Download PhD thesis Multiparametric MRI in detection and staging of prostate

FACULTY OF HEALTH AND MEDICAL SCIENCES
UNIVERSITY OF COPENHAGEN
PhD thesis
Lars Boesen
Multiparametric MRI in detection and staging of
prostate cancer
Academic advisor: Henrik S. Thomsen
This thesis has been submitted 31/08/2014 to the Graduate School of The Faculty of
Health and Medical Sciences, University of Copenhagen
Institutnavn:
Faculty of Health and Medical Sciences,
University of Copenhagen
Name of department:
Department of Clinical Research
Author:
Lars Boesen
Titel og evt. undertitel:
Multiparametrisk MR til detektion og stadie-inddeling af prostatacancer
Title / Subtitle:
Multiparametric MRI in detection and staging of prostate cancer
Subject description:
We investigated the use of multiparametric MRI in detection and
staging of prostate cancer in a Danish setup. Our aims were to evaluate
whether multiparametric MRI could improve the overall detection rate of
clinically significant prostate cancer previously missed by transrectal
ultrasound biopsies and to evaluate the diagnostic accuracy in the
assessment of extracapsular tumour extension and histopathological
aggressiveness.
Academic advisor:
Henrik S. Thomsen
Submitted:
31. August 2014
Grade:
PhD
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Table of Contents
TABLE OF CONTENTS ...................................................................................................... 3
PREFACE ............................................................................................................................ 5
ABBREVIATIONS AND ACRONYMS................................................................................. 7
MANUSCRIPTS .................................................................................................................. 8
INTRODUCTION ................................................................................................................. 9
BACKGROUND ................................................................................................................ 10
Diagnosis of prostate cancer (PCa) ............................................................................................................................... 10
PSA .............................................................................................................................................................................. 10
Digital rectal examination (DRE) ................................................................................................................................ 10
Transrectal ultrasound (TRUS) and TRUS-bx ............................................................................................................. 10
Grading PCa using Gleason score (GS) ...................................................................................................................... 12
Clinical staging of PCa ................................................................................................................................................ 13
Motivation for the PhD study ........................................................................................................................................ 16
MRI OF THE PROSTATE .................................................................................................. 17
Multiparametric MRI (mp-MRI) .................................................................................................................................. 17
Multiparametric MRI sequences .................................................................................................................................. 18
T1-weighted imaging (T1W) ........................................................................................................................................ 18
T2-weighted imaging (T2W) ........................................................................................................................................ 19
Diffusion-weighted imaging (DWI) .............................................................................................................................. 21
Dynamic contrast enhanced MRI (DCE-MRI) ............................................................................................................. 23
Clinical guidelines and Prostate Imaging Reporting and Data System (PIRADS): .................................................... 24
OBJECTIVES AND HYPOTHESIS ................................................................................... 28
SPECIFIC PART ............................................................................................................... 29
Study I: Early experience with multiparametric magnetic resonance imaging-targeted biopsies under visual
transrectal ultrasound guidance in patients suspicious for prostate cancer undergoing repeated biopsy.............. 30
Study II: Prostate cancer staging with extracapsular extension risk scoring using multiparametric MRI: a
correlation with histopathology ..................................................................................................................................... 34
Study III: Apparent diffusion coefficient ratio correlates significantly with Gleason score at final pathology ..... 36
DISCUSSION .................................................................................................................... 38
Detection: Initial diagnosis and prostate biopsy .......................................................................................................... 38
PCa aggressiveness and ADC measurements ............................................................................................................... 41
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Clinical staging of PCa ................................................................................................................................................... 44
Mp-MRI scoring using PIRADS and ECE risk scoring .............................................................................................. 46
Limitations ...................................................................................................................................................................... 48
CONCLUSION ................................................................................................................... 50
FUTURE PERSPECTIVES ................................................................................................ 51
SUMMARY (ENGLISH) ..................................................................................................... 54
SUMMARY (DANISH) ....................................................................................................... 57
REFERENCES .................................................................................................................. 60
APPENDIX ........................................................................................................................ 79
Original articles .............................................................................................................................................................. 79
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Preface
The blossoming idea for this thesis was initiated one afternoon during my residency in 2010 after
having met the third patient in a row with suspicion of prostate cancer and a set of inconclusive or
negative prostate biopsies. As with the two previous patients, I had to explain the reason for
referring him for another set of biopsies. It was evident that there were limitations with the current
diagnostic tools and a need for improvement. I realised that multiparametric MRI of the prostate
seemed to have the ability to solve some of these limitations. However, it was not applied anywhere
in Denmark for clinical management of prostate cancer. Hence, I presented the idea of evaluating
the use of multiparametric MRI in the diagnosis of prostate cancer in a Danish setup to my future
supervisors, Henrik S. Thomsen and Kari J. Mikines, and we promptly formed the basis for this
thesis based on international experience, literature evidence and guidelines.
This PhD thesis is the result of my work as a clinical research associate (2011-2014) at the
Department of Urology, Herlev University Hospital where I worked in close collaboration with the
Department of Diagnostic Radiology. The project was financed externally by The Capital Region of
Denmark (PhD tuition fee) and internally by the Department of Urology (salary) and Diagnostic
Radiology (MRI acquisition).
The thesis contains three separate studies evaluating the use of multiparametric MRI in detection,
assessment of biological aggression and staging of prostate cancer.
Many colleagues have been involved in this project and I wish to thank a number of people without
whom it would not have been possible to complete this thesis. First and foremost, I owe a special
thank you to my principle supervisor Henrik S. Thomsen. Henrik has been fantastic. Always ready
to discuss scientific and practical problems. His enthusiasm and admirable insight into scientific
research have been a great inspiration. I am thankful for our numerous strategic and scientific
discussions, for the constructive criticism and for supporting me and my decisions regarding the
direction of this project along the way. I wish to thank my advisor Kari J. Mikines for support and
valuable comments on the clinical aspects of prostate cancer management and for believing in the
project from the beginning.
A heartfelt and special thank you to my prostate biopsy 'wingman' Nis Nørgaard for our
professional and personal collaboration. I have had an amazing time with Nis in establishing and
implementing MRI/TRUS-guided biopsies at our institution. Furthermore, it has been a great
opportunity for me to work with all the highly-skilled clinicians represented in the prostate cancer
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team at Herlev University Hospital. Thank you for creating a great collegial atmosphere and a
dedicated working environment.
I owe a special thanks to the 'overall mother' of the outpatient clinic Helle Espersen, for her
admirable working effort and keeping track of all the patients continuously as the project grew.
Likewise thank you to Lone Brøgger for being the new "Helle Espersen" in the last part of the
project. A special thank you to our previous Head of Department, Jesper Rye Andersen, and Head
of the Research Unit, Jens Sønksen, for supporting me in my work and providing me with the
opportunity, funding and research facilities to perform this thesis.
I want to thank the Research Unit at the Department of Diagnostic Radiology, Herlev University
Hospital, for granting me the MRI acquisition time and with a special thanks to the dedicated staff,
for providing high-quality imaging and always taking good care of the patients. Thank you to the
MR technicians, Elizaveta Chabanova and Jacob Møller, for setting up and fine-tuning the MRI
prostate acquisition protocols and to Elizaveta for performing many of the examinations.
Thank you to Vibeke Løgager for her enthusiasm and drive as well as her contribution to the MRI
analysis and thank you to Ingegerd Balslev for her thorough and specific examinations of all the
pathological specimens.
I would like to thank statistician Tobias Wirenfeldt Klausen for his time and assistance in any
statistical problem. Thank you to Nanna Bjørn Volqvartz and Mette Schmidt for taking care of many
practical issues and to Nanna for the language revision of the manuscripts and thesis.
I would like to thank present and former PhD- and research students; Torben Kjær, Peter
Østergren, Mikkel Fode, Martin Højgaard and Anders Frey with whom I have enjoyed many
pleasant professional and private discussions.
Last, but not least I want to thank all the patients who participated in the studies.
Many warm and thankful thoughts go to my friends and family, in particularly my wife Julie and
our wonderful daughters Olivia and Karla for their love and huge support during this project.
Lars Boesen
Vedbæk, August 2014
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Abbreviations and Acronyms
PSA= Prostate specific antigen
MRSI = Magnetic resonance spectroscopic imaging
DRE = Digital rectal examination
GFR = Glomerular filtration rate
TRUS = Transrectal ultrasound
OC = Organ-confined
TRUS-bx = TRUS-guided biopsies
ECE = Extra capsular extension
PCa = Prostate cancer
SVI = Seminal vesicle invasion
EPE = Extra prostatic tumour extension
GS = Gleason score
RP = Radical prostatectomy
ISUP = International Society of Urological Pathology
cT = Clinical tumour stage
PZ = Peripheral zone
NVB = Neurovascular bundle
TZ = Transitional zone
MRI = Magnetic resonance imaging
CZ = Central zone
Mp-MRI = Multiparametric MRI
AUC = Area under the curve
ESUR = European Society of Urogenital Radiology
MDT = Multi-disciplinary team
PIRADS = Prostate imaging reporting and data system
BPH = Benign prostate hypertrophy
BIRADS = Breast imaging reporting and data system
Re-biopsy = Repeated biopsy
T1W = T1-weighted
PPA-coil = Pelvic-phased-array coil
T2W = T2-weighted
ERC = Endo-rectal coil
DWI = Diffusion-weighted imaging
AS = Active surveillance
ADC = Apparent diffusion coefficient
PPV = Positive predictive value
DCE = Dynamic contrast enhanced
NPV = Negative predictive value
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Manuscripts
The present PhD thesis is based on the three following articles:
Early experience with multiparametric magnetic resonance imaging-targeted biopsies under
visual transrectal ultrasound guidance in patients suspicious for prostate cancer undergoing
repeated biopsy.
Boesen L, Noergaard N, Chabanova E, Logager V, Balslev I, Mikines K, Thomsen HS.
Scand J Urol 2014, [Epub ahead of print], doi:10.3109/21681805.2014.9
Prostate cancer staging with extracapsular extension risk scoring using multiparametric
MRI: a correlation with histopathology
Boesen L, Chabanova E, Logager V, Balslev I, Mikines K, Thomsen HS.
Submitted
Apparent diffusion coefficient ratio correlates significantly with Gleason score at final
pathology
Boesen L, Chabanova E, Logager V, Balslev I, Thomsen HS.
Submitted
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Introduction
Prostate cancer (PCa) is the second leading cause of cancer-related mortality and the most
frequently diagnosed male malignant disease among men in the Nordic countries. Due to the
introduction of prostate-specific-antigen (PSA) testing there has been a dramatic increase in the
incidence of newly diagnosed PCa over the last 20-30 years. PCa is now detected at earlier stages
causing stage-migration. The lifetime risk of a man being diagnosed with PCa is approx. 17% (one
in six), but only 3-4% (one in thirty) will die of the disease supporting the fact that the majority of
men with PCa never develop a clinical significant disease that will affect their morbidity or
mortality [1]. However, despite earlier detection of PCa, the mortality rate in Scandinavia has
remained virtually unchanged and is one of the highest in the world. Thus, the manifestation of PCa
ranges from indolent to highly aggressive disease. Due to this high variation in PCa progression, the
diagnosis and subsequent treatment planning can be challenging. Active surveillance, surgery and
radiation therapy are standard treatment options for men with localised or locally advanced disease.
There is seldom just one right treatment choice and since surgery and radiation therapy may imply
greater side effects such as impotence, incontinence and/or radiation damage to the bladder or
rectum, it is essential to determine the exact tumour localisation, aggression and stage for optimal
clinical management and therapy selection.
The current diagnostic approach with PSA testing and digital rectal examination followed by
transrectal ultrasound biopsies lack in both sensitivity and specificity in PCa detection and offers
limited information about the aggressiveness and stage of the cancer. Recent scientific work
supports the rapidly growing use of multiparametric magnetic resonance imaging (mp-MRI) as the
most sensitive and specific imaging tool for detection, lesion characterisation and staging of PCa.
Its use may improve many aspects of PCa management, from initial detection of significant tumours
using mp-MRI-guided biopsies to evaluation of biological aggressiveness and accurate staging
which can facilitate appropriate treatment selection. However, the experience with mp-MRI in PCa
management in Denmark has been very limited. Therefore, we carried out this PhD project based on
three original studies to evaluate the use of mp-MRI in detection, assessment of biological
aggression and staging of PCa in a Danish setup with limited experience in mp-MRI prostate
diagnostics. The aim was to assess whether mp-MRI could 1) improve the overall detection rate of
clinically significant PCa previously missed by transrectal ultrasound biopsies, 2) identify patients
with extracapsular tumour extension and 3) categorize the histopathological aggressiveness based
on diffusion-weighted imaging.
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Background
Diagnosis of prostate cancer (PCa)
PCa is suspected by elevated PSA and/or an abnormal digital rectal examination (DRE) and the
diagnosis is made by transrectal ultrasound-guided biopsies (TRUS-bx) [2].
PSA
PSA is a natural enzyme that is produced almost exclusively by the prostatic epithelial cells and is
used as a serum marker for PCa. However, PSA is organ-specific, but not cancer-specific, as benign
conditions such as benign prostatic hypertrophy (BPH), prostatitis and other urinary symptoms may
cause elevated PSA levels. There is no absolute PSA cut-off level that indicates PCa and there is no
PSA level below which a man is guaranteed not to have PCa, although the risk of PCa is associated
with higher levels of PSA [3]. Traditionally, a threshold level ≥4 ng/ml has been established as
suspicious of PCa that trigger biopsies. However, at this cut-off level only about 1/3 men with
elevated levels will in fact have cancer and "normal" levels may falsely exclude the presence of
cancer, supporting the fact that PSA cannot be used to diagnose or exclude PCa [4–8]. The PSA
level is also used in risk stratification of newly diagnosed PCa patients, included into predictive
staging nomograms and for monitoring treatment response [2].
Digital rectal examination (DRE)
DRE is a fundamental part of the clinical examination of the patient where PCa feels hard and
irregular when a tumour is palpable. The majority (70-75%) of PCa lesions are located in the
peripheral zone and are therefore theoretically palpable over a certain size [9]. Still 25% of the
tumours are located in the transitional zone, which cannot be reached by DRE due to the anatomical
location. In addition, as PCa is now detected at earlier stages and at smaller tumour volumes, the
number of palpable tumours is strongly reduced. This makes DRE lack in both sensitivity and
specificity [10–13]. However, suspicious findings at DRE is a predictor for more pathologically
aggressive prostate cancer [14,15] and is a strong indicator for performing prostate biopsies, as it
allows for identification of 18% of men with PCa at "normal" PSA levels [15]. DRE is traditionally
used for clinical tumour staging (cT category), for risk stratification and included into predictive
staging nomograms.
Transrectal ultrasound (TRUS) and TRUS-bx
Transrectal ultrasound (TRUS) is the standard imaging modality for evaluating the prostate. As gold
standard, the diagnosis of PCa is made by histological examination of 10-12 TRUS-bx cores from
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standard zones in the prostate [16]. The role of prostate biopsies has changed over the past decades
from pure cancer detection to be an essential part of clinical management. TRUS is ideal for
determining prostate gland volume and guiding the biopsy needle, but lacks in both sensitivity and
specificity for detection and staging of PCa [16,17]. Most PCa lesions, if visualised on TRUS,
appear hypo-echoic compared to the normal peripheral zone. However, PCa lesions are often
difficult to see, as more than 40-50% of the cancerous lesions are iso-echoic [17,18] and cannot be
identified. In addition, evaluation of the transitional zone on TRUS is very limited due to the
heterogenic appearance often caused by BPH making detection of anteriorly located tumours
particularly difficult. Therefore, there is a high risk that a tumour is either being missed or the most
aggressive part of the tumour is not hit by the systematic standard biopsies (Figure 1a+b). This may
lead to either repeated biopsies (re-biopsy) or an incorrect Gleason score (GS) and risk
stratification. Conversely, multiple biopsies may hit a small clinically insignificant PCa micro-focus
by chance and contribute to over-detection and increase the risk of overtreatment (Figure 1c).
Figure 1: Standard TRUS-bx is a) missing a significant tumour (dark red area), b) missing the most aggressive part of
the tumour (dark red area) and c) an insignificant tumour (pink area) is hit by chance by the systematic biopsies.
Patients with persistent suspicion of PCa after TRUS-bx with negative findings pose a significant
clinical problem due to the high false-negative rates of 20-30% [7,19–21]. This means that up to
30% of the patients with a normal TRUS-bx will in fact have cancer. To overcome this, patients
with negative TRUS-bx often undergo several repeated biopsy procedures that will increase both
biopsy-related costs and may contribute to increased anxiety and morbidity (e.g. infectious
complications) among patients. Furthermore, multiple biopsies can cause inflammation and scar
tissue that may hamper and complicate any subsequent surgical intervention if PCa is diagnosed.
The detection rate at first TRUS re-biopsy is 10-22% [7,22] depending on the initial biopsy
technique with decreasing rates at repeated procedures. Still a significant number of cancers are
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missed [20]. In order to increase the detection rate by TRUS-bx and to overcome the absence of
target identification, some groups have extended the number of cores [23] and others are moving
towards saturation biopsy techniques [24]. This approach may lead to an increased overall detection
rate, but it may also increase the risk of detecting small insignificant well-differentiated tumours
that potentially lead to unnecessary treatment [19,25,26]. The limitations of TRUS-bx have led to
an intense need for an image modality that can improve the detection rate of clinically significant
PCa without increasing the number of diagnosed insignificant tumours and optimally decrease the
number of unnecessary biopsy sessions and cores. The prostate now remains the only solid organ
where the diagnosis is made by “blind” biopsies scattered throughout the organ.
Grading PCa using Gleason score (GS)
The histopathological aggressiveness of PCa is graded by the GS [27,28]. The cancerous tissue is
graded on a scale from 1-5 according to the histopathological arrangement and appearance of the
cancerous cells. This discrepancy between the normal and cancerous tissue reflects the
aggressiveness of the cancer (Figure 2).
Figure 2: The modified Gleason grading system currently used for histopathological grading [29]. In lower Gleason
grade 1 and 2, the cancerous tissue closely resembles normal prostatic tissue and the disparity increases with higher
Gleason grades. (Reprinted with permission from the publisher).
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As more than one class of Gleason grade can be present in the biopsy tissue, a composite GS
(ranging from 2-10) combining ‘the dominant’ and ‘the highest grade’ is assigned. A Gleason grade
≥3 or a GS ≥6 is the cellular pattern most often used as the distinction of cancerous tissue. The GS
assigned after radical prostatectomy differs as it is the sum of ‘the most dominant’ and ‘the second
most dominant’ Gleason grade. The GS is strongly related to the clinical behaviour of the tumour
and is a prognostic factor for treatment response. High GS implies increased tumour aggressiveness
and increased risk of local and distant tumour spread with a worse prognosis [30–32]. Thus, it has
been proposed to divide the GS into risk groups according to the risk of progression and metastasis
[33]. However, the pre-therapeutic risk assessment of a patient with newly diagnosed PCa is based
on the GS from TRUS-bx, which can be inaccurate due to sampling error, confirmed by the fact that
the GS is upgraded in every third patient following radical prostatectomy [34]. Incorrect GS at
biopsy may lead to incorrect risk stratification and possible over- or under-treatment. Furthermore,
the reporting of GS has changed over time with broadening of the Gleason grade 4 criteria [35] in
order to improve the correlation between biopsy and radical prostatectomy Gleason scores and to
better stratify patients to predict clinical outcomes. This has resulted in a significant upgrade of
tumour GS and made it difficult to compare pathological data over time.
Clinical staging of PCa
Clinical staging of PCa is based on the TNM classification [36]. The clinical tumour (cT) stage is
based on 4 main categories (cT1-T4) with subgroups, describing the local extent of the tumour
(Figure 3).
Figure 3: Clinical staging of PCa (cT1-T4) with subgroups. (Source: http://www.prostatecancercentre.com/whatis.html).
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The prognosis and treatment selection of PCa is strongly related to cT stage at diagnosis.
Especially, the distinction between localised (cT1-cT2) PCa and locally advanced disease (cT3cT4) is essential when planning treatment strategies. DRE and TRUS are traditionally used for
clinical staging of PCa. However, as DRE and TRUS lack in both sensitivity and specificity and
often underestimate the size and stage of the cancer [16], the prediction of extra prostatic tumour
extension (EPE) has low accuracy [37,38]. PSA also has limited accuracy in PCa staging as there is
a significant overlap between PSA levels and tumour stage [39–41]. Nevertheless, the clinical
results from DRE, TRUS-bx findings (including GS) and PSA values are used to stratify patients
into risk groups (D'Amico)[42,43] (Table 1).
cT stage
Gleason score
PSA
cT1-T2a
≤6
<10
Intermediate risk
cT2b
7
10-20
High risk
≥cT2c
≥8
>20
Low risk
Table 1: D'Amico risk groups based on cT stage, Gleason score and PSA.
The development of nomograms have increased the diagnostic accuracy of predicting EPE at final
pathology and recurrence after prostatectomy [44–46]. However, the results are based on a
statistical prediction integrating the known intrinsic sampling error of TRUS-bx and do not
incorporate visual anatomic imaging that provides individual information about localisation, side
and possible level of EPE.
Overall, PSA, DRE and TRUS-bx have several limitations regarding detection (Table 2), lesion
characterisation and staging of PCa and there is a need for clinicians to base the therapeutic decision
on more accurate imaging techniques.
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Limitations for PCa detection
PSA
A threshold of 4 ng/ml may miss significant cancer at lower values
Low specificity leading to many unnecessary biopsies
DRE
Low sensitivity as most tumours are non-palpable
TRUS-bx
Low/moderate sensitivity and specificity for PCa detection
Risk of missing significant tumours
Risk of diagnosing insignificant tumours
Multiple non-targeted biopsies are required
Repeated biopsy procedures are necessary
Increased risk of infectious complications and inflammation with multiple biopsies
Possible sampling error leading to incorrect diagnosis of tumour volume, extent and GS
Under-sampling of the anterior region
Table 2: Main limitation with the current diagnostic modalities for PCa detection.
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Motivation for the PhD study
The motivation for performing this PhD study is based on the above-mentioned limitations with the
current diagnostic tools for PCa management. There is an essential need for improved methods in
detection, characterisation and staging of PCa. Mp-MRI seems to have the ability to solve these
limitations. The use of MRI in prostate imaging is not new, as it dates back to the 1980s [47].
However, in the early era, the interpretation relied mainly on morphological imaging and suffered
from poor diagnostic accuracy. Since then, significant improvements in both hardware and software
have been made and with the addition of newer functional MRI sequences in a multiparametric
approach, mp-MRI has emerged internationally as a well-recognised and accurate imaging modality
for cancer detection, lesion characterisation and staging with the ability to change the management
of PCa [48]. However, the experience with mp-MRI in PCa management in Denmark has been very
limited and only two previous Danish studies with mediocre results using prostatic MRI have been
published. One in 2005 assessing the staging ability using conventional morphological imaging [49]
and one in 2011 assessing lesion localisation using combined morphological-, MR spectroscopyand dynamic contrast enhanced imaging [50]. Partly due to these fairly discouraging clinical results,
the use of MRI for PCa management has never been applied in Denmark prior to this thesis.
However, based on the continuous improvement of MRI equipment and sequences combined with
the recent development of clinical MR prostate guidelines [51] that include a structured uniform
scoring system to standardised mp-MRI readings and a guide to obtain high-quality imaging
acquisition, we carried out this PhD study to re-evaluate the use of 'modern' multiparametric MRI in
the diagnostic work-up of PCa.
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MRI of the prostate
MRI of the prostate is performed on either a 1.5 or 3.0 Tesla MRI scanner combined with a pelvicphased-array coil (PPA-coil) placed over the pelvis with or without an endorectal coil (ERC)
depending on the clinical situation. The use of an ERC can enhance image quality, as it is located in
the rectum just posterior to the prostate gland as well as fixate the prostate during the examination,
which might reduce motion artefacts. However, the disadvantages of the ERC are increased scan
time, increased costs and reduced patient compliance due to the location of the coil in the rectum.
The additional image quality of the ERC is valuable on 1.5 T MRI, whereas it is more questionable
on 3.0 T. Due to the increased spatial resolution (the ability to separate two dense structures from
each other) and the increased signal-to-noise ratio on 3.0 T MRI, the majority of prostatic MRI
examinations can be performed with acceptable image quality without an ERC. Although, studies
have shown improved image quality and diagnostic performance with an ERC at 3.0 T [52,53], the
topic is still under debate and several centres reserve the use of an ERC only for staging purposes if
possible extra-prostatic disease is decisive for the treatment plan. The European Society of
Urogenital Radiology's (ESUR) MR prostate guidelines states that the use of an ERC is optional for
detection and preferable for staging at 3.0 T MRI [51].
The MRI image quality is also depending on patient preparation. The administration of an oedema
prior to the examination and an injection of an intestinal spasmolyticum may diminish rectal
peristaltic motion and reduce the intra-luminal air that may cause artefacts on MRI.
Multiparametric MRI (mp-MRI)
The development of mp-MRI offers new possibilities in detection, lesion characterisation and
staging of PCa due to its high resolution and soft-tissue contrast. Published data [48,51,54–56]
supports the rapidly growing use of mp-MRI as the most sensitive and specific diagnostic imaging
modality for PCa management. Mp-MRI can provide information about the morphological,
metabolic and cellular changes in the prostate as well as characterise tissue vascularity and correlate
it to tumour aggressiveness (Gleason score) [57,58].
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Multiparametric MRI sequences
Mp-MRI includes high-resolution anatomical T2-weighted (T2W) and T1-weighted (T1W) images
in combination with one or more functional MRI techniques such as diffusion-weighted imaging
(DWI) and dynamic contrast enhanced (DCE) imaging [51]. Proton MR-spectroscopic imaging
(MRSI) can be used in addition to the other MRI techniques and responds to the changes in tissue
metabolism that typically occurs in PCa. It can be used to distinguish cancer from benign tissue [59]
and provide information about lesion aggressiveness [60]. However, MRSI is technically
challenging and requires high expertise and longer scan time often combined with the use of an
ERC, so many centres do not incorporate MRSI in their standard protocol. The ESUR MR prostate
guidelines do not list MRSI as a requirement for prostate examination, which is why it is not
included in the mp-MRI protocol used in this PhD study.
T1-weighted imaging (T1W)
T1W imaging are used in conjunction with T2W imaging to detect post-biopsy haemorrhage and to
evaluate the contour of the prostate and the neurovascular bundles. T1W imaging cannot be used to
assess the intra-prostatic zonal anatomy due to its low spatial resolution. Post-biopsy haemorrhage
can mimic PCa on T2W imaging, as both cancerous lesions and haemorrhage can appear as dark
hypo-intense areas. It has been reported to occur in 28-95% of patients [61–63]. However, only
haemorrhage will appear as an area with high signal intensity on T1W imaging and can be used to
rule out false- positive findings on T2W imaging [62] (Figure 4a+b).
Figure 4: Peripheral zone haemorrhage (white arrows) causing a) hypo-intense areas on axial T2W imaging and b) high
signal intensity on pre-contrast axial T1W imaging. T1W coronal imaging with increased field of view (c) reveals an
enlarged lymph node by the left iliac vessels (thick white arrow).
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It has been shown that the extent of haemorrhage is lower in a PCa lesion than in the adjacent
benign tissue [61] and the presence of "the excluded haemorrhage sign" on T1W imaging in
conjunction with an area of homogenous low signal intensity on T2W imaging is highly accurate
for PCa detection [63]. In addition, T1W imaging with increased field of view can also be used to
detect enlarged lymph nodes or signs of metastatic disease in the pelvic region (Figure 4c).
T2-weighted imaging (T2W)
High-resolution T2W imaging is the cornerstone in every prostate MRI. T2W imaging with high
spatial resolution provides a good overview of the prostatic zonal anatomy and it allows for
detection, localisation and staging of PCa. The peripheral zone often appears with high signal
intensity due to the high content of water in the glandular tissue opposed to the transitional- and
central zone that often have lower signal intensity (Figure 5). The transitional- and central zone is
often referred in combination as “the central gland”, as the two zones may be difficult to distinguish
on MRI. However, awareness about the location and appearance of the central zone is important as
its manifestation may imitate PCa resulting in a false-positive reading on MRI (Figure 5b). However,
PCa may rarely occur in the central zone, but when it does, it is typically more aggressive [64].
Figure 5: Normal prostate anatomy. T2W images show the peripheral zone (PZ) and transitional zone (TZ) in the a)
axial and c) coronal plane. Axial T2W image at the prostatic base (b) shows the central zone (white arrow) as a hypointense area surrounding the ejaculatory ducts.
The prostatic capsule appears as a thin fibro-muscular fringe of lower signal intensity surrounding
the prostate. PCa in the peripheral zone typically appears as a round or oval area of low signal
intensity in contrast to the higher signal intensity from the homogeneous benign peripheral zone
[65,66] (Figure 6). However, some PCa lesions can be iso-intense on T2W imaging and cannot be
seen.
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Figure 6: T2W imaging of a PCa lesion in the left peripheral zone (white arrow) on a) axial b) sagittal and c) coronal
view. (Source [55]. Reprinted with permission from the publisher).
PCa occurring in the transitional zone is not as distinctly outlined as it often has lower and mixed
signal intensities due to BPH nodules that may interfere with interpretation and mimic PCa. An area
of homogeneous low signal intensity and usually anteriorly located with a lenticular shape are
features of PCa occurring in the transitional zone [67] (Figure 7).
Figure 7: Axial T2W image of a PCa lesion in the right anterior part of the prostate (white arrow).
It has been shown that the degree of signal intensity on T2W imaging is related to the Gleason score
as cancers with a Gleason grade 4 or 5 tend to be more hypo-intense than Gleason grade 3 [68].
Also the growth pattern of the cancer may affect the appearance where “sparse” tumours with
increased intermixed benign prostatic tissue appear more like "normal" peripheral zone than more
dense tumours [69]. Moreover, there are several benign conditions in the prostate (e.g.
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haemorrhage, atrophy, BPH, calcifications and prostatitis) that also can appear as an area of low
signal intensity on T2W imaging causing false-positive readings. A meta-analysis reported an
overall sensitivity and specificity of 0.57-0.62 and 0.74-0.78 for PCa localisation using T2W
imaging alone [70]. Due to this moderate sensitivity and specificity, T2W imaging should be
combined with additional functional MRI techniques such as DWI and DCE imaging to increase the
diagnostic performance.
PCa staging is accompanied by determination of possible EPE (T3-T4 disease). T2W imaging is the
dominant MRI modality for assessment of extracapsular extension (ECE) and seminal vesicle
invasion (SVI), where direct signs of ECE can be visualised as tumour growth outside the prostatic
capsule and into the peri-prostatic tissue. Secondary, indirect signs of ECE include bulging or loss
of capsule, neurovascular bundle-thickening, capsular - irregularity, thickening or retraction,
obliteration of the recto-prostatic angle and abutment of tumour. Similarly, signs of seminal vesicle
invasion (SVI) include expansion of tumour from the prostatic base into the SV, with low T2Wsignal intensity in the lumen, filling in of angle and possible concomitant enhancement (DCE
imaging) and/or impeded diffusion (DWI) [51,71–74] (Figure 8).
Figure 8: T2W imaging of PCa (white arrows) in a) the right peripheral zone with direct sign of extracapsular extension
and b+c) tumour involvement of the seminal vesicles.
Diffusion-weighted imaging (DWI)
DWI is a non-invasive functional MRI technique that assesses changes in diffusion of water
molecules due to microscopic structural changes. By applying different diffusion-weighted
gradients (b-values) to the water protons in the tissue, DWI generates different signal intensities that
quantify the movement of free water molecules. Normal prostatic tissue, especially the peripheral
zone, contains glandular structures where water molecules can move freely without restriction. PCa
21
often depletes the glandular structures and contains more tightly packed cells causing restricted
diffusion. Changes in diffusion are reflected in changes in the signal intensity on DWI where areas
with restricted diffusion will be bright on DWI. DWI is usually performed with different b-values
where low b-values (0-100) predominantly represent a signal decay caused by the perfusion in the
tissue, whereas higher b-values represent water movement in the extra- and intracellular
compartment [75] . The use of DWI provides both qualitative and quantitative information about
the tissue cellularity and structure that can be used for lesion detection and characterisation.
Therefore, a qualitative assessment of an area with high signal intensity on high b-value DWI often
represents an area with restricted diffusion caused by tightly packed cells. The apparent diffusion
coefficient (ADC) is calculated based on the signal intensity changes of at least two b-values to
quantitative asses the degree of diffusion restriction. The calculation of ADC is performed using
build-in software in the MRI scanner or workstation. An ADCmap is generated based on the ADC
value in each voxel of the prostate. Restriction of diffusion causes a reduction in the ADC value and
is dark on the ADCmap [75,76].
PCa typically has higher cellular density and restricted diffusion compared to the surrounding
normal tissue. Therefore, PCa lesions are often bright on high b-value DWI and dark on the ADCmap
with lower ADCtumour values [76–79]. Thus, DWI can help in the differentiation between malignant
and benign prostatic tissue and the use of DWI in the diagnosis of PCa has been proven to add
sensitivity and especially specificity to T2W imaging alone [70,80] (Figure 9).
Figure 9: DWI of PCa in the left peripheral zone (white arrow) on a) axial b1400 b) axial ADC map corresponding to the
same tumour in Figure 6. (Source [55]. Reprinted with permission from the publisher).
Studies have shown an inverse correlation between the mean ADCtumour value calculated from the
cancerous lesion on the ADCmap and the GS [58,81–85] signifying that ADCtumour values can be
22
used as a non-invasive marker of tumour aggression. Attempts have been made to define specific
cut-off values to separate malignant from benign tissue and to further differentiate between GS
groups. However, due to different study methodologies with different b-values, different MRI
equipment and field strengths along with patient variability between studies, a wide range and
inconsistency in mean ADCtumour values have been reported [81,83,86,87]. Furthermore, there is a
considerable overlap between ADC values from malignant and benign tissue [88,89] and a wide
variability depending on the zonal origin [90,91]. Thus, there is no consensus on absolute ADCtumour
cut-off values corresponding to different GS.
Dynamic contrast enhanced MRI (DCE-MRI)
DCE-MRI utilises the fact that malignant and benign prostatic tissues often have different contrast
enhancement profiles. DCE-MRI analysis is based on changes in the pharmacokinetic features of
the tissue mainly due to angiogenesis. DCE-MRI consists of a series of fast high-temporal (the
ability to make fast and accurate images in rapid succession) T1W images before, during and after a
rapid intravenous injection of a gadolinium-based contrast agent. The prostatic tissue is generally
highly vascularised, making a simple assessment of pre- and post-contrast images inadequate for
PCa characterisation [92]. PCa often induces angiogenesis and increased vascular permeability
compared to normal prostatic tissue [93,94] resulting in a high and early contrast enhancement peak
(increased enhancement) followed by a rapid washout of the contrast [95–98] (Figure 10).
Figure 10: DCE-MRI of PCa in the left peripheral zone corresponding to the same tumour in Figure 6 + Figure 9. The
a) dynamic contrast enhanced T1W image and the c) corresponding DCE colour map show early focal contrast
enhancement in the tumour (red area). b) The dynamic DCE-curve L3 (blue) is a typical malignant curve (curve type 3)
with a high peak, rapid early enhancement (high wash-in rate) and early wash-out. The DCE-curve L4 (yellow) is from
a non-malignant region with no early wash-out (curve type 1). (Source [55]. Reprinted with permission from the publisher).
23
There are several methods to describe the pharmacokinetic features in the tissue. Qualitatively by a
visual characterisation of the enhancement curves, quantitatively by applying complex
pharmacokinetic models to determine the contrast exchange rate between different cellular
compartments or semi-quantitative by calculating various kinetic parameters of the enhancement
curves - wash-in/wash-out rate, time to peak etc. In addition, various post-processing software tools
are used to analyse and describe the DCE-MRI including overlaid colourised enhancement maps
that can be used to identify pathological changes and PCa. A detailed description of the analysis of
DCE-MRI can be read in the review by Verma et al.[97].
Previous studies have verified that DCE-MRI in conjunction with other MRI modalities can
increase the diagnostic accuracy of PCa detection [97,99–101] and may even improve the detection
of ECE [102]. The use of DCE-MRI primarily adds sensitivity to the mp-MRI performance and is
essential for detection of local recurrence [103–107]. However, a recent study by Baur et al. [108]
found that DCE-MRI did not add significant value to the detection of PCa. DCE-MRI lack in
specificity as benign conditions, such as hyper-vascularised BPH nodules and prostatitis can mimic
pathological enhancement patterns [97,109]. Thus, DCE-MRI is best analysed in conjunction with
other MRI modalities such as T2W imaging and DWI to achieve optimum sensitivity and
specificity for PCa assessment.
Clinical guidelines and Prostate Imaging Reporting and Data System (PIRADS):
The basic principle of a scoring system for mp-MRI readings is to identify abnormal regions and
grade each region according to the degree of suspicion of PCa based on the appearance on the mpMRI. However, prostate mp-MRI interpretation is challenging and has a steep learning curve where
experienced readers are significantly more accurate than non-experienced readers [110–112]. The
diagnostic accuracy of mp-MRI differs among previously published studies [113–116] partly due to
different study protocols, diagnostic criteria, MRI equipment and expertise, which have led to a
debate about mp-MRI’s readiness for routine use [117]. Mp-MRI has been criticised for the lack of
standardisation and a uniform scoring system. Clinical guidelines [51] have therefore recently been
published to promulgate high-quality mp-MRI acquisition and evaluation. The guidelines are based
on literature evidence and consensus expert opinions from prostate MRI experts from ESUR and
include clinical indications for mp-MRI and a structured uniform Prostate Imaging Reporting and
Data System (PIRADS) to standardise prostatic mp-MRI readings.
The PIRADS classification is a scoring system for prostate mp-MRI similar to the BIRADS for
breast imaging. It is based on the five-point Likert scale and should include 1) a graphic prostate
24
scheme with 16-27 regions 2) a separate PIRADS score for each individual lesion and 3) a max.
diameter measure of the largest lesion. All MRI modalities - e.g. T2W, DWI and DCE imaging –
are scored independently (1-5) on a five-point scale for each suspicious lesion within the prostate
and the summation of all individual scores (ranging 3-15 for 3 modalities) constitute the PIRADS
summation score. In addition, each lesion is given a final overall score (ranging 1-5) according to
the probability of clinically significant PCa being present (Table 3).
Score Criteria
SI=signal intensity
T2W imaging for peripheral zone
1
Uniform high SI
2
Linear, wedge-shaped or geographic area of low SI, usually not well-demarked
3
Intermediate appearances not in categories 1/2 or 4/5
4
Discrete, homogeneous low-signal focus/mass confined to the prostate
5
Discrete, homogeneous low SI focus with ECE/invasive behaviour or mass effect on the capsule
(bulging), or broad (>1.5 cm) contact with the surface
T2W imaging for transitional zone
1
Heterogeneous transition zone adenoma with well-defined margins: “organised chaos”
2
Areas of more homogeneous low SI, however, well-marginated, originating from the transitional
zone/BPH
3
Intermediate appearances not in categories 1/2 or 4/5
4
Areas of homogeneous low SI, ill defined: “erased charcoal drawing sign”
5
Same as 4, but involving the anterior fibro-muscular stroma sometimes extending into the anterior horn
of the peripheral zone, usually lenticular or water-drop shaped
Diffusion-weighted imaging (high b-value images ~ ≥b800)
1
No reduction in ADC compared to normal glandular tissue. No increase in SI on high b-value images
2
Diffuse hyper SI on high -value images with low ADC; no focal features, linear, triangular or
geographical features allowed
3
Intermediate appearances not in categories 1/2 or 4/5
4
Focal area(s) of reduced ADC but iso-intense SI on high b-value image
5
Focal area/mass of hyper SI on the high b-value images with reduced ADC
Dynamic contrast enhanced imaging
1
Type 1 enhancement curve
2
Type 2 enhancement curve
3
Type 3 enhancement curve
+1
Focal enhancing lesion with curve types 2-3
+1
Asymmetric lesion or lesion at an unusual place
Overall final score
1
Clinically significant disease is highly unlikely to be present
2
Clinically significant disease is unlikely to be present
3
Clinically significant disease is equivocal
4
Clinically significant disease is likely to be present
5
Clinically significant disease is highly likely to be present
Table 3: PIRADS classification for T2W, DWI and DCE imaging [51]. Since there is considerable different anatomical
appearance between the peripheral- and transitional zone on T2W imaging, different PIRADS criteria are applied for
the two zones. Illustrative examples of the PIRADS criteria for the MRI modalities are seen in reference [118,119].
25
Extra prostatic tumour extension (EPE)
In addition to the PIRADS classification, each lesion should also be assessed for possible EPE. The
ESUR MR prostate guidelines list a table of mp-MRI findings with a corresponding risk score
stratified into different EPE criteria with concomitant tumour characteristics/findings (Table 4).
Criteria
Findings
Extracapsular extension
(ECE)
Abutment
Irregularity
Neurovascular bundle thickening
Bulge, loss of capsule
Measurable extracapsular disease
Expansion
Low T2 signal
Filling in of angle
Enhancement and impeded diffusion
Adjacent tumour
Effacement of low signal sphincter muscle
Abnormal enhancement extending into sphincter
Adjacent tumour
Loss of low T2 signal in bladder muscle
Abnormal enhancement extending into bladder neck
Seminal vesicles
(SVI)
Distal sphincter
Bladder neck
Score
1
3
4
4
5
1
2
3
4
3
3
4
2
3
4
Table 4: EPE risk scoring of extra prostatic extension [51].
ECE and/or SVI corresponds to locally advanced T3-disease and invasion into the bladder neck,
external distal sphincter, rectum and/or side of the pelvic wall are considered T4-disease, although
only the first two T4-findings are included in the ESUR EPE risk scoring.
Anatomical T2W imaging is the dominant MRI modality for EPE assessment. However, some of
the categories (e.g. SVI) also include findings on functional imaging (enhancement and impeded
diffusion ~ risk score 4). It is recommended that suspicion of EPE should be given an overall score
ranging 1-5 according to the probability of EPE being present. Therefore, the five-point scale is
considered a continuum of risk with higher scores corresponding to higher risk of EPE. However,
not all categories include the total scoring range 1-5 and e.g. functional imaging findings are not
included in the assessment of ECE. Previous studies show that functional imaging may improve
detection of ECE [102,120,121], especially for less experienced readers [111]. Therefore, the
interpretation and overall impression of possible ECE may be influenced by personal opinion when
incorporating functional imaging finding.
26
Overall, the combination of morphological T2W imaging with functional sequences in a
multiparametric approach, preferably on a high-field MRI (e.g. 3T) with or without an endorectal
coil depending on the clinical situation, has shown that mp-MRI can increase the diagnostic
accuracy in detection, characterisation and staging of PCa [100,122–126]. Thus, mp-MRI has the
ability to change the management of PCa [48].
27
Objectives and hypothesis
The main objective of this PhD study is to investigate the use of multiparametric MRI in detection
and staging of PCa in a Danish setup and to assess if multiparametric MRI can
- Improve the overall detection rate of clinically significant PCa previously missed by transrectal
ultrasound biopsies
- Identify patients with extracapsular tumour extension
and
- Categorize the histopathological aggressiveness based on diffusion-weighted imaging.
The secondary purpose is to gain experience in the use of multiparametric MRI for PCa
management in Denmark. This experience may form the basis for the future – using
multiparametric MRI as a diagnostic adjunct in selected patients, as practiced at international
leading PCa MRI centres.
This thesis is based on the following hypotheses:
1. Multiparametric MRI can improve the detection rate of clinically significant PCa in patients with
persistent suspicion after TRUS-bx with negative findings by adding multiparametric MRI-targeted
biopsies towards suspicious lesions.
2. Multiparametric MRI-targeted biopsies allow for a more accurate Gleason grading.
3. Multiparametric MRI is an accurate diagnostic technique in determining PCa clinical tumour
stage and ECE at final pathology.
4. Multiparametric MRI with diffusion-weighted imaging can be used to assess the Gleason score of
PCa tumours.
The use of multiparametric MRI in detection of metastasis (lymph nodes or bone) and potential
recurrence - locally or distant - falls outside the scope of this thesis.
28
Specific Part
This thesis is based on 3 original studies using mp-MRI as a diagnostic tool in the detection,
assessment of biological aggression and staging of PCa. Each study is introduced with introductory
remarks and described briefly in the following part and in more detail in the individual manuscripts
in the appendix.
All studies were approved by the Local Committee for Health Research Ethics (No.H-1-2011-066)
and the Danish Data Protection Agency and were conducted as single institutional studies. The
studies were registered at Clinicaltrials.gov (No.NCT01640262). All patients were included
prospectively and written informed consent was provided.
The mp-MRI examination protocol was the same for all patients in all three studies using two 3.0 T
MRI scanners (Achieva/Ingenia, Philips Healthcare, Best, the Netherlands) with a PPA-coil (Philips
Healthcare, Best, the Netherlands) positioned over the pelvis. If tolerated, a 1 mg intramuscular
Glucagon (Glucagen®, Novo Nordisk, Bagsvaerd, Denmark) injection combined with a 1 mg
Hyoscinbutylbromid (Buscopan®, Boehringer Ingelheim, Ingelheim am Rhein, Germany) intravenous
injection were administered to the patients to reduce peristaltic motion. Tri-planar T2W images
from below the prostatic apex to above the seminal vesicles were obtained. In addition, axial DWI
including 4 b-values (b0, b100, b800 and b1400) along with reconstruction of the corresponding
ADCmap (b-values 100 and 800), together with DCE images before, during and after intravenous
administration of 15 ml gadoterate meglumine (Dotarem 279.3 mg/ml, Guerbet, Roissy CDG, France)
were performed. The contrast agent was administered using a power injector (MedRad, Warrendale,
Pennsylvania, USA) followed by a 20 ml saline flush injection at a flow rate of 2.5 ml/s. For imaging
parameters see Table 5.
Pulse
sequence
TR
(ms)
TE
(ms)
FA
(°)
FOV
(cm)
ACQ matrix
Number
of slices
Thickness
(mm)
Axial DWI, b= 0,
100,800,1400 s/mm2
SE-EPI
4697/4916
81/76
90
18x18
116x118/116x118
18/25
4
Axial T2w
SE-TSE
3129/4228
90
90
16x16/18x18
248x239/248x239
20/31
3
Sagital T2w
SE-TSE
3083/4223
90
90
16x16/16x20
248x242/268x326
20/31
3
Coronal T2w
SE-TSE
3361/4510
90
90
19x19
252x249/424x423
20
3
Coronal T1w
SE-TSE
675/714
20/15
90
40x48/44x30
540x589/408x280
36/41
3.6 / 6
Axial 3d DCE
FFE-3d-TFE
5.7/10
2.8/5
12
18x16
128x111/256x221
18
4 / 4.5
SE = spin echo, EPI = echo planar imaging, TSE = turbo spin echo, TFE = turbo field echo, FFE = fast field echo,
TR = repetition time, TE = echo time, FA = flip angle, ACQ matrix = acquisition matrix.
Table 5 : Sequence parameters for 3.0 Tesla Achieva/Ingenia multiparametric MRI with PPA-coil.
29
Study I: Early experience with multiparametric magnetic resonance imagingtargeted biopsies under visual transrectal ultrasound guidance in patients
suspicious for prostate cancer undergoing repeated biopsy
Introductory remarks
It is evident that TRUS-bx for PCa detection is prone to sampling error [7,19,20], most often caused
by the absence of a target identification. To overcome the lack in sensitivity and specificity for
TRUS-bx, patients with prior negative TRUS-bx findings and persistent suspicion of PCa
frequently undergo several repeated biopsy (re-biopsy) procedures, and still a significant number of
cancers are missed [20]. Similarly, the GS from TRUS-bx can be inaccurate, confirmed by the fact
that the GS is upgraded in every third patient following radical prostatectomy. These limitations in
TRUS-bx have led to an intense need for a way to improve the detection and localisation of
clinically significant PCa. As previously stated, mp-MRI of the prostate seems to have the potential
to solve the problem [48,51,54–56,127]. Studies show that it is feasible to target biopsies towards
the most aggressive part of suspicious lesions seen on mp-MRI and thereby improve the detection
rate of clinically significant PCa [128–134] and achieve a more accurate Gleason grading [57,135].
However, mp-MRI has never been applied at our institution for PCa detection and for guiding
targeted biopsies towards mp-MRI-suspicious lesions prior to this study. The patient population and
results represent our first initial experience with this new technique.
Aim
To investigate the detection rate of PCa by mp-MRI-targeted biopsies in patients with prior negative
TRUS-bx findings without preceded experience for this and to evaluate the clinical significance of
the detected cancers.
Material and methods
Patients scheduled for repeated biopsies were prospectively enrolled. Inclusion criteria required that
all patients had a history of negative TRUS-bx findings and a persistent suspicion of PCa based on
either PSA value, an abnormal DRE or a previous abnormal TRUS-image. The exclusion criteria
were patients previously diagnosed with PCa or contraindication to mp-MRI (pacemaker, magnetic
implants, severe claustrophobia, previous moderate or severe reaction to gadolinium-based contrast
media, impaired renal function with GFR<30 ml/min). Mp-MRI was performed prior to the biopsies
and analysed for suspicious lesions. All identified lesions were registered on a 18-region prostate
diagram (Figure 11) and scored according to the PIRADS classification given a sum of scores
(ranging 3-15) [51].
30
Figure 11: The prostate is divided into 12 posterior and 6 anterior regions. (Reprinted with permission from the publisher
[136,137]).
Additionally, each lesion was classified overall on a Likert five-point scale according to the
probability of clinically significant malignancy being present. The PIRADS and Likert scores were
separately divided into 3 risk groups (high, moderate and low) according to suspicion of PCa.
Initially, all patients underwent repeated standard TRUS-bx (10 cores) (Figure 12) blinded to any
mp-MRI findings.
31
Figure 12: Axial and sagittal scheme of our standard ten TRUS-biopsy cores performed with an end-fire probe. The
biopsy cores extend approximately 17-20 mm from the prostatic rectal surface into the prostate. The biopsies are taken
from a) base – lateral/medial b) mid-gland – lateral and c) apex – lateral/medial. (Modified and reprinted with permission
from the publisher [138]).
32
The standard biopsies were followed by visual mp-MRI-targeted biopsies (mp-MRI-bx) under
TRUS-guidance of any mp-MRI-suspicious lesion considered not to be hit on the systematic TRUSbx (Figure 13).
Figure 13: Mp-MRI (T2W, DWI and DCE imaging) shows a tumour suspicious region in the anterior part of the
prostate (white arrows) that is considered not to be hit by the systematic TRUS-bx. The region is hypo-intense on T2W
imaging, dark on the ADCmap (ADCtumour value 855 (×10-6mm2/sec)) and bright on the DWI-b1400 indicating a solid
tumour mass. The corresponding DCE colour map shows focal enhancement in the region (red area) and the dynamic
DCE-curve (P1) is a typical malignant (type 3 ) curve with rapid early enhancement and early wash-out. The DCEcurve (P2) is from a non-malignant region. The region was classified as high suspicion of prostate cancer (PIRADS
summation score 5-5-5, overall Likert score 5).
Main results
Eighty-three patients with a median of 2(1-5) prior negative TRUS-bx sessions and median PSA of
11(2-97) underwent mp-MRI before re-biopsy. PCa was found in 39/83 (47%) patients using
TRUS- and mp-MRI-bx. There was a total of 156 identified lesions ranging from low to highly
suspicious giving a median of 2 (0-5) per patient. Biopsies were positive for PCa in 52/156 (33%)
mp-MRI identified lesions and mp-MRI identified at least one lesion with some degree of suspicion
in all 39 patients diagnosed with PCa. Both the PIRADS summation score and the overall Likert
classification showed a high correlation with biopsy results (p<0.0001). Five patients (13%) had
cancer detected only on mp-MRI-bx outside the systematic biopsy areas (p=0.025) and another 7
patients (21%) had an overall GS upgrade of at least one grade (p=0.037) based on the mp-MRI-bx.
33
Secondary PCa lesions not visible on mp-MRI were detected by TRUS-bx in 6/39 PCa patients. All
secondary lesions were GS 6(3+3) tumour foci in 5-10% of the biopsy core. No patients had a GS
upgrade based on positive TRUS-bx from non-visible lesions on mp-MRI. Two patients had
insignificant PCa detected providing an overall detection rate of clinically significant PCa of 45%
(37/83 patients) among which 27% (10/37) harboured high-grade (GS ≥ 8) cancer.
Conclusion
Multiparametric MRI before repeated biopsy even without preceded experience can improve the
detection rate of clinically significant PCa by combining standard TRUS-bx with mp-MRI-targeted
biopsies under visual TRUS-guidance and it allows for a more accurate Gleason grading.
Study II: Prostate cancer staging with extracapsular extension risk scoring using
multiparametric MRI: a correlation with histopathology
Introductory remarks
Local staging of PCa plays an important role in treatment planning and prediction of prognosis. It is
evident that DRE and TRUS do not have the ability to correctly localise and stage the extension of
the cancer, thus prediction of ECE has low accuracy [2,37,38]. Radical prostatectomy (RP) provides
great disease control for patients with localised PCa (cT1-T2), while RP for locally advanced
disease (cT3) remains controversial [2,139]. Preoperative accurate knowledge of tumour stage and
possible ECE are crucial in achieving the best surgical, oncological and functional result. Mp-MRI
has emerged as a sensitive and specific image modality for PCa staging and prediction of ECE at
final pathology [48]. However, the diagnostic accuracy differs among studies
[110,114,116,140,141]. Previous studies (including study I in this thesis) have validated the
PIRADS classification for PCa detection and localisation using both targeted biopsies [142–144]
and RP specimen [145] as standard reference, but the ESUR MR prostate guidelines also
recommend a five-point risk scoring for possible EPE. This study represents our experience using
the ESUR MR prostate guidelines scoring of extra prostatic disease focusing on ECE risk scoring in
the preoperative evaluation of PCa staging.
Aim
To evaluate the diagnostic accuracy of preoperative multiparametric MRI with ECE risk scoring in
the assessment of prostate cancer tumour stage and prediction of ECE at final pathology.
34
Material and methods
Patients with clinically localised PCa (cT1-T2) determined by DRE and/or TRUS and scheduled for
RP were prospectively enrolled. All patients underwent mp-MRI (T2W, DWI and DCE imaging)
prior to RP and all lesions were evaluated according to the ESUR MR prostate guidelines' PIRADS
classification and scoring of extra prostatic disease focusing on the ECE criteria. The images were
evaluated by two readers with different experience in mp-MRI interpretation. An mp-MRI T-stage
(cTMRI) and an ECE risk score were assigned. Additionally, suspicion of ECE was dichotomised
into either organ-confined (OC) disease or ECE based on tumour characteristics and personal
opinion incorporating functional imaging findings. All patients underwent RP and the
histopathological results served as standard reference and were compared to the mp-MRI findings
in the assessment of T-stage and ECE.
Results
Eighty-seven patients with median age 65 (range 47-74) and a median PSA 11 (range 4.6-45)
underwent mp-MRI before RP. The correlation between cTMRI and pT showed a spearman rho
correlation of 0.658 (p<0.001) and 0.306 (p=0.004) with a weighted kappa of 0.585 [CI 0.44;0.73]
and 0.22 [CI 0.09;0.35] for reader A and reader B, respectively. The prevalence of ECE after RP
was 31/87 (36%). ECE risk scoring showed an AUC of 0.65-0.86 on the ROC-curve for both
readers and a sensitivity, specificity and diagnostic accuracy of 81% [CI 63;93],78% [CI 66;88] and
79% at the best cut-off level (risk score≥4) for the most experienced reader. When tumour
characteristics were influenced by personal opinion and functional imaging, the sensitivity,
specificity and diagnostic accuracy for prediction of ECE changed to 74% [CI 55;88], 88% [CI
76;95] and 83% for reader A and 61% [CI 0.42;0.78], 77% [CI 0.64;0.87] and 71% for reader B,
respectively.
Conclusion
Multiparametric MRI with ECE risk scoring by a dedicated reader is an accurate diagnostic
technique in determining prostate cancer tumour stage and ECE at final pathology.
35
Study III: Apparent diffusion coefficient ratio correlates significantly with Gleason
score at final pathology
Introductory remarks
The histopathological aggressiveness of PCa is graded by the GS and is strongly related to the
tumours’ clinical behaviour. High GS implies increased tumour aggressiveness and risk of local and
distant tumour spread with a worse prognosis. However, the majority of men diagnosed with PCa
often harbour a non-aggressive low GS tumour focus that seldom develops into a clinical disease
that will affect the morbidity or mortality. The GS from TRUS-bx that is used for pre-therapeutic
classification of tumour aggressiveness can be inaccurate due to sampling error. Incorrect GS at
biopsy may lead to incorrect risk stratification and possible over- or under-treatment. Thus, there is
a need to improve the pre-therapeutic assessment of true GS. Previous studies show that cancerous
tissue has lower DWI-calculated ADCtumour values than benign prostatic tissue (ADCbenign) and that
there is a negative correlation with the GS. However, there is an inconsistency due to different study
methodologies with a wide variability in reported ADCtumour values corresponding to different GS.
To overcome some of this variability, we hypothesise that the ADCratio (defined as the ADCtumour
divided by the ADCbenign value) might be more useful and predictive in determining true GS, as it
may level out some of the variation. This study represents our experience using ADC measurements
(ADCtumour and ADCratio) in the assessment of the GS.
Aim
To evaluate the association between the ADCtumour and the ADCratio calculated from pre-operative
diffusion-weighted MRI with the GS at final pathology and to determine the best parameter for this.
Material and methods
Patients with clinically localised PCa scheduled for RP were prospectively enrolled from study II.
Diffusion-weighted MRI was performed prior to RP as part of the diagnostic workup in study II and
mean ADCtumour values on the ADCmap from all identified malignant tumours were measured. All
patients underwent RP and all tumour foci ≥5 mm in the longest dimension were outlined by the
pathologist on a cross-sectional diagram and selected for comparison with mp-MRI. Using the
histopathological map as a reference, the ADCbenign value was obtained from a non-cancerous area
to calculate the ADCratio. The ADC measurements were correlated with the GS from each selected
tumour foci from the prostatectomy specimen.
36
Results
Seventy-one patients with a median age of 65 (range 47-73) and a median PSA of 10.6 (range 4.646) underwent mp-MRI before RP. There were a total of 104 (peripheral zone=53, transitional
zone=51) separate tumour foci identified on histopathology and were selected for comparison.
There was a statistical significant difference (p<0.001) between mean ADCtumour and mean
ADCbenign values and between mean ADCtumour values of tumours originating in either the
peripheral- or transitional zone. There was no significant difference (p=0.194) in mean ADCratio
between the two zones.
The association between ADC measurements and GS showed a significantly negative correlation
(p<0.001) with spearman rho for ADCtumour (-0.421) and ADCratio (-0.649), respectively. There was
a statistically significant difference between both ADC measurements and the GS groups for all
tumours (p<0.001). The difference remained significant for mean ADCratio when stratified by zonal
origin, but not for mean ADCtumour for tumours located in the transitional zone (p=0.46). ROC-curve
analysis showed an overall AUC of 0.73 (ADCtumour) to 0.80 (ADCratio) in discriminating Gleason 6
from Gleason ≥ 7(3+4) tumours. The AUC remained virtually unchanged at 0.72 (ADCtumour), but
increased to 0.90 (ADCratio) when discriminating Gleason ≤ 7(3+4) from Gleason ≥ 7(4+3).
Conclusion
Preoperative ADC measurements showed a significant correlation with tumour GS at final
pathology. The ADCratio demonstrated the best correlation compared to the ADCtumour and radically
improved accuracy in discriminating GS ≤ 7(3+4) from GS ≥ 7(4+3) tumours.
37
Discussion
This PhD thesis evaluates the use of mp-MRI in the detection, assessment of biological aggression
and staging of PCa in a Danish setup. In this section, the main study results will be discussed and
compared to previous research with a reflection on clinical use, general limitations and finally
future perspectives. More detailed discussions of specific study results and limitations are part of
the main articles in the appendix.
Detection: Initial diagnosis and prostate biopsy
The indication for performing prostate biopsies is driven by non-specific and non-sensitive tests
such as elevated PSA and/or an abnormal DRE assuming that the patient might have PCa. As TRUS
also lacks in both sensitivity and specificity in PCa detection, 10-12 "screening" biopsy cores are
taken systematically from the peripheral zone scattered throughout the prostate hoping to hit the
possible cancer, including the most aggressive part. The accuracy of TRUS-bx in PCa detection
varies widely between studies, especially due to inter-operator variation, various biopsy techniques
and often a poor discrimination of a specific PCa target on TRUS. The low diagnostic yield of
TRUS-bx often leads to repeated biopsy sessions.
In study I, we demonstrated that pre-biopsy mp-MRI for detection of PCa in patients with prior
negative TRUS-bx findings can improve the overall detection rate by adding mp-MRI-bx under
visual TRUS-guidance to standard TRUS-bx even without preceded experience for doing this. We
found an overall PCa-detection rate of 47% (39/83) in patients with a median of 2 prior negative
TRUS-bx sessions among which 26% (10/39) harboured high-grade PCa (GS≥8). According to the
literature, the detection rate at first TRUS re-biopsy is 10-22% [7,22] depending on the initial
biopsy technique with decreasing rates at repeated procedures. Only two patients had insignificant
PCa providing an overall detection rate of clinically significant PCa of 45% (37/83 patients). We
concluded that suspicious lesions seen on mp-MRI can be targeted by biopsies and improve the
detection rate of clinically significant PCa, which is in line with previous studies [128–134]. In our
setting, 5/39 (13%) patients had PCa detected only by mp-MRI-bx and another 7/34 (21%) patients
had an overall GS upgrade cumulating to a total of 12/39 (31%) newly diagnosed PCa patients that
may have had their prognosis and treatment management altered due to the use of mp-MRI as an
adjunct to TRUS-bx.
There are different ways of performing targeted biopsies of mp-MRI-suspicious lesions. In study I
we used visual fusion with cognitive targeting, where the mp-MRI-suspicious lesions are visually
38
matched and registered on the corresponding axial TRUS-image based on zonal anatomy and tissue
landmarks. The physician performing the TRUS uses the mp-MRI findings to select an appropriate
TRUS-region for a targeted biopsy. The overall PCa detection rate in study I is in accordance with
previous findings as outlined in the review by Lawrentschuk et al. [130], although they find a higher
proportion of PCa detected purely by the mp-MRI-targeted biopsy cores. Our high PCa detection
rate of 41% (34/83) using standard end-fire biopsies alone can be explained by the fact that not all
patients included in the study had the initial TRUS-bx performed at our institution. Patients are
often referred to our department for repeated biopsies, as TRUS-bx is limited to a very few highly
experienced operators using an end-fire biopsy probe unlike many of the referring departments
where TRUS-bx is practiced widely by all urologists using a side-fire probe. The end-fire probe
allows for better sampling of the lateral and apical regions of the prostate at standard biopsies where
PCa often resides [146] (Figure 12) Mp-MRI-bx is particularly good at detecting anteriorly located
tumours that are frequently missed by TRUS-bx [147–149], which is confirmed in this study where
more than 70% of the mp-MRI PCa-positive lesions were located in the anterior or apical region
(Figure 1study I). It is our experience that the end-fire biopsy needle is essential for targeting mp-MRIsuspicious lesions as it enters the prostatic surface more perpendicularly and penetrates deeper and
more anteriorly into the prostate facilitating better sampling of the apical and anterior regions. This
is confirmed in a recent study by Ploussard et al. [150] showing increased detection rate of PCa in
highly-suspicious MRI lesions using an end-fire- compared to a side-fire-approach.
However, despite a rather surprisingly high PCa detection rate at standard endfire TRUS-bx, we still
found a significant improvement in the detection rate (p=0.025) and GS upgrading (p=0.037) by
adding mp-MRI-bx as an adjunct to our standard TRUS-bx.
Visual translation of the mp-MRI image onto the greyscale TRUS-image cannot always be accurate.
In eight mp-MRI-suspicious lesions (Figure 2study I), we experienced that the targeted mp-MRI-bx
were negative for PCa compared to the standard cores obtained from the same prostatic region. This
could be caused by the intentional dispersion of the two biopsies, but it is more likely caused by
translation error. There will be a margin of error, when the operator has to visually correlate the mpMRI image onto a real-time 2D TRUS image and translate it all into a 3D representation of the
prostate, especially if the prostate is large or the lesion is located anteriorly [127]. Methods for
improving the accuracy of the targeted biopsies have recently been developed. Fusion software has
enabled a co-registration between the mp-MRI data and real-time TRUS imaging. Fusion of the two
modalities (MR-TRUS) allows a lesion that is marked on the mp-MRI to be transferred onto the
39
real-time TRUS images and identified during the TRUS-procedure. Mp-MRI-bx can then be
targeted towards the marked lesion [118,129,135,142,151–156] with potentially increased accuracy.
Using TRUS as guidance for mp-MRI-bx, either cognitive- or software-based, gives the operator
the advantage of adding mp-MRI-bx to the systematic standard biopsies, which is still the
recommended standard approach [2]. However, there will always be a possible misregistration,
when combining two image modalities. In-bore direct MRI-guided biopsies within the MRI suite is
possible due to the development of increased speed in MRI imaging, MRI compatible instruments
and advanced visualisation software with tools to guide and verify needle placement. Several
studies have been published using both 1.5 T [157,158] and 3.0 T [131,159–163] MRI with good
results and summarised in a recent review by Overduin et al. [164]. Using in-bore mp-MRI-bx,
Hambrock et al. [159] found a PCa detection rate of 59% among which 93% cancers were clinically
significant in a patients cohort with 2 previous negative TRUS-bx sessions using an average of 4
biopsy cores per patient. Similar results were later confirmed by the same group [131] and also
investigated in men without previous prostate biopsies [162].
Although, performing biopsies directly in the MRI suite seems to be the most accurate technique,
the biopsy procedure can be time-consuming, as well as the diagnostic MRI and the biopsy
procedure need to be performed in two different sessions. Some also report that the biopsy device
has limited reach, especially towards the base of the prostate [165].
The diagnostic performance of mp-MRI in PCa detection and localisation is depending on the
tumour size, GS, histological architecture and location [166]. Low-volume (<0.5 ml) and low-grade
(GS 6) tumours are less likely to be identified compared to higher grade (GS≥7) and larger tumours
[167–169], whereas detection of tumours ≥1 ml does not seem to be affected by the GS [167]. Thus,
mp-MRI is not as sensitive in detecting insignificant PCa. Therefore, if only identified mp-MRIsuspicious lesions are targeted by biopsies, the chance of detecting insignificant PCa foci is
reduced. Haffner et al.[138] compared this "targeted-only" strategy against extended systematic
TRUS-bx (12 cores) for detection of significant PCa in 555 patients undergoing initial biopsy and
used the same targeted-biopsy technique with visual/cognitive mp-MRI/TRUS-fusion as we did in
study I. By using this "targeted-only" biopsy approach, only 63% of the referred patients with
clinical suspicion of PCa required subsequent biopsies using a mean of 3.8 cores per patient
(compared to 12 standard cores). In addition, the diagnosis of 13% insignificant cancers were
avoided. These findings were recently confirmed by Pokorny et al. [162] in 223 consecutive biopsynaive men with elevated PSA showing that the mp-MRI "targeted-only" approach can reduce the
40
detection of low-risk PCa and reduce the number of men requiring biopsy while improving the
overall detection rate of intermediate/high-risk PCa.
The location of the PCa lesion affects the sensitivity and specificity of mp-MRI. Transitional-zone
tumours are more difficult to identify, as reported by Delongchamps et al. [170] where sensitivity
and specificity decreased from 80% and 97% in the peripheral zone, to 53% and 83% in the
transition zone. In addition, sparse tumours where PCa growth is intermixed with normal tissue can
also limit the diagnostic performance of mp-MRI in detection of PCa [69].
PCa aggressiveness and ADC measurements
The GS is the most widely used method of grading the histopathological aggressiveness of PCa and
it is the most important prognostic factor for treatment response. Several predictive and prognostic
tools for risk stratification and counselling have been introduced for optimal clinical management
and therapy selection [42,46,171–177]. However, they are all based on the GS from TRUS-bx,
which can be substantially discordant with the true GS verified after radical prostatectomy. This
lack of ability to confidently identify low-grade tumours at biopsy is one of the reasons for the
current issue with overtreatment. Hence, improving the pre-therapeutic assessment of GS may
increase the accuracy of the predictive and prognostic tools and improve the risk stratification when
planning individualised treatment strategies.
In study III, we demonstrated that preoperative DWI-calculated ADC measurements (ADCtumour
value and ADCratio) showed a significant correlation with tumour GS at final pathology. As reported
by others [58,81], we also found that decreasing mean ADCtumour values were associated with higher
GS groups. A retrospective study by Hambrock et al. [82] found a significant inverse correlation
between ADCtumour values and GS for tumours originating in the peripheral zone and Jung et al. [84]
showed that the same holds true for transitional zone tumours. When comparing previous studies, a
wide range in mean ADCtumour values has been reported [81–84,87] with a substantial overlap
corresponding to different GS groups. To overcome some this variability, we hypothesised that the
ADCratio might be more useful and predictive in determining true GS, as it may level out some of
the variation since the ADCratio is not only related to the ADCtumor value, but also to the individual
prostate’s unique signal characteristics. We found that increasing mean ADCratios (increased
difference between ADCtumour and ADCbenign) were associated with higher GS groups and
demonstrated a superior correlation to GS compared to the ADCtumour value. Previous studies have
had similar results calculating the prostate ADCratio for better correlation with GS. Vargas et al. [83]
found a significant inverse correlation with GS using both ADCtumour value and ADCratio and
41
Thörmer et al.[178] showed a high discriminatory power (AUC=0.90) of normalised ADC
(equivalent to ADCratio) between low- and intermediate/high-risk cancer. This was recently
confirmed by Lebovici et al. [179] concluding that the ADCratio may be more predictive of tumour
grade than analysis based on ADCtumour values alone. However, the study was relatively small (n=22
patients) and had prostate biopsies as reference standard. Conversely, Rosenkrantz et al.[180] did
not find any benefit of using normalised ADC compared to the ADCtumour value in terms of AUC
for differentiating benign from malignant tissue in the peripheral zone.
Mp-MRI using DWI-calculated ADCmaps may improve patient management by targeting biopsies
towards areas suspicious of harbouring the most aggressive part of the tumour and thereby
improving prediction of true GS to facilitate better risk stratification. Although not addressed as a
specific endpoint in study I, we found that 7/34 (21%) PCa patients had an overall GS upgrade due
to the use of additional mp-MRI-bx. The GS was upgraded from low- to intermediate/high-grade
cancer in 5/7 patients. Similarly, a prospective study by Siddiqui et al. [135] including 582 patients
showed an overall GS upgrade in 32% using additional mp-MRI-bx. The targeted biopsies detected
67% more GS ≥7(4 + 3) tumours than systematic TRUS-bx alone and missed 36% of GS ≤7(3 + 4)
tumours, thus increasing the detection ratio of high/low-grade cancer. However, definitive
pathology from RP was not available. Using DWI/ADC-guided biopsies, Hambrock et al. [57]
correctly identified true GS at final pathology in 88% compared to 55% using standard TRUS-bx.
The risk of DWI/ADC-guided biopsies mistakenly underscored an area with a Gleason grade 4- or 5
component, as a Gleason grade 3, was less than 5%. The ADCmap may also facilitate PCa detection
and localisation. Watanabe et al. [181] used the ADCmap and ADCtumour value to prospectively
stratify 1448 consecutive biopsy-naive patients into two groups (with or without low ADC lesions).
All patients underwent systematic biopsies and the low ADC-lesion group had additional targeted
biopsies of the low ADC lesions. The PCa detection rate was highest in the targeted biopsy group
and PPV of the mp-MRI findings was 70%-90% depending on anatomical lesion location.
A great benefit in improving the pre-therapeutic assessment of GS is the ability to separate low-risk
(GS 6) from intermediate/high-risk (GS≥7) cancer. We found an overall AUC of 0.75 for the
ADCtumour value in differentiating low-risk GS 6 tumours from intermediate-/high-risk GS ≥ 7(3+4)
tumours. This lies within the AUC levels (0.72-0.76) reported by others [81,182], although higher
AUC values have been reported [82]. The AUC increased to 0.81 for the ADCratio indicating
improved accuracy. This ability to discriminate low-risk from intermediate/high-risk tumours is
important in a clinical situation, as it is often decisive of the treatment selection. As more and more
PCa patients are detected in an earlier stage, there will be an increase in both significant and
insignificant tumours. A major challenge is to correctly assess the aggressiveness of the cancer to
42
determine appropriate treatment to prevent morbidity and mortality. Patients with localised prostate
cancer with low tumour burden may be candidates for active surveillance (AS) depending on the
clinical situation. AS includes close monitoring with PSA, DRE and repeated biopsies. This
regimen is to avoid over-treatment of cancers that are found to be insignificant at diagnosis and
therefore not likely will affect patient morbidity and mortality. It is crucial that these patients are
staged and risk-stratified correctly, so tumour characteristics are not underestimated, and patients
with more advanced disease mistakenly are put in AS instead of having active treatment. Mp-MRI
with ADC measurements can be used to asses PCa aggressiveness as an adjunct to other clinical
parameters such as PSA kinetics and tumour stage in the selection and follow-up of patients
undergoing AS regimens [85,183–186]. Furthermore, mp-MRI can be incorporated into nomograms
and improve the prediction of insignificant cancer [187]. Mp-MRI may reveal early signs of
clinically significant disease and poor prognostic features such as larger tumour volumes or highgrade tumours, especially in the anterior region [188], potentially missed by TRUS-bx [186].
Additional targeted biopsies towards the suspicious regions can be performed along with a possible
re-evaluation of the treatment plan. Conversely, a normal/low suspicious mp-MRI can confirm the
absence of significant PCa, due to its high negative predictive value, thus AS can be implemented.
AS is traditionally reserved for patients without Gleason grade 4- or 5 tumours. However, it has
been addressed that because of the increased reporting of Gleason grade 4 since the ISUP GS
modification in 2005 [27], a low percentage of Gleason grade 4 should not necessarily lead to
immediate exclusion of the AS regimen [189]. This, combined with the recent findings showing
low-volume Gleason grade 4 on needle biopsy is associated with low-risk tumour at radical
prostatectomy [190], makes the differentiation between GS 7(3+4) and GS 7(4+3) clinical
important. In study III, the overall AUC of the ADCtumour value did not change when discriminating
between GS ≤ 7(3+4) and GS ≥ 7(4+3). However, the AUC of the ADCratio changed radically to
0.90 indicating a high clinical value of this ADC parameter.
Although, we found a significant difference between the mean ADC measurements and the GS
groups in study III, there was still a considerable overlap between the groups. Due to this
heterogeneity, a definite cut-off value for separating the GS groups could not be made. DWI largely
reflect the average amount of "fluid" within the tissue as an indirect "glandular ratio". However, the
GS is also influenced by other factors such as cellularity, glandular/cell size and shape, the
appearance of the inter-glandular space and other intermixed histological components, which are
included in the overall pathological assessment of the GS. Moreover, the aggressiveness of PCa is
not only determined by its histological GS. Other factors such as PSA, tumour volume, location and
43
extension including possible EPE have to be taken into account in risk stratification of the patients.
Thus, clinical staging of PCa plays an essential part when planning patient-tailored management
Clinical staging of PCa
Radical prostatectomy (RP) provides great disease control for patients with localised PCa (cT1-T2),
while RP for locally advanced disease (cT3) remains controversial [16,191]. Preoperative accurate
knowledge of tumour stage and possible ECE is crucial in achieving the best surgical, oncological
and functional result. The pre-therapeutic local staging of PCa and prediction of ECE by DRE and
TRUS have low accuracy [37,38]. Accurate pre-therapeutic staging of PCa implies appropriate
estimation of tumour volume, location and possible EPE. The diagnostic accuracy of mp-MRI
staging differs among previous studies [110,114,116,140,141] partly due to different study
protocols, diagnostic criteria, MRI equipment and expertise. In study II, we found a significant
correlation between the tumour stage estimated by mp-MRI (cTMRI) and the pathological specimen
pT) for the most experienced reader with a Spearman rho=0.658 (p<0.001) and moderate to good
agreement using weighted kappa=0.585. Complete agreement between cTMRI and the pathological
stage is difficult to obtain, as mp-MRI does not identify all the small dispersed insignificant tumour
foci that frequently are present within the prostate and are incorporated into the overall evaluation
and reporting of the pathological stage. This can easily cause a discrepancy between a T2a/T2b
stage identified on mp-MRI and a T2c stage reported at pathology for organ-confined (OC)
tumours. However, the exact stage differentiation among OC tumours is of less importance, as
patients with OC disease often can receive potentially curative surgery regardless of the T2-stage.
In contrast, the treatment selection of PCa strongly relies on the identification of patients with ECE.
In study II, we demonstrated that multiparametric MRI with ECE risk scoring by a dedicated reader
is an accurate diagnostic technique in determining tumour stage and ECE at final pathology. The
prevalence of ECE at histopathology was 36% in patients with pre-therapeutic clinically localised
PCa confirming the fact that DRE and TRUS often underestimate the tumour extension and stage.
Mp-MRI using both ECE risk scoring and personal opinion for prediction of ECE at final pathology
showed a diagnostic accuracy of 79-83% with a sensitivity and specificity ranging between 74-81%
and 78-88% for the most experienced reader. These findings are in accordance with previous
studies. A meta-analysis from 2002, covering a time period of 17 years by Engelbrecht et al. [113]
that also included studies conducted in the early period of prostate MRI, reported a combined
sensitivity and specificity of 71% in distinguishing between T2- and T3-disease on 1.5 T MRI
systems. More recent studies at 3.0 T ERC MRI from experienced prostate-MRI experts report
44
higher rates with sensitivity and specificity of 80-88% and 95-100%, respectively [52,192].
Although, we did not directly measure tumour volume in study II, other studies have found a good
correlation between the estimated tumour volume on mp-MRI and the tumour volume from the
radical prostatectomy specimen, especially for tumours ≥0.5 ml [167,193–195]. Identifying the
"index" tumour in particularly has a prognostic significance [196,197]. Clinicians commonly use
PSA levels, clinical stage - determined by DRE and/or TRUS - and biopsy GS combined in
nomograms to predict pT stage at RP. We did not compare preoperative mp-MRI against predictive
nomograms in study II, as the objective was to evaluate the diagnostic accuracy, as a single
parameter in the assessment of tumour stage and prediction of ECE using the ECE risk score.
However, mp-MRI has been found to perform significantly better than nomograms, DRE and
TRUS in visualising the intra-prostatic tumour localisation and possible ECE including predicting
the final pT-stage [44,140,187,198–201].
In recent years, mp-MRI has emerged as the most sensitive and specific imaging tool for PCa
staging [48]. T2W imaging is the dominant MRI modality for staging and EPE evaluation due to its
high spatial resolution for anatomical assessment. However, the use of functional imaging, e.g.
DCE-MRI in conjunction with T2W imaging may improve staging performance [102], especially
for less experienced readers [111]. This is also confirmed in our study II, where inclusion of
personal opinion and functional imaging findings to T2W ECE tumour characteristics gave a slight
increase in the diagnostic accuracy for prediction of ECE for both readers. Accurate staging and
assessment of EPE using DWI is challenging due to lower spatial resolution and increased risk of
image artefacts compared to T2W imaging. However, higher diagnostic accuracy in the diagnosis of
SVI using DWI in conjunction with T2W imaging have been reported [202,203]. Similarly, recent
studies have reported higher diagnostic accuracy using DWI at 3.0 T MRI in conjunction with T2W
imaging regarding the diagnosis of ECE, compared to T2W imaging alone [120,121]. Thus, mpMRI with T2W, DWI and DCE imaging is recommended in the ESUR MR prostate guidelines for
staging [51].
Besides PCa lesion location and staging, mp-MRI can also provide additional information regarding
prostate size, presence of a median lobe or the occurrence of larger vessels surrounding the prostate
for patients undergoing RP. Improved staging performance may also reveal possible tumour
involvement of the neurovascular bundles (NVB) and aid in the selection of patients suitable for
NVB preservation or a wider local resection [204,205]. In addition to local staging, regional lymph
nodes and part of the pelvic bones can also be evaluated on the mp-MRI images depending on the
MRI field of view.
45
Mp-MRI scoring using PIRADS and ECE risk scoring
Different interpretative approaches for mp-MRI have been evaluated in the literature [206]. For
instance, Pinto et. al. [151] suggested that each MRI modality is characterised as either positive or
negative in a binary approach where the summation of positive sequences graded the suspicion of
PCa. Others have often used a variation of the five-point Likert scale to give an overall impression
of the level of suspicion [193]. Recently, the PIRADS classification [51] was developed to provide
a structured uniform algorithm for mp-MRI prostate interpretation and reporting. The PIRADS
score can either be reported as the summation of all individual scores (ranging 3-15) or converted
into an overall final score (ranging 1-5) similar to the Likert five-point scale. In study I, we used
both the PIRADS summation score and the overall Likert scoring system to analyse suspicious
lesions and found a highly significant correlation between positive biopsies and lesion suspicion on
mp-MRI (p<0.001). All but one low-suspicious PCa lesion and all missed secondary PCa lesions on
mp-MRI were GS 6(3+3). These findings underline the potential value of using pre-biopsy mp-MRI
to increase the detection rate of clinically significant PCa previously missed by standard TRUS-bx
and to stratify the patients and lesions according to suspicion on mp-MRI using both the PIRADS
summation score and the overall five-point Likert scale. The clinical value of the PIRADS
summation score is validated in a recent prospective study by Portalez et al. [142] in a
contemporary patient cohort in relation to repeated prostate biopsies. Using PIRADS summation
score≥9 as threshold, the authors report a sensitivity and specificity of 69% and 92%, respectively,
and more interestingly a negative predictive value (NPV) of 95%. This high NPV can predict the
absence of cancer with high confidence and thereby possibly reduce the number of unnecessary
repeated biopsies in patients with low PIRADS scores. In study I, we validated both the PIRADS
summation score and overall Likert score according to biopsy results. Rosenkrantz et al. [145]
recently confirmed the good diagnostic performance in PCa localisation in a retrospective analysis
using both scoring systems with RP specimen as reference standard, although the performance was
better with Likert scoring for transitional tumours. Other groups have also validated the PIRADS
classification for lesion detection and characterisation and found a good association between
suspicion on mp-MRI and PCa [108,118,207]. In the PIRADS summation score, all mp-MRI
modality scores are weighted equally. However, not all modalities are always equal in determining
the presence of clinically significant PCa. For instance, DWI has been reported to be the best
sequence for lesion detection in the peripheral zone [208] and conversely T2W imaging in the
transitional zone [147]. Thus, there may be a "dominating" modality depending on the location of
the lesion. Therefore, an overall final score ranging 1-5 (equivalent to the overall Likert score) that
includes the interpretation of all the individual scores, but driven by the dominant modality might
46
better represent the "true suspicion score". Furthermore, there is an on-going debate about the
necessity of including DCE imaging in the recommended minimum requirements in the ESUR MR
prostate guidelines for PCa detection, as it may not add significant value to T2W imaging and DWI
[108] to improve transitional zone cancer detection and localisation compared to T2W imaging
alone [147]. Furthermore, DCE imaging is not as reliable for detecting transitional zone tumours, as
there is a significant overlap with hyper-vascular BPH findings [88]. However, DCE imaging seems
to have the ability to aid in the differentiating between the normal central zone and PCa based on
the enhancement curves [209], as the appearance of the central zone on T2W imaging and DWI
have many features that may mimic PCa. Moreover, DCE imaging is still recommended for staging
purposes and it is essential for detection of local recurrence [51].
The ESUR MR prostate guidelines also recommend scoring of extraprostatic disease on a five-point
risk scoring scale. In study II, we validated this risk scoring focusing on ECE corresponding to
locally advanced T3a-disease. Although, the ESUR MR prostate guidelines also recommend
individual scoring of SVI (T3b) and bladder neck/distal sphincter involvement (T4-disease), we did
not include these parameters in our study, as we considered the a priori probability of any patient in
our population with clinically localised PCa having SVI, distal sphincter- or bladder neck
involvement to be too low to validate a five-point risk scoring scale.
The ECE risk scoring in study II showed an AUC of 0.65-0.86 on the ROC-curve indicating a high
clinical value for the experienced reader with a sensitivity, specificity and diagnostic accuracy of
81%, 78% and 79% at the optimal risk score cut-off level ≥4. When using a five-point scale, the
ECE score is considered a continuum of risk with higher scores corresponding to higher risk of
ECE. As the ECE risk scoring in the guidelines only evaluates tumour characteristics on T2W
imaging and assigning a preoperative cTMRI staging requires a definitive decision on possible ECE
and SVI, the suspicion of ECE was dichotomised into either organ-confined disease or ECE based
on the established ECE-tumour characteristics and personal opinion incorporating functional
imaging (DWI and DCE imaging) findings. By doing this, the diagnostic accuracy increased for
both readers (71%-83%) and changed sensitivity and specificity to 74% and 88% for the most
experienced reader and 61% and 77% for the less experienced reader in predicting ECE at final
pathology.
The sensitivity and specificity of the mp-MRI reading can be affected by the way the physician
weigh the image findings, especially when deciding on possible ECE in the equivocal cases. Until
recently, RP was restricted to patients with localised PCa while patients with high suspicion of ECE
and/or SVI were referred for radiation therapy. This might influence the physician to value high
specificity with a low number of false-positive readings, so no patients with equivocal mp-MRI
47
findings would be ruled out of possible curative surgery. However, there has been an increasing
interest in performing RP in selected patients with locally advanced T3 disease with good results
[210–213]. This may increase the interest in high-sensitive mp-MRI readings in order to direct the
surgeon to the site of possible ECE to avoid positive surgical margins. Therefore, the mp-MRI ECE
risk score threshold for ECE might be altered depending on the clinical situation. Furthermore,
previous studies show that mp-MRI findings can be combined with clinical findings and
nomograms and increase the overall pre-therapeutic diagnostic staging accuracy [44,187].
The reader performance of two readers with different experience in mp-MRI prostate interpretation
were evaluated in study II. Overall, the most experienced reader A had a significantly higher
performance than reader B in the assessment of ECE using both ECE risk scoring and personal
opinion and was more accurate in predicting the pathological stage. Furthermore, our results
indicate that the overall interpretation of possible ECE in our hands should not only rely on the
ESUR MR prostate guidelines' ECE risk scoring in its current form, but whenever possible also
incorporate functional imaging, especially for less experienced readers. It is evident, that mp-MRI
interpretation has a considerable learning curve and is a specialised task that requires substantial
dedication and experience to allow for acceptable diagnostic results [110,214]. It has been proven
that the diagnostic accuracy in detection of PCa increase significantly [215] through a dedicated
prostate mp-MRI-reader education program and the difference in diagnostic accuracy between the
readers in our study II indicates that the same also applies to our mp-MRI staging performance.
Limitations
Not all patients are suitable for mp-MRI due to absolute/relative contraindications such as a nonMRI compatible pacemakers, magnetic implants, severe claustrophobia as well as previous
moderate or severe reactions to gadolinium-based contrast media for DCE-MRI imaging. Also very
large patients may not fit inside the MRI tube. In our studies, we used a PPA coil positioned over
the pelvis and lower abdomen. In some patients with significant abdominal obesity, we experienced
movement artefacts caused by the synchronised respiratory movement of the PPA-coil. The use of
an additional ERC could possibly be advantageous in these cases. High-quality images can only be
obtained if the patient is able to lie perfectly still while the images are being recorded. Peristaltic
rectal motion and intra-luminal rectal air may cause movement artefacts, but can be reduced by the
administration of an oedema prior to the examination and/or an injection of an intestinal
spasmolyticum. The presence of a hip replacement or other metallic objects near the prostate can
also cause severe artefacts, especially on DWI.
48
Each MRI modality - T2W, DWI and DCE imaging - has its own clinical value and limitations and
should be viewed as complimentary to each other to balance sensitivity and specificity for optimal
interpretation. Hypo-intense signals on T2W imaging in the peripheral zone can be caused by
various benign conditions such as prostatitis, atrophy or supporting tissue and even the appearance
of the central zone at the base of the prostate. The addition of DCE imaging and DWI to T2W
imaging adds sensitivity and specificity to PCa detection and lesion characterisation. BPH nodules
in the transitional zone can have almost identical appearances as PCa lesions with hypo-intensity,
restricted diffusion and early enhancement. Asymmetry, unusual topography and homogenous low
signal on T2W imaging are signs of PCa. However, sparse tumours with fine low-density trabeculae
infiltrating benign prostatic tissue can hardly be distinguished from healthy tissue regardless of the
use of additional functional imaging. In tumour staging, the ability to detect minimal ECE is often
limited. Staging accuracy and determination of ECE require high spatial resolution [51,52,216],
which is why the use of an ERC is recommended by the ESUR MR prostate guidelines [51] as part
of the optimal requirements. However, with a tendency towards more aggressive surgical treatment
of locally advanced T3-disease, the exact differentiation between organ-confound PCa and minimal
ECE probably becomes less important, unless it is a matter of neuro-vascular bundle preservation.
Another major limitation with mp-MRI is the presence of post-biopsy haemorrhage, that can
compromise the examination performance [62] and may persist for up to 6-8 weeks or even longer
[61,217]. The exact timeframe of how long the post-biopsy changes persist is not accurately known
and is probably highly individual from one patient to another. A general consensus on the time
interval between biopsy and mp-MRI has therefore not been reached. Moreover, one retrospective
study suggests not to wait as the haemorrhagic changes do not influence on staging performance
[218]. Nevertheless, the ESUR MR prostate guidelines recommend that the time interval generally
should be at least 3-6 weeks and preliminary T1W imaging should be done to exclude biopsyrelated haemorrhage [51]. If significant haemorrhage is present and interferes with examination
performance, the patient can then be re-scheduled. However, even though it probably does not alter
the final outcome, it is often not feasible in a clinical situation to wait several weeks to months for a
staging mp-MRI in a high-risk PCa patient before deciding on the definitive treatment plan.
49
Conclusion
Mp-MRI prior to repeated biopsies can improve the detection rate of clinically significant PCa and
allows for a more accurate GS by combining standard TRUS-bx with mp-MRI-targeted biopsies
under visual TRUS-guidance. Mp-MRI can provide valuable information about the
histopathological aggressiveness of a PCa lesion and the tumour stage with possible ECE can be
assessed in the pre-therapeutic setting providing important additional information for optimal
patient-tailored treatment planning.
50
Future perspectives
The role of mp-MRI in our department is rapidly evolving. Clearly, standard TRUS-bx will
continue to miss tumours outside the standard biopsy regions and the issue of possible GS undergrading will still be evident. Our gained experience in mp-MRI diagnostics by performing this
thesis and studies has now changed our diagnostic approach for patients referred for repeated
biopsies. Mp-MRI findings are increasingly relied upon and a diagnostic mp-MRI is performed in
all patients with prior negative TRUS-bx and continuous suspicion of PCa. Then additional mpMRI-bx' of suspicious lesions are performed either in a "targeted-only" approach or added to our
standard 10-core TRUS-bx protocol depending on the clinical situation. In study I, we experienced
that some PCa lesions were seen on mp-MRI and scored as moderat/high-suspicious regions, but
the lesions were missed on the targeted mp-MRI-bx and hit on standard TRUS-bx. We suspect it
could be caused by misregistration with visual/cognitive fusion and we are now running a
prospective study using software-based mp-MRI/TRUS-fusion biopsies to see if it can increase the
accuracy of the mp-MRI-bx, as reported by others comparing the two techniques [129,219,220].
The future impact of PCa patients is predicted to increase rapidly within the next decade. As the
post-war "baby boomer" generation continues to age, the incidence of PCa is expected to more than
double within the next decades. The positive results of mp-MRI in PCa management have raised the
question, whether mp-MRI can be used as a screening test before initial biopsy to increase the
detection of aggressive significant PCa while reducing overdetection and possible overtreatment of
insignificant PCa foci [128,221]. Several studies of men with no previous biopsies comparing a mpMRI "targeted-only" approach to a standard TRUS-bx regimen have recently been published
[129,138,181,219,222]. A summarised conclusion of these studies shows a promising tendency to
decrease the overall detection rate of PCa, but with a increased detection of high-grade cancers
using fewer biopsy cores and a decreased detection rate of insignificant tumours. However, mpMRI is not always cancer-specific and prostate biopsies are still necessary to confirm the presence
of PCa in an abnormal lesion. Nevertheless, the continuous development of the mp-MRI techniques
and experience in our department facilitate the future use of mp-MRI as an integrated part in
deciding whether or not to perform prostate biopsies at all and where it should be targeted to
confirm the diagnosis and hit the most aggressive part of the tumour. It could be the beginning
towards the end of blind prostate biopsies [223]. However, mp-MRI-bx may still miss cancer foci
and unnecessary targeted biopsies may be conducted due to false-positive mp-MRI readings. The
cost-effectiveness of the diagnostic mp-MRI and the additional use of mp-MRI-bx in our
51
department have not yet been calculated. Nonetheless, an image-based mp-MRI-strategy seems to
improve patient quality of life by reducing overdiagnosis and overtreatment at comparable costs as
the currents standard TRUS-bx approach [224].
A major clinical issue in PCa management is accurate risk stratification of newly diagnosed PCa
patients and correctly determining if the patient harbours an aggressive cancer that needs active
treatment or an insignificant cancer that may be managed by AS. The use of mp-MRI for staging
purposes is anticipated to become a more integrated part in the clinical decision-making process at
our institution. As mp-MRI has shown promising results in detecting significant PCa missed by
TRUS-bx in men diagnosed with low-risk PCa eligible for AS [225–229], patients considered
eligible for AS in our institution will increasingly undergo mp-MRI to either confirm the absence
of significant PCa or to identify additional suspicious lesions for targeted biopsies. In addition, mpMRI can be repeated and compared over time as a possible non-invasive alternative to repeated
biopsies if necessary. Conversely, newly diagnosed PCa patients with high-risk disease who are
considered suitable for RP now undergo a staging mp-MRI at our institution to confirm eligibility
for surgery and to provide valuable additional information for optimal surgical planning. Mp-MRI
findings can then be combined with clinical findings and nomograms to increase the overall pretherapeutic diagnostic staging accuracy. However, even though study II showed that mp-MRI with
ECE risk scoring evaluated by a dedicated reader is an accurate diagnostic technique in determining
tumour stage and ECE at final pathology, further studies are needed to investigate whether
functional imaging should be included in the ECE risk scoring scale and if so, how to weigh the
individual findings in order to further increase the diagnostic accuracy of the scoring system.
Study III showed that both ADC measurements correlated significantly with the tumour GS at final
pathology, but the ADCratio demonstrated the best correlation especially in discriminating GS ≤
7(3+4) from GS ≥ 7(4+3) tumours. The next step would be to analyse the ADCratio performance in a
true prospective setting by calculating the ADCbenign value prior to surgery without the
histopathological map as guidance and with the risk of incorporating small invisible tumour foci.
This would be more in line with the workflow in clinical practice. In addition, the inclusion of a
second reader to evaluate the inter-observer variation would further explore the diagnostic
performance of the ADC measurements.
Lack of experience and standardisation combined with technically unsuitable equipment and lack of
functional imaging are reasons why there previously has been a large variation in the prostate MRI
readings among different centres. It is evident that mp-MRI interpretation is a specialised task that
requires substantial dedication and experience preferably assembled in a centre of excellence. Then,
52
in addition to PCa detection, other specific questions such as exact tumour location, staging, signs
of high biological aggressiveness and possible preservation of NVB at surgery can be addressed in
close collaboration between urologists, radiologists, oncologists and pathologists in a
multidisciplinary team (MDT) environment to support the clinician’s needs. The MDT approach is
important, as there are several differential diagnostic conditions in the prostate that may influence
the readings as well as the interpretation of the images may be altered depending on the clinical
situation to either value high-sensitive or high-specific readings. Furthermore, the interpretation of
mp-MRI has a considerable learning curve and education with high-volume readings, conduction of
clinical trials comparing results in a close collaboration between radiologists, urologists and
pathologists providing feedback to the diagnostic readings based on the clinical and pathological
results. A dedicated prostate mp-MRI education program to support mp-MRI readers and
technologists interpretatively and technically with certification through reference centres is needed
to apply mp-MRI in clinical practice and allow for acceptable diagnostic results.
The constant improvement of mp-MRI and the on-going development of structured MR prostate
guidelines will continuously improve the management of PCa patients at our institution. The
prostate mp-MRI technique has now been established at our institution, as a first step with the
implementation of this PhD project. However, mp-MRI in Denmark is still a new area of research
and a new available imaging modality in the clinical practice. The objectives for the future are now
to define its specific role in the management of PCa through the continuous development of highquality acquisitions and readings with clinician-tailored structured reporting in good, fast and
simple diagnostic mp-MRI protocols developed for each clinical indication (tumour detection,
staging or node and bone) as recommended by the ESUR MR prostate guidelines.
53
Summary (English)
Background:
Prostate cancer (PCa) is the second leading cause of cancer-related mortality and the most
frequently diagnosed male malignant disease among men in the Nordic countries. The manifestation
of PCa ranges from indolent to highly aggressive disease and due to this high variation in PCa
progression, the diagnosis and subsequent treatment planning can be challenging. The current
diagnostic approach with PSA testing and digital rectal examination followed by transrectal
ultrasound biopsies (TRUS-bx) lack in both sensitivity and specificity in PCa detection and offers
limited information about the aggressiveness and stage of the cancer. Scientific work supports the
rapidly growing use of multiparametric magnetic resonance imaging (mp-MRI) as the most
sensitive and specific imaging tool for detection, lesion characterisation and staging of PCa.
However, the experience with mp-MRI in PCa management in Denmark has been very limited.
Therefore, we carried out this PhD project based on 3 original studies to evaluate the use of mpMRI in detection, assessment of biological aggression and staging of PCa in a Danish setup with
limited experience in mp-MRI prostate diagnostics. The aim was to assess whether mp-MRI could
1) improve the overall detection rate of clinically significant PCa previously missed by transrectal
ultrasound biopsies, 2) identify patients with extracapsular tumour extension and 3) categorize the
histopathological aggressiveness based on diffusion-weighted imaging.
Material and methods
Study I included patients with a history of negative TRUS-bx and persistent suspicion of PCa
scheduled for repeated biopsies. Mp-MRI was performed prior to the biopsies and analysed for
suspicious lesions. All lesions were scored according to the PIRADS classification from the
European Society of Urogenital Radiology's (ESUR) MR prostate guidelines. The lesions were
given a sum of scores (ranging 3-15) and classified overall on a Likert five-point scale according to
the probability of clinically significant malignancy being present. All patients underwent systematic
TRUS-bx (10 cores) and visual mp-MRI-targeted biopsies (mp-MRI-bx) under TRUS-guidance of
any mp-MRI-suspicious lesion not hit on systematic TRUS-bx.
Study II included patients with clinically localised PCa (cT1-T2) determined by digital rectal
examination and/or TRUS and scheduled for radical prostatectomy (RP). Mp-MRI was performed
prior to RP and all lesions were evaluated according to the PIRADS classification and the
extracapsular extension (ECE) risk scoring from the ESUR MR prostate guidelines. The images
54
were evaluated by two readers with different experience in mp-MRI interpretation. An mp-MRI Tstage (cTMRI) and an ECE risk score were assigned. Additionally, suspicion of ECE was
dichotomised into either organ-confined disease or ECE based on tumour characteristics and
personal opinion incorporating functional imaging findings. The RP histopathological results served
as standard reference.
Study III included patients from study II, where mean ADCtumour values from all malignant tumour
foci ≥5 mm identified on histopathology were measured on the corresponding diffusion-weighted
imaging ADCmap. An ADCbenign value was obtained from a non-cancerous area using the
histopathological map as a reference to calculate the ADCratio (ADCtumor divided by ADCbenign). The
ADC measurements (ADCtumour and ADCratio values) were correlated with the Gleason score (GS)
from each tumour foci.
Results:
Eighty-three patients were included in study I. PCa was found in 39/83 (47%) and both the PIRADS
summation score and the overall Likert classification showed a high correlation with biopsy results
(p<0.0001). Five patients (13%) had PCa detected only on mp-MRI-bx outside the systematic
biopsy areas (p=0.025) and another 7 patients (21%) had an overall GS upgrade of at least one
grade (p=0.037) based on the mp-MRI-bx. Clinical significant PCa was found in 37/39 patients
according to the Epstein criteria (2004).
Eighty-seven patients were included in study II and underwent mp-MRI before RP. The correlation
between cTMRI and pT showed a spearman rho correlation of 0.658 (p<0.001) and 0.306 (p=0.004)
with a weighted kappa of 0.585 [CI 0.44;0.73] and 0.22 [CI 0.09;0.35] for reader A and reader B,
respectively. The prevalence of ECE after RP was 31/87 (36%). ECE risk scoring showed an AUC
of 0.65-0.86 on the ROC-curve for both readers and a sensitivity, specificity and diagnostic
accuracy of 81% [CI 63;93],78% [CI 66;88] and 79% at the best cut-off level (risk score≥4) for the
most experienced reader. When tumour characteristics were influenced by personal opinion and
functional imaging, the sensitivity, specificity and diagnostic accuracy for prediction of ECE
changed to 74% [CI 55;88], 88% [CI 76;95] and 83% for reader A and 61% [CI 0.42;0.78], 77%
[CI 0.64;0.87] and 71% for reader B, respectively.
Seventy-one patients were included in study III. The association between ADC measurements and
GS showed a significantly negative correlation (p<0.001) with spearman rho for ADCtumour (-0.421)
and ADCratio (-0.649), respectively. There was a statistical significant difference between both ADC
measurements and the GS groups for all tumours (p<0.001). ROC-curve analysis showed an overall
AUC of 0.73 (ADCtumour) to 0.80 (ADCratio) in discriminating GS 6 from GS ≥ 7(3+4) tumours. The
55
AUC remained virtually unchanged at 0.72 (ADCtumour), but increased to 0.90 (ADCratio) when
discriminating GS ≤ 7(3+4) from GS ≥ 7(4+3).
Conclusion:
Mp-MRI prior to repeated biopsies can improve the detection rate of clinically significant prostate
cancer and allow for a more accurate GS by combining standard TRUS-bx with mp-MRI-targeted
biopsies under visual TRUS-guidance. Mp-MRI can provide valuable information about the
histopathological aggressiveness of a PCa lesion and the tumour stage with possible ECE can be
assessed in the pre-therapeutic setting providing important additional information for optimal
patient-tailored treatment planning.
56
Summary (Danish)
Baggrund:
Prostatacancer (PCa) er den hyppigst diagnosticerede mandlige maligne sygdom i de nordiske lande
og den næst hyppigste kræftrelaterede dødsårsag. PCa er en speciel sygdom, der spænder lige fra
fredelige tilfælde, der ikke kræver behandling over til aggressive former, der forårsager død og tab
af leveår. På grund af denne store variation i sygdommens manifestation, kan diagnose og den
efterfølgende behandlingsplanlægning være udfordrende for klinikeren. Den nuværende
diagnostiske strategi med PSA-test og digital rektal-undersøgelse, efterfulgt af transrektale
ultralydsvejledte biopsier (TRUS-bx), mangler både sensitivitet og specificitet i at detektere PCa og
giver kun begrænset information om cancerens aggressivitet og stadie. Udenlandske studier
understøtter det hastigt voksende brug af multiparametrisk magnetisk resonans (mp-MRI), som
værende det mest sensitive og specifikke billeddiagnostiske værktøj til PCa diagnostik.
Erfaringerne med brug af mp-MRI har i Danmark været meget begrænsede. Derfor har vi udført
dette ph.d. projekt, der er baseret på 3 oprindelige studier, der evaluerer brugen af mp-MRI til
detektion, vurdering af biologisk aggressivitet og lokal stadieinddeling af PCa i et dansk setup med
begrænset forhåndserfaring i mp-MRI prostatadiagnostik. Hovedformålet var at vurdere om mpMRI kunne 1) forbedre detektionen af klinisk signifikant PCa, der tidligere er overset ved TRUS-bx
og 2) identificeret patienter med ekstrakapsulær tumor udvækst og 3) kategorisere den histologiske
aggressivitetsgrad baseret på diffusions-vægtet MR.
Materiale og metoder
Studie I inkluderede patienter med tidligere negative TRUS-bx og vedvarende mistanke om PCa,
hvor der var planlagt fornyede biopsier. Mp-MRI blev udført forud for biopsier og analyseret for
mistænkelige læsioner, der alle blev scoret i henhold til PIRADS klassifikationen fra det
Europæiske Uroradiologiske Selskabs (ESUR) MR prostata retningslinjer. Alle læsioner fik både en
summationsscore (3-15) og en overordnet Likert 5-point score vurderet ud fra sandsynligheden, af
at en klinisk signifikant cancer kunne være til stede. Alle patienter undergik standard TRUS-bx (10
biopsier) samt visuelt mp-MRI målrettede biopsier (mp-MRI-bx) under TRUS-vejledning af alle
mp-MRI mistænkelige læsioner, der ikke blev ramt ved standard TRUS-bx.
Studie II inkluderede patienter med klinisk lokaliseret PCa (cT1-T2) bestemt ud fra rektal
eksploration og/eller TRUS, der alle var planlagt til radikal prostatektomi (RP). Mp-MRI blev
udført forud for RP, og alle læsioner blev bedømt i henhold til PIRADS klassificering og med en
risikoscoring for forekomsten af ekstrakapsulær udvækst (ECE) udgivet fra ESURs retningslinjer.
57
Alle billederne blev analyseret af to læsere med forskellig erfaring indenfor mp-MRI prostata
fortolkning. Et klinisk mp-MRI tumorstadie (cTMRI) og en ECE risikoscore blev tildelt.
Efterfølgende blev mistanke om ECE opdelt i enten organbegrænset sygdom eller ECE baseret på
tumorens egenskaber samt observatørens personlige mening, hvor funktionelle MRI
undersøgelsesresultater blev inddraget. Det histopatologiske undersøgelsesresultat fra RP udgjorde
standardreferencen.
Studie III inkluderede patienter fra studie II, hvor ADCtumour værdier fra diffusions-vægtet MR fra
alle histopatologisk identificerede maligne tumor foci ≥5 mm blev målt på ADCmap'et. Guidet ud fra
det histopatologiske undersøgelsesresultat blev en ADCbenign værdi målt fra et ikke-cancer
involveret område og brugt som reference for beregningen af ADCratio (ADCtumor divideret med
ADCbenign). ADC målingerne (ADCtumour og ADCratio) blev korreleret med Gleason scoren (GS) fra
hvert tumor foci.
Resultater:
Treogfirs patienter blev inkluderet i studie I, hvor PCa blev fundet i 39/83 (47 %). Både PIRADS
summationsscoren og den overordnede Likert score viste en høj korrelation med biopsiresultater (p
<0,0001). Fem patienter (13 %) fik PCa detekteret udelukkende ud fra mp-MRI-bx uden for
standardbiopsiområderne (p = 0,025) og yderligere 7 patienter (21 %) fik en samlet Gleason score
opgradering (p = 0,037) grundet supplerende mp-MRI-bx. Klinisk signifikant PCa blev fundet i
37/39 patienter i henhold til Epsteins kriterier (2004).
Syvogfirs patienter blev inkluderet i studie II og gennemgik mp-MRI før RP. Sammenhængen
mellem cTMRI og pT viste en Spearman rho korrelation på 0,658 (p <0.001) og 0,306 (p=0,004) med
en vægtet kappa på 0,585 [CI 0,44;0,73] og 0,22 [CI 0,09;0,35] for hhv. læser A og B. Forekomsten
af ECE efter RP var 31/87 (35 %). ECE risikoscoring viste en AUC på 0,65-0,86 på ROC-kurven
for begge læsere og en sensitivitet, specificitet og diagnostisk nøjagtighed på 81 % [CI 63;93], 78 %
[CI 66;88], og 79 % ved den optimale cut-off grænse (risikoscore≥4) for den mest erfarne læser.
Sensitiviteten, specificitet og den diagnostisk nøjagtighed i forudsigelse ECE ændrede sig til hhv.
74% [CI 55;88], 88% [CI 76;95] og 83% for læser A, og 61 % [CI 0,42;0,78], 77% [CI 0,64; 0,87]
og 71% for læser B, ved inddragelse af de funktionelle MRI undersøgelsesresultater i en personlig
vurdering.
Enoghalvfjerds patienter blev inkluderet i studie III. Sammenhængen mellem ADC målinger og GS
viste en signifikant negativ korrelation (p <0,001) med Spearman rho for hhv. ADCtumour (-0,421)
og ADCratio (-0,649). Der var en statistisk signifikant forskel mellem de to ADC målinger og GS
grupper (p = 0,001). ROC-kurve analyse viste en AUC på 0,73 (ADCtumour) til 0,80 (ADCratio) i at
58
differentiere GS 6 fra GS ≥ 7(3 + 4) tumorer. AUC forblev uændret på 0,72 for ADCtumour, men steg
til 0,90 for ADCratio, i differentieringen af GS ≤ 7(3 +4) fra GS ≥ 7(4 + 3).
Konklusion:
Mp-MRI forud for fornyede prostatabiopsier kan forbedre detektionen af klinisk betydningsfuld
prostatacancer og give en mere nøjagtig Gleason score ved at kombinere standard TRUS-bx med
mp-MRI målrettede biopsier under visuel TRUS-vejledning. Mp-MRI kan give værdifuld
vejledning om cancerens biologiske aggressivitet og bidrage til den diagnostiske vurdering af
tumorens stadie og eventuel ekstrakapsulær udvækst, så planlægningen af relevant individuel
behandling kan forbedres.
59
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Appendix
Original articles
Study I:
Early experience with multiparametric magnetic resonance imaging-targeted biopsies under
visual transrectal ultrasound guidance in patients suspicious for prostate cancer undergoing
repeated biopsy.
Boesen L, Noergaard N, Chabanova E, Logager V, Balslev I, Mikines K, Thomsen HS.
Scand J Urol 2014, [Epub ahead of print], doi:10.3109/21681805.2014.9
Study II:
Prostate cancer staging with extracapsular extension risk scoring using multiparametric
MRI: a correlation with histopathology
Boesen L, Chabanova E, Logager V, Balslev I, Mikines K, Thomsen HS.
Submitted
Study III:
Apparent diffusion coefficient ratio correlates significantly with Gleason score at final
pathology
Boesen L, Chabanova E, Logager V, Balslev I, Thomsen HS.
Submitted
79
Scandinavian Journal of Urology. 2014; Early Online, 1–10
ORIGINAL ARTICLE
Scandinavian Journal of Urology Downloaded from informahealthcare.com by Danmarks Natur-og on 08/14/14
For personal use only.
Early experience with multiparametric magnetic resonance
imaging-targeted biopsies under visual transrectal ultrasound guidance
in patients suspicious for prostate cancer undergoing repeated biopsy
LARS BOESEN1, NIS NOERGAARD1, ELIZAVETA CHABANOVA2, VIBEKE LOGAGER2,
INGEGERD BALSLEV3, KARI MIKINES1 & HENRIK S. THOMSEN2
1
Departments of Urology, 2Radiology, and 3Pathology, Herlev University Hospital, Herlev, Denmark
Abstract
Objectives. The purpose of this study was to investigate the detection rate of prostate cancer (PCa) by multiparametric
magnetic resonance imaging-targeted biopsies (mp-MRI-bx) in patients with prior negative transrectal ultrasound biopsy
(TRUS-bx) sessions without previous experience of this. Material and methods. Eighty-three patients with prior negative
TRUS-bx scheduled for repeated biopsies due to persistent suspicion of PCa were prospectively enrolled. mp-MRI was
performed before biopsy and all lesions were scored according to the Prostate Imaging Reporting and Data System (PI-RADS)
and Likert classification. All underwent repeated TRUS-bx (10 cores) and mp-MRI-bx under visual TRUS guidance of any
mp-MRI-suspicious lesion not targeted by systematic TRUS-bx. Results.PCa was found in 39 out of 83 patients (47%) and mpMRI identified at least one lesion with some degree of suspicion in all 39 patients. Both PI-RADS and Likert scoring showed a
high correlation between suspicion of malignancy and biopsy results (p < 0.0001). Five patients (13%) had cancer detected only
on mp-MRI-bx outside the TRUS-bx areas (p = 0.025) and another seven patients (21%) had an overall Gleason score upgrade
of at least one grade based on the mp-MRI-bx. Secondary PCa lesions not visible on mp-MRI were detected by TRUS-bx in six
out of 39 PCa patients. The secondary foci were all Gleason 6 (3 + 3) in 5–10% of the biopsy core. According to the Epstein
criteria, 37 out of 39 cancer patients were classified as clinically significant. Conclusion. Using mp-MRI, even without previous
experience, can improve the detection rate of significant PCa at repeated biopsy and allows more accurate Gleason grading.
Key Words: multiparametric MRI, prostate biopsy, prostate cancer, targeted biopsy, transrectal ultrasound, visual fusion
Introduction
Patients with persistent suspicion of prostate cancer
(PCa) after transrectal ultrasound-guided biopsies
(TRUS-bx) with negative findings pose a significant
clinical problem owing to high false-negative rates of
20–30% [1–3]. To overcome this, patients with negative TRUS-bx often undergo several repeated biopsy
(rebiopsy) procedures that will increase biopsyrelated costs and may contribute to increased anxiety
and morbidity among patients. The detection rate at
first TRUS rebiopsy is 10–22% [2,4], with decreasing
rates at repeated procedures. Still, a significant
number of cancers is missed [3]. These limitations
have led to an intense need for a way to improve the
detection rate of clinically significant PCa at TRUSbx. Multiparametric magnetic resonance imaging
(mp-MRI) of the prostate seems to have the potential
to solve the problem [5–7]. Therefore, a prospective
study was carried out on a patient cohort scheduled
for TRUS rebiopsy due to persistent suspicion of PCa
after standard TRUS-bx with negative findings. The
aim was to investigate the value of prebiopsy mp-MRI
on the PCa detection rate at rebiopsy by combining
standard TRUS-bx with mp-MRI-targeted biopsies
(mp-MRI-bx) under visual TRUS guidance and
to evaluate the clinical significance of the detected
PCa.
Correspondence: L. Boesen, Department of Urology, Herlev University Hospital, Herlev Ringvej 75, Herlev, DK 2730, Denmark. Tel: +45 26171034.
E-mail: [email protected]
(Received 20 January 2014; revised 10 March 2014; accepted 13 May 2014)
ISSN 2168-1805 print/ISSN 2168-1813 online 2014 Informa Healthcare
DOI: 10.3109/21681805.2014.925497
2
L. Boesen et al.
Material and methods
This prospective, single-institution study was
approved by the Local Committee for Health
Research Ethics (no. H-1-2011-066) and the Danish
Data Protection Agency. It was registered at
Clinicaltrials.gov (no. NCT01640262).
Scandinavian Journal of Urology Downloaded from informahealthcare.com by Danmarks Natur-og on 08/14/14
For personal use only.
Patients
All patients were prospectively enrolled from
September 2011 to September 2012 after written
informed consent was obtained. Inclusion criteria
required that all patients had a history of negative
TRUS-bx and were scheduled for repeated biopsies
due to persistent suspicion of PCa based on either
prostate-specific antigen (PSA) value, an abnormal
digital rectal examination (DRE) or a previous abnormal TRUS image. All prior TRUS-bx sessions
included 10–12 standard biopsy cores. None of the
patients had previously undergone mp-MRI of the
prostate. The exclusion criteria were patients previously diagnosed with PCa or contraindication to
mp-MRI (pacemaker, magnetic implants, severe
claustrophobia, gadolinium-based MRI contrast
allergy, impaired renal function with glomerular
filtration rate <30 ml/min).
Multiparametric magnetic resonance imaging
All patients underwent mp-MRI before rebiopsy
using a 3.0 T MRI scanner (Achieva; Philips Healthcare, Best, Netherlands) with a six-channel cardiac
pelvic-phased-array coil (Sense; Philips Healthcare,
Best, Netherlands) positioned over the pelvis.
A minimum interval of 3 weeks was left between
the latest TRUS-bx and mp-MRI to reduce biopsyrelated haemorrhagic artefacts. If tolerated by the
patient, a 1 mg intramuscular injection of glucagon
(Glucagen; Novo Nordisk, Bagsvaerd, Denmark)
combined with a 1 mg intravenous injection of hyoscinbutylbromid (Buscopan; Boehringer Ingelheim,
Ingelheim am Rhein, Germany) was administered to
reduce peristaltic motion. Triplanar T2-weighted
images from below the prostatic apex to above the
seminal vesicles and a coronal T1-weighted image
including the small pelvis for detection of haemorrhage and enlarged local lymph nodes were obtained.
In addition, axial diffusion-weighted images including
four b values (b0, b100, b800 and b1400) along with
reconstruction of the corresponding apparent
diffusion coefficient (ADC) map (b values 100 and
800), together with dynamic contrast-enhanced
images before, during and after intravenous administration of 15 ml gadoterate meglumine (Dotarem
279.3 mg/ml; Guerbet, Roissy CDG, France) were
performed. The contrast agent was administered
using a power injector (MedRad, Warrendale, PA,
USA) followed by a 20 ml saline flush injection at a
flow rate of 2.5 ml/s.
Image analysis
On mp-MRI the prostate was divided into 18 regions
of interest according to a modified diagram provided
by the European Consensus Meeting [8] (Figure 1).
Precontrast and coronal T1-weighted images were
used to identify postbiopsy haemorrhage as an area
with high signal intensity to rule out false-positive
findings on T2 weighting. All mp-MRI images
from each patient were reviewed simultaneously by
the same dedicated physician and any suspicious
lesions identified on T2-weighted, diffusion-weighted
(high b-value image and ADC map) or dynamic
contrast-enhanced images were registered on the
modified diagram and scored according to the Prostate Imaging Reporting and Data System (PI-RADS)
classification from the European Society of Urogenital
Radiology (ESUR), giving a sum of scores (ranging
from 3 to 15) [9]. In addition, each lesion was then
classified overall on a five-point Likert scale according
to the probability of clinically significant malignancy
being present (1 = highly unlikely; 2 = unlikely; 3 =
equivocal; 4 = likely; 5 = highly likely). The PI-RADS
and Likert scores were separately divided into three
risk groups (high, moderate and low) according to
suspicion of PCa.
Biopsy: transrectal ultrasound biopsy and
multiparametric magnetic resonance imaging-targeted
biopsy
Initially, all patients underwent standard TRUS
rebiopsy with local gel anaesthetics (Installagel;
Farco-Pharma, Cologne, Germany) using a Hitachi
Preirus ultrasound scanner, a Hitachi EUP-V53W
endfire transducer and a Hitachi EZU-PA5V needle
guide (Hitachi Medical Systems, Europe Holding,
Zug, Switzerland), and a ProMag TruCut, 18 G,
25 cm biopsy needle (Angiotech Medical Device
Technologies, Gainesville, FL, USA). All prostate
biopsies were performed with the endfire technique
in the axial plane by the same operator with 20 years’
experience in TRUS-bx. The operator had no prior
knowledge of the mp-MRI findings before taking the
standard biopsies. Ten TRUS-bx standard cores were
taken systematically from 10 prostatic regions and
marked separately. Then the operator reviewed
the mp-MRI data on a dedicated workstation in the
biopsy room together with the MRI physician. Any
Multiparametric MRI in prostate cancer detection
3
1
(2%)
SV
1
(2%)
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5
(9.6%)
3
(5.8%)
Base
(B)
28
(54%)
0
2
(3.8%)
6
(11.5%)
23
(44%)
0
3
(5.8%)
7
(13.5%)
Mid
(M)
4
(7.7%)
3
(5.8%)
1
(1.9%)
4
(7.7%)
Apex
(X)
1
(2%)
1
(1.9%)
13
(25%)
3
(5.8%)
2
(3.8%)
22
(42%)
4
(7.7%)
1
2
(1.9%) (3.8%)
16
(31%)
R
L
R
L
Figure 1. Modified diagram from the European Consensus Meeting [8]. The prostate is divided into 12 posterior and six anterior regions. The
diagram shows the main location of the 52 multiparametric magnetic resonance imaging (mp-MRI) prostate cancer-positive lesions. Each
number represents the number of suspicious lesions located primarily in that region, n (%). An mp-MRI lesion could involve more than one
prostatic region, but the mp-MRI biopsies were targeted towards only one region containing the bulk of the tumour.
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4
L. Boesen et al.
mp-MRI suspicious lesions were visually matched
and registered on the corresponding axial TRUS
image based on zonal anatomy and tissue landmarks.
Any mp-MRI suspicious lesions not sampled by standard TRUS-bx were then targeted by at least one
additional biopsy core based on visual mp-MRI/
TRUS fusion. An mp-MRI suspicious lesion could
involve more than one prostatic region and the additional biopsy was targeted towards the region containing the bulk of the lesion. If an mp-MRI suspicious
lesion was clearly inside a standard biopsy region and
sampled by the standard biopsy core, no additional
targeted biopsy was taken, to limit the total number of
biopsies. If an mp-MRI suspicious lesion was inside a
standard biopsy region, but it was uncertain whether
the lesion had been sampled by the standard biopsy
core, one additional targeted biopsy was taken from
the same prostatic region and if possible from an
adjacent area guided by visual recognition and often
the systematic biopsy trajectories to disperse the two
biopsies. All biopsies from mp-MRI suspicious
lesions were further marked as an mp-MRI targeted
biopsy (mp-MRI-bx).
Histopathological evaluation
A genitourinary pathologist with more than 9 years of
dedicated experience in prostatic pathology reviewed
and described all the histological biopsy samples. For
each biopsy core positive for PCa, the location and
region according to the diagram, the Gleason score
[10] and the extent of cancer involvement (percentage) in the core were determined. Any signs of
inflammation, high-grade prostatic intraepithelial
neoplasia (HGPIN) or cellular changes suspicious
of adenocarcinoma were outlined in all the other
biopsies.
Criteria for clinical significance
To evaluate the diagnosed cancerous lesions for
clinical significance, the following Epstein criteria
were used: a Gleason score of 7 of higher; PSA density
at least 0.15 ng/ml/cm3; or at least three positive
standard cores/cancer involvement per biopsy core
of 50% or more [11].
Statistical analysis
The patients’ clinical characteristics were stratified by
biopsy results and described by descriptive statistics.
Continuous variables including age, PSA, PSA density, prior biopsy procedures, number of mp-MRI
lesions and number of mp-MRI-bx were compared
using the Wilcoxon rank sum test, and a Fisher’s exact
test was used to compare the cT stage pooled in nonpalpable and palpable tumour groups. The prebiopsy
mp-MRI scores for each identified lesion were
compared with the biopsy results and a chi-squared
analysis was used to determine the correlation
between suspicion on mp-MRI and positive biopsies
for each identified lesion using both PI-RADS and
Likert scoring systems. Cancer detection rates with
mp-MRI-bx and standard TRUS-bx were examined
with the non-conservative McNemar test. The highest
Gleason scores from standard TRUS-bx and mpMRI-bx from each patient were compared. A p value
below 0.05 was considered significant. Statistical
analysis was performed using software SPSS
20.0 (IBM Corporation, USA).
Results
This study prospectively enrolled 89 patients. However, six patients had to be excluded owing to
technical problems with the mp-MRI or claustrophobia. The final study population of 83 patients had a
median of two (range one to six) prior negative
TRUS-bx and a median PSA of 11 ng/ml (range
4.1–97 ng/ml) (Table I).
PCa was detected in 39 out of 83 patients (47%)
and 44 out of 83 patients (53%) had either a benign
condition (n = 34), HGPIN (n = 3) or a lesion
suspicious of adenocarcinoma (n = 7) at pathology.
Lesions ranging from low to high suspicion of PCa
were identified on mp-MRI in all but one patient,
giving a total of 156 identified lesions and median of
two (range none to five) per patient. Biopsies were
positive for PCa in 52 out of 156 (33%) mp-MRI
identified lesions in 39 patients (Figure 1). Additional
mp-MRI-bx were targeted towards 48 out of 52 mpMRI cancer-positive lesions. The remaining four
lesions were sampled by TRUS-bx as the standard
biopsy cores were clearly inside the mp-MRI identified lesions, and thus no extra mp-MRI-bx were
necessary. The mp-MRI-bx correctly detected PCa
in 40 out of 48 mp-MRI cancer-positive lesions that
were targeted by additional mp-MRI-bx. The remaining eight mp-MRI cancer-positive lesions were
detected by TRUS-bx as mp-MRI correctly identified
the suspicious lesions, but the additional mp-MRI-bx
from the same regions were negative (Figure 2).
Both the PI-RADS and the overall Likert scoring
system showed a high correlation with the biopsy
results (p < 0.0001) (Figures 3 and 4, Tables II
and III).
The mp-MRI identified at least one lesion with
some degree of suspicion in all 39 patients diagnosed
with PCa. Each patient had a median of two (range
none to four) extra mp-MRI-bx in addition to the
Multiparametric MRI in prostate cancer detection
5
Table I. Demographic data of the study cohort stratified by biopsy results.
Clinical characteristics
Age (years)
PCa negative
(n = 44)
PCa positive
(n = 39)
61.5 (45–74)
Total
(n = 83)
p
64.0 (49–79)
0.014
63.0 (45–79)
Prior biopsy
2 (1–4)
2 (1–6)
0.124
2 (1–6)
PSA (ng/ml)
11.3 (4.4–97)
10.7 (4.1–65)
0.725
11.0 (4.1–97)
PSA density (ng/ml/cm3)
0.15 (0.05–1.1)
0.24 (0.04–1.0)
0.021
0.18 (0.04–1.1)
Clinical T category
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cT1c
40 (91%)
33 (85%)
73 (88%)
cT2a
3 (7%)
2 (5%)
5 (6%)
cT2b
1 (2%)
2 (5%)
3 (4%)
cT2c
0 (0%)
1 (2.5%)
1 (1%)
cT3a
0 (0%)
1 (2.5%)
1 (1%)
Non-palpable tumour cT1
40 (91%)
33 (85%)
Palpable tumour cT2–cT3
4 (9%)
6 (15%)
0.504
73 (88%)
mp-MRI foci/patient
2 (0–4)
2 (1–5)
0.190
2 (0–5)
mp-MRI-bx/patient
2 (0–4)
2 (0–4)
0.593
2 (0–4)
10 (12%)
Data are shown as median (range) or n (%).
PCa = prostate cancer; PSA = prostate-specific antigen; mp-MRI = multiparametric magnetic resonance imaging; bx = biopsy.
10 standard TRUS-bx, making a total average of 12
biopsy cores per patient. Five patients (13%) had
significant PCa detected only on mp-MRI-bx (p =
0.025), with four out of five (80%) having intermediate/high-grade cancer (Gleason score ‡7). Both
standard TRUS-bx and mp-MRI-bx detected PCa
in 34 out of 39 patients. However, seven out of
34 patients (21%) had an overall Gleason score
upgrade, among which five out of seven patients
went from low-grade (Gleason score 6) to intermediate/high-grade cancer based on the additional mpMRI-bx. A secondary multifocal PCa lesion not visible
on mp-MRI was detected by TRUS-bx in six out of
39 PCa patients. All secondary lesions were Gleason
6 (3 + 3) tumour foci in 5–10% of the biopsy core. No
patients had a Gleason score upgrade based on positive
mp-MRI lesions (n)
52
mp-MRI-bx (n)
Positive (40)
Negative (12)
TRUS-bx positive in
same lesion (n)
TRUS-bx negative in
same lesion (n)
TRUS-bx clearly
inside mp-MRI
lesion-no
additional
mp-MRI-bx
TRUS-bx uncertain
whether inside
mp-MRI lesion-one
extra adjacent
mp-MRI-bx
30
10
4
8
Figure 2. Multiparametric magnetic resonance imaging (mp-MRI) suspicious lesions positive for prostate cancer at biopsy. bx = biopsy;
TRUS = transrectal ultrasound.
6
L. Boesen et al.
A.
Cancer
Negative biopsy
Positive biopsy
25
20
Count
10
5
0
4
5
6
7
8
9 10 11 12
PI-RADS score (3–15)
13
14
15
B.
Cancer
Negative biopsy
Positive biopsy
100.0%
11%
80.0%
56%
60.0%
Percent
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15
94%
89%
40.0%
44%
20.0%
0.0%
6%
Low
Moderate
High
MRI riskgroup (PI-RADS)
Figure 3. Biopsy results for each multiparametric magnetic resonance imaging (MRI) lesion correlated with (a) Prostate Imaging Reporting
and Data System (PI-RADS) score and (b) PI-RADS risk group classification (high: PI-RADS score 13–15; moderate: 10–12; low: <10).
Multiparametric MRI in prostate cancer detection
7
A.
Cancer
Negative biopsy
50
Positive biopsy
40
Count
20
10
0
1
2
3
4
Likert score (1–5)
5
B.
Cancer
Negative biopsy
100.0%
Positive biopsy
23%
80.0%
60.0%
85%
Percent
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30
98%
40.0%
77%
20.0%
15%
0.0%
2%
Low
Moderate
High
MRI riskgroup (PI-RADS)
Figure 4. Biopsy results for each multiparametric magnetic resonance imaging (MRI) lesion correlated with (a) Likert score and (b) Likert risk
group classification (high: Likert score 4 + 5; moderate: Likert score 3; low: Likert score 1 + 2).
TRUS-bx from non-visible lesions on mp-MRI. Two
patients had insignificant PCa detected according to
the criteria, providing an overall detection rate of
clinically significant PCa of 45% (37 out of 83 patients),
among which 27% (10 out of 37) harboured high-grade
(Gleason score ‡8) cancer.
8
L. Boesen et al.
Table II. Biopsy results correlated with Prostate Imaging Reporting and Data System (PI-RADS) risk group classification and relation to
Gleason score.
Gleason score
MRI suspicion
Positive biopsy
Negative biopsy
Lesions (n)
6
7 (3 + 4)
7 (4 + 3)
8–10
High
32
4
36
6
11
4
11
Moderate
15
19
34
5
6
3
1
Low
5
81
86
4
1
Total
52
104
156
15
18
7
12
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MRI = magnetic resonance imaging.
Table III. Biopsy results correlated with Likert risk group classification and relation to Gleason score.
Gleason score
MRI suspicion
High
Moderate
Positive biopsy
Negative biopsy
Lesions
(n)
6
7 (3 + 4)
7 (4 + 3)
8–10
7
12
7
12
43
13
56
10
14
8
44
52
4
4
Low
1
47
48
1
Total
52
104
156
15
18
MRI = magnetic resonance imaging.
Discussion
Before this study, mp-MRI had never been applied at
this institution for PCa detection or for guiding
targeted biopsies towards mp-MRI-suspicious
lesions. The patient population and results represent
the authors’ initial experience with this new technique. The main objective was to evaluate whether
prebiopsy mp-MRI in this setting could improve the
overall detection rate of clinically significant PCa by
adding mp-MRI-bx under visual TRUS guidance to
standard TRUS-bx without previous experience of
this. The results show that this is possible. An overall
PCa detection rate of 47% (39 out of 83) was found,
with 26% (10 out of 39) harbouring high-grade cancer
(Gleason score ‡8) among patients with a median of
two (range one to six) prior negative TRUS-bx and a
median PSA of 11 ng/ml (range 4.1–97 ng/ml). There
was no significant difference in PSA and cT stage
between PCa-positive and PCa-negative patients.
There was only a significant difference in age and
PSA density, which is not surprising, as age and high
PSA relative to prostate volume are known risk factors
for PCa (Table I). Only two patients had insignificant
PCa detected according to the criteria, providing an
overall detection rate of clinically significant PCa of
45% (37 out of 83 patients). Five patients (13%) had
significant PCa detected only on the mp-MRI-bx
outside the systematic biopsy regions. This overall
PCa detection rate is in accordance with previous
findings as outlined in the review by Lawrentschuk
and Fleshner [12], although they found a higher
proportion of PCa detected purely by the mp-MRItargeted biopsy cores.
In the authors’ department, standard TRUS-bx is
limited to a very few highly experienced operators
using an endfire biopsy probe. Ching et al. [13]
showed that in standard biopsies the endfire probe
allows for better sampling of the lateral and apical
regions of the prostate, where tumours often reside. In
the authors’ experience, the endfire biopsy needle
enters the prostatic surface perpendicularly and penetrates deeper and more anteriorly into the prostate.
Especially in the apical regions, the standard biopsy
core often samples the entire height of the prostate.
This may enable better sampling of apical and
anteriorly located tumours on TRUS-bx, causing
an increased detection rate with standard biopsies.
This was confirmed in the present study as more than
70% of the mp-MRI PCa-positive lesions were
located in the anterior or apical region (Figure 1).
Despite a rather surprisingly high PCa detection
rate using standard biopsies, a significant improvement (p = 0.025) in the overall detection rate was
found by adding mp-MRI-bx as an adjunct to the
standard 10-core TRUS-bx.
With the development of more targeted biopsy
strategies, the cancer detection rate may be assessed
better by lesion instead of on a per-patient basis [14].
At least one tumour-suspicious lesion was identified
on mp-MRI in all 39 patients diagnosed with PCa.
A highly significant correlation between positive biopsies and lesion suspicion on mp-MRI (p = 0.0001) was
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Multiparametric MRI in prostate cancer detection
found using both the PI-RADS classification and
Likert scoring. If mp-MRI showed a high suspicion
of PCa on either PI-RADS or Likert scoring, then
89% (32 out of 36) and 76% (43 out of 56) of the
lesions were positive at biopsy, respectively. On the
other hand, only 2% (one out of 48) with Likert and
6% (five out of 86) with PI-RADS low suspicion on
mp-MRI were positive for PCa. All but one lowsuspicious lesion was Gleason score 6. Six patients
had evidence of multifocal disease on biopsy, where
separate secondary PCa lesions were not visible on
mp-MRI and were detected only by TRUS-bx. However, mp-MRI identified all of the patients’ dominating index PCa lesions; the missed secondary lesions
were all small Gleason score 6 (3 + 3) tumours with 5–
10% cancer involvement per biopsy core. These findings underline the potential value of using prebiopsy
mp-MRI to increase the detection rate of clinically
significant PCa previously missed by standard TRUSbx and to stratify the patients and lesions according to
suspicion on mp-MRI using both the PI-RADS and
Likert scoring systems. This was confirmed in a recent
study by Portalez et al. [15], in which the ESUR
PI-RADS scoring was prospectively validated in a
contemporary patient cohort in relation to repeated
prostate biopsies. Using a PI-RADS score of 9 or
above as the threshold, the authors report a sensitivity
and specificity of 69% and 92%, respectively, and a
negative predictive value of 95%. In the context of
deciding on repeated biopsies, this high negative
predictive value can predict the absence of cancer
with high confidence and thereby possibly reduce
the number of unnecessary rebiopsies.
The mp-MRI-bx were positive for PCa in 40 out of
52 mp-MRI cancer-positive lesions. The remaining
12 mp-MRI cancer-positive lesions were sampled
only by standard TRUS-bx. Additional mp-MRI-bx
were targeted towards eight out of 12 lesions as it was
uncertain whether the standard core had sampled the
mp-MRI-identified lesions. These additional mpMRI-bx were negative compared with the standard
cores from the same prostatic regions, which may be
explained by the fact that the mp-MRI-bx were taken
from adjacent areas within the same region to disperse
the two biopsies. However, it may also be a result of
misregistration between the suspicious lesion seen on
mp-MRI and the visual match on the corresponding
axial TRUS image. Visual translation of the mp-MRI
image to the grey-scale TRUS image may not always
be accurate. The operator has to visually correlate the
mp-MRI image on to a real-time two-dimensional
TRUS image and translate it all into a threedimensional representation of the prostate based on
zonal anatomy and tissue landmarks. There will be a
9
margin of error, especially if the prostate is large or the
lesion is located anteriorly [7]. Methods for improving
the accuracy of targeted biopsies, including real-time
MRI–TRUS image fusion [6,14] and in-gantry mpMRI-guided biopsies [16,17], show promising results.
Standard TRUS-bx detected PCa in 34 out of
39 patients, where seven out of 34 (21%) patients
had an overall Gleason score upgrade due to the use of
additional mp-MRI-bx. The Gleason score was
upgraded from low-grade to intermediate/high-grade
cancer in five out of seven patients. This is in line with
studies showing a correlation between mp-MRI and
PCa aggressiveness represented by the Gleason score
[16,18–20]. Overall, using prebiopsy mp-MRI, five
patients had PCa detected only by mp-MRI-bx and
another seven patients had an overall Gleason score
upgrade, making a total of 12 out of 39 (31%) newly
diagnosed PCa patients who may have had their
prognosis and treatment decision altered owing to
the use of mp-MRI as an adjunct to TRUS-bx.
This study has some limitations. Not all patients
included in the study had the initial TRUS-bx performed at the authors’ institution. This could cause a
bias in comparison of the PCa detection rate between
studies. Using the combination of TRUS-bx and mpMRI-bx, a high overall PCa detection rate of 47% was
found at median third time biopsy with a high proportion of significant tumours. This can partly be
explained by the fact that the patient population in
this study was prone to harbouring a significant
tumour, as the patients usually presented rising
PSA levels without any other benign explanations
and where third time biopsy was indicated. These
patients would also be more likely to benefit from
mp-MRI-targeted biopsies as they all had negative
standard TRUS-bx previously.
Another limitation is the lack of a gold standard
reference as a totally embedded prostatectomy specimen. Whether a cancer was missed on negative biopsies
could not be determined, and a true false-negative rate
for TRUS-bx and mp-MRI-bx could not be assessed in
this study. However, all patients in the study underwent
standard TRUS-bx in 10 regions blinded to any mpMRI findings regardless of whether mp-MRI identified
a suspicious lesion or not. This made it possible to
determine whether TRUS-bx detected PCa lesions
that were not visible on mp-MRI and to correlate the
findings with clinical significance.
In conclusion, this prospective study shows that
using multiparametric MRI before repeated biopsy,
even without previous experience, can improve the
detection rate of clinically significant PCa by combining standard TRUS-bx with mp-MRI-targeted
biopsies under visual TRUS guidance, and allows
more accurate Gleason grading.
10
L. Boesen et al.
Declaration of interest: The authors have no
conflicts of interest.
[12]
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1
Prostate cancer staging with extracapsular extension risk scoring using
multiparametric MRI: a correlation with histopathology
Boesen L, Chabanova E, Logager V, Balslev I, Mikines K, Thomsen HS.
Submitted
Abstract
Objectives: To evaluate the diagnostic performance of preoperative multiparametric MRI with
extracapsular extension (ECE) risk scoring in the assessment of prostate cancer tumour stage (Tstage) and prediction of ECE at final pathology.
Materials and Methods: Eighty-seven patients with clinically localised prostate cancer scheduled
for radical prostatectomy were prospectively enrolled. Multiparametric MRI was performed prior to
prostatectomy and evaluated according to the ESUR MR prostate guidelines by two different
readers. An MRI clinical T-stage (cTMRI), an ECE risk score and suspicion of ECE based on tumour
characteristics and personal opinion were assigned. Histopathological prostatectomy results were
standard reference.
Results: Histopathology and cTMRI showed a spearman rho correlation of 0.658 (p<0.001) and a
weighted kappa=0.585 [CI 0.44;0.73] (reader A). ECE was present in 31/87 (36%) patients. ECE
risk scoring showed an AUC of 0.65-0.86 on ROC-curve for both readers with sensitivity and
specificity of 81% and 78% at best cut-off level (reader A), respectively. When tumour
characteristics were influenced by personal opinion, the sensitivity and specificity for prediction of
ECE changed to 61%-74% and 77%-88% for both readers, respectively.
Conclusions: Multiparametric MRI with ECE risk scoring is an accurate diagnostic technique in
determining prostate cancer clinical tumour stage and ECE at final pathology.
2
Key words:
Prostate cancer; Magnetic resonance imaging; Tumour staging; Guidelines; Scoring methods
Key Points:
 Multiparametric MRI is an accurate diagnostic technique for preoperative prostate cancer
staging
 ECE risk scoring predicts extracapsular tumour extension at final pathology
 ECE risk scoring shows an AUC of 0.86 on the ROC-curve
 ECE risk scoring shows a moderate inter reader agreement (K=0.45)
 Multiparametric MRI provides essential knowledge for optimal clinical management
Abbreviations and Acronyms:
DRE = Digital rectal examination
TRUS = Transrectal ultrasound
PCa = Prostate cancer
EPE = Extra prostatic tumour extension
RP = Radical prostatectomy
cT = Clinical tumour stage
NVB = Neurovascular bundle
MRI = Magnetic resonance imaging
Mp-MRI = Multiparametric MRI
PIRADS = Prostate imaging reporting and data system
T2W = T2-weighted
DWI = Diffusion weighted imaging
ADC = Apparent diffusion coefficient
DCE = Dynamic contrast enhanced
ECE = Extracapsular extension
SVI = Seminal vesicle invasion
GS = Gleason score
ERC = Endorectal coil
3
INTRODUCTION
Digital rectal examination (DRE) and transrectal ultrasound (TRUS) are traditionally used for
clinical staging of prostate cancer (PCa), but both lack in sensitivity and specificity, as well as
TRUS often underestimates the size and stage of the tumour [1]. Thus, prediction of extracapsular
tumour extension (ECE) by DRE and TRUS has low accuracy [2,3].
Radical prostatectomy (RP) provides great disease control for patients with localised PCa (cT1-T2),
while RP for locally advanced disease (cT3) remains controversial [1,4]. Recovery of erectile
function and continence after RP is related to surgical techniques and preservation of the
neurovascular bundles (NVB). Preoperative accurate knowledge of tumour stage and possible ECE
are crucial in achieving the best surgical, oncological and functional result with total tumour
resection while trying to preserve both potency and continence.
Recent findings support the rapidly growing use of mp-MRI as the most sensitive and specific
imaging tool for PCa staging [5]. However, the diagnostic accuracy of mp-MRI staging and
prediction of ECE differs among studies [6–10], which has led to a debate about mp-MRI’s
readiness for routine use [11]. Clinical guidelines [12] from prostate MRI experts have therefore
recently been published including a structured uniform reporting and scoring system (PIRADS) [11]
to standardise prostatic MRI readings. Previous studies have validated the PIRADS classification
for PCa detection and localisation using both targeted biopsies [13–15] and RP specimen [16] as
standard reference. In addition, the guidelines also recommend using a risk score of possible ECE.
Based on these recommendations, we carried out this prospective study of a patient cohort with
clinically localised PCa based on DRE and TRUS findings scheduled for RP. The aim was to
investigate the diagnostic accuracy of preoperative mp-MRI with ECE risk scoring in the
assessment of tumour stage (T-stage) and prediction of ECE at final pathology.
MATERIALS & METHODS
This prospective single institutional study was approved by the Local Committee for Health
Research Ethics (No.H-1-2011-066) and the Danish Data Protection Agency. It was registered at
Clinicaltrials.gov (No.NCT01640262).
Patients
All patients had provided written informed consent and were prospectively enrolled between
September 2011 and September 2013. Inclusion criteria required that all patients were diagnosed
4
with clinically localised PCa determined by DRE and TRUS and scheduled for RP based on clinical
assessment of age, co-morbidity, PSA and biopsy Gleason score. No patients had prior treatment for
PCa. The exclusion criteria were patients with contraindication to mp-MRI (pacemaker, magnetic
implants, severe claustrophobia, previous moderate or severe reaction to gadolinium-based contrastmedia or impaired renal function with GFR<30 ml/min). No patients were excluded from RP due to
preoperative mp-MRI findings.
Multiparametric MRI
All patients underwent mp-MRI prior to RP using a 3.0 T MRI scanner (Achieva (n=71 patients) and
Ingenia (n=16 patients), Philips Healthcare, Best, the Netherlands) with a pelvic-phased-array coil
(Philips Healthcare, Best, the Netherlands) positioned over the pelvis. We did not use an endorectal
coil (ERC), due to lack of availability. If tolerated, a 1 mg intramuscular Glucagon (Glucagen®,
Novo Nordisk, Bagsvaerd, Denmark) injection combined with a 1 mg Hyoscinbutylbromid
(Buscopan®, Boehringer Ingelheim, Ingelheim am Rhein, Germany) intravenous injection were
administered to the patient to reduce peristaltic motion. Tri-planar T2W images from below the
prostatic apex to above the seminal vesicles were obtained. In addition, axial diffusion-weighted
images (DWI) including 4 b-values (b0, b100, b800 and b1400) along with reconstruction of the
corresponding apparent diffusion coefficient (ADC) map (b-values 100 and 800), together with
dynamic contrast enhanced (DCE) images before, during and after intravenous administration of 15
ml gadoterate meglumine (Dotarem 279.3 mg/ml, Guerbet, Roissy CDG, France) were performed. The
contrast agent was administered using a power injector (MedRad, Warrendale, Pennsylvania, USA)
followed by a 20 ml saline flush injection at a flow rate of 2.5 ml/s. For imaging parameters see
table 1.
Image analysis
All tumour suspicious lesions were evaluated according to the PIRADS classification from ESUR
[12] giving a sum of scores (ranging 3-15). Lesions with PIRADS summation score≥10 equivalent
to a moderate or high-risk group [15] or PIRADS overall score≥4 [17] were considered to be
possible malignant lesions and were used to predict a cT-stage based on mp-MRI (cTMRI )
according to the TNM-classification [18]. Pre-contrast T1W-images were used to identify postbiopsy haemorrhage as an area with high signal intensity to rule out false positive findings on T2W.
The lesion most suspicious of ECE were evaluated using the ESUR MR prostate guideline scoring
of extra prostatic disease [12] focusing on the ECE criteria (Table 2). The ECE tumour
characteristics were first assessed according to the following findings: a) no sign of ECE, b)
capsular abutment, c) capsular irregularity, retraction or thickening, d) neurovascular bundle
5
thickening, e) capsular signal loss or bulging and f) direct sign of tumour tissue in the extra prostatic
tissue. The findings were subsequently associated with the ECE risk score ranging 0-5 (Figure 1).
Suspicion of possible SVI was based on the following findings: a) low T2W signal in the lumen, b)
filling in of angle and/or c) enhancement/impeded diffusion of the seminal vesicles. The ECE
tumour characteristics in the guidelines only evaluate T2W findings and assigning a preoperative
cTMRI stage requires a definitive decision of possible ECE and/or SVI. Therefore, the suspicion of
ECE was dichotomised into either organ-confined (OC) disease or ECE based on the established
ECE tumour characteristics and personal opinion incorporating functional imaging (DWI and DCE)
findings. Equivocal cases with strong suspicion of ECE on mp-MRI were read as positive and
conversely equivocal cases with low suspicion of ECE were read as negative. All mp-MRI images
from each patient were analysed by a dedicated MRI prostate physician (reader A) with two years
of experience in prostate mp-MRI interpretation. All image modalities (T2W, DWI and DCE) were
used simultaneously to predict cTMRI and dichotomising ECE suspicion and only T2W imaging
were used to assess ECE tumour characteristics according to the guideline. Only qualitative visual
assessment was used for DCE MRI analysis. In addition, all images were reassessed independently
from reader A by a second reader B with extensive experience in general abdominal MRI, but only
limited experience in prostate mp-MRI interpretation. The readers had access to preoperative PSA
and knew that the patients had biopsy-proven clinically localised PCa, but were blinded to any
histopathological tumour findings.
Histopathological evaluation
All patients underwent RP. The surgeon was not aware of any mp-MRI findings. The specimens
were coated with ink and fixed in formalin. The basis, including the bases of the seminal vesicles
and the apex, were cut in sagittal sections whereas the remaining prostate was cut into 4-5 mm
sections in a plane perpendicular to the rectal surface corresponding to the plane used for axial mpMRI. The rest of the seminal vesicles were cut longitudinal. The slices were then further cut into
microscopic sections and stained with haematoxylin and eosin. All cancerous areas, including
presence and location of any extra prostatic extension (EPE), defined as either ECE and/or SVI,
were outlined by an experienced pathologist based on the histopathological results. ECE was
defined as tumour cell growth into the extra prostatic tissue, and SVI was defined as tumour
infiltration of the seminal vesicles. The pathological T-stage (pT) was defined using the TNM
classification[18].
6
Statistical analysis
The patients’ clinical characteristics were calculated and compared in two groups (organ-confined
and extra prostatic disease) based on the histopathological results. Continuous variables including
age, PSA and percentage positive biopsy cores were compared using the Wilcoxon Rank sum test or
a Student’s t test. A Fisher’s exact test or a chi-square test were used to compare the T-stage
determined by DRE (cTDRE) and TRUS (cTTRUS) divided into T1 or T2 stage, the cTMRI stage, the
biopsy GS and the D’Amico risk group.
The cTMRI was compared to pT for accuracy using weighted kappa statistics and a spearman rank
order calculation. A receiver operating characteristic curve (ROC-curve) with an area under the
curve (AUC) value was generated to analyse the predictive accuracy of the ECE risk scoring scale
in detecting ECE at pathology. An optimal risk score cut-off level, representing the best trade-off
between sensitivity and specificity, was determined for the most experienced reader A. In addition,
the overall diagnostic accuracy, sensitivity, specificity, positive predicted value (PPV) and negative
predictive value (NPV) of mp-MRI in predicting ECE by combining ECE tumour characteristics
with personal opinion and in predicting SVI were calculated for both readers. Inter reader reliability
was calculated using kappa statistics [19]. A P-value below 0.05 was considered significant.
Statistical analysis was performed using software SPSS 20.0 (IBM Corporation, US).
RESULTS
Ninety-three patients were prospectively enrolled. However, 6 patients were excluded due to mpMRI technical problems or claustrophobia. The final study population of 87 patients with a median
age of 65 (range 47-74) and a median PSA of 11 (range 4.6-45) underwent mp-MRI before RP.
Clinical and demographic data are stratified in two groups (organ-confined and extra prostatic
disease) by the histopathological results (Table 3). There was no significant difference in PSA,
cTDRE, cTTRUS and D’Amico risk group between patients with organ-confined or EPE disease. There
was a significant difference in age, percentage of positive biopsy cores, biopsy GS and cTMRI
between the groups.
Mp-MRI identified a tumour in all 87 patients. The correlation between cTMRI and pT showed a
spearman rho correlation of 0.658 (p<0.001) and 0.306 (p=0.004) with a weighted kappa of 0.585
[CI 0.44;0.73] and 0.22 [CI 0.09;0.35] for reader A and reader B, respectively. The inter reader
agreement for the readers in determining cTMRI was kappa=0.44 [CI 0.2;0.66]. The prevalence of
EPE after RP was 32/87 (37%) including 31/87 (36%) with ECE and 5/87 (6%) with SVI. One
patient had SVI without concomitant ECE at pathology. Each ECE tumour characteristic (Figure 2)
7
were stratified into ECE risk score groups (Figure 3). Mp-MRI ECE risk scoring for the most
experienced reader A showed an AUC of 0.86 on the ROC-curve (Figure 4) with a sensitivity of
81% [CI 63;93], a specificity of 78% [CI 66;88] and a diagnostic accuracy of 79% at the optimal
risk score cut-off level ≥4 (Table 4). Using this cut-off level, 6/31 patients with ECE were missed
and 12/56 patients had a false-positive mp-MRI (Figure 3) (Table 4). When mp-MRI findings were
dichotomised into either OC or ECE influenced by personal opinion, the false-positive rate dropped
to 7/56 patients at the expense of increased false-negative readings where 8/31 patients with ECE
were missed giving a diagnostic accuracy of 83% with sensitivity, specificity, PPV and NVP of
74% [CI 55;88], 88% [CI 76;95], 77% [CI 56;90], and 86% [CI 74;94] for prediction of ECE,
respectively. For the less experienced reader B, ECE risk scoring showed an AUC of 0.65 (Figure
4) and a sensitivity, specificity and diagnostic accuracy of 51% [CI 33;70], 69% [CI 52;78] and
61% at the risk score cut-off level ≥4 determined by reader A. The sensitivity, specificity and
diagnostic accuracy changed to 61% [CI 0.42;0.78], 77% [CI 0.64;0.87] and 71% when ECE risk
scoring was influenced by personal opinion. The inter reader agreement kappa value between reader
A and B was 0.40 [CI 0.19;0.60] in distinguishing OC from ECE disease and 0.45 [CI 0.21;0.68] in
agreement of ECE risk scores. Reader A detected 4/5 (80%) patients with SVI and one patient with
pT3a had evidence of SVI (T3b) on mp-MRI due to low T2W signal caused by intraluminal SV
infiltration with amyloid.
DISCUSSION
The prevalence of EPE at histopathology was 37% in patients with clinically localised PCa
confirming the fact that DRE and TRUS often underestimate the tumour extension and stage.
Using mp-MRI for clinical staging instead of DRE and TRUS, we found a significant correlation
between the cTMRI stage and pT for the most experienced reader A with a Spearman rho=0.658
(p<0.001) and moderate agreement using weighted kappa=0.585 [CI 0.44;0.73]. The prognosis of
PCa is highly related to the tumour stage. Complete agreement between cTMRI and the pathological
stage is difficult to obtain, as mp-MRI does not identify all the small dispersed insignificant tumour
foci that frequently are present within the prostate and are incorporated into the overall evaluation
and reporting of the pathological stage. This can easily cause a discrepancy between a T2a/T2b
stage identified on mp-MRI and a T2c stage reported at pathology for organ-confined tumours.
However, the exact stage differentiation among OC tumour is of less importance, as patients with
OC often can receive potentially curative surgery. In contrast, the treatment selection of PCa
strongly relies on the distinction between OC (T2) and ECE (T3) disease. The development of
8
nomograms based on PSA, DRE and TRUS biopsy findings have increased the diagnostic accuracy
of predicting ECE at final pathology [20–22]. Nevertheless, the results are based on a statistical
prediction and do not incorporate visual anatomic imaging that provides individual information
about localisation, side and possible level of ECE. Mp-MRI has been found to perform significantly
better than nomograms, DRE and TRUS in visualising the intraprostatic tumour localisation and
possible ECE including predicting the final pT-stage [9,23–25]. ROC-curve analysis of ECE risk
scoring showed a high AUC (0.86), indicating a high clinical value of the scoring system when
interpreted by a dedicated reader reached a sensitivity and specificity of 81% and 78% at best cutoff level ≥4. A cut-off at this level includes both direct sign of tumour growth through the capsule
(risk score 5 - ECE highly likely to be present) and also indirect signs such as tumour bulging, loss
of capsular signal and neurovascular bundle thickening (risk score 4 - ECE likely to be present). By
also including the equivocal cases with cut-off level ≥ risk score 3 (capsular retraction, irregularity
or thickening), the sensitivity increases to 94% with a decrease in specificity to 68%, but more
interestingly, the NPV increases to 95% indicating a high clinical value to almost definitive rule out
ECE at this level. However, the inter reader agreement kappa value (0.45) signifies moderate
consistency between the readers and indicates that there are differences in the image interpretation
of the individual ECE tumour characteristics.
The purpose of the ESUR PIRADS classification is to introduce a structured uniform scoring
system with less subjectivity in order to standardise prostatic mp-MRI readings and facilitate
consistency between readers. This approach is well suited for PCa lesion detection and localisation,
as each MRI modality in each suspicious lesion is scored independently providing a summation of
all individual scores. In addition, an overall final score (ranging 1-5) according to the probability of
clinically significant PCa being present, can be assigned. Similarly, the guidelines also recommend
that the probability of extra prostatic disease should be scored on a five-point risk scale and provide
individual tumour characteristics with associated risk scores for ECE, SVI, distal sphincter- and
bladder neck involvement. We only evaluated the ECE criteria in this study, as we considered the a
priori probability of patients having SVI, distal sphincter- or bladder neck involvement in our
population with clinically localised PCa to be too low to validate a five-point risk score. The fivepoint risk scale is considered a continuum of risk with higher scores corresponding to higher
probability of ECE. However, ECE risk scoring does not include risk score=2 or findings on
functional imaging. The assessment of ECE tumour characteristics is based only on T2W imaging.
Previous studies show that functional imaging may improve detection of ECE [26–28], especially
for less experienced readers [29]. Therefore, the interpretation and overall impression of possible
9
ECE may be influenced by personal opinion when incorporating functional imaging findings. This
applies to our study, as the diagnostic accuracy (71%-83%) increased for both readers when
incorporating personal opinion and functional imaging into the evaluation of ECE and changed
sensitivity and specificity to 61%-74% and 77%-88%, respectively. This overall diagnostic
performance is in accordance with previous findings. A meta-analysis by Engelbrecht et al. [30]
reported a combined sensitivity and specificity of 71% in distinguishing between T2- and T3
disease on 1.5 T MRI systems. However, more recent studies at 3 T ERC MRI report higher rates
with sensitivities and specificities of 80-88% and 95-100% [31,32]. The sensitivity and specificity
of an mp-MRI reading can be affected by the way the physician analyses the images when
incorporating personal opinion, especially when deciding on possible ECE in the equivocal cases.
Until recently, RP was restricted to patients with localised PCa while patients with high suspicion
of ECE and/or SVI were referred for radiation therapy. This might influence the physician to value
high specificity with a low number of false-positive readings, so no patients with equivocal mpMRI findings would be ruled out of possible curative surgery. There has been an increasing interest
in performing RP in selected patients with locally advanced disease as some studies have shown
promising results [33–36]. If the tendency towards performing RP in selected patients with T3
disease continues, the value of high sensitivity readings increases in order to direct the surgeon to
the site of possible ECE to avoid positive surgical margins. Therefore, the ECE risk score cut-off
level in table 4 might be altered to either value high sensitive or high specific readings depending
on the clinical situation. Mp-MRI findings can then be combined with clinical findings and
nomograms and increase the overall pre-therapeutic diagnostic staging accuracy [20,37].
We evaluated the reader performance of two readers with different experience in mp-MRI prostate
interpretation. Overall, the most experienced reader A had a significantly higher performance than
reader B in the assessment of ECE using both ECE risk scoring and personal opinion and was more
accurate in predicting the pathological stage. Furthermore, our results indicate that the overall
interpretation of possible ECE in our hands should not only rely on ECE risk scoring in its current
form, but whenever possible also incorporate functional imaging, especially for less experienced
readers. It is evident, that mp-MRI interpretation has a considerable learning curve and is a
specialised task that require substantial dedication and experience to allow for acceptable diagnostic
results [7,38]. A dedicated reader education program on prostate mp-MRI interpretation is
associated with a statistical significant increase in diagnostic accuracy [39].
This study has some limitations. There might have been a selection bias at inclusion, as all patients
had clinically localised disease and were included at time of surgery. Patients with clinically locally
10
advanced disease had already been excluded from surgery and thereby this study, which could
cause an overestimation of mp-MRI specificity and an underestimation of sensitivity. Moreover, the
readers were not blinded to PSA and knew the patients had clinically organ-confined disease when
doing the mp-MRI readings; however, we find this situation more reflective of everyday clinical
practice.
We used only a pelvic-phased-array coil for staging purposes, and in spite of promising results at
3.0 T MRI, the use of an ERC might have improved image quality and staging accuracy [32,39] and
is recommended by the ESUR MR prostate guidelines [12] as part of the optimal requirements.
Conclusion
Multiparametric MRI with ECE risk scoring by a dedicated reader is an accurate diagnostic
technique in determining prostate cancer tumour stage and ECE at final pathology. However,
further studies have to investigate whether functional imaging should be included in the ECE risk
scoring scale and if so, how to weigh the individual findings in order to increase the diagnostic
accuracy of the scoring system
11
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after radical prostatectomy as initial treatment for cT3 prostate cancer. BJU Int
2012;110:1709–13.
[36]
Spahn M, Briganti A, Capitanio U et al. Outcome predictors of radical prostatectomy
followed by adjuvant androgen deprivation in patients with clinical high risk prostate cancer
and pT3 surgical margin positive disease. J Urol 2012;188:84–90.
[37]
Shukla-Dave A, Hricak H, Akin O et al. Preoperative nomograms incorporating magnetic
resonance imaging and spectroscopy for prediction of insignificant prostate cancer. BJU Int
2012;109:1315–22.
[38]
Ruprecht O, Weisser P, Bodelle B, Ackermann H, Vogl TJ. MRI of the prostate:
interobserver agreement compared with histopathologic outcome after radical prostatectomy.
Eur J Radiol 2012;81:456–60.
14
[39]
Turkbey B, Merino MJ, Gallardo EC et al. Comparison of endorectal coil and nonendorectal
coil T2W and diffusion-weighted MRI at 3 Tesla for localizing prostate cancer: correlation
with whole-mount histopathology. J Magn Reson Imaging 2014;39:1443–8.
15
FIGURES
Figure 1: Prostate cancer (white arrows) tumour characteristics corresponding to different ECE risk-score
groups a) ECE risk score 1 – tumour with capsular abutment b) ECE risk score 3 – tumour with capsular
thickening c) ECE risk score 4 – tumour with capsular bulging and d) ECE risk score 5 – tumour with direct
sign of ECE.
16
Figure 2: Tumour characteristics correlated to the histopathology in organ-confined (OC) or extracapsular
tumour extension (ECE) clusters for reader A and B.
17
Figure 3: ECE risk groups correlated to the histopathology in organ-confined (OC) or extracapsular tumour
extension (ECE) clusters for reader A and B.
18
Figure 4: Receiver operating characteristic curves (ROC) for extracapsular tumour extension (ECE) risk
scoring for reader A and B.
19
TABLES
Table 1: Sequence parameters for 3.0 Tesla Achieva (n=71)/Ingenia (n=16) multiparametric MRI
with PPA-coil.
Pulse
sequence
TR
(ms)
TE
(ms)
FA
(°)
FOV
(cm)
ACQ matrix
Number
of slices
Thickness
(mm)
18x18
116x118/116x118
18/25
4
Sequence
Axial DWI, b= 0,
100,800,1400 s/mm2
SE-EPI
4697/4916 81/76
90
Axial T2w
SE-TSE
3129/4228
90
90
16x16/18x18 248x239/248x239
20/31
3
Sagittal T2w
SE-TSE
3083/4223
90
90
16x16/16x20 248x242/268x326
20/31
3
Coronal T2w
SE-TSE
3361/4510
90
90
20
3
Coronal T1w
SE-TSE
675/714
20/15
90
36/41
3.6 / 6
Axial 3d DCE
FFE-3d-TFE
5.7/10
2.8/5
12
18
4 / 4.5
19x19
252x249/424x423
40x48/44x30 540x589/408x280
18x16
128x111/256x221
SE = spin echo, EPI = echo planar imaging, TSE = turbo spin echo, TFE = turbo field echo, FFE = fast field echo,
TR = repetition time, TE = echo time, FA = flip angle, ACQ matrix = acquisition matrix.
Table 2: The ESUR MR prostate guidelines risk scoring of extracapsular extension [11]. The
probability of ECE is scored on a five-point scale, providing an ordinal risk score scale with higher
scores corresponding to higher risk of ECE.
Criteria
Tumour characteristics
Extracapsular extension
Capsular abutment
Capsular irregularity, retraction or thickening
Neurovascular bundle thickening
Bulge or loss of capsule
Measurable extracapsular disease
Score
1
3
4
4
5
20
Table 3: Comparison of the demographic data of the study cohort stratified by the histopathological
results into organ-confined (OC) and extra prostatic tumour extension (EPE).
Clinical characteristics
Age (years), median [range]
PSA (ng/ml), median [range]
Positive biopsy cores (%), mean [range]
OC (n=55)
EPE (n=32 )
P-value
63 [47-74]
10.0 [4.6-44]
28 [10-70]
66.5 [54-73]
12.0 [5.4-45.0]
37 [10-90]
.001
.152
.027
cTDRE category, n (%)
Non-palpable tumour
Palpable tumour
cT1
cT2
46 (84%)
9 (16%)
23 (72%)
9 (28%)
.272
cTTRUS category, n (%)
Non-visual tumour
Visual tumour
cT1
cT2
33 (60%)
22 (37%)
16 (50%)
16 (50%)
.380
cTMRI category, n (%)
Organ-confined tumour
Extra prostatic tumour
cT2
cT3
49 (93%)
6 (7%)
8 (25%)
24 (75%)
<.0001
Biopsy Gleason score, n (%)
Gleason score 6
Gleason score 7
Gleason score 8-10
20 (36%)
29 (53%)
6 (11%)
3 (9%)
23 (72%)
6 (19%)
.021
D’Amico risk group, n (%)
Low
Intermediate
High
14 (25%)
28 (51%)
13 (24%)
3 (9%)
18 (56%)
11 (34%)
.163
21
Table 4: Diagnostic performance of extra capsular tumour extension (ECE) risk scoring depending
on cut-off level and inclusion of personal opinion.
pT
ECE risk score
Sensitivity
Specificity
PPV
NPV
Accuracy
[CI 95%]
[CI 95%]
[CI 95%]
[CI 95%]
[CI 95%]
0.82
0.71
0.72
OC
ECE*
Total
54
22
76
0.29
0.96
2
9
11
[0.14;0.48]
[0.88;0.99]
56
31
87
44
6
50
0.81
0.78
12
25
37
[0.63;0.93]
56
31
87
38
2
40
0.94
0.68
18
29
47
[0.79;0.99]
[0.54;0.80]
56
31
87
49
8
57
0.74
0.88
7
23
30
[0.55;0.88]
[0.76;0.95]
56
31
87
81
1
82
0.80
0.99
[0.29;0.97]
[0.93;0.99]
Reader A
OC
Cut-off level 5
ECE
Total
Cut-off level ≥ 4
OC
ECE
Total
Cut-off level ≥ 3
OC
ECE
Total
Inclusion of
personal opinion
OC
ECE
Total
No SVI
SVI MRI
SVI
Total
[0.48;0.97] [0.60;0.81]
0.68
0.88
0.79
[0.66;0.88] [0.50;0.82] [0.76;0.95]
0.62
0.95
0.77
[0.46;0.75] [0.83;0.99]
0.77
0.86
0.83
[0.56;0.90] [0.74;0.94]
0.80
0.99
1
4
5
82
5
87
43
12
55
0.61
0.77
13
19
32
[0.42;0.78]
[0.64;0.87]
56
31
87
70
2
72
0.60
0.85
0.20
0.97
12
3
15
[0.15;0.94]
[0.76;0.92]
[0.5;0.48]
[0.90;0.99]
82
5
87
0.98
[0.29;0.97] [0.93;0.99]
Reader B
Inclusion of
personal opinion
OC
ECE
Total
No SVI
SVI MRI
SVI
Total
*ECE is equivalent to SVI at pathology for the SVI MRI category.
0.59
0.78
0.71
[0.41;0.76] [0.65;0.88]
0.84
1
Apparent diffusion coefficient ratio correlates significantly with Gleason
score at final pathology
Boesen L, Chabanova E, Logager V, Balslev I, Thomsen HS.
Submitted
Abstract
Purpose:
To evaluate the correlation between apparent diffusion coefficient measurements (ADCtumor
and ADCratio) and the Gleason score from radical prostatectomy specimens.
Materials and Methods: Seventy-one patients with clinically localized prostate cancer
scheduled for radical prostatectomy were prospectively enrolled. Multiparametric MRI was
performed prior to prostatectomy and mean ADC values from both cancerous (ADCtumor) and
benign (ADCbenign) tissue were measured to calculate the ADCratio (ADCtumor divided by
ADCbenign). The ADC measurements were correlated with the Gleason score from the
prostatectomy specimens.
Results: The association between ADC measurements and Gleason score showed a
significant negative correlation (p<0.001) with spearman rho for ADCtumor (-0.421) and
ADCratio (-0.649), respectively. There was a statistically significant difference between ADC
measurements and the Gleason score for all tumors (p=0.001). ROC-curve analysis showed an
overall AUC of 0.73 (ADCtumor) to 0.80 (ADCratio) in discriminating Gleason 6 from Gleason
≥7 tumors. The AUC changed to 0.72 (ADCtumor) and 0.90 (ADCratio) when discriminating
Gleason ≤7(3+4) from Gleason ≥7(4+3).
Conclusion: ADC measurements showed a significant correlation with tumor Gleason score
at final pathology. The ADCratio demonstrated the best correlation compared to the ADCtumor
value and radically improved accuracy in discriminating Gleason ≤7(3+4) from Gleason
≥7(4+3) tumors.
Key words: Prostate cancer, Diffusion-weighted MRI, Gleason score, Prostatectomy.
2
INTRODUCTION
The Gleason Score (GS) of prostate cancer (PCa) is strongly related to the tumors’ clinical
behavior and is a prognostic factor for treatment response (1). High GS implies increased
aggressiveness and risk of local and distant tumor spread with a worse prognosis. However,
the majority of men diagnosed with PCa harbor a non-aggressive low GS tumor that seldom
develops into a clinical disease that will affect the morbidity or mortality. Thus, pretherapeutic accurate classification of tumor aggressiveness is essential when planning patienttailored treatment. The GS from transrectal ultrasound-guided biopsies (TRUS-bx) can be
inaccurate due to sampling error, confirmed by the fact that the GS is upgraded in every third
patient following radical prostatectomy (2). Incorrect GS at biopsy may lead to incorrect risk
stratification and possible over- or under-treatment.
Cancerous tissue has lower DWI-calculated apparent diffusion coefficient (ADCtumor) values
than benign prostatic tissue (ADCbenign) and there is a correlation with the GS (3–8). However,
there is an inconsistency due to different study methodologies (different b-values, different
ways to measure ADC values, different MRI equipment and field strengths). Furthermore,
there is a wide variability in ADC values depending on the prostatic zone and even a
considerable inter-patient variability within the same zone. Therefore, a wide range in mean
ADCtumor values has been reported with a substantial overlap corresponding to different GS
risk groups. Thus, there is no consensus on absolute mean ADCtumor cut-off values separating
the risk groups. To overcome this variability, the ADCratio (defined as the ADCtumor value
divided by the ADCbenign value from non-cancerous tissue) might be more useful and
predictive in determining true GS, as it may level out some of the variation.
Therefore, we studied a patient cohort with clinically localized PCa scheduled for radical
prostatectomy (RP). The aim was to investigate the association between ADC measurements
(ADCtumor value and ADCratio) calculated from pre-operative DWI tumor foci and the GS at
final pathology.
MATERIALS AND METHODS
This single institutional study was part of a prospective investigation on prostate cancer
staging using multiparametric MRI (unpublished data). It was approved by the Local
Committee for Health Research Ethics (No.H-1-2011-066) and the Danish Data Protection
Agency. It was registered at Clinicaltrials.gov (No.NCT01640262).
3
Patients
All patients had provided written informed consent and were prospectively enrolled between
September 2011 and September 2013. The inclusion criteria were 1) diagnosis of PCa and 2)
scheduled for RP based on clinical assessment of age, co-morbidity, tumor stage, PSA and
biopsy GS. The exclusion criteria were patients with prior treatment for PCa or
contraindication to multiparametric MRI (pacemaker, magnetic implants, severe
claustrophobia, previous moderate or severe reaction to gadolinium-based contrast media,
impaired renal function with GFR<30 ml/min). No patients had prior treatment for PCa or
were excluded from RP due to preoperative MRI findings.
Multiparametric MRI
All patients underwent multiparametric MRI (mp-MRI) prior to RP using a 3.0 T MRI
scanner (Achieva, Philips Healthcare, Best, the Netherlands) with a 6-channel pelvic-phased-array
coil (Sense, Philips Healthcare, Best, the Netherlands) positioned over the pelvis. If tolerated, a 1
mg intramuscular Glucagon (Glucagen®, Novo Nordisk, Bagsvaerd, Denmark) injection
combined with a 1 mg Hyoscinbutylbromid (Buscopan®, Boehringer Ingelheim, Ingelheim am
Rhein, Germany) intravenous injection were administered to the patient to reduce peristaltic
motion. Tri-planar T2W images from below the prostatic apex to above the seminal vesicles
were obtained. In addition, axial DWI including 4 b-values (b0, b100, b800 and b1400) along
with reconstruction of the corresponding ADC map, together with dynamic contrast-enhanced
T1W images before, during and after intravenous administration of 15 ml gadoterate
meglumine (Dotarem 279.3 mg/ml, Guerbet, Roissy CDG, France) were performed. The contrast
agent was administered using a power injector (MedRad, Warrendale, Pennsylvania, USA)
followed by a 20 ml saline flush injection at a flow rate of 2.5 ml/s. For imaging parameters
see Table 1.
Image analysis
All tumor suspicious foci were evaluated by the same dedicated MR-prostate physician
according to the PIRADS classification from ESUR (9). Lesions with PIRADS summation
score≥10 equivalent to a moderate or high-risk group (10) or PIRADS overall score≥4 (11)
were considered to be a possible malignant lesion. ADC maps were generated from the MRIworkstation software using two DWI sequences b100 and b800 s/mm2 eliminating b0 to try to
reduce the diffusion contribution from micro-capillary perfusion. The ADC map was
4
reviewed simultaneously with DWI (b1400) and T2W images. The slice of the ADC map
containing the largest tumor extent was selected for analysis and a region of interest (ROI)
was drawn in the centre of the tumor excluding the tumor edges. The mean ADCtumor value
was generated by the workstation and recorded for analysis. Pre-contrast T1W images were
used to identify post-biopsy hemorrhage as an area with high signal intensity to rule out falsepositive findings. The prostate was divided into 12 regions on mp-MRI according to a sextant
scheme – right and left apex, mid and base for both the peripheral- and transitional zone.
Image correlation with histopathology
The RP specimens were coated with ink and fixed in formalin. The basis, including the bases
of the seminal vesicles, and the apex were cut in sagittal sections whereas the remaining
prostate was cut into 4-5 mm sections in a plane perpendicular to the rectal surface
corresponding to the plane used for axial mp-MRI. The slices were then further cut into
microscopic sections and stained with haematoxylin and eosin. All cancerous tumor foci were
outlined on a cross-sectional diagram according to the 12 regions scheme by an experienced
pathologist based on the histopathological results. Considering specimen thickness and
imaging parameters, all tumor foci ≥5 mm in the longest dimension were selected for
comparison with mp-MRI. The pathologist outlined the zonal origin and GS for all tumor foci
selected for comparison. If a patient had multiple tumor foci separated by non-cancerous
tissue, each focus was considered separately. The GS of every foci was separately divided
into 4 risk groups indicating low- (GS=6), intermediate-low (GS=7(3+4)), intermediate-high
(GS=7(4+3)) and high (GS=8-10) risk cancers, as the intermediate risk group (GS=7) was
subdivided into GS 7(3+4) and GS 7(4+3) for sub analysis. The pathologist was blinded to
any mp-MRI measurements.
The histopathological diagram was visually matched with the mp-MRI using axial T2W and
DWI/ADC images, subjectively taking into account alterations in the prostate shape and size
caused by the preservation of the specimen. A tumor focus had to be in the same region on
both histopathology and mp-MRI to be considered a match. Using the histopathological map
as a reference, an additional ROI in similar size as the tumor-ROI was placed in the same
prostatic region, but in a non-cancerous area to obtain the ADCbenign value for calculation of
the ADCratio (Figure 1). If a tumor filled out an entire region, the additional ROI was placed in
the nearest region with non-cancerous tissue, preferably in the same side of the prostate and
always in the same zone (peripheral- or transitional zone). The ADCratio was calculated by
dividing the ADCtumor value with the ADCbenign value. The axial T2W images were used
5
exclusively for anatomical orientation based on anatomic landmarks rather than directing the
placements of the ROI on the ADC map. Additional tumor foci ≥5 mm missed by the
prospective readings of the mp-MRI, but identified on histopathology, were retrospectively
identified on the mp-MRI and included in the analysis. In addition, the longest tumor diameter
on the ADC map was measured. The physician was blinded to the GS when matching the
tumor foci and calculating the ADC measurements.
Statistical analysis
Demographic data were described by descriptive statistics including age, PSA, cT stage, pT
stage, D'Amico risk group and characteristics of the cancerous lesions. Before performing the
statistical analysis, all numeric parameters were controlled to ensure that they fitted the
normal distribution. A Spearman correlation coefficient was used to assess the direct
correlation between ADC measurements and the GS. Mean ADCtumor and mean ADCbenign
values were compared as well as mean ADC measurements were compared according to
zonal origin using a students t test. General estimation equation analyses were used to assess
the association between the mean ADC measurements and the GS groups taking into account
multiple lesions per patient. Analyses were performed for all tumor foci regardless of location
as well as stratified by zonal origin. Box plots of ADC measurements were plotted according
to each GS group for all tumors.
Receiver operating characteristic (ROC) curves were generated and area under the curve
(AUC) was calculated to assess the ADC measurements’ ability to discriminate between GS 6
and GS ≥ 7 and between GS ≤ 7(3+4) and GS ≥ 7(4+3). The ADC measurement with the
highest AUC was identified.
A p-value below 0.05 was considered significant. Statistical analysis was performed using
software SPSS 20.0 (IBM Corporation, US).
RESULTS
Seventy-one patients with a median age of 65 (range 47-73) and a median PSA of 10.6 (range
4.6-46) were prospectively enrolled and underwent mp-MRI before RP. There were a total of
104 (peripheral zone = 53, transitional zone=51) separate tumor foci identified on
histopathology giving a mean of 1.5 per patient. Demographic data are summarized in Table
2. There was a statistically significant difference (p<0.001) between mean ADCtumor and mean
ADCbenign values and between mean ADCtumor values of tumors originating in either the
6
peripheral- or transitional zone. There was no significant difference (p=0.194) in mean
ADCratio between the two zones (Table 3).
The association between ADC measurements and GS showed a significant negative
correlation with spearman rho using both ADCtumor value and ADCratio, respectively (Table 4).
Overall, the ADCratio demonstrated a superior correlation compared to the ADCtumor value,
with the highest correlation ratio for tumors originating in the peripheral zone.
Overall, there was a statistical significant difference between both ADC measurements and
the GS groups for all tumors (Table 5). The difference in mean ADCratio remained significant
when stratified by zonal origin. However, the difference in mean ADCtumor value only
remained significant for tumors located in the peripheral zone. Box-whisker plots of mean
ADC measurements according to each GS group for all tumors showed an inverse correlation
with higher GS groups (Figure 2).
ROC-curve analysis showed an overall AUC of 0.73 (CI 0.62-0.83) for the ADCtumor value
and 0.80 (CI 0.71-0.89) for the ADCratio in the ability to discriminate GS 6 from GS≥ 7
tumors. The AUC remained virtually unchanged at 0.72 (CI 0.62-0.82) for the ADCtumor
value, but increased to 0.90 (CI 0.82-0.97) for the ADCratio when discriminating between GS
≤ 7(3+4) and GS ≥ 7(4+3) (Figure 3).
DISCUSSION
We found that tumor foci have significantly lower mean ADCtumor values compared to noncancerous tissue (ADCbenign) regardless of zonal origin. Several studies have previously
reported a correlation between mean ADC values and cellular density and a significant
difference in mean ADC values in differentiating malignant from benign tissue for diagnostic
purposes (3,12–16). As confirmed in the previous studies, we also found that tumors
originating in the transitional zone have significantly lower mean ADCtumor values than
tumors originating in the peripheral zone. However, there was no significant difference in
mean ADCratio between the two zones, which can be explained by the fact that the ADCtumor
value variation between the zones is leveled out when calculating the ratio, as the lower
transitional ADCtumor value is divided by a matching lower transitional ADCbenign value.
Our study showed a significant inverse correlation between mean ADCtumor value (Spearman
rho= -0.421) and ADCratio (Spearman rho= -0.649) with GS at final pathology. There was a
statistically significant difference between the two ADC measurements and the GS groups for
all tumors and the difference in mean ADCratio remained significant also when stratified by
7
zonal origin. However, the difference in mean ADCtumor value only remained significant for
tumors located in the peripheral zone and not in the transitional zone, which is in line with
previous findings (5,17). As reported by others (5,18), we also found that decreasing mean
ADCtumor values were associated with higher GS groups. A retrospective study by Hambrock
et al. (6) found a significant inverse correlation between ADCtumor values and GS for tumors
originating in the peripheral zone and Jung et al. (8) showed that the same holds true for
transitional zone tumors. In the present study, an increasing mean ADCratio was associated
with higher GS groups and demonstrated the best correlation to GS compared to the ADCtumor
value. To our knowledge, only a few previous studies have had similar results calculating the
prostate ADCratio for better correlation with GS. Vargas et al. (7) found a significant inverse
correlation with GS using both ADCtumor value and ADCratio and Thörmer et al. (19) showed a
high discriminatory power (AUC=0.90) of normalized ADC (equivalent to ADCratio) between
low- and intermediate/high-risk cancer. This was recently confirmed by Lebovici et al. (20)
concluding that the ADCratio may be more predictive of tumor grade than analysis based on
ADCtumor values alone. However, the study was relatively small (n=22 patients) and used
prostate biopsies as reference standard. Conversely, Rosenkrantz et al. (21) did not find any
benefit of using normalized ADC (ADC relative to urine ADC) compared to the ADCtumor
value in terms of AUC for differentiating benign from malignant tissue in the peripheral zone.
We found an overall AUC of 0.73 for the ADCtumor value in differentiating low-risk GS 6
tumors from intermediate-/high-risk GS ≥ 7 tumors. This lies within the AUC levels (0.720.76) reported by others (5,22), although higher AUC values have been reported (6). The
AUC increased to 0.80 for the ADCratio indicating improved accuracy. This ability to
discriminate low-risk from intermediate/high-risk tumors is important in a clinical situation,
as it is often decisive of treatment selection. However, as shown by Langer et al. (23) small
low-grade tumors in the peripheral zone tend to grow in between normal prostatic tissue as
sparse tumors and have ADCtumor values more similar to normal peripheral zone, making the
discrimination between GS 6 and GS 7(3+4), especially with a low-volume Gleason grade 4
component, difficult. The GS does not provide information about the amount of each Gleason
grade component. A vast range in ADCtumor values for GS 7 tumors have been reported
representing the heterogeneous nature of this group. The Gleason grade 4 component of this
group can constitute all from 1% to 95% of the tumors and can be located anywhere within
the tumor volume making ADC measurements in a ROI on a single slice challenging. The
reporting of GS has changed over time with broadening of the Gleason grade 4 criteria (24),
8
which most probably have led to an GS 7 upgrade for some tumors previously interpreted as
GS 6. As a result, some patients with a low-volume Gleason grade 4 component should not
necessarily automatically be excluded from possible surveillance regimens, such as active
surveillance (25,26). Furthermore, it has been established that patients with GS 7(4+3) have a
worse prognosis following radical prostatectomy regarding biochemical recurrence, rate of
positive lymph nodes and eventually metastatic disease and death compared to patients with
GS 7(3+4) (27–34). This, combined with the recent findings showing low-volume Gleason
grade 4 on needle biopsy is associated with low-risk tumor at radical prostatectomy (35),
makes the differentiation between GS 7(3+4) and GS 7(4+3) clinically important. The overall
AUC of the ADCtumor value did not change when discriminating between GS ≤ 7(3+4) and GS
≥ 7(4+3). However, the AUC of the ADCratio changed radically to 0.90 indicating a high
clinical value of this ADC parameter.
Overall, we found that the ADCratio demonstrated the best correlation to GS compared to the
ADCtumor value and improved accuracy when discriminating both between GS 6 and GS ≥ 7
and between GS ≤ 7(3+4) and GS ≥ 7(4+3). By calculating the ADCratio some of the intra- and
inter-patient variation that may exist when using the mean ADCtumor value (4) can be leveled
out as the ADCratio is not only related to the ADCtumor value, but also to the individual
prostate’s unique signal characteristics, thus it may provide a more consistent ADC
measurement. Similarly, the ADCratio might be more applicable when comparing
examinations using different equipment, field strength and sequences.
ADC measurements may be used to asses PCa aggressiveness as an adjunct to other clinical
parameters such as PSA kinetics and clinical T-stage in the selection and follow-up of patients
undergoing active surveillance regimens (36–38). ADC measurements can be repeated and
compared over time and may provide a non-invasive alternative to repeated biopsies.
However, although there was a significant difference between the mean ADC measurements
and the GS groups, a considerable overlap between the groups was evident. Due to this
heterogeneity, a definite cut-off value for separating the GS groups could not be made.
This study has limitations. We only included patients undergoing radical prostatectomy which
could cause a selection bias. Patients with low-risk tumor on TRUS-bx are more likely to be
included in active-surveillance regimens and are not included in this study making it difficult
to apply the results to this group of patients. Similarly, patients with high-risk disease with
9
very high GS often do not undergo radical prostatectomy, which is also evident in this study
with only a small number of tumors (n=7) in the high GS group.
Not all tumor foci ≥ 5 mm on histopathology were seen in the prospective analysis of the mpMRI images. Therefore, additionally ADCtumor values and all ADCbenign values were done
using histopathology as guidance, which is not in line with the workflow in clinical practice,
where the true ADCbenign value cannot be calculated without the risk of incorporating small
invisible tumor foci in a prospective setting. However, the prospective ability of DWI and
ADC measurements for PCa detection were not part of our scope and therefore are not
addressed in this study. As we excluded tumor foci < 5 mm, the diagnostic performance of the
ADC measurements cannot with certainty be applied to the analysis of smaller tumor foci, as
well as a tumor focus has to gain a certain size for a ROI to be placed inside it.
The visual matching of mp-MRI and histopathology may potentially be imperfect due to
alterations in prostate shape and size caused by the preservation of the specimen, despite the
best effort to subjectively take this into account. There are several ways to measure the
ADCtumor values from tumor foci. We used a simple approach by drawing a single ROI in the
centre of the tumor on a single slide with the largest tumor diameter and recorded the mean
ADCtumor value. This may be an easy and clinical practical approach, but may not address the
full heterogeneity of the ADCtumor value. Others have used a "freehand ROI" drawn along the
tumor edges (7), a volumetric analysis (22) or the ADC entropy (39). Similarly, when
calculating the ADCratio, we draw a ROI of similar size as the tumor-ROI in a non-cancerous
area subjectively selected for analysis guided by the histopathological map. This measurement
may also be associated with some operator error in terms of measuring the full heterogeneity
of the non-cancerous tissue.
In conclusion, ADC measurements showed a significant correlation with tumor GS at final
pathology. The ADCratio demonstrated the best correlation compared to the ADCtumor value
and radically improved accuracy in discriminating GS ≤ 7(3+4) from GS ≥ 7(4+3) tumors.
ADC measurements may provide valuable additional information about the histopathological
aggressiveness of PCa in the pre-therapeutic assessment and planning of patient-tailored
treatment.
ACKNOWLEDGEMENTS
The authors thank statistician Tobias Wirenfeldt Klausen for his statistical contribution.
10
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14
TABLES
Table 1: Sequence parameters for 3 Tesla multiparametric MRI with pelvic-phased-array coil
Pulse
TR
TE
FA
FOV
ACQ
Number
Slice
sequence
(ms)
(ms)
(°)
(cm)
matrix
of slices
(mm)
100,800,1400 s/mm2
SE-EPI
4697
81
90
18x18
116x118
18
4
Axial T2w
SE-TSE
3129
90
90
16x16
248x239
20
3
Sagittal T2w
SE-TSE
3083
90
90
16x16
248x242
20
3
Coronal T2w
SE-TSE
3361
90
90
19x19
252x249
20
3
Coronal T1w
SE-TSE
675
20
90
40x48
540x589
36
3.6
Axial 3d DCE
FFE-3d-TFE
5.7
2.8
12
18x16
128x111
18
4
Sequence
Axial DWI, b= 0,
SE = spin echo, EPI = echo planar imaging, TSE = turbo spin echo, TFE = turbo field echo, FFE = fast field echo,
TR = repetition time, TE = echo time, FA = flip angle, ACQ matrix = acquisition matrix.
15
Table 2: Patient characteristics
Clinical characteristics
Patients n=71
Value
Age (years), median [range]
65 [47-73]
PSA (ng/ml), median [range]
10.6 [4.6-46]
cTDRE category, n (%)
Non-palpable tumor
cT1
55 (78%)
Palpable tumor
cT2
16 (22%)
Organ-confined tumor
pT2
39 (55%)
Extra-prostatic tumor
pT3
32 (45%)
pT category, n (%)
Included tumors, n
Tumors/patient, mean [range]
Tumor diameterADC (mm), median [range]
104
1.5 [1-4]
13.6 [5.5-39]
Zone of origin, n (%)
Peripheral zone
53 (51%)
Transitional zone
51 (49%)
Gleason score group, n (%)
Gleason score 6
26 (25%)
Gleason score 7(3+4)
49 (47%)
Gleason score 7(4+3)
22 (21%)
Gleason score 8-10
7 (7%)
D’Amico risk group, n (%)
Low
12 (17%)
Intermediate
37 (52%)
High
22 (31%)
16
Table 3: Mean ADCtumor values and ADCratio stratified by zonal origin
Peripheral zone (n=53) Transitional zone (n=51)
Parameter
Overall (n=104)
Mean (CI 95%)
Mean (CI 95%)
*p-value
Mean (CI 95%)
2968 (2844;3091)
2397 (2286;2508)
<0.001
2688 (2589;2787)
1468 (1349;1587)
1113 (1041;1184)
<0.001
1294 (1217;1371)
<0.001
<0.001
0.49 (0.46;0.52)
0.47 (0.44;0.49)
ADCbenign
(×10-6mm2/sec)
ADCtumor
(×10-6mm2/sec)
**p-value
ADCratio
<0.001
0.194
0.48 (0.46;0.50)
*p-value < 0.05 represents significant difference in mean ADC values between the peripheral- and transitional
zone.
**p-value < 0.05 represents significant difference between mean ADC value of non-cancerous tissue and tumor
CI 95% is the 95% confidence interval of the mean.
Table 4: Spearman rho correlation between ADC measurements and Gleason score overall
for all tumors and stratified by zonal origin
Spearman rho
Zonal origin
ADCtumor
ADCratio
Peripheral zone
-0.515
-0.663
Transitional zone
-0.249
-0.605
Overall
-0.421
-0.649
All statistical values are significant (p<0.05).
17
Table 5: Mean ADCtumor value and ADCratio according to Gleason score groups for all tumors
and stratified by zonal origin
Zonal origin
ADCtumor (×10-6mm2/sec)
ADCratio
n
Mean (CI 95%)
Mean (CI 95%)
Peripheral zone
GS 6
18
1699 (1534;1863)
0.57 (0.53;0.61)
(n=53)
GS 7(3+4)
22
1472 (1293;1651)
0.50 (0.46;0.53)
GS 7(4+3)
9
1207 (1098;1316)
0.40 (0.36;0.43)
GS 8-10
4
995 (780;1210)
0.35 (0.29;0.40)
<0.001*
<0.001*
p-value
Transitional zone
GS 6
8
1158 (1017;1298)
0.53 (0.50;0.57)
(n=51)
GS 7(3+4)
27
1150 (1054;1248)
0.49 (0.47;0.52)
GS 7(4+3)
13
1034 (857;1210)
0.39 (0.34;0.45)
GS 8-10
3
990 (737;1243)
0.38 (0.31;0.46)
0.46
<0.001*
p-value
All tumor foci
GS 6
26
1532 (1375;1689)
0.56 (0.53;0.59)
(n=104)
GS 7(3+4)
49
1295 (1188;1402)
0.49 (0.47;0.51)
GS 7(4+3)
22
1104 (993;1217)
0.39 (0.36;0.43)
GS 8-10
7
993 (829;1157)
0.36 (0.31;0.41)
<0.001*
<0.001*
p-value
*p-value ≤ 0.05 is statistically significant.
18
FIGURES
Figure 1: PCa tumor foci in the left peripheral zone (white arrows) on a) axial T2W imaging
with b) corresponding ADCmap with a ROI placed in the tumor (ADCtumor value = 989×106
mm2/sec) and a ROI placed in a non-cancerous area (ADCbenign value = 2826×10-6mm2/sec) to
calculate the ADCratio = 0.35. The c) histopathological examination of the radical
prostatectomy specimen showed a corresponding PCa GS 7(4+3).
19
a)
b)
Figure 2: Box-whisker plot of a) mean ADCtumor value and b) ADCratio for all tumors
stratified by GS groups. The horizontal line represents the median. The circles indicate
outliers.
20
a)
b)
Figure 3: ROC-curve analysis for determining tumor aggressiveness using ADCtumor value
and ADCratio for all tumors to discriminate between a) GS 6 and GS ≥ 7 and between b) GS ≤
7(3+4) and GS ≥ 7(4+3).