3. University of Copenhagen Ørsted•DTU
Faculty of Health Sciences Center for
Dept. of Ultrasound Fast Ultrasound Imaging
Herlev Hospital
Ph.D. Thesis
New Digital Techniques in Medical
Ultrasound Scanning
Morten Høgholm Pedersen
July 4, 2003
Advisor:
Prof. Dr. Med. Bjørn Quistorff
Project advisors:
Dr. Med. Torben Larsen
Prof. Dr. Techn. Jørgen Arendt Jensen

4. c 2003 by
Morten Høgholm Pedersen
mhp@dadlnet.dk
ISBN 87-91184-23-1

5. to Karin
my Love

7. 5
Contents Overview
Preface 11
Acknowledgements 13
Summary 15
Resum´e 17
Abbreviations, Notation, and Units 19
I Three-Dimensional Ultrasound Imaging 21
1 Ultrasound and 3D Imaging 23
2 Clinical Use of 3DUS 37
II Clinical Trial: 3DUS of Cervical Cancer 45
3 Introduction 47
4 Material and Methods 55
5 Results 71
6 Discussion 95
III Pre-clinical trial: Coded Excitation 103
7 Introduction 107
8 Material and Methods 117
9 Results 129
10 Discussion 133
IV Conclusion 135
11 Overall Discussion and Perspectives 137
V Appendices and Bibliography 141
A FIGO Stages 143
B The Cohen Kappa Value 145
C Software Documentation 147
D Publications 153
Bibliography 181

8. 6 CONTENTS OVERVIEW

9. 7
Contents
Preface 11
Acknowledgements 13
Summary 15
Resum´e 17
Abbreviations, Notation, and Units 19
I Three-Dimensional Ultrasound Imaging 21
1 Ultrasound and 3D Imaging 23
1.1 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.2 Ultrasound Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.2.1 Attenuation and Time Gain Compensation . . . . . . . . . . . . 25
1.2.2 Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
1.2.3 Dynamic Images and Framerate . . . . . . . . . . . . . . . . . 27
1.3 3D Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
1.4 3D Visualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
1.4.1 Depth Cues . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
1.4.2 Surface Rendering and Segmentation . . . . . . . . . . . . . . 29
1.4.3 Volume Rendering . . . . . . . . . . . . . . . . . . . . . . . . 30
1.4.4 Slicing and Intersecting Planes . . . . . . . . . . . . . . . . . . 31
1.5 3D Ultrasound Scanning and Visualization . . . . . . . . . . . . . . . . 31
1.6 3DUS Visualization and Software . . . . . . . . . . . . . . . . . . . . 34
2 Clinical Use of 3DUS 37
2.1 3DUS and Specialities . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2 3DUS in Obstetrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.3 3DUS in Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
II Clinical Trial: 3DUS of Cervical Cancer 45
3 Introduction 47
3.1 Pathogenesis, Pathology, and Epidemiology . . . . . . . . . . . . . . . 48
3.2 Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.3 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

10. 8 Contents
3.5 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.6 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.7 Ultrasound Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.8 Aim of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4 Material and Methods 55
4.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.1.1 Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.1.2 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.1.3 Exclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.1.4 Contraindications and Drop-outs . . . . . . . . . . . . . . . . . 57
4.1.5 Measurement Parameters . . . . . . . . . . . . . . . . . . . . . 57
4.1.6 Power Calculations . . . . . . . . . . . . . . . . . . . . . . . . 58
4.2 Conventional Ultrasound Scanning . . . . . . . . . . . . . . . . . . . . 58
4.2.1 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4.2.2 Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.3 Three-dimensional US Scanning . . . . . . . . . . . . . . . . . . . . . 59
4.3.1 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.3.2 Acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.3.3 Registration of Results . . . . . . . . . . . . . . . . . . . . . . 61
4.4 Clinical Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.5 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.5.1 Equipment and Methods . . . . . . . . . . . . . . . . . . . . . 62
4.5.2 Registration of Results . . . . . . . . . . . . . . . . . . . . . . 63
4.6 Pathological Evaluation - Gold Standard . . . . . . . . . . . . . . . . . 63
4.7 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.8 Trial Approval, Safety, and Patient Strain . . . . . . . . . . . . . . . . 64
4.8.1 Ultrasound Safety . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.8.2 MRI Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.8.3 Influence on Treatment . . . . . . . . . . . . . . . . . . . . . . 65
4.8.4 Data Integrity and Security . . . . . . . . . . . . . . . . . . . . 65
4.9 Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.9.1 Data Format Conversion Tool . . . . . . . . . . . . . . . . . . 65
4.9.2 3DUS Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.9.3 3DUS volume Measurements . . . . . . . . . . . . . . . . . . 67
4.9.4 MRI Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.9.5 Assembling Histological Slices . . . . . . . . . . . . . . . . . 68
5 Results 71
5.1 3DUS Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.2 Comparison between 3DUS and Clinical Staging . . . . . . . . . . . . 74
5.3 Comparing to Histology Results . . . . . . . . . . . . . . . . . . . . . 78
5.4 Imaging after Conization . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.5 Tumor Volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.6 Tumor Location Comparison . . . . . . . . . . . . . . . . . . . . . . . 81
5.7 MRI Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.8 Comparison of Tumor Morphology . . . . . . . . . . . . . . . . . . . . 83
5.9 Addendum - Case Story . . . . . . . . . . . . . . . . . . . . . . . . . . 84

11. Contents 9
6 Discussion 95
6.1 Patient Participation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.2 Technical Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.3 Image Acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6.4 Comparison to Histology and MRI . . . . . . . . . . . . . . . . . . . . 97
6.5 3DUS Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
6.6 Bladder and Rectal Invasion . . . . . . . . . . . . . . . . . . . . . . . 99
6.7 Tumor Size and Limitations . . . . . . . . . . . . . . . . . . . . . . . 99
6.8 Conization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
6.9 Clinical use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
6.10 Improved Trial Protocol - Suggestion . . . . . . . . . . . . . . . . . . . 100
6.11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
III Pre-clinical trial: Coded Excitation 103
7 Introduction 107
7.1 Aim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
7.2 Coded Excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
7.3 Signal-to-noise Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
7.4 Duration and Bandwidth . . . . . . . . . . . . . . . . . . . . . . . . . 109
7.5 Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
7.6 Pulse Compression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
7.7 Temporal Sidelobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
7.8 Expected SNR Improvement . . . . . . . . . . . . . . . . . . . . . . . 115
8 Material and Methods 117
8.1 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
8.2 Pulses and Intensities . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
8.3 Acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8.4 Data Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8.5 Automatic TGC Post-Correction . . . . . . . . . . . . . . . . . . . . . 122
8.6 Image Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
8.7 Estimation of Penetration Depth . . . . . . . . . . . . . . . . . . . . . 124
8.8 Image Quality Comparison . . . . . . . . . . . . . . . . . . . . . . . . 125
8.9 Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
9 Results 129
9.1 Limitations and Artifacts . . . . . . . . . . . . . . . . . . . . . . . . . 129
9.2 Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
9.3 Image Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
10 Discussion 133
IV Conclusion 135

12. 10 Contents
11 Overall Discussion and Perspectives 137
11.1 3D Ultrasound Scanning of Cervix Cancer . . . . . . . . . . . . . . . . 137
11.2 Coded Excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
11.3 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
V Appendices and Bibliography 141
A FIGO Stages 143
B The Cohen Kappa Value 145
C Software Documentation 147
C.1 Image Registration Tool . . . . . . . . . . . . . . . . . . . . . . . . . . 148
C.2 3D Data Conversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
C.3 Raw Binary Data Format . . . . . . . . . . . . . . . . . . . . . . . . . 149
C.4 Signal Processing and Movie Creation . . . . . . . . . . . . . . . . . . 152
D Publications 153
D.1 Review Paper: 3DUS in Obstetrics & Gynecology . . . . . . . . . . . . 153
D.2 Case Report: 3DUS of Monoamniotic Twins . . . . . . . . . . . . . . . 163
D.3 Paper: Chirp Coded Excitation in US . . . . . . . . . . . . . . . . . . . 167
D.4 Related Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
D.5 Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Bibliography 181

13. 11
Preface
”New Digital Techniques in Medical Ultrasound Scanning” is derived from the fact that
most if not all new imaging techniques in medical ultrasound scanning heavily depend
on new possibilities in computers and other digital electronics.
This work was initiated from the Center of Fast Ultrasound Imaging (CFU), located at
the Technical University of Denmark (DTU) with Prof. Dr. Techn. Jørgen Arendt Jensen
as head, in collaboration with the medical ultrasound manufacturer B-K Medical A/S
and the former dept. of Ultrasound at Herlev Hospital.
The purpose of the center is to develop fast imaging methods and create better flow
images. At the moment of writing, several new methods have been developed, e.g. coded
excitation, synthetic aperture imaging, different transverse flow methods. In combina-
tion they will most likely be able to produce real time three-dimensional high-resolution
gray-scale and flow images. At CFU an experimental ultrasound scanner have been
developed from ground up making investigation of almost all kinds of imaginable ultra-
sound imaging methods possible. This includes in-vivo clinical trials.
Since real-time three-dimensional imaging always have been ’the right’ way in my
eyes, and since the techniques developed at CFU ultimately will end up with that, it was
natural to start out investigating some of the current technology and its possibilities.
Three-dimensional ultrasound has been proposed and tried for almost half a century
ago [1–5]. But not until the later years it has been clinically feasible, and all available
systems are enabled by powerful computer systems. This thesis gives a review of three-
dimensional ultrasound imaging (3DUS) with a special focus on 3DUS within obstetrics
and gynecology. Then a clinical trial evaluating transrectal 3DUS in cervical cancer is
presented.
One of the techniques developed at CFU and now abundantly used with other tech-
niques under development is coded excitation. Simulations and laboratory test show
great improvement in signal-to-noise ratio with this method, but would it perform in-
vivo? That was the question of the second part of this thesis, were coded excitation were
evaluated on healthy volunteers.
This work was supported by grant 9700883 and 9700563 from the Danish Science
Foundation and by B-K Medical A/S.

14. 12 Preface

15. 13
Acknowledgements
I would like to thank several people for invaluable help and friendliness during the last
years when I was struggling with this work. The following acknowledgement will make
any Oscar reward speech seem minute.
First of all I would like to thank professor MD DMSc Hans Henrik Holm, the father
of Danish ultrasound in medicine, for initially engaging me in this work and being a
most inspiring advisor.
CP MD DMSc Torben Larsen for invaluable encouragement, help, and inspiration
during the project as my primary project advisor and until recently head of the Dept.
of Ultrasound, Herlev Hospital - my professional and scientific home from 1999 until it
was engulfed at the end of 2002.
Professor MSc DTSc Jørgen Arendt Jensen for initiating the work involving me
as the only medical doctor in the Center for Fast Ultrasound Imaging at the Technical
University of Denmark, providing one of the most interesting and innovative biomedical
research environments existing today.
Thanks to professor MD DMSc Bjørn Quistorff, who has served as my advisor on
several occasions since 1993 - during medical school, during full-time research at the
NMR Center, University of Copenhagen 1993-4, and finally now taking over the role as
main advisor after Hans Henrik Holm’s retirement in 2001.
A great thankyou to all clinical partners in the planning phase and during the clinical
trial. At the dept. of gynecology a thanks to CP MD DMSc Benny Andreasson and
especially CP MD PhD Connie Palle for her invaluable help. Also thanks to the doctors
and nurses at the dept. of gynecology for including and evaluating patients.
Thanks to doctors at the dept. of Pathology for preparing and evaluating and prepar-
ing tissue to create histological data. Especially DC PhD Beth Bjerregaard for her
readiness and engagement.
CP MD DMSc Carsten Thomsen at Dept. of Diagnostic Imaging, Rigshospitalet,
who were so kind to make MR scanners and equipment available to me just like that,
when Herlev Hospital were not able to. Also thanks to CP MD Ajay M. Chauhan for
his help and engagement in a part of the trial that never really became.
MSc PhD Markus Nowak Lonsdale, my old friend from la dolce vita at the NMR
Center, for helping me extracting and converting MR data from scanners.
A special thanks to all earlier employees at the former dept. of Ultrasound at Herlev
Hospital for their warm reception of me starting out in the ultrasound field. It goes for
all nurses, secretaries, and doctors without exception. I would specially like to mention
my good colleague and office mate SS MD Nis Nørgaard and not least SS MD Bjørn
Skjoldbye who has been very enthusiastic teaching me diagnostic and interventional
ultrasound
And of course a thank to all the patients being willing to participate in the clinical
trial, and to the volunteers participating in the study of coded excitation.

16. 14 Acknowledgements
PhD MSc Thanassis Misaridis for preparing my way in coded excitation. MSc Kim
L. Gammelmark for chewing the FDA and AUIM documentation on intensity measure-
ments with me and helping performing the measurements as shown on national televi-
sion.
All my current and former good colleagues at CFU for contributing to an enthusiastic
atmosphere Peter Munk, Malene Schlaikjer, Svetoslav I. Nikolov, Borislav G. To-
mov, Louse K. Taylor, Jesper Udesen, Frederik Gran, and Paul D. Fox (all skilled
researches with lots of fine academic titles).
Associate professor MD Jørgen Hilden and assistant professor MSc Charlotte Hinds-
berger for a statistical kick-start in both projects.
Professor of medicine PhD Olaf von Ramm, PhD MSc Dr. Patrick Wolf, and MD
Manish Assar at Center for Emerging Cardiovascular Technology, Duke University for
letting me stay for some very interesting weeks at your lab.
A thanks to Bjørn Fortling and Robert H. Owen from B-K Medical for lending me
the L3Di viewer. PhD FCCPM Aaron Fenster for giving me access to the LIS file
format. Rolf Nejsum, Cephalon A/S for supplying the 3D View 2000 program and PhD
Armin Schoisswohl, Kretztechnik now GE Medical for information on the Kretz file
format.
Karina and Poul for letting me snore in their basement during the final composing
of this document.
My parents for everything. My sister and graphics designer Lise Høgholm Pedersen
for designing the cover.
Finally the greatest possible thanks to my dearly beloved wife Karin to who I am
greatly indebted for standing me, my geeky way of living, and for making this, at sev-
eral occasions enervating, project possible. Thankyou for being to our children what no
one else can. I am looking forward to see you all :-) Thanks to Magnus and Mikkel for
bearing with me when I was only interested in ’voksen-kedeligt’.
In case I have forgot anyone here I, sincerely apologize - God sees all.
Title Abbreviations
CP Chief Physisian (Overlæge)
DMSc Doctor of Medical Science (Dr. Med.)
DTSc Doctor of Technical Science (Dr. Techn.)
FCCPM Have no clue !
MD Medical Doctor (Cand. Med.)
MSc Master of Science
PhD Doctor of Philosophy
SS Staff Specialist (Afdelingslæge)

17. 15
Summary
This thesis treats new digital techniques in medical ultrasound scanning by dealing with
two subjects: 1) Three-dimensional ultrasound scanning with a special focus on its ap-
plication to cervical cancer staging, and 2) Ultrasound scanning using coded excitation
as a way to improve ultrasound image quality.
Three-dimensional ultrasound scanning have been suggested almost 50 years ago, but
have just recently been commonly available in clinical settings. The results published
until now is reviewed, with a special focus on three-dimensional ultrasound scanning
in obstetrics and gynecology. A clinical trial, evaluating the diagnostic value of three-
dimensional transrectal scanning of cervical cancer as a staging tool is undertaken. Al-
though a limited number of participants (23) has been achieved, results are promising
and shows good agreement with clinical and especially histologic results. Further opti-
mizations of the method, as suggested, will undoubtedly make it a valuable tool that can
provide important diagnostic information in the treatment of cervical cancer.
Despite the enormous development in medical ultrasound imaging over the last de-
cades, penetration depth with satisfying image quality is often a problem in clinical
practice. Coded excitation, which has been used for years in radar technique to increase
signal-to-noise ratio, has recently been introduced in medical ultrasound scanning. In
the present study coded excitation using frequency modulated ultrasound signals is im-
plemented and evaluated in-vivo. The results show significant increase in penetration
depths and image quality. The approximately 10 dB increase in signal-to-noise ratio
offered by coded excitation can alternatively be used to allow imaging at higher frequen-
cies and thereby increasing spatial resolution without any loss of penetration. Future
real-time three-dimensional imaging techniques, already implemented at ultrasound re-
search centers, depend heavily on coded excitation as an enabling technology, and the
technique will undoubtedly soon be present in most clinical scanners.

18. 16 Summary

19. 17
Resum´e
Denne PhD afhandling omhandler nye digitale metoder i medicinsk ultralydscanning.
Dette belyses med to studier: ”Tredimensional ultralydscanning af livmoderhalskræft”
og ”Kodet excitation”.
Tredimensional ultralydscanning er ikke nogen ny tanke. Ideen blev fremlagt og af-
prøvet for næsten 50 ˚ar siden, men først for nylig er teknikken blevet almindeligt til-
gængelig i klinikken. Publicerede resultater indtil nu gennemg˚as i afhandlingen med
specielt fokus p˚a teknikkens anvendelse indenfor obstetrikken og gynækologien. Et kli-
nisk studium af tredimensional transrektal scanning som et værktøj til stadiebestem-
melse af livmoderhalskræft er gennemført. P˚a trods af et forholdsvis lavt deltageran-
tal (23) er resultaterne lovende med god overensstemmelse mellem den nye metode,
klinisk stadieinddeling og ikke mindst patologiske resultater. Den yderligere optimer-
ing af metoden, som foresl˚as, vil utvivlsomt gøre den til et værdifuldt værktøj, der kan
tilvejebringe vigtig diagnostisk information i behandlingen af cervix cancer.
Selvom udviklingen indenfor medicinsk ultralydscanning gennem de sidste ˚artier har
været enorm, er tilstrækkelig indtrængningsdybde med tilfredsstillende billedkvalitet
stadig ofte et reelt problem i den kliniske praksis. Kodede signaler, som har været brugt
i radar-teknik i adskillige ˚ar til at forbedre signal-støj-forholdet, er for nylig blevet in-
troduceret i medicinsk ultralydscanning. I denne afhandling præsenteres et studie, hvor
frekvens-modulerede ultralydsignaler er implementeret i et eksperimentelt system og
afprøvet in-vivo. Resultaterne viser en signifikant forbedret billedkvalitet med forøgelse
af indtrængningsdybden p˚a omkring 2 cm. Forbedringen i signal-støj-forholdet p˚a om-
kring 10 dB ved brug af kodede signaler kan alternativt anvendes til at forøge ultralydfre-
kvensen og dermed opn˚a højere opløsning uden tab af indtrængningsdybde. Fremtidige
teknikker til tredimensional real-time scanning under udvikling er stærkt afhængige af
kodede signaler og teknikken vil utvivlsomt snart være at finde i de fleste kliniske scan-
nere.

20. 18 Resum´e

21. 19
Abbreviations, Notation, and Units
Abbreviations
3D : Three-Dimensional
3D-TRUS : Three-Dimensional Transrectal Ultrasound Scanning
3DUS : Three-Dimensional Ultrasound Scanning
4D : Four-Dimensional
4DUS : Four-Dimensional Ultrasound Scanning (Real-time 3DUS)
CFU : Center for Fast Ultrasound Imaging
CIN : Cervical Intraepithelial Neoplasia
CIS : Carcinoma In Situ (equal to CIN-3)
CT : Computerized Tomography
ECRM : Endocavitary Rotational Mover
EF : Ejection Fraction
EGA : Examination under General Anesthesia.
FIGO : International Federation of Gynecology and Obstetrics
FM : Frequency Modulation
FOV : Field of View
fps : frames per second
GB : Gallbladder
HPV : Human Papilloma Virus
IV : Intravenous
magiq : Minimum Average Good Image Quality (depth: dmagiq)
maui : Maximum Average Usable Image (depth: dmaui)
MHP : Morten H. Pedersen
MI : Mechanical Index
MR : Magnetic Resonance
MRI : Magnetic Resonance Imaging
PSF : Point Spread Function
RASMUS : Remotely Accessible Software-configurable Multi-channel Ultrasound
System
ROI : Region-Of-Interest
SNR : Signal-to-Noise Ratio
STA : Synthetic Transmit Aperture
TBP : Time-Bandwidth Product
TGC : Time-Gain Compensation
TRUS : Transrectal Ultrasound Scanning
US : Ultrasound Scanning
VAS : Visual Analog Scale

22. 20 Abbreviations, Notation, and Units
Symbols and Notation
Symbol : Explanation
φ(t) : Phase modulation function
Φ(t) : Signal phase
a(t) : Amplitude modulation function
F
←→ : Fourier Transform
˜s(t) : Hilbert transform of s(t)
x∗y : Convolution of x and y
x∗(t) : Complex conjugate (a+ib)∗ = (a−ib)
Variables and Units
Variable [ Unit ] Name Definition
MI [ none ] Mechanical Index Pr.3/
√
fc
EF [ % ] Ejection Fraction Vejected/Venddiastolic
BW [ Hz ] Bandwidth
E [ J ] Energy
P [ W ] Power
I [ W/m2] Intensity
f0 [ Hz ] Center frequency
t [ s ] Time
T [ s ] Pulse duration (time)
lp [ m ] Pulse length
V [ l ] Volume

23. 21
Part I
Three-Dimensional Ultrasound
Imaging

25. 23
Chapter 1
Ultrasound and 3D Imaging
I depict men as they ought to be,
but Euripides portrays them as they are.
Sophocles - Aristotle
Contents
1.1 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.2 Ultrasound Scanning . . . . . . . . . . . . . . . . . . . . . . . . 24
1.3 3D Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
1.4 3D Visualization . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
1.5 3D Ultrasound Scanning and Visualization . . . . . . . . . . . . 31
1.6 3DUS Visualization and Software . . . . . . . . . . . . . . . . . 34
In this chapter the physics, principles, and instrumentation behind ultrasound imaging
will be briefly reviewed. Then three-dimensional imaging and visualization will be re-
viewed in general and in ultrasound.
1.1 Ultrasound
Ultrasound is sound with a frequency (f) above the human audible range, i.e. above
20 kHz. In medical ultrasound this means the megahertz range (roughly 1-20 MHz). At
such high frequencies the wavelength (λ) is small and the sound behaves like light in
the sense that it can be directed, reflected, and diffracted. These properties are used for
ultrasound imaging.
λ =
c
f
(1.1)
As seen in equation (1.1) the wavelength also depends on the propagation speed of sound
(c), which differs between materials (Table 1.1). The sound speed is determined by the
material mass density (ρ0) and acoustic impedance (Z):
Z = ρ0 ·c. (1.2)
In human tissue sound speeds lies around 1500 m/s (Table 1.1) and a sound speed
of 1540 m/s has become a de-facto standard speed used when constructing ultrasound
scanners.
The difference in impedance between tissues is the whole basis of ultrasound imag-
ing, since the reflection of sound occurs on borders between materials with different
impedances. Otherwise we would not get any signal back when scanning. The mag-
nitude of the reflected sound depends on the difference in impedances. The reflection

26. 24 Chapter 1 Ultrasound and 3D Imaging
Table 1.1: Sound speed, character-
istic acoustic impedance, and density
for different materials and tissues en-
countered in medical ultrasound scan-
ning. Data from [6–8].
Material Speed Impedance Density
[m/s] [kg/m2
s] [kg/m3
]
Air 333 0.40·103 1.2
Blood 1566 1.66·106 1.06·103
Bone 2070-5350 3.75-7.38·106 1.38-1.81·103
Brain 1505-1612 1.55-1.66·106 1.03·103
Fat 1446 1.33·106 0.92·103
Kidney 1567 1.62·106 1.04·103
Lung 650 0.26·106 0.40·103
Liver 1566 1.66·106 1.06·103
Muscle 1542-1626 1.65-1.74·106 1.07·103
Spleen 1566 1.66·106 1.06·103
Water 1480 1.48·106 1.00·103
pressure coefficient for sound propagating from tissue with impedance Z1 into tissue
with Z2 is:
Rp =
pr
pi
=
Z2 cosθi −Z1 cosθt
Z2 cosθi +Z1 cosθt
, (1.3)
where pi and pr is the incidence and reflected pressure respectively, θi and θt the angles
of incidence and transmission. The transmission angle depends on the incidence angle
according to Snell’s law:
c1
c2
=
sinθt
sinθi
. (1.4)
The transmitted pressure is also depending on impedances and angles:
Tp =
pt
pi
=
2Z2 cosθi
Z2 cosθi +Z1 cosθt
. (1.5)
The intensity I [W/m2] of a plane wave with peak pressure p0 travelling through a material
with the impedance Z0 can be shown to be:
I =
p2
0
2Z0
, (1.6)
which can be used to calculate the transmitted and reflected intensities.
Ultrasound can be generated by a so-called transducer that converts electrical energy
into acoustic and vice-versa. A transducer is made of piezo-electric materials that de-
form when an electric potential is applied and also produces a potential when deformed
mechanically. To emit sound an AC signal at the desired frequency must be applied to
the transducer, just as an electrical AC signal can be measured from the crystal when it
is deformed by sound.
1.2 Ultrasound Scanning
The simplest form of ultrasound scanning is to emit a short pulse (1-3 cycles) and then
record the returning echo-signal. The signal amplitude at different times (t) after trans-
mission corresponds to reflections at different depths (d) which can be calculated when
knowing the propagation speed of sound (c):
d =
c·t
2
. (1.7)
To be useful for scanning, the emitted sound wave must have a direction, which can be
achieved by increasing the size (called aperture) of the transducer. This way the sound

27. 1.2 Ultrasound Scanning 25
intensity will be concentrated in a direction (see Fig. 1.1). To get even better directional
concentration (focus) of the sound a concave transducer surface can be used. Since the
distance from the surface to the focus point is the same on the whole transducer surface
the sound waves originating from every part of the surface will reach the focus point at
the same time (Fig. 1.2). By cutting the transducer into several (usually 64-256) smaller
elements all individually connected to their own signal generator and receiver, the focus
point can be determined electronically and dynamically. This is done using different
times of emission (delays) for each element (see Fig. 1.3). Delays can also be used to
steer the sound in any desired direction (Fig. 1.4). Such a transducer is called an array
transducer.
An example of a received signal is showed in Fig. 1.5(a) as a function of time. The
signal magnitude is largest at the start due to strong reflections at the surface just after
emission. Just at 10 ms and around 12 ms small peaks are seen which are structures
in the tissue with higher reflection coefficient. In Fig. 1.5(b) the magnitude of the sig-
nal is found and the time scale on the abscissa is converted to depth using (1.7). The
magnitude or so-called envelope of a signal can be found taking the absolute value of
the complex analytical signal found using the Hilbert Transform [9], where ˜g(t) it the
Hilbert transform of g(t):
envelope = |g(t)+i· ˜g(t)|. (1.8)
To compress the high dynamic range in ultrasound signals logarithmic compression is
used, and as shown in Fig. 1.5(c) the small spikes at 8 and 10 cm are now more vis-
ible. We now have a so-called A-line or A-mode (Amplitude mode) scan. To create
an ultrasound image, all you have to do is to convert the amplitude values into bright-
ness values, project the line on a monitor, tilt the transducer or electronically change the
beam direction a bit and repeat the process. This way an ultrasound B-mode (Brightness
mode) image is achieved. Just like an old fashioned radar the image is built up line by
line scanning the whole sector (Fig. 1.5(d)). If an electronically steered array transducer
is used, it does not need to be moved, but the beam can be steered using different delay
values.
1.2.1 Attenuation and Time Gain Compensation
Table 1.2: Attenua-
tion values in differ-
ent tissues. Data from
[8; 10].
Tissue Attenuation
[dB/MHz·cm]
Liver 0.6-0.9
Kidney 0.8-1.0
Spleen 0.5-1.0
Fat 1.0-2.0
Bone 16.0-23.0
Blood 0.17-0.24
Plasma 0.01
To make things worse, ultrasound is heavily attenuated when traversing tissue. The
attenuation is different in different types of tissue (Table 1.2) and also proportional to the
distance travelled and the center frequency of the sound. For instance sound at 4 MHz
travelling through 20 cm of liver forth and back, will be attenuated approximately
20 cm · 4 MHz · 0.9 dB/MHz/cm = 72 dB = 3980 times. (1.9)
At 20 cm depth (total length 40 cm) the attenuation will be 15.8 million times. To
compensate for this, the received signal is amplified depending on the depth it comes
from. That means an exponentially increasing gain with time, to yield an A-line with
amplitudes more or less proportional to the strength of the reflectors. To determine the
necessary amplification an attenuation of 0.5 dB MHz−1 cm−1 is normally assumed in
scanners. This time depending amplification is called time gain compensations (TGC),
and is already applied by the scanner on the signals in Fig. 1.5. To adjust for differences
between patients and scanning locations the user can further adjust the amplification at

28. 26 Chapter 1 Ultrasound and 3D Imaging
Figure 1.1: Directional beam emitted by planar surface (aperture).
Figure 1.2: Mechanical focus by a concave transducer surface.
Figure 1.3: Focusing electronically using delays.
Figure 1.4: Electronic steering of beam using delays.
0 1 2
x 10
−4
−1
−0.5
0
0.5
1
Time [s]
Signal[V]
RF Signal
(a) Raw sampled signal from
transducer after TGC.
0 5 10 15
0
0.2
0.4
0.6
0.8
1
Depth [cm
SignalEnvelope[V]
Envelope
(b) Signal amplitude after enve-
lope detection.
0 5 10 15 20
−70
−60
−50
−40
−30
−20
−10
0
10
Depth [cm
Signal[dB]
Log Compressed Envelope
(c) Log compressed signal. (d) Scanned image showing the
location of the A-line (dot-
ted white line) plotted in
(a-c).
Figure 1.5: A single echo signal used for one A-line and the location where it is recorded from.
Note that the two small peaks at 8 and 10 cm in (c) corresponds to the vessel walls traversed by
the dotted line in (d).

29. 1.2 Ultrasound Scanning 27
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
32
0.8 mm distance
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
32
0.4 mm distance
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
0.2 mm distance
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
Point spread function
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
0.2 mm distance
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
0.4 mm distance
Lateral [mm]
Axial[mm]
−2 −1.5 −1 −0.5 0 0.5 1 1.5 2
29
29.5
30
30.5
31
31.5
0.8 mm distance
Figure 1.6: US im-
age of single point
(middle image) and
two displaced points.
Image widths are
4 mm.
the different depths manually. Some scanners have features to automatically optimize
the TGC settings. A way to do this based on image information has also been developed
and presented in this thesis (see Section 8.5 on page 122).
1.2.2 Resolution
The spatial resolution of an ultrasound imaging system depends on several factors. Even
though we are able to focus the sound energy in a desired direction, it is not perfectly
focused. Also, it is only maximally focused in a certain depth. Several techniques are
used to circumvent these limits, traditionally by using so-called dynamic receive, where
the electronic delays of each transducer element is changed during receive, to yield an
optimal focus on the spatial location where the sound received at a particular moment
originates from. Better transmit focus is obtained in the displayed image by combining
several images with different transmit focus settings. Finally a technique called synthetic
transmit aperture (STA) [11] achieves perfect focus in all depths without loosing frame-
rate.
To measure the spatial imaging resolution we use the point spread function (PSF) of
the system. PSF is the image generated of a point in space when using the imaging
system to depict it. The bigger the PSF the lower the resolution. In Fig. 1.6 the PSF and
images of two points with different axial and lateral distances are shown. The images
are made using the ultrasound simulation toolbox Field II [12], which is developed by
Jensen and freely available1. A linear array with 200 elements, 0.1 mm pitch, 50%
fractional bandwidth, center frequency of 7.5 MHz focused at 30 mm was simulated. A
delta function pulse was used as excitation.
In an ultrasound scanning (US) system the PSF depends on focus, center frequency,
transducer aperture, number of sub-elements in electronic arrays, and the emitted ul-
trasound waveform. The reader is referred to ultrasound textbooks for further details
[13]. As a rule of thumb the maximal temporal (axial) resolution (ra) of a conventional
ultrasound system is equal to half the length (lp) of the pulse with duration T:
ra =
lp
2
=
c·T
2
, (1.10)
and the lateral resolution is always worse.
1.2.3 Dynamic Images and Framerate
Since conventional US images are build up line by line, the total time (tI) to acquire an
image is proportional to the number of lines (nL) in the image. It also depends on the
desired scan depth (d):
tI = nL
2d
c
, (1.11)
yielding a frame rate fI [Hz]:
fI =
1
tI
. (1.12)
A realistic example could be:
fI = 192·
2·15 cm
1540 m/s
−1
= 26.7 Hz, (1.13)
1Can be downloaded from: http://www.es.oersted.dtu.dk/staff/jaj/field/

30. 28 Chapter 1 Ultrasound and 3D Imaging
Pixel
Voxel
Picture
Volume
Figure 1.7: A picture is built up by pixels, a volume by voxels.
which is sufficient for real-time imaging in conventional 2D US systems. The problem
arises when one wish to do real time 3D US imaging in which case the frame rate is
divided by the number of desired lines in the elevational direction. In the example above
that would yield 26,7 Hz / 192 = 0.14 Hz presuming same elevational resolution and
coverage as laterally. This can hardly be called real-time imaging.
1.3 3D Imaging
To create an image of a three-dimensional structure we need a technique to acquire the
spatial information. We could slice the structure and take a photograph of each slice to
get this information. This can be done with structures that are not needed afterwards,
like tissue samples for instance. A living patient would probably object to this approach,
though. Therefore less interfering methods are normally used.
Computerized tomography (CT) and magnetic resonance imaging (MRI) are two mo-
dalities that are more or less ideal for three-dimensional imaging. Both techniques can
depict any desired part of the body, although CT are superior imaging bone and MRI
soft tissue. Since CT is a slice imaging technique it can only acquire transaxial slices
whereas MRI can acquire slices in any desired orientation. In addition MR does not
inflict any ionizing radiation and is therefore preferable if possible. Both techniques are
used in the daily clinic for 3D imaging.
Like images are usually represented by rectangular grids consisting of many small
picture elements (pixels), volumes can be represented by a regular three-dimensional
cartesian grid consisting of volume elements called voxels (Fig. 1.7). Like a radar image
might be more efficiently represented by a grid of polar coordinates, volume data can
also be represented in other ways than using the rectangular grid. We will come back to
this in Section 1.5 on page 31.

31. 1.4 3D Visualization 29
Interposition
Relative size
Relative height
Brightness
Perspective
Perspective above
Lightening
Several cues
Figure 1.8: Depth
cues
1.4 3D Visualization
Volume acquisition is only half of the job. Visualization of the obtained data is the next
task and at time of writing still the Achilles heel of 3D imaging. Simple objects, such as
a sphere, a cube, or the surface of a body are relatively simple to visualize using means
we already know from our knowledge of human vision. But when we need to visualize
complex structures with several objects, surrounded by other objects or intertangled with
each other, the job becomes more difficult. First, I will describe techniques to visualize
3D structures of fairly simple objects, and later how to convey the structural information
of more complex objects.
The main reason for doing 3D imaging of course is the fact that our world is (at
the least) three-dimensional. We often think of our selves capable of having three-
dimensional vision, which is an exaggeration. It is more like 2.5D or to be specific
stereo vision. Our two eyes both are 2D cameras, but the combination of the two with
information of their relative position enables our brain to extract three-dimensional in-
formation - to calculate the relative distance to objects. In addition so-called cues help
deciding the relative position of viewed objects. I deal with those in the following, since
they are used by 3D visualization software.
1.4.1 Depth Cues
Our eyes and brain daily use minute features in the images projected on the retina to
calculate the relative position of objects in space. The features are called depth cues.
Features as interposition (order), relative size, relative height, coloring, perspective dis-
tortion, and lightning (Fig. 1.8) are all examples of image features that indicate the rel-
ative position of objects in space. This knowledge is relatively easy to implement in
visualization software mimicking the real world to produce some perception of depth in
the resulting image.
In addition to these monocular cues, our stereoscopic vision can use the minute dif-
ferences in the two images seen by the eyes to calculate distance to objects. This can be
done because the difference in location of features in the two retinal images are inversely
proportional to the distance between the viewer and the corresponding object (Fig. 1.9).
This can also be mimicked by visualization software by showing different pictures to
left and right eye of the observer. Special glasses with shutters synchronized with the
screen or glasses with two built-in displays can provide that. Also holographic screens
have been made, where the observed image depends on the viewing angle.
Another way to obtain the same information is to animate the rendered view for in-
stance by rotation. This virtual turning of the volume is analogous to the physical turning
and tumbling we automatically do when examining a physical object. The animation can
either be a movie of a rotating volume or it can be an interactive process where the user
can manipulate the objects on the monitor in real-time.
1.4.2 Surface Rendering and Segmentation
Surfaces are easily displayed by a computer (like the ’flat men’ in Fig. 1.8) by simple
projection of 3D coordinates on a 2D plane. By coloring surfaces according to their di-
rection relative to virtual light sources, 3D perception is created (e.g. spheres in Fig. 1.8).

32. 30 Chapter 1 Ultrasound and 3D Imaging
To use surface rendering one needs to know the exact coordinates of the surface to visu-
alize. This is not a problem in 3D visualization of human created objects - such as cars
and houses, since they are all designed on computers.
Within the medical world one rarely posses the coordinates to describe the surfaces
of the objects one wishes to visualize. An exception is the result of a laser scanning of
a patients surface. But usually the data we acquire are volume data; a three-dimensional
matrix with a value at every point (voxel). That could be a Hounsfield number, mag-
netic resonance signal, ultrasound echo amplitude, or radioactivity value. In such data
algorithms to find surfaces must be applied. This process is called segmentation and is
relatively simple in volume data where objects can be segmented on a simple threshold
value, such as a Hounsfield value for bone being distinctly different from other tissue.
In most cases, though, this process is not a trivial one and usually cannot be automated
but relies on ´a priori knowledge of skilled persons.
1.4.3 Volume Rendering
To bypass the problems of segmentation a visualization technique called volume render-
ing is applied. Since no natural control points describing objects exist in scanned data,
this technique projects every single voxel of a volume onto the two-dimensional image
plane (Fig. 1.10). This is very much like the projection happening when taking an X-ray
image, where the resulting brightness in each location of the image depends on the total
attenuation along the ray from the x-ray tube to the collimator.
The x-ray image can be mimicked by using the voxel values in our volume as a den-
sity function τ(x,y,z), like the Hounsfield numbers obtained from CT scanning. The
resulting volume rendered image can then calculated using the function:
I(i, j) = I0 exp

−
s
0
τ(
−→
Di,j ·t)dt

, (1.14)
where I(i, j) is the resulting image pixel, I0 is the light intensity before the ray enters
the volume, and τ(
−→
Di,j ·t) is the density value at the location t along the ray determined
by the directional vector
−→
Di,j for the corresponding image location (i, j). By applying a
Figure 1.9: Stereo vision.
The spatial distance be-
tween an object and the
observer (Dobject) is in-
versely proportional to the
distance in the merged im-
age between the two differ-
ent projections of the ob-
ject seen by the left and
right eye respectively.
Dcircle
Dsquare
(a) Projection of a circle and
square on the to retinas.
dcircle ∼ 1
Dcircle
dsquare ∼ 1
Dsquare
(b) Merged image from left
and right eye.

33. 1.5 3D Ultrasound Scanning and Visualization 31
(a) Projection of a two-dimensional image consist-
ing of numerous pixels onto a one-dimensional
image line
(b) Projection of a three-dimensional volume onto a two-dimensional im-
age plane (volume rendering)
Figure 1.10: Volume rendering illustrated with the analogy of two-dimensional projection (a)
on a one-dimensional ’screen’. The resulting pixel is calculated from the pixels traversed along
the rays trajectory through the object. The same is the case in three dimensions (b).
threshold or range operation to the density values so that only values above the threshold
or within a range are 1 (opaque) and others 0 (transparent), one can perform a segmen-
tation on a voxel basis. This way a segmentation of the structures in the volume can be
done, e.g. to render only bone structures and create an image looking very much like
surface rendering. Coloring can be obtained by repeating the process for different colors,
typically red, green, and blue. By applying different transfer functions to τ(x,y,z) for
each color different structures can be emphasized. An example showing the results of
manipulating the applied transfer function is shown in Fig. 1.11 on the following page.
Numerous volume rendering methods that provide very realistic images of volume
data have been developed. See Schroeder et al. [14] for an introduction and Max [15]
for more details.
1.4.4 Slicing and Intersecting Planes
Visualization of a full volume by volume rendering can not always convey the structural
information. For instance a volume rendering of a car would not give detailed informa-
tion on the construction details. For the same reason cut planes and so-called exploded
views are often used for such visualization. The same techniques can be and often are
used in visualization of three-dimensional medical data-sets (Fig. 1.12 on page 33. Dif-
ferent ways of cutting volumes with virtual scalpels that remove parts of a volume are
available in most visualization software.
A common way of viewing 3D data is three orthogonal planes (Fig. 1.13). The three
planes (frontal, sagittal, and axial) should be oriented according to the standard radi-
ological orientation for tomographic imaging. The orientation showed in Fig. 1.13 is
convenient, with standard orientation, and left/right - superior/inferior correspondence
between adjacent images.
1.5 3D Ultrasound Scanning and Visualization
Three-dimensional ultrasound scanning is more or less the same as conventional two-
dimensional scanning. Instead of moving the scan line in a single plane it is moved
to cover the desired volume. The only problem is the time it takes to cover a whole
volume, which directly affects the frame rate, or rather volume rate. Therefore most

34. 32 Chapter 1 Ultrasound and 3D Imaging
(a) Transaxial slice viewed from above
with white infarction in right side.
(b) Change of gray-scale transfer function
almost removing surrounding black
void.
(c) Black void removed, white infarction
mapped to yellow-read to enhance it.
Here looking at frontal cut through both
hemispheres.
(d) Viewpoint moved to the right and brain
tissue made more transparent allowing
infarction to be seen through normal
white matter.
(e) Brain almost transparent with thin dark
rim.
(f) Seen from front above without cuts and
with transparent brain tissue.
(g) Brain tissue changed to fully opaque
hiding infarct and mimicking surface
rendering.
(h) Normal tissue almost invisible, just a
gray cloud.
(i) Everything but infarction fully removed,
mimicking surface rendering of infarc-
tion.
Figure 1.11: Examples of different opacity and color settings. The rendered volume is a mouse
brain with a large infarction in the right hemisphere acquired using diffusion weighted MRI.
(Data courtesy of Kenneth E. Smith, NMR Center, University of Copenhagen)

35. 1.5 3D Ultrasound Scanning and Visualization 33
(a) Volume rendering of MRI data set cut open. (b) Thyroid with cyst visualized by ’tissue
cube’, with an additional oblique cut-
ting plane.
(c) Niche view of same MRI data set. (d) Niche view of thyroid cyst.
Figure 1.12: Volume cutting tecniques.
Figure 1.13: Three orthogonal views: Frontal, Axial, and Sagittal.

36. 34 Chapter 1 Ultrasound and 3D Imaging
(a) Linear translation. (b) Fan translation. (c) Rotation around image
center line.
(d) Freehand acquisition
Figure 1.14: Acquisition of static 3D volumes using compounding of spatially registered 2D
images.
three-dimensional US imaging done so far have been static 3D acquisitions, where the
temporal resolution is traded off for volume information.
Most solutions use movement of a conventional electronic linear or curved array trans-
ducer in some predefined way, e.g. linear motion, tilting, or rotation (Fig. 1.14). This
way a volume is covered by conventional 2D tomographic images, with information of
each’s location that can be used to subsequently reconstruct the volume. The motion is
usually motorized and dedicated transducers with build-in motors and position sensors
makes acquisition easy. Magnetic tracking devices mounted on the transducer, that re-
port the current spatial location and rotation, can be used to allow freehand acquisition
(Fig. 1.14(d)).
Another more effective approach is the use of two-dimensional transducer arrays [16–
19] (Fig. 1.15). This allows the ultrasound beam to be steered in any desired direction
electronically, which increases the acquisition rate but does fully solve the problem with
low frame rates. Different attempts, such as emitting a broad beam and receive in mul-
tiple direction simultaneously have been used [20] yielding full volume acquisition at a
rate of 25 Hz but with fairly low spatial resolution. New approaches such as synthetic
aperture imaging combined with coded excitation seem promising, though, capable of
producing real-time high-resolution volume scanning [11].
Figure 1.15: 2D
Transducer with 208
elements 1.6 3DUS Visualization and Software
Visualization of three-dimensional ultrasound data is fundamentally the same as visu-
alizing other type of data. But ultrasound images are in many ways more troublesome.
Resolution wise they are just as good and in many cases better than both MRI and CT
images. But ultrasound artifacts which are abundantly represented in most images cause
severe problems. First of all, the speckle pattern distributed everywhere in the images
makes it almost impossible to discern tissues based on their gray scale values, as one can
do with CT and MR images. Speckle reduction techniques such as compound imaging
[21] or image processing (XRes, Philips) have been done with some success. Other ar-
tifacts such as shadowing, enhancement, velocity differences, mirroring etc. all degrade
the 3D image. In conventional two-dimensional US scanning those artifacts are often
useful to characterize the tissue provided the examiner is aware of the ultrasound propa-
gation direction. By changing transducer position the artifacts change accordingly. But
in the 3D case, the static volume does not provide that possibility and the beam direc-
tion is not always visible when examining the data set, which is often done off-line after

37. 1.6 3DUS Visualization and Software 35
the acquisition. Therefore new artifacts and misinterpretations can arise. For instance,
a shadow cast from a superficial attenuating structure becomes a hypo-echoic region if
a slice perpendicular to the sound direction is made below. As a consequence it is im-
portant always to examine slices with different orientation when diagnosing from 3D
ultrasound - just as it is in conventional US scanning.
Several visualization software packages exist, but for ultrasound data the software is
usually dedicated to data from a single manufacturers US machines or an integrated part
of the scanner. Two programs will be shortly reviewed here, L3Di by B-K Medical A/S2
and the program 3D View 2000 (GE Medical)3.
The first, L3Di, is integrated with the US scanner and used both for acquisition and vi-
sualization. This system is used for acquisition in the clinical trial in this thesis (Part II on
page 47). Although it has limited volume rendering abilities, the slicing interface is re-
sponsive and easy to use consisting of a tissue box one can rotate and cut by as many
planes as desired (Fig. 1.12(b) on page 33). It also can display three orthogonal planes
(Fig. 1.16(a)) and follows the standard radiological orientations, but the planes can-
not be rotated with respect to the acquired volume, so another orientation of the organ
would result in non-standard planes. Since one of the big benefits from 3D scanning
is the independence of acquisition angles this is definitely a major flaw. One of the
great strengths of the L3Di program is the ability to mark different locations by lines
or polygons. When evaluating a volume in different cutting planes it is important to be
able to mark up features to be able to re-locate them in planes with other orientations.
For instance measuring the volume of a tumor requires certainty of its limits, which can
rarely be determined using cutting planes of only one orientation. Since the actual vol-
ume measurement procedure (e.g. planimetry) usually only allows a very limited set of
planes, this ’mark-up’ feature is invaluable. The approach is illustrated later in this thesis
(Fig. 4.11 on page 67).
The second program, 3D View 2000, is also an integrated part of the Kretz Voluson
ultrasound scanner. Furthermore it can run on a standard PC and is freely available
as a demo version4. Although having less responsive user interaction when slicing, it
has a very useful orthogonal slices view. Alignment of the volume relative to the three
planes are done easily. The orientation of the three standard planes is a bit awkward
though (Fig. 1.16(b)). The volume rendering is better compared to the L3Di software
and animated sequences of a rotating volume can be saved for display on other PC’s.
On the downside, it is not possible to mark-up features before performing measurement,
which is a real drawback.
2Originally developed by the former Life Imaging Systems, Ontario, Canada.
3Developed by Kretztechnik AG, Austria.
4From http://www.sonoportal.net - 2003.05.01 - Measurement functions disabled

38. 36 Chapter 1 Ultrasound and 3D Imaging
(a) The orthogonal views of the B-K Medical L3Di system. The views are oriented the same way
as in Fig. 1.13, only the placement is different.
(b) Three orthogonal views in the Kretz interface. It can not be change to have the standard
orientation as in Fig. 1.13. The lower right 3D view can be changed between viewing from
one of the 6 sides of a cube.
Figure 1.16: Layout of Kretz and B-K Medical’s orthogonal planes view.

39. 37
Chapter 2
Clinical Use of 3DUS
2D, or not 2D:
That is the question,
but not 4 me!
Why?
4D!
Unknown 4D Geek at the former:
Dept. of Ultrasound, Herlev Hosptial
Contents
2.1 3DUS and Specialities . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2 3DUS in Obstetrics . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.3 3DUS in Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . 42
2.1 3DUS and Specialities
Three-dimensional US (3DUS) in medicine has been presented decades ago[1–5; 22],
but during the later years the technical development has made it a feasible modality in
daily clinical practise. Especially within obstetrics and cardiology 3DUS has found uses.
General abdominal ultrasound encompasses a wide range of examinations and clini-
cal challenges and takes up a major part of the time in an ultrasound department. With
regards to 3DUS, this area remains one of the biggest challenges due to several factors
that make three-dimensional imaging and visualization difficult. First of all, the ab-
domen is ”a mess”. Intestines, vessels, and organs intermingle and move around. This
means that relations change all the time. Most of the organs, especially the gut, are de-
formable which results in artifacts if acquisition times are too long or transducer pressure
changes or moves during acquisition - which is not uncommon in 3DUS. Several of the
organs (liver, spleen, kidneys) and neoplasms are big, which makes them difficult to de-
pict within a single acquired volume of interest (depending on the acquisition method).
This is in particular the case when using fast (4D) acquisition methods to overcome the
movement and deformation artifacts, since these methods until now have had a very lim-
ited field-of-view (FOV). Another factor, the abundant air in the guts, makes imaging
of larger volumes difficult, since you cannot be sure to have a continuous large surface
area with ”sound access” to the organ you wish to depict. This problem is also caused
by the ribs covering some of the upper abdominal organs. Often the natural boundaries
between organs are very discrete, if visible at all. This makes visualization of organs
much more difficult compared to e.g. obstetric imaging, where the fetus is surrounded
by ’black’ water. To visualize abdominal organs some kind of segmentation must be
done before visualization, as mentioned in Section 1.4.2.

40. 38 Chapter 2 Clinical Use of 3DUS
Figure 2.1: Bladder tumor depicted in original transverse scan (left), reconstructed sagittal
(center), and using 3D volume rendering (right). Acquisition made using ATL HDI 5000 and
experimental A3Di workstation
One of the first published works on 3DUS in medicine [5] impressively depicts ab-
dominal organs and tumors. Since then, depictions of the gallbladder (GB) [23] includ-
ing evaluation of dynamics of the gallbladder comparing the ejection fraction (EF) in
patients with gallstones and normal volunteers [24] has been undertaken. The latter,
showed highly significant differences in EF between normal GB, GB with stones, and
GB with wall thickening. The interesting question; whether the 3D EF measurement can
predict development of GB stones, remains unanswered. A method that overcomes the
problem of limited FOV when scanning large organs like the liver has been described
[25].
Laparoscopic 3DUS evaluating liver lesions [26] has been reported. In this work,
a magnetic tracking device was built into the laparoscopic US transducer. Portal vein
invasion have been demonstrated using intravascular 3DUS [27], and contrast enhanced
detection of intra-abdominal trauma using 3DUS has been investigated [28].
Organ volume measurements, such as splenic volume [29] estimation, is possible us-
ing 3DUS, but the clinical advantage over 2DUS remains to be demonstrated. The ac-
curacy of volume measurements using 3DUS is also demonstrated by Gilja et al. [30],
where kidney volumes are determined using both 3DUS and MRI, showing close agree-
ment. Bladder volume estimation using 3DUS vs. 2DUS has been shown to be more
accurate [31]. 3DUS has also been used to visualize fistulas [32] in transplanted kidneys
and urinary stones [33]. Visualization of bladder tumors is another relatively easy task
that might be useful for the treating surgeon (see Fig 2.1).
Prostate volume estimations are more accurately done using 3DUS [34], especially
when operators are non-radiologists. This is undoubtedly one of the forces of 3DUS, i.e.
that inexperienced operators can do the acquisition, and then evaluate the information
afterwards supported by automated software and/or experts.
Examination of anal canal injuries [35] demonstrated how 3D-TRUS facilitates length
and thickness measurements of the sphincter, not readily possible using conventional
transducers1. In obstructing rectal cancers 3DUS can be used to provide the image
planes that would otherwise not be possible to obtain [36]. A comparative study have
not been able to detect any improvements in rectal cancer staging using 3DUS instead
of conventional scanning [37], though.
Stereoscopic visualization of breast tumors using 3DUS has been presented [38] but
remains to be proven as useful. A very convincing work has been published [39] in
which reconstructed planes perpendicular to sound direction (parallel to skin surface)
1Except from the B-K Medical Model 8558 bi-plane transducer depicted in Fig. 4.6(a) on page 61

41. 2.1 3DUS and Specialities 39
Figure 2.2: 3DUS of anal canal: Acquired volume (left), orthogonal cutting planes (center),
and volume rendering of wall (right). Acquisition made using B-K Medical L3Di system and
rotating transducer.
were used to discriminate between benign and malicious looking tumors. The borders
of malignant tumors usually had a star shaped formation whereas benign lesions tended
to be round. The often very pronounced shadowing seen in breast tumors, is obviously
circumvented using this technique. A proper randomized controlled study, which should
be easy to perform provided the necessary equipment (e.g. Kretz Voluson 730D) is
accessible, remains to be done. An apparatus for semi-automatic breast biopsy [40] has
been constructed allowing 3DUS verification of biopted site, but not improving biopsy
accuracy [41; 42]. A less clumsy 4DUS monitored freehand biopsy system, seems more
relevant.
In musculoskeletal ultrasound 3DUS of rotator cuff lesions have been reported [43]
to, not convincingly, improve the diagnostic accuracy.
Visualization of vessels based on power doppler imaging, has been reported in several
works without any significant benefits. A method that might be useful is 3D measure-
ment of carotid atherosclerotic plaque volume [45] - for instance as response to medical
treatment [46]. Intravascular ultrasound (IVUS) transducers have been made to explore
the inside of vessels and their pathologies. The most common transducers are rotating
side-viewing devices, but also forward-viewing devices, that do not need to be able to
pass the imaged section of the vessel (in the case of stenosis), have been constructed [47]
Impressive 3D imaging of the neonatal brain has recently been published [48]. This
study illustrates that the availability of all sectional planes is one of the major forces of
conventional 3DUS.
Within cardiology flow measurements using 3DUS have been performed in several
studies, but the inherent mismatch between temporal imaging resolution and flow events
makes such recordings of limited value and quality. Synchronization with heart activ-
ity (ECG gating) allows reconstruction of real time 3D volumes acquires over several
presumably identical heart cycles. This approach is widely used in cardiology. Real
time 3DUS (4DUS) has been used on an experimental basis in cardiology since the
early nineties [16; 20]. The real time scanning, which is not based on ECG-gating and
reconstruction, provides beat-to-beat estimations of stroke volumes [49–51], more ac-
curately determined than using 2DUS [52]. Even intracardiac probes providing 4DUS
have been constructed [53]. The limited resolution of the available real-time scanner,
has prevented it from gaining a place in daily work-up. But dynamic examination of
contractibility, valve function, and accurate flow measurements all in three dimensions
seems worth waiting for.
Interventional ultrasound has been combined with 3DUS in a limited number of stud-

42. 40 Chapter 2 Clinical Use of 3DUS
ies. For instance 3DUS guided brain surgery has been performed [54], where ultrasound
provides guidance for tumor resection with the capability to update volumetric infor-
mation during surgery and precisely guide instruments during surgery. CT and MR
scanning are both slower and sensitive to tissue position shift between imaging and in-
tervention. Also in upper abdominal intervention 3DUS has found use. Monitoring and
guiding intrahepatic procedures such as transvenous liver biopsies (TLB) and transjugu-
lar intrahepatic portosystemic shunt (TIPS) placement, which normally done solely by
the aid of fluroscopy, can be done with 3DUS yielding lower error rates and needle
passes [55; 56]. Also tumor cryo- or radiofrequency ablation can benefit from 3DUS
[55] - potentially combined with instrument tracking devices such as UltraguideTM [57].
2.2 3DUS in Obstetrics
The use of 3DUS in this speciality until and including 1999 is reviewed in the published
paper [58] which can be found in the Appendix D.1 on page 153 and is assumed read
prior to reading this section. The following will concentrate on publications from 2000
until the time of writing.
(a) Original transverse image (b) Reconstructed
sagittal image
(c) Reconstructed frontal image
(C-plane)
(d) Volume rendered
3DUS image
Figure 2.3: Fetus at 8 weeks of gestations
The availability of 3DUS offers an opportunity to (hopefully more accurately) redo
measurements of fetuses in all stages of development - a task which has been undertaken
by several authors - e.g. fetal [59], fetal brain [60], cerebellar [61], renal [62], adrenal
[63], and upper arm [64] volumes. This subject will not be explored further here.
Most of the work done can be divided into three major groups examining: fetal struc-
tures & malformations, twins (including conjoined twins), and vascular structures (pla-
centa & umbilical cord).
Examination of malformations is one of the strong sides of 3DUS in obstetrics. The
fetus is usually surrounded by amniotic fluid and its surface therefore depicted well
using volume rendering without any needs for segmentation (Fig. 2.3). Malformations
impacting the fetal face and other parts of the surface (abdominal wall defects, spinal
defects) are readily revealed and recognized since it is more or less a matter of just
looking at the fetus. The review by Benoit [65] shows several examples on what kind of
3D images to expect at different fetal ages. Sex identification and detection of anomalous
Figure 2.4: Gender
genitalia can be facilitated using 3DUS [66; 67] (see Fig. 2.4). Facial deformations
such as micrognathia associated with several hundreds of genetic disorders are important
findings, which may be facilitated using 3DUS [68–70]. As suggested earlier [71] the
more frequently seen cleft lips and palates may more easily be detected and visualized
using 3DUS. This has been supported by more recent findings by the same group [72].

43. 2.2 3DUS in Obstetrics 41
(a) Mono-amniotic twins at 18 weeks of gesta-
tion recorded using freehand acquisition [76]
(b) Umbilical cord knot recorded with 3D color
Doppler scanning [76]
(c) Mono-amniotic twins (17 weeks) (d) Twins di-choriotic (1. trimester)
Figure 2.5: 3DUS of twins
Measurements on lumbar spinal canal [44] cross-sectional areas and volumes at different
levels have been performed at different gestational ages in an attempt to describe the
normal development, as defective fetal development is considered a risk factor in adult
back pain. Characterization of spina bifida including determination of the exact level of
the defect, which is very important to prognosis and parental counselling, can be done
more accurately using 3DUS [73]. Even a study of fetal behavior has been published
[74].
Three-dimensional ultrasound provides an excellent tool for depicting twins, their
choriocity [75; 76] (Fig. 2.5), size differences, and any kind of conjunction (e.g. [77;
78]).
Doppler measurements on fetus, umbilical cord (Fig. 2.5), and placenta [79] combined
with 3DUS seems speculative. The relatively low Doppler sensitivity, slow acquisition
of Doppler images, and angle variance makes the resulting reconstructions of very un-
reliable quality, and clinical decisions based on such data seems questionable - and no
published studies have to my best knowledge been able to change that yet (including
[76]). 4DUS of the fetal heart has also been undertaken [80], but quality suffers heavily

44. 42 Chapter 2 Clinical Use of 3DUS
from the lack of resolution in current 4D systems.
To summarize, a lot of works about 3DUS in obstetrics have been published over the
last 10 years, but the lack of works providing firm evidence for the blessings of 3DUS is
striking.
2.3 3DUS in Gynecology
The use of 3DUS in gynecology until and including 1999 is also reviewed in [58] (Ap-
pendix D.1 on page 153). Since then no major breakthroughs have been published.
For instance 3D power Doppler examination of adnexal masses to predict malignan-
cies are reported to have sensitivity, specificity, and positive predictive values ranging
from 100, 75, and 50% [81] to 100, 99.08, and 91.67% [82] - results demanding repeated
experiments by others in reasonably sized double-blinded experiments. Examination of
ovarian stroma by so-called Doppler flow intensity [83], should be able to prove that
ovarian flow decreases with age. In my opinion this study, as other concluding on so-
called Doppler intensity2, is on thin ice - primarily due to huge sensitivity to parameter
settings of the US machine, which can rarely be controlled fully by the operator. Sec-
ondly because of the great variance of penetration and image quality between patients.
To perform such studies at least an internal reference like comparison to a contralateral
identical organ or temporal comparison of the same organ would be required. A sounder
foundation using quantitative measurement methods e.g. flow velocities or absolute flow
measurements would be preferred. As demonstrated in [84] the differences in the color-
based flow indices were higher between left and right ovary, than between dominant
and non-dominant ovary in women examined in late follicular phase before in vitro fer-
tilization. Not even between dominant and non-dominant follicle shells differences in
flow intensities could be found. To my best knowledge no color-pixel-based methods
has been able to provide solid tools to predict cancer or other pathology in 2D nor in
3D. Transit time studies using an ultrasound contrast agent and Doppler have been made
with results that indicate a useful method [85]. In [86] ovarian torsion is examined using
3DUS and color indices in a single case. On that basis it is overstated that the diagno-
sis can be better made using 3DUS power Doppler than 2D Doppler. Despite that, the
presence of a reference (i.e. the opposite healthy ovary) makes this kind of investigation
more sound.
In measuring the number of antral follicles no difference could be found between 2-
and 3DUS [87], which is really not surprising. A thorough 2D scan covering the whole
ovary contains just as much information as a 3D scan. Counting simple objects as folli-
cles will be almost the same procedure using either technique. However, a stored 3DUS
acquisition will serve as firm documentation of the volume scanned and will enable a
re-examination of the organ (Fig. 2.6).
Virtual hysteroscopy has been examined [88], where transvaginal 3DUS with intra-
uterine hypoechoic contrast fluid is visualized like the view through a hysteroscope.
This method is faster and easier for the patient and allows views not always obtainable
in conventional hysteroscopy. Furthermore bleeding does not obscure view and infor-
mation from beneath the endometrial surface is available. Therapeutic procedures is not
possible as for now, color and tactile information is not available either. On the other
2Roughly spoken the amount of colored pixels divided by the same number plus number of uncolored
pixels in a region

45. 2.3 3DUS in Gynecology 43
Figure 2.6: Three orthogonal slices of an ovary
hand, a combination of 3DUS or 4DUS and intervention is not unlikely in the future,
as well as remote palpation (e.g. elastography and acoustic streaming) might replace
photographic color imaging and instrumental palpation.
3DUS measurement of endometrial volume seems in several works to be a better
parameter than (mid-sagittal) endometrial thickness, which is the standard measure used
conventionally. It shows better reproducibility (intra- and interobserver) [89; 90] and
has earlier been suggested to more accurately predict malignancy in post-menopausal
women [91]. Also in in vitro fertilization (IVF) endometrial volume measurement might
find a place [92–94] replacing endometrial thickness.
A descriptive study has described 3DUS of the cervix in pregnant women at high
risk for premature delivery [95]. This work shows that 3DUS of the cervix is a feasible
method, usually providing good visualization of cervical size and morphology.

46. 44 Chapter 2 Clinical Use of 3DUS

47. 45
Part II
Clinical Trial: 3DUS of Cervical
Cancer

49. 47
Chapter 3
Introduction
True ease in writing comes from art, not chance,
As those move easiest who have learned to dance.
’Tis not enough no harshness gives offence,
The sound must seem an echo to the sense.
William Shakespeare
Contents
3.1 Pathogenesis, Pathology, and Epidemiology . . . . . . . . . . . . 48
3.2 Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.3 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.5 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.6 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.7 Ultrasound Scanning . . . . . . . . . . . . . . . . . . . . . . . . 50
3.8 Aim of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Every year almost 500 women in Denmark are diagnosed with cervical cancer, and al-
most 200 die from it (see Table 3.1). Fortunately the number of new incidences have
been steadily declining over the last decades. This is generally dedicated to the sys-
tematic screening program, where women are offered regular cytological examination
of cells obtained by cervical smear, but remains to be proven. Sixty years ago cervical
carcinoma was the dominant cancer killer in American women. Over the last 10 years
the number of deaths from cervix cancer has not decreased, though.
The treatment consists of either surgery or radiation therapy combined with adjuvant
chemotherapy. Which treatment is offered depends on disease spread (FIGO stages -
see App. A). Stages IA, IB, and IIA are usually treated surgically whereas IIB - IV are
treated by radiation therapy.
Table 3.1: Incidence and deaths from cervical carcinoma in Denmark (source: Sund-
hedsstyrelsen - Cancerregisteret, Døds˚arsagregisteret).
Year 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Incidence 591 540 517 532 470 488 489 478 427 425 -
Per 100.000 21 19 18 18 16 17 17 16 14 14 -
Deaths - 230 - - - - 177 - 193 176 191

50. 48 Chapter 3 Introduction
3.1 Pathogenesis, Pathology, and Epidemiology
Most cervical cancers are squamous cell derived (planocellular) carcinomas develop-
ing from the transformation zone [96, p 579] between the cylindrical epithelia of the
endocervix and the squamous cell epithelia of the exocervix. At this location epithe-
lial metaplasia occur,1 which can further develop into cervical intraepithelial neoplasia
(CIN), divided into three grades: CIN-1 mild dysplasia, CIN-2 moderate dysplasia, and
CIN-3 severe dysplasia and carcinoma in situ (CIS). These are all limited by the base-
ment membrane not invading the underlying stroma, and therefore are not recognized as
cancer [97, pp 513-8]. The proportion of squamous cell derived cancers (∼75%) has de-
creased from earlier (∼95% [98]), probably due to earlier discovery of CIN by cervical
smear screening, which prevents development into invasive cancer. Adenocarcinomas
account for approximately 12% (earlier 5%) with a peak debut a few years later, and are
associated with the same risk factors as squamous cell derived cancer
Cancer usually develops from CIN as a precursor, with a peak incidence rate around
50 years of age (Table 3.2), apx. 25 years after CIN-1 and CIN-2 and 10-15 years after
CIN-3 [97, pp 514].
Table 3.2: Incidence by age in year 1998 (source: Sundhedsstyrelsen - Cancerregisteret, Nye
tal fra Sundhedsstyrelsen. ˚Argang 6. nr. 6 2002.).
Age 0-14 15-29 30-44 45-59 60-74 75+ Total
Incidence 0 40 127 105 90 63 425
Percentage 0.0% 9,4% 29,9% 24,7 21,2% 14,8% 100%
Cervix cancer is associated with smoking, multiple sexual partners, early age first
coitus, and the number earlier sexual partners of the woman’s partner. CIN and inva-
sive cancers are closely associated with human papilloma virus (HPV) infections, which
today is considered the primary risk factor [99].
3.2 Disease
Initial symptoms are vaginal bleeding, especially after voiding, defaecation, intercourse,
or bath. Gradually it evolves into continues bleeding and purulent malodorous discharge
due to necrosis and infection. Cervical cancer spreads by direct growth into surrounding
tissue and to adjacent lymph nodes (pelvic, para-aortic, hypogastric and external iliac
nodes). Hematogenous spread is rare. Direct extension accounts for frequent ureteral
obstruction leading to renal failure, a common cause of death in patients with advanced
disease.
3.3 Staging
Accurate staging is of utmost importance to an effective treatment and quality assur-
ance. This is done according to the guidelines made by the International Federation of
Gynecology and Obstetrics - FIGO (Appendix A). The primary part of the staging is
gynecological examination under general anesthesia (EGA2). This includes inspection,
1Metaplasia is conversion of one differentiated cell type to another.
2In the following EGA and clinical staging according to the FIGO criterea will be used synonymously.

51. 3.4 Treatment 49
bimanual vaginal and rectal palpation, to thoroughly evaluate the vaginal and parametrial
invasion, if any. Cystoscopy and proctoscopy are done in the same session. Additionally
colposcopy, endocervical curettage, hysteroscopy, IV urography, and X-ray of lungs and
skeleton are allowed for assigning the stage. Other examinations, such as US, MRI, CT,
laparoscopy, arterio- and venography might also be useful for treatment planning, but
must not change the assigned FIGO stage. This is because all techniques are not gener-
ally available. At Herlev Hospital IV urography has several years ago been replaced by
US because it is faster, more comfortable for the patient, causes no exposure to radiation,
and has no adverse effects. At the same session far metastases in liver, retroperitoneum,
and groins can be detected and biopsed. Hydronephrosis from ureteral obstruction due
to parametrial tumor invasion or pressure from enlarged lymph nodes [100] is demon-
strated with high sensitivity and specificity compared to IV urography [101–104].
Earlier investigations have demonstrated that the clinical staging has an inaccuracy3
around 40-60% [105–109], especially due to retroperitoneal lymph node metastases, but
also due to inaccurate evaluation of local spread. Therefore other supplemental methods
have been tried (see Section 3.6).
3.4 Treatment
Stage IA1 cancers are treated by conization or hysterectomy including the superior (1-
2 cm) part of the vagina. Stage IA2 and IIA are usually treated by so-called radical
hysterectomy (Wertheim’s or Okabayashii’s operations) removing uterus, upper vagina
(up to two thirds), connective tissue in pelvis laterally for uterus and the vagina including
lymph nodes along the iliac vessels and in the obturator foramen. In more advanced
stages (≥IIB) or in patients not suitable for surgery, radiation therapy combined with
chemotherapy are used.
In the early stages (IB & IIA) no difference in survival between the surgery and ra-
diation therapy have been shown [110]. But in the case of stage IIB or higher, surgery
yields markedly worse results, wherefore radiation- and adjuvant chemotherapy are used.
Adverse effects to radiation such as dyspareunia, eliminated ovarian function, cystitis,
proctitis and fistulas imply that surgery is preferred if possible. Furthermore, surgery
offers a better evaluation of tumor spread e.g. to the pelvic and para-aortic lymph nodes.
Finally, the option to employ radiotherapy later on in case of pelvic relapses remains.
This is advantageous in contrast to secondary surgery where radiation damages make
that very difficult and associated with considerable morbidity.
3.5 Prognosis
The relative survival after diagnosis of cervix cancer is around 85, 65, and 60 percent
at 1, 5, and 10 years respectively [111]. This depends heavily on the actual stage, with
5-years relative survivals being apx. 96, 87, 65, 35, and 10 percent for stages IA, IB, II,
II, and IV respectively [112], which makes the total survival heavily dependant on the
distribution of stages (Table 3.3).
3The word inaccuracy means: Percentage of incorrect clinical stagings when compared to result after
surgery and histological examination as gold standards.

52. 50 Chapter 3 Introduction
Table 3.3: Relative distribution on stages at dis-
covery in Denmark 1980-5 [112].
Stage I II III IV
Fraction 50% 25% 18% 7%
3.6 Imaging
Like any other diagnostic work-up, the cervical cancer diagnosis and treatment planning
depend on different imaging modalities. Even though FIGO puts constraints on methods
to use for staging, every conceivable modality is still allowed for treatment planning.
Computerized tomography (CT) has been used in cervix cancer for several years
[113], primarily to plan and follow radiation therapy, i.e. cancers in higher stages (≥IIB)
[114].
Magnetic Resonance Imaging (MRI), which in addition to the structural imaging
also can perform physiological (fMRI - functional MRI) and biochemical measurements
(NMR Spectroscopy), is a fast evolving technology - inescapable in most medical spe-
cialities. Furthermore, like ultrasound it is inherently safe without ionizing radiation.
Comparisons of MRI to pathological staging have showed higher accuracies determin-
ing stage, parametrial invasion, and lymph node involvement than CT and clinical stag-
ing [115; 116], although others have demonstrated equal results comparing MRI and CT
[117]. Results vary substantially, though, and no firm conclusions can be drawn. For
an excellent review on MRI’s role in imaging cervical carcinoma see Boss et al. 2000
[116].
MRI examination often shows a tendency to overstage, which can in part be attributed
to the relatively low resolution [116] making exact decisions on parametrial extension
from the cervix difficult. Therefore endorectal MR coils have been developed4 [118]
to yield higher resolution [119]. Again, no big difference in accuracy has been gained
[120–122], not even when using an integrated combined endorectal/phased array body
coil [123]. Intravaginal coils have been tried out too [124].
To conclude, MRI might be promising, but no firm evidence that it can change treat-
ment and prognosis exists. Nevertheless, it might very well be the most accurate single
modality to determine tumor size and spread (local and through lymphatic vessels) in
large tumors. MRI offers a large field-of-view and depicts soft tissue very well, but suf-
fers a bit from limited spatial resolution. Since MRI has no adverse effects - i.e. relies
neither on radiation nor on invasion - it definitely remains an attractive way to evaluate
patients.
3.7 Ultrasound Scanning
Ultrasound scanning has been used as a part of the work-up since 1995 at Herlev Hospi-
tal. Combined abdominal and transvaginal scanning has been used to evaluate kidneys,
local tumor spread, and regional lymph nodes.
Transabdominal ultrasound scanning has no place in evaluating early (<IIB) cer-
vical tumors, simply because the deep pelvic structures cannot be visualized properly
4Originally developed for imaging rectal carcinoma

53. 3.7 Ultrasound Scanning 51
transabdominally. When tumors are large or spreading, transabdominal ultrasound scan-
ning may be valuable depicting the size of tumor masses. However, evaluation of lymph
node status, which is very important prognostically has been attempted in only one pub-
lished study [101] with unsatisfactory sensitivity and specificity (66.67% and 78,53%
respectively). Assessment of bladder involvement has also been examined with limited
success [125].
Transvaginal ultrasound scanning as a staging tool has only been evaluated in one
serious work [126] and reported in a few cases [127; 128], which seems a bit odd consid-
ering the direct access to the involved organ. The first study indicates that transvaginal
US might be an excellent tool for the staging, though. Evaluation of bladder wall in-
vasion using transvaginal US has been reported too [129] and criticized [130]. Doppler
measurements of resistance index (RI) has been evaluated too [131] with limited value.
Transrectal ultrasound scanning5 used as a diagnostic procedure for cervix cancer
is probably the most successful. It is first described in 1979 [133] primarily to assess
the local spread. Several works [126; 130; 134–144] have been published without clear
conclusions.
Others [110] have shown that tumor size (below or above 4 cm in diameter) is impor-
tant for survival. This has also been incorporated into the FIGO classifications, making
the distinction between stage IB1 (tumor <4 cm) and IB2 (tumor >4 cm) - a distinction
not routinely used in Denmark, and others have demonstrated that a one-dimensional
diameter measure is not a good prognostic predictor [145].
I has been proposed that tumor volume better than size (diameter) would indicate a
need for postoperative adjuvant chemotherapy [146; 147]. This advocates for three-
dimensional examination techniques.
Three-dimensional US In a published work [148] the authors could not conclude
that 3DUS had a higher accuracy determining tumor volume than 2D ultrasound, even
though they did! The authors compared the result of 2D measurements, where the vol-
umes are calculated using the formula for a prolated ellipsoid having three orthogonal
diameters: π/6 ×d1 ×d2 ×d3. 3D measurements were done using planimetry. The two
results were compared to the volume found from the surgical specimen, but the ’real’ vol-
ume was found by measuring three diameters (like for 2DUS). This way the ’Gold Stan-
dard’ became just as inaccurate as the 2D measurements. A higher accuracy determining
volumes using 3DUS vs. 2DUS has been established in other studies [31; 34; 149–151].
The impact of such results on treatment and prognosis still remains to be estimated.
Transrectal 3DUS The reasons for choosing three-dimensional transrectal US (3D-
TRUS6) of the cervix in the present trial were that it can be difficult to cover the whole
cervix from one view-point transvaginally. This is due to introduced air and a limited
contact surface since both transducer and cervix are usually convex / spherical structures.
Also a very irregular tumor extending into the vagina would be difficult to cover in
one sweep. Finally, the transrectal route is in contrast to ones immediate beliefs more
gentle to the patient since direct contact with the tumor and thence extensive bleeding
5First use reported [132] by Watanabe for prostate scanning and developed 2 years earlier.
6In the following chapters 3DUS and 3D-TRUS will be used synonymously.

54. 52 Chapter 3 Introduction
can be avoided. From the experience with transrectal scanning of the prostate and anal
sphincter, we know that transrectal scanning is well tolerated by most patients.
Our first attempts showed promising results with good delineation of tumor (Fig. 3.1).
Tumor was usually depicted as a slightly hypoechoic structure compared to the surround-
ing cervical tissue, a discernation not always possible. For instance when the tumor had
infiltrated most of the cervix (Fig. 3.2).
If it would be possible to obtain good quality volumes depicting the whole cervix,
thorough examination of the volume after the scanning session might deliver exact knowl-
edge of tumor extension, size, and relations.
3.8 Aim of Study
Three-dimensional transrectal ultrasound scanning might provide a more accurate pre-
diction of operability. Potentially adverse effects associated with radiotherapy can then
be avoided in patients who by means of a more precise staging can be offered surgical
treatment. The unfortunate although few patients assigned for surgical treatment, where
the operation shows inoperability, might avoid this situation and the frequent complica-
tions, if more accurate staging techniques were available.
The purpose of the trial was to evaluate three-dimensional transrectal US scanning of
cervical cancer. This were done by comparison with clinical staging, MRI, and patho-
logical results.
• Primarily, by assessing the ability to predict surgical operability from the depiction
of tumor spread. For a more detailed view the actual staging results will also be
compared.
• Secondly, the tumor volume estimated by 3DUS will be compared to histological
volume estimation.
• Thirdly, the morphologic description, i.e. the tumor location of tumor spread, will
be compared within modalities.
The methods used in this study are all relatively new in the field. Therefore a part of the
work was to find out which approaches were feasible in a clinical setting.

55. 3.8 Aim of Study 53
(a) Transaxial view of a well-defined tumor (b) Tumor delinieated by area markers
(c) Tumor traversing left border of cervix (frontal view)
(d) Oblique view (e) Combined frontal and sagittal view
Figure 3.1: Clearly visualized tumor that extends into left parametrium.

56. 54 Chapter 3 Introduction
(a) Tumor that cannot be discriminated from cervix. Tumor is seen
to extend into right parametrium.
(b) Tumor extending into left parametrium.
(c) Measurement of tumor equalling cervical volume (axial
view)
(d) Frontal view
(e) Sagittal view. (f) Another tumor extending into left parametrium
Figure 3.2: Tumors that fill up the entire cervix inseparable from cervical tissue. Several of
them show tumor growth into parametria.

57. 55
Chapter 4
Material and Methods
Give us something else,
give us something new,
indeed for Heaven’s sake give us rather the bad,
and let us feel that we are still alive,
instead of constantly going around in deedless
admiration for the conventional
Carl Nielsen
Contents
4.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.2 Conventional Ultrasound Scanning . . . . . . . . . . . . . . . . 58
4.3 Three-dimensional US Scanning . . . . . . . . . . . . . . . . . . 59
4.4 Clinical Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.5 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.6 Pathological Evaluation - Gold Standard . . . . . . . . . . . . . 63
4.7 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.8 Trial Approval, Safety, and Patient Strain . . . . . . . . . . . . . 64
4.9 Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.1 Study Design
The trial was a prospective comparative study, where all patients participating were to
be examined using three-dimensional transrectal ultrasound scanning, endorectal MRI
in addition to standard diagnostic work-up (see Fig. 4.1).
4.1.1 Patients
Approximately 100 women are referred to Herlev Hospital every year from Copenhagen,
Roskilde and Frederiksborg Counties. Around 40% of those are treated by surgical
operation, whereas the rest are offered radiotherapy. The study was planned to run for
approximately one year.
4.1.2 Inclusion Criteria
All patients with histologically confirmed cervical carcinoma referred to Herlev Hospital
for treatment of primary tumor.

58. 56 Chapter 4 Material and Methods
3DUS
staging
Surgery
(clin. stage <
IIB)
3DUS Volume
Reconstruction
Ultrasound
Scanning
Pathological
Staging
Histological 3D
reconstruction
Clinical
Evaluation in
Gen. Anesth.
Yes
Clinical Staging
Operation
MR-scanning
3D MR Volume
Reconstruction
MRI staging
All
a) apx. 40%
b) apx. 60%
Brachy- &
chemotherapy
No
Figure 4.1: Chart showing patient flow and examinations done in trial.

59. 4.1 Study Design 57
4.1.3 Exclusion
Fulfilment of one of following criteria led to exclusion of patients from the study:
1. Not Danish speaking patient
2. Age below 18 years
3. Pregnancy
4. Stages 0 (carcinoma in situ) and IA1
5. Patients referred to simple hysterectomy due to histological proof of inva-
sion between >3 mm and ≤5 mm after conization, i.e. IA2 patients where
tumor is already removed.
It is assumed that IA1 patients already treated with conization are not referred for treat-
ment, and therefore not included in the study.
4.1.4 Contraindications and Drop-outs
If, for some reason, parts of the examinations were impossible perform or otherwise
contraindicated (e.g. rectal stenosis, claustrophobia, excessive pains), the result was
noted as insufficient, with information of the reason. Results from patients leaving the
trial were kept, with consent from the patient. For instance ultrasound scanning results
from patients refraining from participation in MR scanning were kept if accepted by the
patient.
4.1.5 Measurement Parameters
For each patient three different evaluations of disease spread were to be performed;
ultrasound scanning, magnetic resonance imaging, and clinical gynecologic work-up in-
cluding examination under general anesthesia (EGA) including procto- and cystoscopy.
The comparison of the different modalities was impaired by the fact, that we would not
get a gold-standard result (histologic examination - see Section 4.6) in the proportion of
patients, that were not operated upon.
The primary parameter of measurement were operability (Table 4.1) based on the
spread of disease. It is a binary value obtained by application of a threshold between
stage IIA (operable) and IIB (non-operable).
To get a more detailed understanding of the differences between modalities the ranked
scale (Table 4.1) representing the FIGO and TNM stages were also used for comparison.
This (not independent) measure allowed estimation of agreement between modalities
and with pathological results. Since we did neither expect EGA nor 3DUS to be able
to distinguish a cervical IA stage tumor from a disease free cervix, nor differentiate be-
tween IA1 and IA2, these were all included in ranked scale stage 1. The FIGO staging
does allow conization to be performed during clinical examination to make this distinc-
tion.
Tumor volume estimated from US, MRI, and histologic reconstruction were used as
a secondary measure. From clinical examination no volume were available - only an
indication of size since the distinction between stage IB1 and IB2 is lesion size less or
greater than 4.0 cm corresponding to a threshold of 33.5 ml assuming a spherical lesion1.
1Volume of a sphere is: V = 4π
3 r3 = π
6 d3 ≈ 1
2 d3

60. 58 Chapter 4 Material and Methods
Table 4.1: Measurement scales (ranked scale and binary value) used for stage comparisons.
Ranked Binary 3D-TRUS MRI Clinical TNM
scale (operability)
1 1 1a1 1a1 IA1 T1a1
1a2 1a2 IA2 T1a2
2 1b1 1b1 IB1 T1b1
3 1b2 1b2 IB2 T1b2
4 2a 2a IIA T2a
5 0 2b 2b IIB T2b
6 3a 3a IIIA T3a
7 3b 3b IIIB T3b
8 4a 4a IVA T4
9 4b 4b IVB M1
The tertiary measure was a comparison of the locations of tumor judged by the differ-
ent modalities. This comparison was done based on a morphologic description scheme
(see Section 4.3.3).
Comparison between two- and three-dimensional US was not undertaken, since inde-
pendency of the two examinations would require two examiners and randomization of
who should do each of the 2DUS and 3DUS examinations.
4.1.6 Power Calculations
Power calculations to estimate the number of patients needed to make a conclusive study,
were not possible due to the fact, that the method has not been evaluated before. Addi-
tionally, published works report great differences in the ratio of operable / non-operable
cases [105; 107–109; 152]. The calculation would therefore have to be based on bare
judgement, resulting in purely hypothetical results.
Instead, the following argumentation was used: If no significant improvement in diag-
nostic accuracy can be shown in a hundred cases, which is one fifth of the total number
of yearly cases in Denmark, then the benefit must be limited. Since both US and MRI
are diagnostic methods without adverse effects, this approach seems reasonable.
4.2 Conventional Ultrasound Scanning
Each patient underwent traditional examination consisting of transabdominal US imme-
diately before 3D-TRUS. Transvaginal scanning were done only to determine position of
the uterus and cervix to make transrectal scanning as smooth and painlessly as possible.
4.2.1 Equipment
A conventional ultrasound machine (Panther 2002 ADI, B-K Medical A/S, Herlev, Den-
mark) was used. Transabdominal scans were acquired using a multi-frequency 2,7-
5 MHz curved array transducer (model no. 8565), transvaginal scans using a dedicated
6,5 MHz transducer (Model no. 8561) and superficial scans (groin for enlarged lymph
nodes) using a 5-8 MHz linear array transducer (Model no. 8560).

61. 4.3 Three-dimensional US Scanning 59
FNAB x 2 (at least)
from at least one nodule
Enlarged
lymphnodes
above promontorium - with
smallest diameter
>10mm
Yes
Suspicious liver lesion(s)? Yes
TRUCUT 0,9 x 3
(2 for histology, 1 form electron
microscopy) +
FNAB x 2 from at least one
lesion
No
NoNo further biopsies
US Examination
Figure 4.2: Flow diagram for biopsy procedure during examination of cervix cancer
Figure 4.3: Transrectal transducer in-situ. In real life the uterus falls back when patient is in
supine position, and a full bladder additionally helps retroverting the uterus.
4.2.2 Procedure
Abdominal scanning were performed as part of the routine examination to assess kidneys
(hydronephrosis), liver (metastases), retroperitoneum (enlarged lymph nodes - metas-
tases), uterus (size, position, shape and pathologic changes), peritoneum (ascites), blad-
der (wall regularity), and groins (enlarged lymph nodes).
In case of enlarged lymph nodes (least diameter greater than 10 mm) in retroperi-
toneum suggesting metastasis [153], above the promontory (terminal line) two fine nee-
dle aspiration biopsies (FNAB) were performed. Suspicious lesions in the liver were
biopted using a 0,9 mm Tru-Cut needle for histological examination and electron mi-
croscopy supplemented with two passes of FNAB for cytologic examination. This
biopsy procedure is the standard work-up at the ultrasound department and not initiated
by the present trial (see Fig. 4.2).
Only results from this conventional US were given to the doctors performing the FIGO
staging.
4.3 Three-dimensional US Scanning
4.3.1 Equipment
For transrectal scanning a dedicated bi-plane 5-7,5 MHz prostate transducer (B-K Med-
ical model no. 8558) with two arrays were used (Fig. 4.3). The curved array were trans-
versely oriented in relation to the cervix (Fig. 4.5(a)) producing a sector scan image.