Download Role of Multiparametric MRI in the diagnosis of Prostate Cancer

Role of Multiparametric MRI in the diagnosis of Prostate Cancer: Update
Background
Prostate cancer (Pca) is actually considered the most common non-cutaneous
neoplasm of male gender, with an incidence in 2014 of 233,000 men in the US,
has the second most elevated death rate after lung cancer [1]. While the
incidence rate of Pca has increased considerably in the last 30 years, the
mortality rate has decreased over the last 20 years, indeed only 10% of patients
die due to this neoplasm [2]. One of the reasons of this low mortality is certainly
due to the screening campaign which for decades was carried out through the
use of serum PSA, allowing in many cases an early diagnosis of the disease [3].
As it’s known, however, PSA is not a tumor-specific marker and very often
results in false positives findings. Problems arising from false positives are often
lead to the execution of unnecessary interventional procedures, burdened with
many side effects and lot of stress for the patient [4]. Other diagnostic tools that
have been so far to assist the PSA in the diagnosis of prostate cancer are the
digital rectal examination (DRE) and the prostate trans-rectal ultrasound
(TRUS). These diagnostic tools, however, do not lead often to satisfactory
results because of their low sensitivity and specificity [5]. Ultrasound-guided
prostate biopsy is the only tool that certainty allows the histological presence of
tumor. This procedure, despite is invasive and poorly tolerated by the patient, it
was estimated to be the cause of many false negatives,
in a quite high
percentage of 39-52% [6]. This so high value is substantially due to several
factors: first of all, the biopsy procedure is often practiced by random samplings
with pre-established sextants. The low sensitivity of ultrasound in distinguish
neoplastic tissue is a very limiting factor and the intrinsic limit of the bioptic
approach in sampling particularly difficult areas to reach as the apex or lateral
margins of the gland [7]. In addition, in according to the EAU guidelines, the
sampling of the prostatic anterior portion is not sampled in the first biopsy,
although in this area origins 30% of prostate tumors [8]. Magnetic Resonance
Imaging (MRI) has established itself for several years as an elevate accurate
diagnostic tool in detecting prostate cancer. MRI is currently able to provide not
only highly detailed information on anatomic and glandular structure, but,
through the functional sequences, it provides invaluable information about the
intrinsic characteristics of the tissue as cellularity, vascularization quote and
metabolic asset. Sequences that combine this study protocol are represented
by morphological, the diffusion-weighted imaging (DWI), the dynamic contrastenhanced (DCE) and magnetic resonance spectroscopy imaging (MRSI). For
the opportunity to assess multiple organ parameters during the same MR
examination, this study protocol earned the name of multiparametric magnetic
resonance (mp-MRI) [9].
A sequence that lately is arousing great interest is the Diffusion Tensor Imaging
(DTI). This sequence uses DWI acquisitions to examine the fluid of the myelin
sheath of the axon, in a given voxel, to determine the direction and the vector of
the nerve fiber examined. To obtain a correct image representation, DTI should
utilize at least six DWI acquisitions. Tractography graphic image is
reconstructed by 3D Elaboration of specific reconstruction algorithms regarding
fiber or group of fibers included into the region of interest. Tractography
graphical representation is expressed by different colors that represent the
different directions of the fibers [10].
Technical Features
Prostate mp-MRI examination can be conducted on different types of magnets,
with both a 1.5 Tesla field strength and 3 Tesla (T). Initially, the study was
conducted only on 1.5 T magnets, by utilizing single surface phased array coils
(PA). This configuration allowed a good highlight of the pelvis by a purely
morphological point of view. However, the use of single phased array coil do not
allows an accurate analysis of smaller dimension structures, both in
morphological sequences (T1, T2), or by functional approach. The diagnostic
performance of MRI with a single PA coil stands around 71% of sensitivity, 74%
of specificity and an overall diagnostic accuracy of 77% [11]. Afterwards with the
introduction of endo-rectal coil (ERC), the diagnostic performance have
increased considerably. ERC coil, due to its intimal adjacency to the prostate,
allowed a better morphological representations of the gland and surrounding
pelvic structures. For a correct use of functional sequences as DWI and MRSI,
the only use of PA coil is often limited by image artifacts and poorly diagnostic
results [12]. MRI at 1.5 T with ERC, currently reached excellent diagnostic
performance with sensitivity and specificity values of 81 and 94% respectively
[13]. The use of ERC, however, can lead to various kind of problems like patient
discomfort, often responsable of movements, or the presence of artifacts related
to malpositioning of the coil. Air in rectal bulb can be as well a pretty common
cause of ERC artifact. Currently MR study of the prostate can be conducted on
high field strenght magnets like 3T. 3T magnets can obtain very accurate
anatomical representations, in detail, and morphological representation with
high performance in functional sequences, by utilizing the only PA surface coil.
3T field strenght allows, regard to 1.5T, an increase of signal / noise ratio (SNR),
spatial resolution, temporal resolution and better proportion of specific
absorption rate (SAR). There have been numerous comparative studies
between 1.5 T magnets and 3T, in order to evaluate the diagnostic accuracy,
image quality and the duration of the entire examination; the widely accepted
conclusion has been that an examination conducted with a 1.5T magnet with
both surface and ERC, can be comparable by diagnostic performance and
image quality to a 3T magnet with a single surface coil [14]. An examination
conducted with a 3T magnet and surface coil shows a great diagnostic accuracy
of 95%, with sensitivity and specificity of 84% and 95% respectively, with PPV of
74% and NPV of 95%. By associating ERC to 3T it can be reached the higher
diagnostic accuracy combination technique. This technical combination is
capable of a diagnostic accuracy of 97%, with sensitivity and specificity of 88
and 98% respectiively and a PPV of 82% and NPV 99% [15].
Technological evolution associated with high-performance magnets also allowed
not only to optimize sequences already present in protocol, such as DWI and
spectroscopy, but furthermore to develop new applications like intra voxel
incoherent motion (IVIM) and diffusion tensor imaging (DTI). The use of ERC is
mandatory for the evaluation of recurrence following prostatectomy or RT,
whereas the close proximity of the coil with the suspected area, allows a better
evaluation of the signal. The utilize of an ERC on 1.5T magnets actually
compared by detecting performances, with a 3T with the only PA surface coil. A
locoregional staging with 1.5T magnet with the single PA coil is not
recommended for the high risk of misinterpreting suspected areas or relapses
[16] (Fig. 1).
The morphological study consists in sequences TSE or FSE T1 and T2weighted on different spatial planes. The axial sequence outlines a field
examination consisting in a plane passing through the bladder dome upwardly,
until the perineal floor inferiorly, extended on the sides to the coxo-femoral
joints. The study conducted in the axial plane must necessarily be integrated
with acquisitions on sagittal and coronal plane. Sagittal plane allows a better
assessment of glandular rear profile and its relationships with the bladder and
rectum. Coronal acquisition, instead, obliqued slightly along the prostatic main
axis, allows an excellent evaluation of transition and peripheral zones, especially
as regards the peripheral lateral and antero-lateral horns. The multi-planar study
represents an important tool also for the volume of the organ, evaluation hardly
obtainable by other imaging methods. The morphological study is represented
substantially by T2-W sequences, that allow to obtain high resolution images
with elevated anatomic representation. Due to this sequence we are able to
distinguish in an optimally the structures that constitute the glandular zonal
anatomy and the associated structures such as urethra, seminal vesicles and
the adjacent organs. With this sequence many facilities that before the advent of
MRI could only be assumed, as the prostatic capsule, the pseudocapsule and
anterior fibro-muscular stroma (AFMS), can now be described in detail [17].
The peripheral zone in T2 sequence appears markedly hyperintense due to
abundant presence of glandular tissue, the transitional zone instead,
representing the central adenoma, appears composed of multiple nodules of
various shapes and sizes, which can present heterogeneous signal intensity,
according to the varies nodule nature. The two typology of nodules that normally
are present in the context of prostatic transitional zone are represented by
adenomatous type and the stromal type nodule. The adenomatous nodule is
characterized by a homogeneous high signal intensity on T2-w, with a thin
hypointense capsule around, this is a nodule composed entirely of prostatic
fluid, of very common finding and no particular difficulties in its characterization.
Instead more difficult to characterize appears the stromal nodule. This very
frequent entity is characterized by homogeneously hypointense signal in T2-w
images, usually with a thin hypointense capsule around [18]. Differential
diagnosis occurs when there is suspicion of a concomitant carcinoma in the
transition zone, as the morphological appearance of the tumor looks very similar
to the stromal nodule [19]. Another very common finding is represented by
prostatitis.
The prostate gland is very often site of inflammatory events, sometimes
asymptomatic, so it's not uncommon to find alterations in morphology in signal
intensity characterized by widespread hypointensity in T2-w, or stripe-like
hypointensities, from periurethral region extending radially along the peripheral
parenchyma. Prostate cancer occurs in T2-w images as an hypointense signal
alteration, usually homogeneous and of variable form. The morphological
sequence also allows the evaluation of the AFMS. This crescent-shaped
anatomical zone is characterized by homogeneous and markedly hypointense
signal in T2-w, located at the extreme anterior part of the gland. A cancer in this
area shows higher signal intensity than the surrounding tissue, often with a
round shape and protruding externally on the glandular. margin The distal
prostatic urethra is recognizable as a ring of low signal intensity at the level of
the lower portion of the gland. T1-weighted sequences, however, allow a better
view of the neurovascular bundles and allow to highlight any post-bioptic
hemorrhagic spot. The typical T1-w appearance of the prostate do not allow a
clear highlight of a CaP, which appears isointense compared to the normal
glandular parenchyma [20]. The seminal vesicles on T2-weighted images are
characterized by a variable signal intensity, by depending on the composition of
the fluid content, that physiologically gradually decreases with the age, leading
to a reduction of the signal and the volume of such structures. On sagittal plan
become more appreciable and measurable the relations between the rectum
and the Denonvilliers fascia (which appears slightly hypointense), so important
for cancer staging. Tumor identification in the central gland is quite difficult,
mainly due to the heterogeneity of the tissues determined by a set of benign
stromal and glandular of this area. However, peculiar characteristics such illdefined margins, absence of capsule, lens-shaped or irregular areas are
suspicious for cancer in transition zone [21]. Even post-biopsy bleeding spots
can generate erroneous interpretations, simulating the appearance of cancer in
T2-w (Fig.). The differential diagnosis is carried out on the basis of the
comparison between the T1 and T2-w images, which are hyperintense in T1-w
for the presence of blood [22]. The morphological study also allows to make a
locoregional staging by the evaluation of prostatic capsule or periprostatic fat
invasion.
Diffusion-Weighted Imaging (DWI) is an mp-MRI sequence that
analyzes the water molecules movement between the tissues and macromolecules, the so-called Brownian motion, evaluating their movement and free
diffusion. Brownian motion is the random movement, tied by the thermal energy,
to which are subject the molecules in a fluid. The diffusion is manifested as a
stream of particles from a region with higher concentration to another with a
lower concentration, influenced by the cellularity of the tissue [23].
An increased tissue cellularity, as occurs in a neoplasm, causes a restriction of
the water molecules diffusion, emphasized by the sequence DWI. DWI
hypointense signal is an expression of free diffusion, while the hyperintensity is
characteristic of restricted diffusion [24]. According to this theory, differences in
the structure and architecture of cell tissues may be detectable by mp-MRI due
to the difference of diffusion intensity signal between healthy and pathological
tissues. The normal tissue presents therefore a low cellularity and consequently
a high diffusion signal, while on the contrary, outbreaks of CaP are composed of
tightly adherent cellular elements, with reduced extracellular space, that match
on the DWI images to areas of restricted diffusion (high-signal intensity). The
CaP limits the movement of water molecules in the tissues due to increased
cellularity, of subverting the cellular architecture and parenchymal structural
alterations, which tend to fibrosis. Determining factor for diffusion sequence is
represented by the coefficient "b". This parameter expresses the degree of
sequence sensitization, which depends on the distance, intensity and duration of
the two gradients to the base of the diffusion process. The higher the "b" factor,
increases the sensitivity and then weighting-in diffusion, this allows to erase the
background signal in order to make more evident the cell density. DWI
sequence retains an intrinsic component of T1 and especially T2 weighting,
which can simulate a framework of restricted diffusion (T2 shine- through effect).
Currently the utilized b values in the various study protocols vary considerably
from author to author, according to the type of study, the equipment and the
operator experience. The actually equipment allow to obtain high b values of
both 1.5T and 3T magnets, however, the highest b values (> 2000 s/mm²) are
exclusive prerogative of 3T magnets, allowing a more accurate assessment of
tissue diffusivity and a complete reduction of T2 shine-through effect.
Informations obtained by DWI sequences is processed by software that uses
them to reconstruct a quantitative graphic map based on the diffusion coefficient
values called apparent diffusion coefficient map (ADC). The map thus obtained
reflects the average values of each individual voxels present in the examination
field, appearing graphically as the negative of the DWI sequence, thereby
removing the residual T2 weighting, responsible for the effect T2 shine-through.
The DWI sequence, according to the PI-RADS classification system [25] is
currently considered the dominant sequence as regards the detection of CaP in
the peripheral zone. The tumor appears as an area of strong high signal
intensity, compared to the surrounding tissue, which is transformed into a
hypointensity in the ADC map. Because of the ADC quantitative values
obtained, it has recently been possible to stratify CaP aggressiveness, by
correlation between ADC values and Gleason score [26].
The Dynamic Contrast Enhancement (DCE) perfusion examination, is a
sequence that utilizes the use of the paramagnetic contrast agent to highlight
the vascular pattern of the tissue. CaP has a strong blood supply conferred by
neo-angiogenesis, whereas the tumor shows a more rapid and intense
enhancement than the surrounding parenchyma. In order to highlight the
difference between the enhancement of tumor tissue than in healthy tissue,
dynamic fast T1-weighted sequences, allow a quick covering of the entire gland
volume (fig.1). Time resolution plays a key role in this type of sequences, in fact
many are the sections acquired in unit of time, the greater diagnostic accuracy
in assessing the different pattern of enhancement. The images obtained are first
evaluated qualitatively, in order to identify areas of suspicion enhancement,
later, due to post-processing, images are processed to obtain semi-quantitative
and
quantitative
informations
[27].
Quantitative
and
semi-quantitative
elaborations allow to obtain the enhancement time / intensity (T/I) curves both
the purely quantitative values. The evaluation of the T/I curves is based on
factors that consider both the early phase of enhancement, by calculating the
breadth of the curve and peak contrast enhancement. Basing on the curve
shape, it is possible to distinguish three different types of T/I curves: type 1,
where after an initial peak there’s a witnessing continuous growth curve, type 2
where after the initial peak the curve settles on a plateau, type 3 where following
the initial peak is followed by a rapid wash-out with concomitant decrease of the
curve [28]. The quantitative data that can be extrapolated from the dynamic
sequence
are
manifold,
dedicated
softwares
can
provide
quantitative
information about each stage of the dynamic sequence. Most useful data in
characterization of the tissue are represented by enhancement integral, Time to
Peak, the maximum slope of increase and the mean time to Enhance (Fig. 3).
These values represent the mostly quantitative used values for the evaluation of
CaP. Currently it tends to give more importance to the first phase of the T/I
curve, that relative to the wash-in peak. Lately has been shown that the CaP is
very heterogeneous on the basis of the curve, as it were highlighted
malignancies who presented curves of both type 1, 2 and 3. Currently the use of
the DCE sequence is rather controversial because of conflicting results emerged
in the literature. The CaP may have discordant vascular pattern characterized
by a curve trend that reflects all 3 type described, in spite of the type 3 was
considered typical of the tumor. Moreover, the presence of stromal type nodules
in the transition zone, with vascular pattern very similar to CaP, does not allow a
proper distinction between the two clinical entities.
Clinical Indications
The indications to perform a prostate mp-MRI are varied. Mp-MRI can be used
in every stage of the diagnosis and treatment of prostate cancer. Regarding the
primary diagnosis, mp-MRI plays a key role because it allows direct visualization
of the suspicious lesion, indicating the size, location and indicating the supposed
degree of aggressiveness [29]. This information in the primary diagnosis initially
allow to target the biopsy the lesion so-called "index", then provides information
about the invasion of the capsule and infiltration of surrounding organs in order
to plan the most appropriate treatment. For these reasons it is important to
include mp-MRI in the diagnostic protocol as "first line" examination in order to
take advantage of its high diagnostic performance to avoid TRUS-guided
random biopsies. Mp-MRI exam performed as first-line step is usable for various
categories of patients. Among the various categories are those with clinical
suspicion of cancer (elevated PSA and clinical examination positive), those with
previous negative biopsies and increasing PSA value, patients underwent
radical prostatectomy (RP) or radiation therapy (RT) in follow up for recurrence
and patients with low grade cancer in active surveillance (AS).
Actually the group most represented is that of the patients who come to the mpMRI with behind already one or more negative prostate biopsies. The problems
that emerge in these patients are different. First, the execution of one or more
prostate random biopsies is responsible of economic expenditure and significant
stress by the patient, second, the outcomes post-biopsy bleeding remain even
for several months in the prostatic parenchyma creating problems of differential
diagnosis. It is not uncommon for a patient already subjected to random
biopsies are negative after mp-MRI [30].
For these reasons, the radiological community prefers to avoid making of MRI
examination after biopsy, or at least not before 40-60 days of completion of the
biopsy. MRI is indicated in the post-operative follow up after RP or in post-RT for
the evaluation of the integrity of the surrounding organs and recurrence
research [31].
A clinical application of mp-MRI is represented of follow up of patients with lowgrade malignancy in AS. Mp-MRI through the use of DW sequences is able to
evaluate ADC value and then to quantify the proportion of cell tissue density, as
to highlight a stationarity in time or an increase of the cellularity, index of
disease progression [32] (fig.2).
Considerations
the increasing role of mp-MRI in the diagnosis and management of prostate
cancer, has over time brought with it many disputes of a technical and
methodological management. including disputes over the years have driven
most of the scientific debates that count on the use of the ERC. As it is known,
the use of the ER coil is a tool which, on the one hand increases the diagnostic
performance of the study RM, of the other, however, it is often considered
unnecessary if not harmful due to the number of artifacts that can cause. there
have been numerous studies over the years on the comparison of various
diagnostic performance, with both 1.5T and between 1.5 and 3T. the findings
have
established
that
diagnostic
performance
between
1.5T
magnet,
significantly improved when using the ERC. Instead in comparative studies
between 1.5 and 3T, the results were often conflicting, so as to conclude that
the diagnostic performance of a 1.5T MRI with ERC, would be comparable to
those of 3T with the surface single coil [33].
a dispute rather than inflames debates between urologists and radiologists is the
role of the mp-MRI in the diagnostic workup of patients with suspected prostate
cancer. Until now RM prostate has been included in the guidelines after the first
urological prostate biopsy with negative results. the radiological community for
years proposes to perform the MRI before performing the first biopsy. The
reasons that move this proposal are manifold: the first of a practical nature is
that after the prostate biopsy for several months remain parenchymal
hemorrhagic foci that make difficult the evaluation and that in some cases even
camouflage the tumor. Another motivation is that, due to the high diagnostic
performance achieved by the current equipment, mp-MRI is able to determine
the "index" lesion to sample, in order to aim in a precise way the guided biopsy.
Similarly a negative mp-MRI examination is able to procrastinate the execution
of a random ultrasound guided prostate biopsy [34].
Obviously mp-MRI performed before each prostate biopsy finds great difficulties
both organizational and in economic terms. Not all facilities are unable to cope
with the high number of examinations to be performed, often at the expense of
the patient who is waiting for a long time to carry out the examination.
Another part of the current debate is the role of MRI in active surveillance of
prostate cancer. Active surveillance is a particular method of management that
monitors over time the patient with low-grade prostate cancer, in a clinicallaboratory investigations. Mp-MRI has been inserted in the therapeutic algorithm
of active surveillance due to its high ability to identify suspect areas and
especially the opportunity to provide information on the cellularity of the lesions
with quantitative values. In this way in the course of an active surveillance
program, following the increase in PSA it is possible to evaluate the actual
increase in cellularity in order to schedule a biopsy right on the lesion that
presents the greatest change in the value of ADC [35].
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Fig. 1: Multiparametric study of normal prostate with endorectal coil. A: T2weighted TSE axial and B: T2-weighted TSE coronal plane, show a good
anatomic representation. C: Dynamic contrast-enhanced (DCE) axial plane,
and D: apparent diffusion coefficient (ADC) show no areas of suspicion pattern.
Fig. 2 : 54 years old patient with Pca Gleason 6 (3+3) in right AFMS (arrow). A:
axial T2-w TSE shows the tumor as an area of signal hypointensity. B: axial
diffusion weighted imaging (DWI) b= 0, 500, 1000, 3000 mm2/sec and C: ADC
map show an high restriction of water diffusivity corresponding to the tumor. D:
perfusion map shows an area of intense pathologic enhancement.
Fig. 3 : 68 years old patient with Pca Gleason 7 (3+4) in right peripheral zone
(arrow). A: axial T2-w TSE shows the tumor as an area of signal hypointensity.
B: axial diffusion weighted imaging (DWI) b= 0, 500, 1000, 3000 mm2/sec and
C: ADC map show an high restriction of water diffusivity corresponding to the
tumor. D: perfusion map shows an area of intense pathologic enhancement.