1. health and fitness
2. disease
3. cancer

VISIONS 10 . 06 ULTRASOUND
Transrectal Ultrasound
in Prostate Cancer:
State of the Art
Stijn W.T.P.J. Heijmink M.D.1
Marijke Eijkemans1
Joop van de Kant
Jelle O. Barentsz M.D. Ph D.1
Introduction
The current prostate cancer disease burden is
considerable due to the high prevalence of the
disease, widespread early detection, and the
relatively long survival time since many men will die
with rather than due to prostate cancer. In the United States, one in every three new cases of cancer in
men is prostate cancer1. Worldwide, in 2002, it was
predicted that 679,023 men received the diagnosis
while 221,002 died of the disease2. Thus, prostate
cancer had the highest incidence of all cancers in
men in developed countries. Transrectal ultrasound
(TRUS) plays an important role in the diagnosis and
subsequently in therapeutic decision-making. This
A
B
Department of
Radiology, Radboud
University Nijmegen
Medical Center
1
44
Fig. 1: Zonal
anatomy of the
prostate on TRUS.
(A) A grey-scale
image of a 61-yearold man with
prostate cancer.
(B) The central gland
(CG) and peripheral
zone (PZ) are
outlined on the
TRUS image.
Fig. 2: An example
of grey-scale TRUS of
prostate cancer.
(A) Grey-scale image
of the prostate of a
65-year-old man prior
to surgical emoval
of the prostate.
The right peripheral
zone (arrows) had a
distinctly lower echogenicity compared with
the left peripheral zone
(arrowheads).
(B) On histopathology
this area corresponded
with cancer (T).
A
B
article will discuss the anatomy of the prostate and
the features of prostate cancer, as well as the stateof-the-art TRUS techniques available in prostate
cancer imaging.
Prostate anatomy and prostate
cancer features
On TRUS, two prostate zones are distinguishable:
the outer peripheral zone and inner central gland
(Fig. 1). Prostate cancer is a multifocal disease: while
nearly 70-80% of all cancers occur in the peripherFig. 3: An example of
unenhanced colour Doppler
TRUS of prostate cancer.
(A) Colour Doppler image
of the prostate of a 65year-old man prior to
surgical removal of the
prostate. An asymmetrical
colour Doppler signal enhancement (white circle)
is observed in the right
peripheral zone of the
prostate at the apex.
(B) Histopathology
confirmed the presence
of the cancer (T) outlined
in yellow.
A
al zone3, many have concurrent foci in the central
gland. The cancer foci are homogeneously distributed across the entire peripheral zone4. Before the
advent of the prostate-specific antigen test, a blood
test indicating the possibility of the presence of
prostate cancer, in the late 1980s, most cancers were
detected only by digital rectal examination. Consequently, many cancers were large and advanced.
Currently, since most prostate cancers are detected
with the prostate-specific antigen test, most cancers
are smaller and less advanced. Prostate cancer was
reported to be correlated with an increased number
of blood vessels due to angiogenesis5,6.
B
45
VISIONS 10 . 06 ULTRASOUND
A
B
Fig. 4: An example of unenhanced power Doppler TRUS of prostate
cancer. (A) Power Doppler image of the prostate of a 59-year-old
man before surgical removal of the prostate showed markedly increased
Doppler signal ventrally in the left central gland (white circle).
(B) Histopathology confirmed the presence of the cancer (T) outlined
in yellow.
State-of-the-art TRUS
techniques
Grey-scale TRUS
Grey-scale TRUS is the oldest ultrasound technique for the assessment of the prostate. In the early 1980s, it was established that the paramount
TRUS feature of prostate cancer was the presence of
Fig. 5: An example of unenhanced Advanced Dynamic Flow™ TRUS
of prostate cancer. (A) Advanced Dynamic Flow™ image of a
61-year-old man before surgical removal of the prostate showing a distinct
area of increased flow in the right lateral peripheral zone (arrows). (B)
Histopathology onfirmed the presence of the cancer (T) outlined in yellow.
B
an area of hypoechogenicity (Fig. 2). Presently, with the development of highfrequency (8-10 MHz) probes the peripheral
zone can be visualized in ever more detail.
Nevertheless, studies that performed biopsy
on areas of hypoechogenicity alone achieved relatively low (18-53%) predictive values in populations
with prevalences around 33%7. Thus, in the era of
the prostate-specific antigen test searching for
hypoechogenicity alone is insufficient to detect
most prostate cancers.
Doppler TRUS
Doppler imaging adds functional information to
the background anatomical grey-scale image. Conventional Doppler TRUS can display the relatively
large blood vessels, providing an indication of the location of a clustering of vessels. Because prostate
cancer was correlated with an increase in the number of blood vessels, Doppler TRUS can aid in correctly localizing prostate cancer. In clinical practice,
no clear difference exists between colour Doppler
(Fig. 3) and power Doppler (Fig. 4) TRUS. No clear
advantage in cancer detection was observed with
the use of conventional Doppler. These conventional Doppler techniques can only visualize relatively
large blood vessels. A novel technique is Advanced Dynamic Flow™ (Fig. 5), which due to
its higher resolution is able to display smaller vessels. By using wide-band Doppler (i.e.
B
A
B
C
D
E
F
narrow-band frequency transmission) high resolution
can be achieved. To further increase sensitivity, the center frequency is changed according to the depth and the
signal is filtered by waveform shaping. Due to the employment of a high frame rate it can be used real-time.
The technique can be used in both unenhanced and
contrast-enhanced TRUS.
Contrast-enhanced TRUS
Administration of an ultrasound contrast agent
enhances the depiction of the microvasculature of
prostate cancer. Recently, prostate cancer biopsy
studies have shown that the yield per biopsy core taken
increased significantly with the use of contrastenhanced Doppler targeted biopsy8,9. Contrast agents
that have been used most frequently in prostate cancer
are Levovist® (Schering, Berlin, Germany) and SonoVue®
(Bracco, Milan, Italy). Neither drug has been approved by
the FDA and EMEA for regular clinical prostate imaging.
Fig. 6: An example of contrast harmonic imaging TRUS of prostate
cancer in the same patient as in Fig. 5. (A) At 19 s after a 2.4 ml bolus
injection of SonoVue® (Bracco, Milan, Italy), a symmetrical enhancement
of the central gland (arrowheads) was observed.
(B) At 22 s, also the peripheral zone started to enhance. An area in the
right peripheral zone (arrow) showed marked enhancement compared
with the rest of the peripheral zone.
(C-D) This area (arrows) continued to enhance with the same intensity as
the left and right central gland (arrowheads).
(E-F) From 36 s on, a washout of the signal was revealed in the area
(arrows).
47
VISIONS 10 . 06 ULTRASOUND
A
B
C
D
Fig. 7: An example of SonoVue® (Bracco, Milan, Italy) -enhanced
microflow imaging (MFI) in contrast-harmonic mode in a 59-year-old
patient with prostate cancer before surgical removal of the prostate.
(A) Image at 30 seconds after start of a 2.4 ml bolus injection of
SonoVue®: at the first signs of enhancement in the prostate (arrow) the
MFI mode is switched on. (B) One second later, an area of early enhancement in the left ventral part of the prostate (arrows) is visible.
(C) A few frames later, this area (arrows) continued to enhance compared
with other prostatic tissue. Also note the start of enhancement of normal
prostatic tissue (arrowhead). (D) At 32 s after start of the bolus injection,
both areas (arrows and arrowheads) continued to increase in enhancement. (E-G) At 34-39 s, the ventral area (arrows) with increased
microbubble signal markedly increased while the signal of the normal
prostatic tissue (arrowheads) increased only slightly. (H) At 43 s, the
entire prostate has enhanced and distinction between the area of
cancer and healthy tissue is more difficult. (I) Histopathology confirmed
the presence of a large ventral cancer (T).
48
Differences are the composition of the shell and the
internal gas substance. Generally, the microbubbles
are smaller than 7 mm in order to pass even the
smallest blood vessels in the body. The optimal resonance frequency of SonoVue® (which has a microbubble diameter of approximately 5 mm) is 5
MHz. At higher acoustic output power the microbubbles expand more easily than they contract,
which causes a non-linear wave pattern that is
transmitted back to the probe10. Several different
contrast-specific techniques are currently available in prostate TRUS, inter alia contrast-harmonic imaging, microflow imaging, intermittent or
flash imaging, and Vascular Recognition Imaging.
Furthermore, the administration of the contrast
agent can be performed with either a bolus injection or a continuous infusion.
Contrast harmonic imaging (CHI) is a new form
of signal reception analysis while scanning with a
low probe output power (mechanical index < 0.1).
This technique uses the non-linear response of the
microbubbles to receive only frequencies that are
twice or more times the frequency transmitted by
the ultrasound probe. These frequencies are referred
to as harmonic frequencies. Because prostate tissue
emits substantially less harmonic frequencies than
the microbubbles, the contrast between microbubbles (i.e. the microvasculature) and the tissue is
enlarged. In prostate cancer, the cancer foci display
a fast (usually within 30 seconds) start of enhancement with high wash-in and fast washout of the
contrast agent signal (Figure 6). Thus, the imaging
window in which the agent is visible for contrastenhanced imaging of prostate cancer is considerably
shorter than in liver imaging. Typically, one minute
E
F
G
H
I
Low MI Pulse Subtraction
A low Mechanical Index bi-pulse method using
alternating phases. Receiving echoes are summated. While linear signals from tissue are
cancelled the non-linear signals from the contrast agent are enhanced.
VRI (Vascular Recognition Imaging)
This low MI mode enables visualization of vascular and perfusion information superimposed
on the grey-scale information or separately.
The grey-scale image provides information on
position and orientation. The micro-bubble
flow direction is coded in red or blue where as
the stationary or slow moving bubbles, representing tissue, are displayed in green.
after a bolus injection with SonoVue® most of the
contrast agent signal will have faded, also when
using low mechanical index techniques (see Fig. 6EF). Subsequently, after switching to conventional
Doppler modes, the contrast agent can still be seen
to increase the Doppler signal in the prostate.
Microflow imaging (MFI) is an advanced form of
CHI in which the harmonic signal due to the flow of
the microbubbles in CHI mode is continuously followed and added in real-time mode. This technique
amplifies the signal of the microbubbles and is of
MFI (Micro Flow Imaging)
In a situation where the number of micro-bubbles is rather low or flow is slow a “holding” of
the maximum intensities can trace the bubbles
or reconstruct the micro-vessels.
Micro Flow Imaging can be combined with a
flash replenishment technique where the
maximum hold starts immediately after the
bubble destruction. This method allows visualization of the micro-vasculature repeatedly.
49
VISIONS 10 . 06 ULTRASOUND
A
B
C
D
E
F
Fig. 8: An example of SonoVue® (Bracco, Milan, Italy)-enhanced
Advanced Dynamic Flow imaging in a 55-year-old patient
with prostate cancer before surgical removal of the prostate.
(A-E) After bolus injection contrast administration, early enhancement was observed in the right peripheral zone (arrows).
(F) Only at 42 s after start of the administration the left (arrowheads) starts to enhance while the right peripheral zone already
shows contrast agent signal washout (arrows).
(G) Histopathology confirmed the presence of cancer (T) in the
right peripheral zone.
50
G
A1
A2
A3
A4
Fig. 9: (A) Region of interest enhancement analysis in a 59-year-old
patient with prostate cancer before surgical removal of the prostate.
The 2.4 ml SonoVue® (Bracco, Milan, Italy) bolus injection in contrast
harmonic imaging mode was captured on cine film. Contrast enhancement-time curves were calculated from the cine film using Toshiba
software. The contrast enhancement-time curves for the region in the
right central gland (A) showed markedly earlier and more intense enhancement compared with the region in the right peripheral zone (B).
(B) In the same patient, the parametric image of the start of enhancement was calculated using Toshiba software from the data set obtained
during contrast harmonic imaging. One area (arrows) showed a markedly earlier start of enhancement than the rest of the prostate.
B
particular use when administering a bolus injection in
which the actual acquisition time is short, as is the case
in the prostate (Fig. 7), and the contrast agent concentration decreases rapidly. A disadvantage is that one
cannot follow the contrast agent signal washout.
During MFI it is of utmost importance not to move the
TRUS probe, since motion by either the patient or the
examiner may cause the examination to be uninterpretable since signals from different locations within the
prostate are added erroneously.
An additional option that can be used in both CHI and
MFI mode is to replenish the field of view of the probe
by briefly increasing the mechanical index for 3 to 5
frames and thus destroying the microbubbles in
the plane of the probe. In the literature this technique is often referred to as intermittent scanning. This allows the prostate capillary bed to refill with contrast agent, much like the first-pass
effect after giving a bolus injection. The advantage of this method is the ability to perform multiple contrast inflow examinations at different
levels of the prostate during a single bolus injection. Vascular Recognition Imaging (VRI) uses low
(< 0.1) acoustic power and visualizes both the
prostate vascularization and the perfusion of the
contrast agent at the same time. Much like
51
VISIONS 10 . 06 ULTRASOUND
conventional colour Doppler, it displays the movement of microbubbles and distinguishes contrast
agent wash-in/wash-out and perfusion of
microbubbles by means of a colour display (Fig. 8).
Also, stationary microbubbles are colour-coded. This
contrast-enhanced TRUS technique comes closest to
the conventional Doppler technique and is therefore
likely to be easily interpretable for the radiologist or
urologist performing the examination. Because the
central gland is well-vascularized it can sometimes
be difficult to distinguish cancer from benign prostatic hyperplasia.
Clinical
applications
These state-of-the-art TRUS techniques may be
applied in clinical practice in a number of situations:
in patients scheduled for biopsy after abnormal
digital rectal examination or abnormal prostatespecific antigen levels; in patients with previously
negative standard TRUS-biopsies in which biopsies
were not Doppler- or contrast-enhancement targeted; in patients scheduled for surgical removal of the
prostate in order to accurately determine the exact
location of the cancer and its proximity to the
neurovascular bundles in order to prevent positive
surgical margins; in patients who are scheduled for
brachytherapy in order to plan the seed implantation
more accurately.
Future
challenges
An important future development is threedimensional coverage of the prostate during
contrast administration. This allows for a standardized capture of the entire gland at multiple time
points, as has already been performed in dynamic
contrast-enhanced magnetic resonance imaging11,12,
and helps to objectify the examination and reduce
operator dependency.
Furthermore, from data gathered in CHI mode at
a fixed plane through the prostate, signal intensitytime curves can be obtained off-line (Fig. 9A).
Another feature is the parametric mapping of
certain parameters obtained from the contrast
enhancement, for example the time to the start of
the enhancement (Figure 9B). Thus, the whole
contrast-enhancement period can be displayed in
one image and objectified.
Conclusions
52
In the prostate-specific antigen test screening
population in which cancer is detected at an early
stage, novel contrast-specific techniques such as
contrast harmonic imaging, intermittent scanning,
and Doppler-based Vascular Recognition Imaging
are currently available to aid the detection and
localization of prostate cancer in regular clinical
practice.
Acknowledgments
The authors wish to acknowledge Christina A. Hulsbergen-v.d. Kaa, MD,
PhD, for her histopathological analysis of all surgical specimens,
and Thomas Hambrock, MBChB, for his assistance with the TRUS
examination.
Literature
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56:106-130
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002.
CA Cancer J Clin 2005; 55:74-108
3. Chen ME, Johnston DA, Tang K, Babaian RJ, Troncoso P. Detailed
mapping of prostate carcinoma foci: biopsy strategy implications.
Cancer 2000; 89:1800-1809
4. McNeal JE, Redwine EA, Freiha FS, Stamey TA. Zonal distribution
of prostatic adenocarcinoma. Correlation with histologic pattern
and direction of spread. Am J Surg Pathol 1988; 12:897-906
5. Bigler SA, Deering RE, Brawer MK. Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol
1993; 24:220-226
6. Wilson NM, Masoud AM, Barsoum HB, Refaat MM, Moustafa MI,
Kamal TA. Correlation of power Doppler with microvessel density
in assessing prostate needle biopsy. Clin Radiol 2004; 59:946-950
7. Heijmink SW, van Moerkerk H, Kiemeney LA, Witjes JA, Frauscher
F, Barentsz JO. A comparison of the diagnostic performance of systematic versus ultrasound-guided biopsies of prostate cancer. Eur
Radiol 2006; 16:927-938
8. Pelzer A, Bektic J, Berger AP, et al. 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. J Urol 2005; 173:1926-1929
9. Halpern EJ, Ramey JR, Strup SE, Frauscher F, McCue P, Gomella LG.
Detection of prostate carcinoma with contrast-enhanced sonography using intermittent harmonic imaging. Cancer 2005;
104:2373-2383
10. Cosgrove D, Eckersley R. Contrast-enhanced ultrasound: Basic
physics and technology overview. In:Lencioni R, ed. Enhancing the
role of ultrasound with contrast agents. First ed. Milan: SpringerVerlag Italia, 2006; 3-14
11. Fütterer JJ, Engelbrecht MR, Huisman HJ, et al. Staging Prostate
Cancer with Dynamic Contrast-enhanced Endorectal MR Imaging
prior to Radical Prostatectomy: Experienced versus Less Experienced Readers. Radiology 2005; 237:541-549
12. Fütterer JJ, Heijmink SWTPJ, Scheenen TWJ, et al. Dynamic contrast-enhanced MR and proton MR spectroscopic imaging in localizing prostate cancer. Radiology 2006; In press