SB detected more patients (2) with Gleason score 4 and 5.
DISCUSSION
Transrectal US guided prostate SB is the standard technique for diagnosing PC. Studies have shown that a single set
of 6 biopsies may miss clinically detectable PC in 15% to 34%
of men.12⫺14 Recently groups advocated a higher number of
biopsy cores to improve cancer detection. However, Naughton
et al reported no increase in cancer detection when comparing 6 vs 12 biopsy cores.15 Our results comparing 10 vs 14
cores demonstrated that there is no significant improvement
in cancer detection by increasing the number of biopsy cores.
To improve further our detection of PC and limit the number
of biopsy cores per patient we introduced microbubble contrast agents to optimize the diagnostic value of transrectal
color Doppler US.
It has been demonstrated that tumors larger than 1 mm2
must recruit new blood vessels to grow larger.16 This neovascularity results in more blood flow but much of the flow is in
small vessels less than 100 ␮m. Conventional color Doppler
US cannot detect flow in such small vessels because of the
limited spatial resolution of US equipment and slow flow in
these vessels. However, intravascular US contrast agents
can enhance the back scattered echo from blood flow in small
vessels.17 US contrast agents provide clear enhancement of
the Doppler signal from the human prostate.
There are few studies of contrast enhancement in the human prostate. Ragde et al reported on 15 patients in whom
Echogen® was administered for enhanced color Doppler imaging.17 They concluded that contrast enhanced US may be a
useful technique for imaging prostatic blood flow and it may
enable the more accurate identification of malignant lesions.
Bogers et al performed contrast enhanced, 3-dimensional
power Doppler US in 18 cases suspicious for prostate cancer
based on an increased tPSA of greater than 4.0 ng/ml or
abnormal digital rectal examination.18 In 12 of 13 cases
contrast enhanced US was considered suspicious for cancer.
Contrast enhanced US showed 85% sensitivity and 80% specificity compared with the 38% sensitivity of unenhanced US.
A limitation of this study is the small number of patients and
the relatively high mean PSA of 18.6 ng/ml.
In our series of 380 men cancer was detected by CECD and
SB in 104 (27.4%) and 105 (27.6%), respectively. Although
the detection rates were almost similar, for targeted biopsy
cores (32.6% or 233 of 715) the detection rate was significantly better than for SB cores (17.9% or 257 of 1,430,
p ⬍0.01, table 3) and CD in a patient with PC was 3.1-fold
more likely to detect PC than SB. However, contrast enhanced imaging failed to detect 39 cancers (10.2%). There are
some factors that might explain why contrast enhanced imaging missed several cancers. 1) Targeted biopsies were performed into hypervascular areas in the PZ. That means that
TZ cancers, which represent about 21.7% of cancers, were not
detected using this approach. 2) Since we used an end fire
probe for targeted biopsies, it seems possible that this approach is less accurate than the sagittal approach, which was
performed for SB. 3) Operator dependence seems to be higher
for the targeted technique than for the systematic one.
The reason why we did not perform targeted biopsies into
Total No.
5
6
83
44
4
1
143 (37.6)
the TZ is based on the fact that changes in benign prostatic
hyperplasia often demonstrate hypervascularity that cannot
be differentiated from the hypervascularity caused by malignant tissue. It might be possible that with new techniques,
such as dynamic assessment of contrast agent enhancement,
this problem will be overcome. However, this must be evaluated in further studies.
The limitations of this study are different US systems and
US probes. Thus, we cannot definitely exclude an overlap
between SB and CECD biopsy cores. An advantage of the
biplane probe used is related to the fact that it allows the
simultaneous display of the transverse and sagittal planes.
This seems to be helpful for exactly guiding SB, whereas
CECD was performed with a single plane probe only. Furthermore, the sagittal approach has been shown to provide
better core specimens than the transverse biopsy approach,
which was used for targeted biopsies. However, resolution of
the end fire probe is higher than that of the biplane probe
used (frequency 9 vs 7.5 MHz).
An important issue in our study was how we performed
biopsy. We performed 10 systematic and 5 targeted biopsies,
which is completely different than a study design comparing
10 vs 15 cores. The reason is that the 5 CECDs were performed in approximately 80% of 1 hypervascularized area of
the PZ only. In a previous study we have observed that
multiple cores from 1 hypervascularized area were more
likely to detect cancer than fewer less cores from 1 hypervascularized area. Furthermore, since we have the Tyrolean
PSA screening program, the majority of our patients with
cancer had only 1 hypervascularized area. Multiple hypervascularized areas are more likely to be associated with
prostatitis in our population.19 The increase in PC detection
was mainly related to CECD, which can detect areas that
cannot be seen on gray scale US and are often not included in
the SB approach.
CONCLUSIONS
We clearly observed that CECD improves PC detection.
This techniques allows the detection of lesions that cannot be
found on gray scale US or SB. The reason is that CECD
allows the assessment of neovascularity associated with
prostate cancer. However, combined CECD and SB allows
maximal PC detection with a detection rate of 37.6% in our
patients with PSA 4 to 10 ng/ml.
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