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Imaging Prostate Cancer: Current and Future Applications

Imaging Prostate Cancer: Current and Future Applications

ABSTRACT: Various treatment options are available for adenocarcinoma of the prostate—the most common malignant neoplasm among men in the United States. To select an optimum management strategy, we must be able to identify an organ-confined disease (in which local therapy such as surgery or radiation may be beneficial) vs prostate cancer beyond the confines of the gland (for which other treatment approaches may be more appropriate). At present, no standard imaging modality can by itself reliably diagnose and/or stage adenocarcinoma of the prostate. Standard transrectal ultrasound, magnetic resonance imaging (MRI), computed tomography, bone scans, and plain x-ray are not sufficiently reliable when used alone. Fortunately, advances in imaging technology have led to the development of several promising modalities. These modalities include color and power Doppler ultrasonography, ultrasound contrast agents, intermittent and harmonic ultrasound imaging, MR contrast imaging, MRI with fat suppression, MRI spectroscopy, three-dimensional MRI spectroscopy, elastography, and radioimmunoscintigraphy. These newer imaging techniques appear to improve the yield of prostate cancer detection and staging, but are limited in availability and thus require further validation. This article reviews the status of current imaging modalities for prostate cancer and identifies emerging imaging technologies that may improve the diagnosis and staging of this disease. [ONCOLOGY 15(3):325-342, 2001]

Introduction

Adenocarcinoma of the prostate
remains the most common malignant neoplasm and the second cause of cancer-specific death among men in the
United States.[1,2] For the year 2000, the number of new cases of prostate
cancer in the United States is estimated to be 180,400, with 31,900 expected
deaths.[1,2] Because early disease is usually asymptomatic, the need for
reliable diagnostic modalities to identify patients with early-stage prostate
cancer is essential if effective therapy is to be contemplated.

Determining the extent of disease in newly diagnosed patients is
another critical issue. More than one-third of patients with apparent clinically
localized prostate cancer already have extraprostatic disease.[3,4] Pretreatment
identification of this group of high-risk patients is essential for the
selection of an optimum therapy.[5] If the disease is confined to the prostate,
it could be curable with definitive local therapy such as surgery or radiation.
Conversely, if the disease extends beyond the confines of the gland, other
treatment approaches may be more appropriate.[6]

Improvements in screening and diagnosing prostate cancer
occurred with the use of prostate-specific antigen (PSA) and the development of
gray-scale transrectal ultrasound (TRUS) biopsy techniques.[7-10] Years of
experience have shown that TRUS-directed biopsy, while very useful, has several
limitations.[11-13] Prospective TRUS imaging data have demonstrated that
conventional gray-scale TRUS is slightly superior to random chance in detecting
prostate cancer.[14] The present trend is to increase the number of biopsies in
order to compensate for the limitations of imaging alone.

The traditional lesion-directed biopsy led to the development of
the six-core or "sextant" biopsy technique. Today, the trend is to
perform 8 to 10 biopsies to more adequately sample the prostate gland. These
additional biopsies tend to be laterally directed.[15] This increase in the need
for additional biopsies is partly due to current limitations in adequately
identifying cancer with noninvasive imaging.

Imaging remains an essential part of specific management
approaches to prostate cancer, such as the use of TRUS in prostate brachytherapy
and cryotherapy. Imaging modalities used to diagnose and stage prostate cancer
include magnetic resonance imaging (MRI) and computed tomography (CT).[5,6] Bone
scans and plain x-rays are used to detect distant metastasis.[6] However, the
ability of these modalities to detect and stage prostate cancer is limited.[5]

The need for a more accurate imaging test has led to the
development of new imaging technologies for both the diagnosis and staging of
prostate cancer. These recent advances include Doppler imaging, contrast
imaging,[16-20] MRI spectroscopy, and radioimmunoscintigraphy.[21-31] This
article will review and critically assess the current status of prostate cancer
imaging modalities, as well as discuss the evolving role of these newer imaging
technologies.

Ultrasound Imaging Modalities

Gray-Scale Transrectal Ultrasonography

The role of gray-scale TRUS as an imaging modality for the
prostate was firmly established in the 1980s with the introduction of
high-frequency (7-MHz) transducers, the use of real-time ultrasound imaging, the
development of biplanar probes, and the clinical applicability of outpatient
transrectal biopsy. Gray-scale TRUS is frequently used to guide prostate
biopsies (Figure 1) and for the evaluation of a patient with a palpably abnormal
digital rectal examination or abnormal laboratory tests suggestive of prostate
cancer (eg, elevated PSA). In some instances, TRUS may be used to monitor
responses following a prostate cancer treatment in which the prostate was left
in situ.

Limitations of Gray-Scale TRUS: Although gray-scale TRUS was
a major achievement in improving the diagnostic yield of prostate cancer—especially
in cases of nonpalpable disease (ie, stage T1c)—experience has shown TRUS to
have several limitations. The subjective nature of the exam and the expertise of
the clinician may affect the interpretation of images.[13] Interpretation of
real-time, gray-scale TRUS images is also restricted by limitations of human
visual perception. A recent study[13] showed that an expert user was not able to
discriminate among images with more than 32 gray levels out of 256 displayed on
a gray-scale image. Therefore, any technical improvement of ultrasound scanners
may not always be perceived by human interpretation.

Perhaps the most troubling aspect of standard gray-scale TRUS is
the nonspecific, echogenic nature of the tumor itself. Very early studies[7,9]
suggested that prostate cancer was associated with hyperechogenicity. Presently,
prostate cancer is believed to have an echogenicity that is less than that of
normal prostate gland tissue (hypoechoic), with some series reporting 60% to 97%
of cases as hypoechoic.[32,33]

Hyperechoic cancers are now considered very rare, and some
authors have even questioned their true existence. If present, hyperechoic
prostate cancers are usually carcinomas of the comedo type or cancers that have
invaded areas of calcification or corpora amylacea. Egawa et al[34] reported
hyperechogenic prostate cancer to account for 1.3% of cases in a contemporary
series.

Up to 25% of tumors are reported to be isoechoic (the same
echogenicity as the normal prostate tissue).[34] Isoechoic tumors are almost
impossible to detect because a clear distinction between the tumor and
surrounding prostate gland tissue cannot be made on the basis of echogenicity.
In such cases, the presence of secondary signs—such as glandular asymmetry,
capsular bulging, and areas of attenuation—might prove helpful.

Echogenic discrepancies may again be a useless diagnostic
criterion in cases where the tumor diffuses and totally replaces an entire zone
or the entire gland. Overall, the presented data suggest that gray-scale TRUS
alone is unreliable in diagnosing prostate cancer and must always be performed
with a biopsy to evaluate for cancer.

Early studies generated enthusiasm about the role of TRUS in
improving the staging of locally advanced prostate cancer.[7] However, this
enthusiasm soon faded when other studies failed to demonstrate that TRUS was
better than a digital rectal exam for the detection of local extension.[35] The
ability of TRUS to detect a neurovascular bundle or seminal vesicle involvement
is operator dependent and is associated with a high false-positive rate for
seminal vesicle involvement.[5]

In general, an accurate assessment of locally advanced disease
is frequently difficult; available ultrasound units do not have adequate
resolution to detect the microscopic extension associated with many cases of
locally advanced disease. This was reflected in staging studies that reported
low predictive values of gray-scale TRUS ranging from 18% to 60%.[12] For these
reasons, gray-scale TRUS is considered by most to be a nonreliable tool for
staging locally advanced disease.

Doppler Imaging

The Doppler shift frequency is an effect that applies to all
wave motion. Discovered by Austrian physicist Christian Doppler (1803-1853), the
effect refers to a change in wave frequency caused by the motion of a wave
source, receiver, or reflector. Acoustic Doppler effect is frequently
experienced in our daily life, for example, with approaching and receding sirens
or train whistles. Mathematically, this effect is represented by the following
formula:

fD = 2f0vcosq/c

where fD is the Doppler frequency shift,
f0 is the incident
frequency, v is the flow velocity, c is the speed of sound in tissue, and q
is
the angle between the ultrasound beam and flow direction.[12] Simply put, this
equation measures the difference in frequency of returning echoes and emitted
frequency.

Principles of Use in Medicine: Doppler ultrasound is mainly
used in medicine to detect the presence or absence of blood flow in vessels, its
direction, and its characteristics. In urology, this technology has been
frequently applied to detect the velocity of renal blood flow, penile
vasculature, and to assess neovascularity in renal, testicular, and prostate
tumors [36-39].

Flow can be detected either by pulsed-wave Doppler (which
displays the frequency shift or velocity as spectral waves) or color Doppler
imaging, also known as color-flow imaging.[12] Color-flow imaging provides a
two-dimensional (2D), cross-sectional, real-time, color-coded Doppler shift that
is superimposed on the real-time gray-scale anatomic display.[13] It displays
the range of the mean frequency shift or velocities of red blood cells within
flowing blood as colors of the spectrum. Flow toward the transducer is depicted
in various shades of red, and flow away from the transducer is characterized by
shades of blue.[40]

Normally, the prostate gland should demonstrate symmetrical,
low-to-absent color-flow signal intensity, with the periurethral area exhibiting
some flow and the outer gland showing minimal to no flow.[39,41,42] Several
studies have demonstrated that malignant prostate tissue can sometimes be
associated with abnormal vascular patterns.[43-48] Detection of these abnormal
blood flow patterns within prostatic tumors is the main application of Doppler
ultrasound in prostate cancer imaging.

Early Clinical Results: Early results using pulsed Doppler
were disappointing,[39] and slightly better results were reported later with the
use of color Doppler imaging.[42] Rifkin et al[39] reported their experience in
619 patients in whom color Doppler imaging was used as an adjunct to gray-scale
TRUS. Using TRUS biopsies of foci lesions identified with gray-scale imaging or
from sites showing flow abnormality on color Doppler imaging scans, they
confirmed the presence of 132 cancers in 121 men. A total of 123 men (93%) had
corresponding gray-scale abnormalities, and 114 men (86%) demonstrated abnormal
flow on color Doppler imaging. Nine patients (7%) showed no obviously
identifiable abnormality on gray-scale scanning but had distinctly abnormal flow
on color Doppler scanning.

Kelly and associates[49] reported a sensitivity of 96% for TRUS
alone and 87% for color Doppler imaging. The addition of color Doppler imaging
increased the positive-predictive value (PPV) from 0.53 using TRUS alone to 0.77—but
at a cost of reduced sensitivity. In only 1 case out of 158, color Doppler
imaging suggested the diagnosis of malignancy independently of TRUS. The authors
concluded that color Doppler imaging improves the PPV of TRUS, but has no
demonstrable value over TRUS alone in the diagnosis of prostate cancer.

Correlation With Biopsy Findings: Newman and coworkers[50]
correlated color Doppler imaging results with the histologic findings from
site-specific transrectal core biopsies. In this study, color Doppler imaging
had a sensitivity of 49%, specificity of 93%, and PPV of 62%, and was able to
detect at least one focus of carcinoma in seven patients with no gray-scale
abnormalities. The findings indicated that focal peripheral zone
hypervascularity on color Doppler imaging is associated with an increased
likelihood of prostate cancer or inflammation on biopsy—often without a focal
gray-scale abnormality. Although the authors suggested that color Doppler
imaging may help identify an appropriate site for biopsy, they stated that a
negative color Doppler imaging scan should not preclude biopsy, since it has a
limited sensitivity in the detection of all sites of cancer.

Patel and Rickards[51] investigated the discriminative value of
the amount of color flow on Doppler ultrasound within the peripheral zone of the
prostate. The histologic outcome of 274 guided biopsies was correlated with the
grade of color flow on ultrasound hard-copy images. They noted that normal color
flow was seen with both normal and abnormal prostate biopsies. Results of the
study demonstrated that with the greatest color flow, specificity for the
diagnosis of an abnormal prostate (either cancer or prostatitis) is very high,
and that with prostatitis, a markedly increased color flow reflects the severity
of inflammatory cellular reaction. Nevertheless, the authors concluded that
grading the amount of color flow with Doppler ultrasound is of limited
diagnostic usefulness.

Predictive Value of Tumor Vascularization: The prognostic
significance of detecting an increased flow within a given tumor has also been
investigated. Findings of several studies have indicated that tumor
vascularization may correlate with its potential for rapid growth and distant
metastasis.[44-47] Brawer et al[46] demonstrated that the histologic
determination of microvessel density in prostatic carcinoma is an independent
predictor of pathologic stage, and, hence, malignant potential.

Thus, quantification of tumor angiogenesis may guide prostate
cancer treatment strategies. This issue was partly addressed in a study by
Littrup et al,[52] in which cancers with a high color flow had significantly
higher mean Gleason scores than cancers without demonstrable color flow,
particularly in African-American men.

Our group previously demonstrated that color-coded Doppler flow
within the tumor correlates with both tumor grade and stage, and that increased
flow is associated with a higher Gleason score and higher incidence of seminal
vesicle invasion. Our study findings also indicated that increased flow noted on
color Doppler imaging is independently predictive of the likelihood of
biochemical relapse following radical prostatectomy.[53]

Drawbacks of Color Doppler Imaging: Although studies suggest
that color Doppler imaging has potential prognostic significance, it still has
two major pitfalls: overlap with prostatitis and low sensitivity in the
detection of tumor blood flow within a prostatic carcinoma. Its failure to
detect tumor blood flow may be partly attributed to the fact that the presence
or absence of tumor flow may be influenced by tumor size or volume, with tumors
smaller than
2 mm in diameter being avascular and those at least 1 cm3 possessing
vascularity.[54] Other technical factors may also contribute to the failure of
tumor blood flow detection: (1) The limited spatial resolution on color Doppler
makes it difficult to detect blood flow in very small vessels, and (2)
low-volume flow results in frequency shifts below the noise level, and
consequently, cannot be detected.[13]

Power Doppler: More recently, the amplitude or power of the
Doppler shift (known as power Doppler) has been encoded into color Doppler and
used to detect flow. The main advantage of power Doppler is its ability to
detect slower flow with less reliance on the Doppler angle.[55]

Our group recently compared the accuracy of gray-scale TRUS,
color Doppler imaging, and power Doppler imaging in the detection of prostate
cancer, and then assessed the influence of operator experience on test
results.[14] Our study indicated that gray-scale TRUS and Doppler imaging are
minimally effective in prostate cancer detection, that there is no benefit of
power Doppler over color Doppler imaging, and that there is no apparent benefit
from increased operator experience with Doppler imaging. We did, however,
observe that with gray-scale TRUS or Doppler, foci abnormalities were 2.5 times
more likely to contain cancer than adjacent tissues with normal ultrasound
findings. While Doppler flow studies may provide some prognostic data, the
routine use of this technique for the diagnosis of prostate cancer does not
appear to be warranted at the present time.

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