PhD thesis - Herlev Hospitalthesis based on international experience, literature evidence and guidelines. This PhD thesis is the result of my work as a clinical research associate

F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S

U N I V E R S I T Y O F C O P E N H A G E N

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

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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

DRE = Digital rectal examination

TRUS = Transrectal ultrasound

TRUS-bx = TRUS-guided biopsies

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

ESUR = European Society of Urogenital Radiology

PIRADS = Prostate imaging reporting and data system

BIRADS = Breast imaging reporting and data system

T1W = T1-weighted

T2W = T2-weighted

DWI = Diffusion-weighted imaging

ADC = Apparent diffusion coefficient

DCE = Dynamic contrast enhanced

MRSI = Magnetic resonance spectroscopic imaging

GFR = Glomerular filtration rate

OC = Organ-confined

ECE = Extra capsular extension

SVI = Seminal vesicle invasion

GS = Gleason score

ISUP = International Society of Urological Pathology

PZ = Peripheral zone

TZ = Transitional zone

CZ = Central zone

AUC = Area under the curve

MDT = Multi-disciplinary team

BPH = Benign prostate hypertrophy

Re-biopsy = Repeated biopsy

PPA-coil = Pelvic-phased-array coil

ERC = Endo-rectal coil

AS = Active surveillance

PPV = Positive predictive value

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 (cT3-

cT4) 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

Low risk cT1-T2a ≤6 <10

Intermediate risk cT2b 7 10-20

High risk ≥cT2c ≥8 >20

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 spectroscopy-

and 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 pelvic-

phased-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 hypo-

intense 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 T2W-

signal 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

22

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 ADCmap 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

23

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).

24

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 mp-

MRI. 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

25

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


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


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



+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].

26

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 Score

Extracapsular extension Abutment

1

(ECE)

Irregularity

3

Neurovascular bundle thickening

4

Bulge, loss of capsule

4

Measurable extracapsular disease

5

Seminal vesicles

Expansion

1

(SVI)

Low T2 signal

2

Filling in of angle

3

Enhancement and impeded diffusion

4

Distal sphincter

Adjacent tumour

3

Effacement of low signal sphincter muscle

3

Abnormal enhancement extending into sphincter

4

Bladder neck

Adjacent tumour

2

Loss of low T2 signal in bladder muscle

3

Abnormal enhancement extending into bladder neck 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.

27

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].

28

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.

29

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.

30

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

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].

31

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.

32

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]).

33

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 TRUS-

bx (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 DCE-

curve (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.

34

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


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.

35


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.

36

Study III: Apparent diffusion coefficient ratio correlates significantly with Gleason score at final pathology


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.


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.

37

Results

Seventy-one patients with a median age of 65 (range 47-73) and a median PSA of 10.6 (range 4.6-

46) 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.

38

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

39

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-MRI-

suspicious 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 mp-

MRI 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

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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-MRI-

suspicious 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 biopsy-

naive men with elevated PSA showing that the mp-MRI "targeted-only" approach can reduce the

41

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

42

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

43

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 high-

grade 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

44

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

45

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, mp-

MRI 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.

46

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

47

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

48

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 non-

MRI 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.

49

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 biopsy-

related 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.

50

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.

51

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 under-

grading 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 mp-

MRI-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 mp-

MRI "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, mp-

MRI 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

52

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, mp-

MRI 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 pre-

therapeutic 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,

53

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 high-

quality 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.

54

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 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.


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

55

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 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

56

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.

57

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 mp-

MRI 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.

58

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

59

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.

60

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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


Submitted

Study III:

Apparent diffusion coefficient ratio correlates significantly with Gleason score at final

pathology


Submitted

Scandinavian Journal of Urology. 2014; Early Online, 1–10

ORIGINAL ARTICLE

Early experience with multiparametric magnetic resonanceimaging-targeted biopsies under visual transrectal ultrasound guidancein patients suspicious for prostate cancer undergoing repeated biopsy

LARS BOESEN1, NIS NOERGAARD1, ELIZAVETA CHABANOVA2, VIBEKE LOGAGER2,INGEGERD BALSLEV3, KARI MIKINES1 & HENRIK S. THOMSEN2

1Departments of Urology, 2Radiology, and 3Pathology, Herlev University Hospital, Herlev, Denmark

AbstractObjectives. The purpose of this study was to investigate the detection rate of prostate cancer (PCa) by multiparametricmagnetic 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 negativeTRUS-bx scheduled for repeated biopsies due to persistent suspicion of PCa were prospectively enrolled. mp-MRI wasperformed 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 anymp-MRI-suspicious lesion not targeted by systematic TRUS-bx. Results.PCa was found in 39 out of 83 patients (47%) andmp-MRI identified at least one lesion with some degree of suspicion in all 39 patients. Both PI-RADS and Likert scoring showed ahigh correlation between suspicion of malignancy and biopsy results (p < 0.0001). Five patients (13%) had cancer detected onlyonmp-MRI-bx outside the TRUS-bx areas (p = 0.025) and another seven patients (21%) had an overall Gleason score upgradeof at least one grade based on the mp-MRI-bx. Secondary PCa lesions not visible on mp-MRI were detected by TRUS-bx in sixout of 39 PCa patients. The secondary foci were all Gleason 6 (3 + 3) in 5–10% of the biopsy core. According to the Epsteincriteria, 37 out of 39 cancer patients were classified as clinically significant. Conclusion. Using mp-MRI, even without previousexperience, 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 significantclinical problem owing to high false-negative rates of20–30% [1–3]. To overcome this, patients with neg-ative TRUS-bx often undergo several repeated biopsy(rebiopsy) procedures that will increase biopsy-related costs and may contribute to increased anxietyand morbidity among patients. The detection rate atfirst TRUS rebiopsy is 10–22% [2,4], with decreasingrates at repeated procedures. Still, a significantnumber of cancers is missed [3]. These limitations

have led to an intense need for a way to improve thedetection rate of clinically significant PCa at TRUS-bx. Multiparametric magnetic resonance imaging(mp-MRI) of the prostate seems to have the potentialto solve the problem [5–7]. Therefore, a prospectivestudy was carried out on a patient cohort scheduledfor TRUS rebiopsy due to persistent suspicion of PCaafter standard TRUS-bx with negative findings. Theaim was to investigate the value of prebiopsy mp-MRIon the PCa detection rate at rebiopsy by combiningstandard TRUS-bx with mp-MRI-targeted biopsies(mp-MRI-bx) under visual TRUS guidance andto evaluate the clinical significance of the detectedPCa.

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 HealthcareDOI: 10.3109/21681805.2014.925497

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This prospective, single-institution study wasapproved by the Local Committee for HealthResearch Ethics (no. H-1-2011-066) and the DanishData Protection Agency. It was registered atClinicaltrials.gov (no. NCT01640262).

Patients

All patients were prospectively enrolled fromSeptember 2011 to September 2012 after writteninformed consent was obtained. Inclusion criteriarequired that all patients had a history of negativeTRUS-bx and were scheduled for repeated biopsiesdue to persistent suspicion of PCa based on eitherprostate-specific antigen (PSA) value, an abnormaldigital rectal examination (DRE) or a previous abnor-mal TRUS image. All prior TRUS-bx sessionsincluded 10–12 standard biopsy cores. None of thepatients had previously undergone mp-MRI of theprostate. The exclusion criteria were patients previ-ously diagnosed with PCa or contraindication tomp-MRI (pacemaker, magnetic implants, severeclaustrophobia, gadolinium-based MRI contrastallergy, impaired renal function with glomerularfiltration rate <30 ml/min).

Multiparametric magnetic resonance imaging

All patients underwent mp-MRI before rebiopsyusing a 3.0 T MRI scanner (Achieva; Philips Health-care, Best, Netherlands) with a six-channel cardiacpelvic-phased-array coil (Sense; Philips Healthcare,Best, Netherlands) positioned over the pelvis.A minimum interval of 3 weeks was left betweenthe latest TRUS-bx and mp-MRI to reduce biopsy-related haemorrhagic artefacts. If tolerated by thepatient, a 1 mg intramuscular injection of glucagon(Glucagen�; Novo Nordisk, Bagsvaerd, Denmark)combined with a 1 mg intravenous injection of hyos-cinbutylbromid (Buscopan�; Boehringer Ingelheim,Ingelheim am Rhein, Germany) was administered toreduce peristaltic motion. Triplanar T2-weightedimages from below the prostatic apex to above theseminal vesicles and a coronal T1-weighted imageincluding the small pelvis for detection of haemor-rhage and enlarged local lymph nodes were obtained.In addition, axial diffusion-weighted images includingfour b values (b0, b100, b800 and b1400) along withreconstruction of the corresponding apparentdiffusion coefficient (ADC) map (b values 100 and800), together with dynamic contrast-enhancedimages before, during and after intravenous admin-istration of 15 ml gadoterate meglumine (Dotarem

279.3 mg/ml; Guerbet, Roissy CDG, France) wereperformed. The contrast agent was administeredusing a power injector (MedRad, Warrendale, PA,USA) followed by a 20 ml saline flush injection at aflow rate of 2.5 ml/s.

Image analysis

On mp-MRI the prostate was divided into 18 regionsof interest according to a modified diagram providedby the European Consensus Meeting [8] (Figure 1).Precontrast and coronal T1-weighted images wereused to identify postbiopsy haemorrhage as an areawith high signal intensity to rule out false-positivefindings on T2 weighting. All mp-MRI imagesfrom each patient were reviewed simultaneously bythe same dedicated physician and any suspiciouslesions identified on T2-weighted, diffusion-weighted(high b-value image and ADC map) or dynamiccontrast-enhanced images were registered on themodified diagram and scored according to the Pros-tate Imaging Reporting and Data System (PI-RADS)classification from the European Society of UrogenitalRadiology (ESUR), giving a sum of scores (rangingfrom 3 to 15) [9]. In addition, each lesion was thenclassified overall on a five-point Likert scale accordingto the probability of clinically significant malignancybeing present (1 = highly unlikely; 2 = unlikely; 3 =equivocal; 4 = likely; 5 = highly likely). The PI-RADSand Likert scores were separately divided into threerisk groups (high, moderate and low) according tosuspicion of PCa.

Biopsy: transrectal ultrasound biopsy andmultiparametric magnetic resonance imaging-targetedbiopsy

Initially, all patients underwent standard TRUSrebiopsy with local gel anaesthetics (Installagel�;Farco-Pharma, Cologne, Germany) using a HitachiPreirus ultrasound scanner, a Hitachi EUP-V53Wendfire transducer and a Hitachi EZU-PA5V needleguide (Hitachi Medical Systems, Europe Holding,Zug, Switzerland), and a ProMag TruCut, 18 G,25 cm biopsy needle (Angiotech Medical DeviceTechnologies, Gainesville, FL, USA). All prostatebiopsies were performed with the endfire techniquein the axial plane by the same operator with 20 years’experience in TRUS-bx. The operator had no priorknowledge of the mp-MRI findings before taking thestandard biopsies. Ten TRUS-bx standard cores weretaken systematically from 10 prostatic regions andmarked separately. Then the operator reviewedthe mp-MRI data on a dedicated workstation in thebiopsy room together with the MRI physician. Any

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1(2%)

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28(54%)

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16(31%)

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13(25%)

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3(5.8%)

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0 0

Figure 1. Modified diagram from the European ConsensusMeeting [8]. The prostate is divided into 12 posterior and six anterior regions. Thediagram shows the main location of the 52 multiparametric magnetic resonance imaging (mp-MRI) prostate cancer-positive lesions. Eachnumber represents the number of suspicious lesions located primarily in that region, n (%). An mp-MRI lesion could involve more than oneprostatic region, but the mp-MRI biopsies were targeted towards only one region containing the bulk of the tumour.

Multiparametric MRI in prostate cancer detection 3

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mp-MRI suspicious lesions were visually matchedand registered on the corresponding axial TRUSimage based on zonal anatomy and tissue landmarks.Any mp-MRI suspicious lesions not sampled by stan-dard TRUS-bx were then targeted by at least oneadditional biopsy core based on visual mp-MRI/TRUS fusion. An mp-MRI suspicious lesion couldinvolve more than one prostatic region and the addi-tional biopsy was targeted towards the region contain-ing the bulk of the lesion. If an mp-MRI suspiciouslesion was clearly inside a standard biopsy region andsampled by the standard biopsy core, no additionaltargeted biopsy was taken, to limit the total number ofbiopsies. If an mp-MRI suspicious lesion was inside astandard biopsy region, but it was uncertain whetherthe lesion had been sampled by the standard biopsycore, one additional targeted biopsy was taken fromthe same prostatic region and if possible from anadjacent area guided by visual recognition and oftenthe systematic biopsy trajectories to disperse the twobiopsies. All biopsies from mp-MRI suspiciouslesions were further marked as an mp-MRI targetedbiopsy (mp-MRI-bx).

Histopathological evaluation

A genitourinary pathologist with more than 9 years ofdedicated experience in prostatic pathology reviewedand described all the histological biopsy samples. Foreach biopsy core positive for PCa, the location andregion according to the diagram, the Gleason score[10] and the extent of cancer involvement (percent-age) in the core were determined. Any signs ofinflammation, high-grade prostatic intraepithelialneoplasia (HGPIN) or cellular changes suspiciousof adenocarcinoma were outlined in all the otherbiopsies.

Criteria for clinical significance

To evaluate the diagnosed cancerous lesions forclinical significance, the following Epstein criteriawere used: a Gleason score of 7 of higher; PSA densityat least 0.15 ng/ml/cm3; or at least three positivestandard cores/cancer involvement per biopsy coreof 50% or more [11].

Statistical analysis

The patients’ clinical characteristics were stratified bybiopsy results and described by descriptive statistics.Continuous variables including age, PSA, PSA den-sity, prior biopsy procedures, number of mp-MRIlesions and number of mp-MRI-bx were comparedusing theWilcoxon rank sum test, and a Fisher’s exact

test was used to compare the cT stage pooled in non-palpable and palpable tumour groups. The prebiopsymp-MRI scores for each identified lesion werecompared with the biopsy results and a chi-squaredanalysis was used to determine the correlationbetween suspicion on mp-MRI and positive biopsiesfor each identified lesion using both PI-RADS andLikert scoring systems. Cancer detection rates withmp-MRI-bx and standard TRUS-bx were examinedwith the non-conservativeMcNemar test. The highestGleason scores from standard TRUS-bx and mp-MRI-bx from each patient were compared. A p valuebelow 0.05 was considered significant. Statisticalanalysis was performed using software SPSS20.0 (IBM Corporation, USA).

Results

This study prospectively enrolled 89 patients. How-ever, six patients had to be excluded owing totechnical problems with the mp-MRI or claustropho-bia. The final study population of 83 patients had amedian of two (range one to six) prior negativeTRUS-bx and a median PSA of 11 ng/ml (range4.1–97 ng/ml) (Table I).PCa was detected in 39 out of 83 patients (47%)

and 44 out of 83 patients (53%) had either a benigncondition (n = 34), HGPIN (n = 3) or a lesionsuspicious of adenocarcinoma (n = 7) at pathology.Lesions ranging from low to high suspicion of PCawere identified on mp-MRI in all but one patient,giving a total of 156 identified lesions and median oftwo (range none to five) per patient. Biopsies werepositive for PCa in 52 out of 156 (33%) mp-MRIidentified lesions in 39 patients (Figure 1). Additionalmp-MRI-bx were targeted towards 48 out of 52 mp-MRI cancer-positive lesions. The remaining fourlesions were sampled by TRUS-bx as the standardbiopsy cores were clearly inside the mp-MRI identi-fied lesions, and thus no extra mp-MRI-bx werenecessary. The mp-MRI-bx correctly detected PCain 40 out of 48 mp-MRI cancer-positive lesions thatwere targeted by additional mp-MRI-bx. The remain-ing eight mp-MRI cancer-positive lesions weredetected by TRUS-bx as mp-MRI correctly identifiedthe suspicious lesions, but the additional mp-MRI-bxfrom the same regions were negative (Figure 2).Both the PI-RADS and the overall Likert scoring

system showed a high correlation with the biopsyresults (p < 0.0001) (Figures 3 and 4, Tables IIand III).The mp-MRI identified at least one lesion with

some degree of suspicion in all 39 patients diagnosedwith PCa. Each patient had a median of two (rangenone to four) extra mp-MRI-bx in addition to the

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10 standard TRUS-bx, making a total average of 12biopsy cores per patient. Five patients (13%) hadsignificant PCa detected only on mp-MRI-bx (p =0.025), with four out of five (80%) having interme-diate/high-grade cancer (Gleason score ‡7). Bothstandard TRUS-bx and mp-MRI-bx detected PCain 34 out of 39 patients. However, seven out of34 patients (21%) had an overall Gleason score

upgrade, among which five out of seven patientswent from low-grade (Gleason score 6) to intermedi-ate/high-grade cancer based on the additional mp-MRI-bx. A secondarymultifocal PCa lesion not visibleon mp-MRI was detected by TRUS-bx in six out of39 PCa patients. All secondary lesions were Gleason6 (3 + 3) tumour foci in 5–10% of the biopsy core. Nopatients had aGleason score upgrade based on positive

mp-MRI-bx (n)

mp-MRI lesions (n) 52

Positive (40)

30

TRUS-bx negative insame lesion (n)

TRUS-bx positive insame lesion (n)

10

Negative (12)

4

TRUS-bx clearlyinside mp-MRI

lesion-noadditional

mp-MRI-bx

TRUS-bx uncertainwhether inside

mp-MRI lesion-oneextra adjacent

mp-MRI-bx

8

Figure 2. Multiparametric magnetic resonance imaging (mp-MRI) suspicious lesions positive for prostate cancer at biopsy. bx = biopsy;TRUS = transrectal ultrasound.

Table I. Demographic data of the study cohort stratified by biopsy results.

Clinical characteristicsPCa negative

(n = 44)PCa positive(n = 39) p

Total(n = 83)

Age (years) 61.5 (45–74) 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

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%) 0.504 73 (88%)

Palpable tumour cT2–cT3 4 (9%) 6 (15%) 10 (12%)

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)

Data are shown as median (range) or n (%).PCa = prostate cancer; PSA = prostate-specific antigen; mp-MRI = multiparametric magnetic resonance imaging; bx = biopsy.


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Cancer

11%

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Low Moderate High

Negative biopsyPositive biopsy

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Figure 3. Biopsy results for each multiparametric magnetic resonance imaging (MRI) lesion correlated with (a) Prostate Imaging Reportingand Data System (PI-RADS) score and (b) PI-RADS risk group classification (high: PI-RADS score 13–15; moderate: 10–12; low: <10).

6 L. Boesen et al.

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TRUS-bx from non-visible lesions on mp-MRI. Twopatients had insignificant PCa detected according tothe criteria, providing an overall detection rate of

clinically significantPCaof45%(37outof83patients),amongwhich27%(10outof 37)harbouredhigh-grade(Gleason score ‡8) cancer.

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40

30

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CancerNegative biopsy

Positive biopsy

Cancer

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15%

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20.0%

0.0%

77%

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2%

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Negative biopsy

Positive biopsy

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431 2 5

Figure 4. Biopsy results for each multiparametric magnetic resonance imaging (MRI) lesion correlated with (a) Likert score and (b) Likert riskgroup classification (high: Likert score 4 + 5; moderate: Likert score 3; low: Likert score 1 + 2).


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Discussion

Before this study, mp-MRI had never been applied atthis institution for PCa detection or for guidingtargeted biopsies towards mp-MRI-suspiciouslesions. The patient population and results representthe authors’ initial experience with this new tech-nique. The main objective was to evaluate whetherprebiopsy mp-MRI in this setting could improve theoverall detection rate of clinically significant PCa byadding mp-MRI-bx under visual TRUS guidance tostandard TRUS-bx without previous experience ofthis. The results show that this is possible. An overallPCa 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 oftwo (range one to six) prior negative TRUS-bx and amedian PSA of 11 ng/ml (range 4.1–97 ng/ml). Therewas no significant difference in PSA and cT stagebetween PCa-positive and PCa-negative patients.There was only a significant difference in age andPSA density, which is not surprising, as age and highPSA relative to prostate volume are known risk factorsfor PCa (Table I). Only two patients had insignificantPCa detected according to the criteria, providing anoverall detection rate of clinically significant PCa of45% (37 out of 83 patients). Five patients (13%) hadsignificant PCa detected only on the mp-MRI-bxoutside the systematic biopsy regions. This overallPCa detection rate is in accordance with previousfindings as outlined in the review by Lawrentschukand Fleshner [12], although they found a higher

proportion of PCa detected purely by the mp-MRI-targeted biopsy cores.In the authors’ department, standard TRUS-bx is

limited to a very few highly experienced operatorsusing an endfire biopsy probe. Ching et al. [13]showed that in standard biopsies the endfire probeallows for better sampling of the lateral and apicalregions of the prostate, where tumours often reside. Inthe authors’ experience, the endfire biopsy needleenters the prostatic surface perpendicularly and pene-trates deeper and more anteriorly into the prostate.Especially in the apical regions, the standard biopsycore often samples the entire height of the prostate.This may enable better sampling of apical andanteriorly located tumours on TRUS-bx, causingan increased detection rate with standard biopsies.This was confirmed in the present study as more than70% of the mp-MRI PCa-positive lesions werelocated in the anterior or apical region (Figure 1).Despite a rather surprisingly high PCa detection

rate using standard biopsies, a significant improve-ment (p = 0.025) in the overall detection rate wasfound by adding mp-MRI-bx as an adjunct to thestandard 10-core TRUS-bx.With the development of more targeted biopsy

strategies, the cancer detection rate may be assessedbetter by lesion instead of on a per-patient basis [14].At least one tumour-suspicious lesion was identifiedon mp-MRI in all 39 patients diagnosed with PCa.A highly significant correlation between positive biop-sies and lesion suspicion on mp-MRI (p = 0.0001) was

Table II. Biopsy results correlated with Prostate Imaging Reporting and Data System (PI-RADS) risk group classification and relation toGleason 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

MRI = magnetic resonance imaging.

Table III. Biopsy results correlated with Likert risk group classification and relation to Gleason score.

Gleason score

MRI suspicion Positive biopsy Negative biopsyLesions(n) 6 7 (3 + 4) 7 (4 + 3) 8–10

High 43 13 56 10 14 7 12

Moderate 8 44 52 4 4

Low 1 47 48 1

Total 52 104 156 15 18 7 12

MRI = magnetic resonance imaging.

8 L. Boesen et al.

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found using both the PI-RADS classification andLikert scoring. If mp-MRI showed a high suspicionof PCa on either PI-RADS or Likert scoring, then89% (32 out of 36) and 76% (43 out of 56) of thelesions were positive at biopsy, respectively. On theother hand, only 2% (one out of 48) with Likert and6% (five out of 86) with PI-RADS low suspicion onmp-MRI were positive for PCa. All but one low-suspicious lesion was Gleason score 6. Six patientshad evidence of multifocal disease on biopsy, whereseparate secondary PCa lesions were not visible onmp-MRI and were detected only by TRUS-bx. How-ever, mp-MRI identified all of the patients’ dominat-ing index PCa lesions; the missed secondary lesionswere all small Gleason score 6 (3 + 3) tumours with 5–10% cancer involvement per biopsy core. These find-ings underline the potential value of using prebiopsymp-MRI to increase the detection rate of clinicallysignificant PCa previously missed by standard TRUS-bx and to stratify the patients and lesions according tosuspicion on mp-MRI using both the PI-RADS andLikert scoring systems. This was confirmed in a recentstudy by Portalez et al. [15], in which the ESURPI-RADS scoring was prospectively validated in acontemporary patient cohort in relation to repeatedprostate biopsies. Using a PI-RADS score of 9 orabove as the threshold, the authors report a sensitivityand specificity of 69% and 92%, respectively, and anegative predictive value of 95%. In the context ofdeciding on repeated biopsies, this high negativepredictive value can predict the absence of cancerwith high confidence and thereby possibly reducethe number of unnecessary rebiopsies.The mp-MRI-bx were positive for PCa in 40 out of

52 mp-MRI cancer-positive lesions. The remaining12 mp-MRI cancer-positive lesions were sampledonly by standard TRUS-bx. Additional mp-MRI-bxwere targeted towards eight out of 12 lesions as it wasuncertain whether the standard core had sampled themp-MRI-identified lesions. These additional mp-MRI-bx were negative compared with the standardcores from the same prostatic regions, which may beexplained by the fact that the mp-MRI-bx were takenfrom adjacent areas within the same region to dispersethe two biopsies. However, it may also be a result ofmisregistration between the suspicious lesion seen onmp-MRI and the visual match on the correspondingaxial TRUS image. Visual translation of the mp-MRIimage to the grey-scale TRUS image may not alwaysbe accurate. The operator has to visually correlate themp-MRI image on to a real-time two-dimensionalTRUS image and translate it all into a three-dimensional representation of the prostate based onzonal anatomy and tissue landmarks. There will be a

margin of error, especially if the prostate is large or thelesion is located anteriorly [7]. Methods for improvingthe accuracy of targeted biopsies, including real-timeMRI–TRUS image fusion [6,14] and in-gantry mp-MRI-guided biopsies [16,17], show promising results.Standard TRUS-bx detected PCa in 34 out of

39 patients, where seven out of 34 (21%) patientshad an overall Gleason score upgrade due to the use ofadditional mp-MRI-bx. The Gleason score wasupgraded from low-grade to intermediate/high-gradecancer in five out of seven patients. This is in line withstudies showing a correlation between mp-MRI andPCa aggressiveness represented by the Gleason score[16,18–20]. Overall, using prebiopsy mp-MRI, fivepatients had PCa detected only by mp-MRI-bx andanother seven patients had an overall Gleason scoreupgrade, making a total of 12 out of 39 (31%) newlydiagnosed PCa patients who may have had theirprognosis and treatment decision altered owing tothe 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 per-formed at the authors’ institution. This could cause abias in comparison of the PCa detection rate betweenstudies. Using the combination of TRUS-bx and mp-MRI-bx, a high overall PCa detection rate of 47% wasfound at median third time biopsy with a high pro-portion of significant tumours. This can partly beexplained by the fact that the patient population inthis study was prone to harbouring a significanttumour, as the patients usually presented risingPSA levels without any other benign explanationsand where third time biopsy was indicated. Thesepatients would also be more likely to benefit frommp-MRI-targeted biopsies as they all had negativestandard TRUS-bx previously.Another limitation is the lack of a gold standard

reference as a totally embedded prostatectomy speci-men.Whether a cancerwasmissedonnegativebiopsiescould not be determined, and a true false-negative rateforTRUS-bx andmp-MRI-bx could not be assessed inthis study.However, all patients in the studyunderwentstandard TRUS-bx in 10 regions blinded to any mp-MRIfindings regardless ofwhethermp-MRI identifieda suspicious lesion or not. This made it possible todetermine whether TRUS-bx detected PCa lesionsthat were not visible on mp-MRI and to correlate thefindings with clinical significance.In conclusion, this prospective study shows that

using multiparametric MRI before repeated biopsy,even without previous experience, can improve thedetection rate of clinically significant PCa by com-bining standard TRUS-bx with mp-MRI-targetedbiopsies under visual TRUS guidance, and allowsmore accurate Gleason grading.


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Declaration of interest: The authors have noconflicts of interest.

References

[1] Ukimura O, Coleman JA, de la Taille A, Emberton M,Epstein JI, Freedland SJ, et al. Contemporary role ofsystematic prostate biopsies: indications, techniques, andimplications for patient care. Eur Urol 2013;63:214–30.

[2] Djavan B, Ravery V, Zlotta A, Dobronski P, Dobrovits M,Fakhari M, et al. Prospective evaluation of prostate cancerdetected on biopsies 1, 2, 3 and 4: when should we stop?J Urol 2001;166:1679–83.

[3] Shariat SF, Roehrborn CG. Using biopsy to detect prostatecancer. Rev Urol 2008;10:262–80.

[4] Roehrborn CG, Pickens GJ, Sanders JS. Diagnostic yield ofrepeated transrectal ultrasound-guided biopsies stratified byspecific histopathologic diagnoses and prostate specific anti-gen levels. Urology 1996;47:347–52.

[5] Sciarra A, Barentsz J, Bjartell A, Eastham J, Hricak H,Panebianco V, et al. Advances in magnetic resonance imag-ing: how they are changing the management of prostatecancer. Eur Urol 2011;59:962–77.

[6] Delongchamps NB, Peyromaure M, Schull A, Beuvon F,Bouazza N, Flam T, et al. Prebiopsy magnetic resonanceimaging and prostate cancer detection: comparison ofrandom and targeted biopsies. J Urol 2013;189:493–9.

[7] Cornud F, Delongchamps NB, Mozer P, Beuvon F,Schull A, Muradyan N, et al. Value of multiparametricMRI in the work-up of prostate cancer. Curr Urol Rep2012;13:82–92.

[8] Dickinson L, Ahmed HU, Allen C, Barentsz JO, Carey B,Futterer JJ, et al. Magnetic resonance imaging for the detec-tion, localisation, and characterisation of prostate cancer:recommendations from a European consensus meeting.Eur Urol 2011;59:477–94.

[9] Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S,Villeirs G, et al. ESUR prostate MR guidelines 2012. EurRadiol 2012;22:746–57.

[10] Epstein JI. An update of the Gleason grading system. J Urol2010;183:433–40.

[11] Ploussard G, Epstein JI, Montironi R, Carroll PR, Wirth M,Grimm M-O, et al. The contemporary concept of significant

versus insignificant prostate cancer. Eur Urol 2011;60:291–303.

[12] Lawrentschuk N, Fleshner N. The role of magnetic reso-nance imaging in targeting prostate cancer in patients withprevious negative biopsies and elevated prostate-specificantigen levels. BJU Int 2009;103:730–3.

[13] Ching CB, Moussa AS, Li J, Lane BR, Zippe C, Jones JS.Does transrectal ultrasound probe configuration really mat-ter? End fire versus side fire probe prostate cancer detectionrates. J Urol 2009;181:2077–82; discussion 2082–3.

[14] Pinto PA, Chung PH, Rastinehad AR, Baccala AA,Kruecker J, Benjamin CJ, et al. Magnetic resonance imag-ing/ultrasound fusion guided prostate biopsy improves can-cer detection following transrectal ultrasound biopsy andcorrelates with multiparametric magnetic resonance imaging.J Urol 2011;186:1281–5.

[15] Portalez D, Mozer P, Cornud F, Renard-Penna R, Misrai V,Thoulouzan M, et al. Validation of the European Society ofUrogenital Radiology scoring system for prostate cancer diag-nosis on multiparametric magnetic resonance imaging in acohort of repeat biopsy patients. Eur Urol 2012;62:986–96.

[16] Hambrock T, Somford DM, Hoeks C, Bouwense SAW,Huisman H, Yakar D, et al. Magnetic resonance imagingguided prostate biopsy in men with repeat negative biopsiesand increased prostate specific antigen. J Urol 2010;183:520–7.

[17] Roethke M, Anastasiadis AG, Lichy M, Werner M,Wagner P, Kruck S, et al. MRI-guided prostate biopsydetects clinically significant cancer: analysis of a cohort of100 patients after previous negative TRUS biopsy. World JUrol 2012;30:213–18.

[18] Hambrock T, Hoeks C, Hulsbergen-van de Kaa C,Scheenen T, Fütterer J, Bouwense S, et al. Prospectiveassessment of prostate cancer aggressiveness using 3-T dif-fusion-weighted magnetic resonance imaging-guided biop-sies versus a systematic 10-core transrectal ultrasoundprostate biopsy cohort. Eur Urol 2012;61:177–84.

[19] Hambrock T, Somford DM. Relationship between ApparentDiffusion Coefficients at 3.0-T MR imaging and Gleasongrade in peripheral zone prostate cancer. Radiology 2013;259:453–61.

[20] Turkbey B, Shah VP, Pang Y, Bernardo M, Xu S,Kruecker J, et al. Is apparent diffusion coefficient associatedwith clinical risk scores for prostate cancers that are visible on3-T MR images? Radiology 2011;258:488–95.

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http://www.ncbi.nlm.nih.gov/pubmed/23021971?dopt=Abstract























































1

Prostate cancer staging with extracapsular extension risk scoring using

multiparametric MRI: a correlation with histopathology


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 (T-

stage) 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 contrast-

media 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 post-

biopsy 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 mp-

MRI. 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


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 mp-

MRI 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 cut-

off 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 five-

point 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 mp-

MRI 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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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.

Sequence

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

Sagittal 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



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 Score

Extracapsular extension Capsular abutment 1

Capsular irregularity, retraction or thickening 3

Neurovascular bundle thickening

4

Bulge or loss of capsule

4

Measurable extracapsular disease 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 OC (n=55) EPE (n=32 ) P-value

Age (years), median [range]

63 [47-74] 66.5 [54-73] .001

PSA (ng/ml), median [range]

10.0 [4.6-44] 12.0 [5.4-45.0] .152

Positive biopsy cores (%), mean [range] 28 [10-70] 37 [10-90] .027

cTDRE category, n (%)

Non-palpable tumour cT1 46 (84%) 23 (72%) .272

Palpable tumour cT2 9 (16%) 9 (28%)

cTTRUS category, n (%)

Non-visual tumour cT1 33 (60%) 16 (50%) .380

Visual tumour cT2 22 (37%) 16 (50%)

cTMRI category, n (%)

Organ-confined tumour cT2 49 (93%) 8 (25%) <.0001

Extra prostatic tumour cT3 6 (7%) 24 (75%)

Biopsy Gleason score, n (%)

Gleason score 6

20 (36%) 3 (9%) .021

Gleason score 7

29 (53%) 23 (72%)

Gleason score 8-10 6 (11%) 6 (19%)

D’Amico risk group, n (%)

Low

14 (25%) 3 (9%) .163

Intermediate

28 (51%) 18 (56%)

High 13 (24%) 11 (34%)

21

Table 4: Diagnostic performance of extra capsular tumour extension (ECE) risk scoring depending

on cut-off level and inclusion of personal opinion.

ECE risk score

pT Sensitivity Specificity PPV NPV Accuracy

OC ECE* Total [CI 95%] [CI 95%] [CI 95%] [CI 95%] [CI 95%]

Reader A

Cut-off level 5 OC

54 22 76 0.29 0.96 0.82 0.71 0.72

ECE 2 9 11 [0.14;0.48] [0.88;0.99] [0.48;0.97] [0.60;0.81]

Total 56 31 87

Cut-off level ≥ 4

OC 44 6 50 0.81 0.78 0.68 0.88 0.79

ECE 12 25 37 [0.63;0.93] [0.66;0.88] [0.50;0.82] [0.76;0.95]

Total 56 31 87

Cut-off level ≥ 3

OC 38 2 40 0.94 0.68 0.62 0.95 0.77

ECE 18 29 47 [0.79;0.99] [0.54;0.80] [0.46;0.75] [0.83;0.99]

Total 56 31 87

Inclusion of

personal opinion

OC 49 8 57 0.74 0.88 0.77 0.86 0.83

ECE 7 23 30 [0.55;0.88] [0.76;0.95] [0.56;0.90] [0.74;0.94]

Total 56 31 87

SVI MRI

No SVI 81 1 82 0.80 0.99 0.80 0.99 0.98

SVI 1 4 5 [0.29;0.97] [0.93;0.99] [0.29;0.97] [0.93;0.99]

Total 82 5 87

Reader B

Inclusion of

personal opinion

OC 43 12 55 0.61 0.77 0.59 0.78 0.71

ECE 13 19 32 [0.42;0.78] [0.64;0.87] [0.41;0.76] [0.65;0.88]

Total 56 31 87

SVI MRI

No SVI 70 2 72 0.60 0.85 0.20 0.97 0.84

SVI 12 3 15 [0.15;0.94] [0.76;0.92] [0.5;0.48] [0.90;0.99]

Total 82 5 87

*ECE is equivalent to SVI at pathology for the SVI MRI category.

1

Apparent diffusion coefficient ratio correlates significantly with Gleason

score at final pathology


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, pre-

therapeutic accurate classification of tumor aggressiveness is essential when planning patient-

tailored 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 MRI-

workstation 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 false-

positive 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.


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 non-

cancerous 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 (0.72-

0.76) 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 mp-

MRI 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 sequence (ms) (ms) (°) (cm) matrix of slices (mm)

Axial DWI, b= 0,

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



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%)

pT category, n (%)

Organ-confined tumor pT2 39 (55%)

Extra-prostatic tumor pT3 32 (45%)

Included tumors, n

104

Tumors/patient, mean [range]

1.5 [1-4]

Tumor diameterADC (mm), median [range] 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) Overall (n=104)

Parameter Mean (CI 95%) Mean (CI 95%) *p-value Mean (CI 95%)

ADCbenign

2968 (2844;3091) 2397 (2286;2508) <0.001 2688 (2589;2787) (×10-6

mm2/sec)

ADCtumor

1468 (1349;1587) 1113 (1041;1184) <0.001 1294 (1217;1371) (×10-6

mm2/sec)

**p-value <0.001 <0.001

<0.001

ADCratio 0.49 (0.46;0.52) 0.47 (0.44;0.49) 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

ADCtumor (×10-6

mm2/sec) ADCratio

Zonal origin n Mean (CI 95%) Mean (CI 95%)

Peripheral zone

(n=53)

GS 6 18 1699 (1534;1863) 0.57 (0.53;0.61)

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)

p-value <0.001* <0.001*

Transitional zone

(n=51)

GS 6 8 1158 (1017;1298) 0.53 (0.50;0.57)

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)

p-value 0.46 <0.001*

All tumor foci

(n=104)

GS 6 26 1532 (1375;1689) 0.56 (0.53;0.59)

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)

p-value <0.001* <0.001*

*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 = 989×10-

6mm

2/sec) and a ROI placed in a non-cancerous area (ADCbenign value = 2826×10

-6mm

2/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

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.

a)

b)

20

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).

a)

b)

Documents

PhD thesis - Herlev Hospitalthesis based on international experience, literature evidence and guidelines. This PhD thesis is the result of my work as a clinical research associate