Key words
prostate - MR imaging - imaging sequences - neoplasms
Introduction
Prostate cancer is the most common malignancy in men, but only about 10 % of patients
die from that cancer. While the incidence rate in the last 30 years has increased
four-fold, the mortality rate has decreased over the last 20 years [1]. This can be primarily attributed to the early detection of prostate cancer as a
result of the common practice of testing the prostate-specific antigen (PSA) in the
peripheral blood. Trendsetting studies indicate that the current diagnostic and therapeutic
approach must be fundamentally rethought. Wilt et al. could not show a significant
reduction in the mortality rate for patients with a localized tumor who underwent
a radical prostatectomy compared to patients who were simply monitored [2]. In addition to possible postoperative complications, radical prostatectomy was
associated with a significantly higher morbidity rate (incontinence, erectile dysfunction)
[2]. Like radical prostatectomy, radiation therapy is also associated with significant
side effects, such as loss of potency, in up to 50 % of patients [3]. Although prostate cancer can be effectively treated in many cases by radical therapies
in the case of early diagnosis, not all patients seem to benefit from such treatments.
Therefore, new management strategies, such as active surveillance and watchful waiting,
as well as organ-preserving focal therapy options are currently being evaluated in
studies.
Selecting the most suitable diagnostic and therapeutic approach for the individual
patient is a significant challenge. As a matter of fact, MRI with its multiparametric
imaging is shaking the foundations of established diagnostic and therapeutic paradigms
and is now being used for the planning of diagnostic punctures and radical treatments.
In the future it will become increasingly important for patient stratification with
regard to therapeutic approach and treatment monitoring [4].
The following provides an overview of the current status of multiparametric MRI of
the prostate and an interpretation of relevant findings. The role of multiparametric
MRI in the diagnosis of prostate cancer including systematic and targeted biopsy and
its potential in conservative and minimally invasive treatments will also be discussed.
Multiparametric MRI of the prostate
Multiparametric MRI of the prostate
Due to its high soft tissue contrast, high resolution, and ability to simultaneously
image functional parameters, MRI provides the best visualization of the prostate compared
to other imaging methods. In the case of MRI scanners with a field strength of 1.5 T,
it has proven to be advantageous to use a dedicated endorectal coil particularly for
the local staging of prostate cancer [5]. In the case of MRI scanners with a field strength of 3 T and the associated higher
signal-to-noise ratio, the image quality is so good even without an endorectal coil
that the coil is not necessary for detection purposes. This should result in greater
patient acceptance and should further support the broader use of multiparametric MRI
in the coming years.
Multiparametric MRI refers to the combination of morphological sequences and functional
imaging techniques. Standard T2-weighted (T2w) and T1-weighted (T1w) turbo-spin-echo
sequences are used for visualization of the morphology while diffusion-weighted imaging
(DWI), dynamic contrast-enhanced imaging (DCE) and MR spectroscopic imaging can be
combined for the functional sequences.
Morphological imaging (T2- and T1-weighted imaging)
Morphological imaging (T2- and T1-weighted imaging)
High-resolution axial T2-TSE is the backbone of every MR image of the prostate. This
is typically supplemented by a sagittal and possibly a coronal T2-TSE sequence which
facilitates evaluation of the seminal vesicle in particular. T2-weighted (T2w) imaging
allows precise visualization of the zonal anatomy of the prostate with a peripheral
and central zone and a transition zone ([Fig. 1a]). Moreover, nodular, glandular, stromal, and cystic changes in benign prostate hyperplasia
(BPH) can be reliably visualized ([Fig. 1b]). Prostate carcinomas can be detected in T2w imaging on the basis of their low-signal,
classic oval shape as well as their space-occupying nature once they reach a certain
size ([Fig. 2], [3]). The diagnostic accuracy of T2w imaging alone is highly variable according to the
literature. This is primarily due to the differences in study design (e. g. prostatectomy
versus biopsy as reference standard, type of reading, detection versus staging) and
in the examined study population (e. g. patients with known prostate cancer versus
patients after multiple biopsies). For T2w imaging without functional sequences, the
sensitivity and specificity for prostate cancer are approximately 57 – 83 % and 62 – 82 %
[6]
[7]. The diagnostic limitations of T2w imaging alone are due to the often similar nature
of regularly occurring acute and chronic inflammation of the prostate and hemorrhages,
which also cause a hypointense pattern in T2w imaging. Prostatitis typically has a
striated, slightly hypointense appearance and sometimes cannot be morphologically
differentiated from prostate cancer in T2w imaging ([Fig. 4], [5]). Hemorrhages have a very variable appearance in T2w imaging and can be detected
in T1w imaging on the basis of their hyperintensity ([Fig. 6a, b]). Bleeding is a regular occurrence after biopsy. Therefore, MRI of the prostate
should not be performed until at least 6 – 8 weeks after biopsy to avoid unnecessary
diagnostic impediments. However, hemorrhages can also persist for several months.
Therefore, it is useful to know that bleeding can also serve as a diagnostic aid for
detection. In a prostate that is hyperintense in T1w imaging due to post-bioptic hemorrhagic
changes, hypointense island-like areas on the T1w images that correlate with areas
that are hypointense on the T2w images can be an indication of prostate cancer (hemorrhage
exclusion sign) [8]. It is presumed that the anticoagulative effect of the citrate which is highly concentrated
in normal prostate tissue but is low in cancer tissue results in increased bleeding.
Well vascularized and perfused cancer tissue is probably also a better site of degradation
for bleeding residues than normal prostate tissue. With respect to a more exact diagnosis
in the case of bleeding residues, diffusion-weighted imaging and MR spectroscopy have
proven to be advantageous in particular [9]
[10]. At present, morphological imaging should normally be combined with at least two
functional sequences in order to significantly increase the sensitivity and specificity
of MRI [11]
[12]
[13]. These will be introduced in the following.
Fig. 1 a Normal prostate of a 30-year-old man. The transition zone (TZ) is still highly localized
around the urethra. It is surrounded by the central zone (CZ) in the basal segments
and by fibromuscular tissue (FM). The majority of the prostate is comprised of the
peripheral zone (PZ). b Nodular changes in benign prostate hyperplasia in an older patient enlarge the transitional
zone with consecutive compression of the central zone and the peripheral zone.
Fig. 2 Prostate cancer of the peripheral zone: Axial T2 TSE with a hypointense lesion on
the right side in the peripheral zone (arrow). After targeted biopsy under MRI guidance,
an acinar prostate adenocarcinoma with a Gleason score of 3 + 4 = 7 was able to be
detected. The additional smaller foci on the left side of the peripheral zone should
also be mentioned (*).
Fig. 3 Prostate cancer of the transitional zone: Axial T2 TSE with homogeneously hypointense
lesion ventral left paramedian (*). While the benign hyperplastic nodule has a distinct
hypointense border on the right in the transitional zone (arrow), the border around
the focus is unclear (erased charcoal sign. There is a ventral protrusion in the contour
of the cancer.
Fig. 4 Prostatitis: Axial T2 TSE with slightly hypointense, striated changes on both sides
diagnosed in histology as chronic prostatitis.
Fig. 5 Granulomatous prostatitis. Axial T2 TSE a and corresponding ADC map b of a patient with PSA values between 6 – 8 ng/ml and three transrectal ultrasound-guided
biopsies without detecting cancer. The extensive and partially significantly T2w hypointense
changes (arrow) were able to be diagnosed as granulomatous prostatitis after targeted
MRI-guided biopsy. The finding in T2w imaging would also be consistent with imaging
of an advanced diffusely growing prostate cancer.
Fig. 6 Post-puncture bleeding can be mistaken for prostate cancer in T2 imaging due to its
hypointense appearance (a, axial T2 TSE). Hyperintense post-puncture hemorrhagic changes can be detected on
both sides in the peripheral zone in the corresponding axial T1 TSE slice b.
Diffusion-weighted imaging
Diffusion-weighted imaging
Diffusion-weighted imaging visualizes the Brownian molecular motion of water. It has
become an important part of oncological imaging since malignant tumors are typically
comprised of densely arranged cells whose numerous cell membranes limit this Brownian
molecular motion [14]. Prostate cancers are thus visualized on highly diffusion-weighted images (typically
upper b-values of 800 – 1000 s/mm2 in prostate imaging) as areas with high signal intensity ([Fig. 7a]). Diffusion coefficients (apparent diffusion coefficient, ADC) can be calculated
from the diffusion-weighted data. In the ADC maps, areas with normal diffusion can
then be differentiated as having high signal intensity and those with diffusion restriction
as having comparatively low signal intensity ([Fig. 7b]). Most studies showed that DWI is a very useful addition to morphological imaging
and can increase sensitivity in particular by 10 – 25 % [15]
[16]
[17]. Since hyperplastic stromal nodules can have pronounced diffusion restriction in
BPH, DWI must be evaluated together with morphological imaging (T2w) especially when
assessing the central portions of the prostate gland [16].
Fig. 7 a Axial DWI with a b-value of 1000 shows a lesion ventral right with a hyperintense
signal. b This area has low signal intensity in the corresponding ADC map. With normal diffusion,
the peripheral zone of the prostate has high signal intensity in the ADC and low signal
intensity in the b-1000. After prostatectomy, an acinar prostate adenocarcinoma with a
Gleason score of 4 + 3 = 7 was able to be diagnosed ventral right in the patient.
Studies in recent years have increasingly examined the capabilities of DWI with respect
to evaluating the aggressiveness of prostate cancer. It was able to be shown that
the ADC value has a negative correlation with the Gleason score, i. e., low ADC values
are seen primarily in high-grade aggressive prostate cancers [15]
[18]. Results regarding the ability to differentiate low-grade tumors (Gleason score
3 + 3 = 6) and high-grade tumors (Gleason score > 4 + 3 = 7) in the peripheral zone
are very promising since they may be able to help to better determine patient risk
potential [19]
[20]. However since there can still be relevant overlapping of the ADC values in the
different Gleason groups, additional studies are needed to implement this grading
potential of diffusion-weighted imaging in the clinical routine. However, DWI will
play an important role in differentiating patients with a low risk from those with
a high risk and separating them with respect to management [21].
Dynamic contrast-enhanced (DCE) MRI
Dynamic contrast-enhanced (DCE) MRI
Contrast-enhanced MRI sequences can be used to assess the vascularity and permeability
of tissues. Gadolinium-containing extracellular T1w contrast agent is typically administered
intravenously for this purpose [22]. Fast T1w gradient echo sequences with a temporal resolution of 4 – 10 seconds are
primarily used in prostate imaging. Measurements should be performed over a period
of up to approximately 5 minutes after contrast agent application [13]. The enhancement can be displayed in the form of curves over time thus helping to
characterize tissues. Prostate cancers are characterized by fast wash-in (early peak
enhancement) and fast wash-out compared to healthy tissue (type III curve). Enhancement
typically increases steadily (type I) in the given measurement time in cancer-free
tissue, while a curve with a plateau (type II) occurs relatively frequently both in
healthy tissue and in cancer tissue [22]. On the basis of enhancement curves, gadolinium concentrations in tissue and tissue
transport constants in the direction of the tumor interstitium (Ktrans) and back in the direction of the blood plasma (kep) can be calculated using suitable mathematical models (two-compartment Tofts model).
Prostate cancers are characterized by an increase in the tissue transport constants
which can be displayed using color coding in pharmacokinetic parameter maps ([Fig. 8]) [23]. The currently available studies do not provide a clear conclusion regarding the
improvement of prostate cancer detection via DCE. Some studies were able to show an
improvement of the diagnostic accuracy of conventional MRI (T2w and T1w) when supplemented
by DCE imaging [24]
[25]. However, it is problematic in the case of DCE that hyperplastic nodules in BPH
can enhance and wash out quickly like prostate carcinoma foci and Ktrans and kep can be accordingly increased, thus limiting the sensitivity and specificity of DCE
in the central portions of the prostate gland in particular [26]
[27]. In addition, inflammation can often have greater vascularity and tissue permeability,
which also limits the sensitivity and specificity of DCE for the detection of prostate
cancer. However, it was able to be shown that the local staging of prostate cancer
and the detection of local tumor relapses after definitive therapy can be significantly
improved using dynamic T1w sequences with good temporal resolution [28]
[29].
Fig. 8 a-c Axial T1 GRE unenhanced a. After contrast agent administration, an area with early enhancement is seen on the
right in the peripheral zone (b, ROI1) with significant washout in the late-phase image c. The enhancement can be graphically shown as SI/time curve d. A type III curve (red) with early enhancement is a typical finding in the case of
prostate cancer, while healthy prostate tissue is characterized by a steady slow wash-in
(type I, green). Parameter maps represent an alternative. High transport constants
Ktrans e and kep f can confirm suspicion of prostate cancer. In this example a minimally differentiated
prostate adenocarcinoma with a Gleason score of 4 + 5 = 9 was diagnosed after prostatectomy.
MR spectroscopy
MR spectroscopy allows spatially resolved visualization of chemical substances in
an organ. The healthy prostate gland produces an ample amount of a citrate-containing
secretion, resulting in a high citrate content and a low choline level. In the case
of prostate cancer, the choline level is significantly elevated and the citrate content
is reduced due to the metaplastic processes of the cell membranes. The relationship
between these two metabolites can therefore be used as a measure of malignancy [30]. MR spectroscopy increases the specificity of the MRI examination in particular,
but can also be used to evaluate tumor volume [31]
[32]. The diagnostic accuracy of the morphological MRI examination can be increased by
MR spectroscopy from 52 % to 75 % [10].
The basic requirement for good spectral resolution of the individual metabolites is
a homogeneous magnetic field in the field of measurement and sufficient suppression
of the fat and water signal during the measurement. In addition to sequence adjustments,
this usually requires multiple shimming steps and saturation bands around the prostate
to be manually adjusted to the individual prostate anatomy. Together with these preparations,
MR spectroscopy at 1.5 T requires a measurement time of 13 – 20 minutes. Evaluation
and interpretation are complex and often only possible after appropriate physical
adjustments. Even if automatic segmentation algorithms are able to automatically detect
the prostate in the near future thus minimizing measurement preparations, MR spectroscopy
will remain limited in its daily use due to the significant time investment and the
high level of physical-medical expertise required.
Structured interpretation and communication of MRI findings in the prostate (MR PI-RADS)
Structured interpretation and communication of MRI findings in the prostate (MR PI-RADS)
In 2012 the European Society of Urogenital Radiology (ESUR) created the Magnetic Resonance
Prostate Imaging Reporting and Data System (MR PI-RADS) as part of its MRI guidelines
for prostate imaging [13]. Based on the breast imaging reporting and data system (BI-RADS), a standardized
method for reporting multiparametric MRI of the prostate for the detection of prostate
cancer is proposed here. The goal was to standardize image interpretation and to simplify
communication between the radiologist and colleagues in other departments.
Based on clearly defined criteria according to PI-RADS, every lesion suspicious for
tumor within the prostate is assigned a point value between 1 and 5 for every sequence
performed as part of multiparametric MRI (consisting of at least T2w, DWI, and DCE).
Moreover, a total point value is calculated for every lesion suspicious for tumor
[33]. Thus, a statement regarding the probability of the presence of a clinically significant
prostate cancer should be possible: A point value of 1 means that a lesion is probably
benign, while a point value of 5 indicates a high probability of malignancy. The development
of PI-RADS and the criteria contained therein for the assignment of point values are
based on published literature and an expert consensus. Since being published in February
2012, PI-RADS has been evaluated in multiple studies.
The point values of T2w, DWI, and DCE were added to form a total point value for lesions
suspicious for tumor. Good and reproducible diagnostic accuracy was documented for
the total point values calculated in this manner [33]
[34]
[35]
[36]
[37].
Standardization of image interpretation in research and the clinical routine is an
important milestone that should accelerate the acceptance of multiparametric MRI in
the coming years. The results of clinical studies should be easier to compare using
PI-RADS. Moreover, PI-RADS makes it possible to formulate guidelines for diagnostic
clarification and perhaps even for the treatment of prostate cancer. The present data
indicates that a biopsy should be performed in the case of lesions with PI-RADS ≥ 4
while monitoring via MRI and PSA could be sufficient in lesions with PI-RADS ≤ 3.
MRI and prostate biopsy
The standard prostate biopsy is the transrectal ultrasound (TRUS)-guided systematic
prostate biopsy. Urological studies in particular have shown that the detection rate
increases as expected with the number of samples so that approximately 6 samples are
currently taken from each lateral lobe in accordance with the recommendations of the
professional associations [38]
[39]. However, the entire context of the diagnostic weaknesses of TRUS biopsy only becomes
clear with MR imaging and visualization of prostate cancer [40]. The rate of carcinomas in the ventral portion of the prostate gland as well as
in an extreme lateral position in the peripheral zone and on the apex of the gland
is significant in patients with multiple negative ultrasound-guided biopsies. It was
shown that patients with a diagnosis of prostate cancer in the ventral portions of
the gland by direct MRI-guided biopsy have a higher clinical risk than those with
a diagnosis of prostate cancer in the peripheral zone [41].
Direct MRI-guided biopsies
Direct MRI-guided biopsies
All direct MRI-guided biopsy techniques have in common that MRI is performed during
the biopsy and the images are used to guide the biopsy needle. Therefore, the biopsy
equipment must be MRI-compatible. MRI-guided biopsies should be performed on a 1.5 T
or 3 T unit since exact visualization of the lesions during biopsy is of essential
importance. Direct MRI-guided biopsies can be performed via transgluteal, transperineal,
and transrectal access [41]
[42]
[43]. Transrectal biopsy is the most common and most accepted direct MRI-guided biopsy
technique since there are no special requirements regarding anesthesia or sterility
in contrast to the transperineal and transgluteal methods. Transrectal MRI-guided
biopsy is typically performed after simply coating the rectal mucous membrane with
a disinfecting and locally anesthetizing gel [44]. The patient is premedicated with antibiotics as in standard transrectal ultrasound-guided
biopsies. Transrectal MRI-guided biopsy can be evaluated as the most exact prostate
biopsy method on the basis of the present data ([Fig. 9]): In populations with multiple negative systematic ultrasound-guided biopsies detection
rates of 41 – 59 % could be achieved with direct MRI-guided prostate biopsy with the
majority of the tumors being classified as clinically relevant [41]
[45]
[46]
[47]. As shown in [Fig. 9], the targeted clarification of non-clinically relevant cancers is also important
since this can resolve the diagnostic dilemma of an increasing PSA with a negative
biopsy thus creating a foundation for noninvasive and minimally invasive strategies,
such as active surveillance or focal therapy.
Fig. 9 a Patient with a negative ultrasound-guided biopsy in history and increasing PSA value;
12 ng/ml at the time of MRI. Coronal T2 TSE with lesion suspicious for cancer measuring
a maximum of 5 × 7 mm in the peripheral zone. b Targeted biopsy under direct MRI guidance yielded a total sample length of 12 mm
with 4 mm of an acinar prostate adenocarcinoma (Gleason score 3 + 3 = 6).
MRI/ultrasound fusion biopsy
MRI/ultrasound fusion biopsy
A multiparametric MRI scan is performed prior to every targeted biopsy to identify
lesions that are suspicious for carcinoma and to evaluate whether targeted biopsy
techniques are suitable. A possibility to improve reporting would be to create a drawing
of the location of the suspicious focus in addition to the written findings. This
drawing can then be used during a planned biopsy to perform a greater number of biopsies
in certain regions of the prostate. The procedure is similar for cognitive fusion
in which ultrasound-guided biopsy is performed immediately after viewing the MRI scan.
The objective here is to evaluate the regions suspicious on MRI in a targeted manner
and to identify focal lesions on the B-mode image [48]. The prostate must be viewed in both modalities on the same (or at least comparable)
image plane. Otherwise, it is extremely difficult to recognize complex structures
in the prostate. Navigation is facilitated by detection of the urethra, prominent
hyperplastic nodules, or cysts. Peuch et al. were able to detect 15 % more clinically
relevant cancers per TRUS biopsy in their study by viewing the MRI images immediately
prior to biopsy [48]. However, the cognitive fusion can be expected to be highly examiner-dependent.
Therefore, software-based fusion of MRI datasets with ultrasound images would be desirable.
Software on the latest ultrasound devices can fuse previously imported MRI datasets
three-dimensionally and in real time with the B-mode image of an ultrasound examination.
An electromagnetic unit that is coupled to the ultrasound probe and can track the
movements of the probe is positioned next to the patient table during the biopsy for
this purpose [48]
[49]. By selecting individual reference points on the MRI images and the B-mode image,
the MRI images are adjusted and moved in parallel with the ultrasound scan ([Fig. 10]). This makes it possible to use the ultrasound probe to navigate to and biopsy lesions
evaluated as suspicious for cancer in the preceding multiparametric MRI scan [48]. Software-supported 3 D real-time fusion is currently under intense evaluation.
Multiple workgroups were already able to document a significantly higher detection
rate of clinically relevant prostate cancers compared to systematic ultrasound-guided
biopsy [49]
[50]
[51].
Fig. 10 a MRI-ultrasound 3 D fusion in real time. After the MRI images (right T2 TSE axial)
are imported, freely selectable reference points are selected in the T2 image and
B-mode image. a Based on this information, the two datasets are combined by software so that the
T2 image is adjusted in accordance with the movement of the ultrasound probe so that
as shown in this example it is possible to navigate to the lesion suspicious for tumor
in the right peripheral zone. b After the lesion is precisely targeted, it can be biopsied under ultrasound guidance.
To date, the different direct MRI-guided biopsy techniques and MRI/ultrasound fusion
biopsy have not been evaluated in a direct comparison with respect to MRI preparation
and examination time, cost, and diagnostic accuracy. However, the possibility of software-based
fusion of MRI and ultrasound images in real time is a milestone in the bioptic diagnosis
of prostate cancer and will probably be used more widely in coming years.
MRI for active surveillance
MRI for active surveillance
Not all patients with prostate cancer benefit from radical surgery or radiation therapy,
in particular under consideration of possible peri- and post-therapeutic complications
including incontinence and erectile dysfunction [2]. In particular patients with low-grade prostate cancer (Gleason ≤ 6) can benefit
from surveillance and watchful waiting. Multiparametric MRI can play a significant
role in identifying suitable patients [52]. In the case of patients under surveillance, multiparametric MRI can help in the
follow-up period to detect paraclinical parameters, such as PSA value and results
of a rebiopsy, as well as any tumor progress and to initiate appropriate treatment.
Such progress can be detected on the basis of an increase in size but in the future
also on the basis of changes in functional sequences like DWI and DCE in terms of
dedifferentiation. MRI could also significantly reduce the number of necessary rebiopsies,
thus making management less invasive for patients. To date, multiparametric MRI has
not been an integral part of diagnostic algorithms of large prospective studies for
examining morbidity and mortality among patients under watchful waiting or active
surveillance. However, the role of multiparametric MRI is being explicitly examined
in studies currently in progress regarding this topic. Corresponding evidence-based
data can therefore be expected in the near future.
MRI and minimally invasive therapies
MRI and minimally invasive therapies
A number of minimally invasive, focal, organ-preserving methods have been used in
recent years as further alternatives to the radical treatment of prostate cancer.
The goal of these methods is to ablate tumor tissue within the prostate while maintaining
tumor-free areas of the prostate gland and preserving the periprostatic tissue and
structures. These procedures seek to avoid typical peri- and postoperative complications.
From the histopathological processing of prostatectomy specimens, it is known that
prostate cancer is usually multifocal. However, a so-called “index lesion”, a tumor
focus that is significant on the basis of size and differentiation (Gleason score),
seems to be decisive for patient prognosis also in these patients [53]. The goal of a minimally invasive treatment must therefore not necessarily be to
achieve tumor-free status but to ablate significant tumor foci. Imaging per multiparametric
MRI makes it possible to determine the exact location of relevant tumor foci in order
to thus guide focal therapies as in diagnostic biopsies [54]. The methods used to date for the prostate include cryotherapy, high-intensity focused
ultrasound, and laser-induced thermoablation [55]. Other methods, such as irreversible electroporation (IRE), are currently being
evaluated in studies [56]. Significant tumor foci that are generally accessible for ablation can be identified
via multiparametric MRI. Moreover, MRI will become increasingly important in the image-guided
use of locally ablative procedures [54]
[55]. The PSA value remains a valuable marker for follow-up evaluation and for detecting
relapses. The exact role that multiparametric MRI will play in treatment monitoring
after minimally invasive therapy and as an instrument in long-term follow-up must
be examined in the coming years.
