UNIVERSITY OF HELSINKI REPORT SERIES IN PHYSICS HU-P-D113 DIFFRACTION-ENHANCED X-RAY IMAGING OF IN VITRO BREAST TUMOURS Jani Keyriläinen Division of X-ray Physics Department of Physical Sciences Faculty of Science University of Helsinki Helsinki, Finland Department of Oncology Helsinki University Central Hospital Helsinki, Finland ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Science of the University of Helsinki, for public criticism in Auditorium D101 of the Department of Physical Sciences (Physicum), Gustaf Hällströmin katu 2, on October 29th, 2004, at 12 o’clock noon. Helsinki 2004 ISSN 0356-0961 ISBN 952-10-1655-8 ISBN 952-10-1656-6 (pdf-version) http://ethesis.helsinki.fi/ Helsinki 2004 Yliopistopaino PREFACE This thesis is based on research done at the Division of X-ray Physics, Department of Physical Sciences, University of Helsinki (HU, Finland), at the Medical Beamline ID17, European Synchrotron Radiation Facility (ESRF, Grenoble, France), and at the departments of Oncology, Pathology and Radiology, Helsinki University Central Hospital (HUCH, Finland), all of which are acknowledged. I wish to express my gratitude to Professor Juhani Keinonen, Ph.D., Head of the Department of Physical Sciences, and to Professor Seppo Manninen, Ph.D., former Head of the Division of X-ray Physics, for the opportunity to work at the Department. I also wish to thank Professor Heikki Joensuu, M.D., Ph.D., Head of the Department of Oncology, and William Thomlinson, Ph.D., former Beamline Responsible, ID17, for allowing me to use the outstanding working facilities of their institutions. I am most grateful to my supervisors, Professor Pekka Suortti, Ph.D., Department of Physical Sciences, and Docent Mikko Tenhunen, Ph.D., Chief Physicist of the Department of Oncology, for proposing to me the topic of this study and guiding me throughout this research work. Professor Suortti introduced me to the physics of X-ray diffraction; without the benefit of his world-renowned expertise in the subject, I would never have attempted work in it. I admire Docent Tenhunen’s profound and wide knowledge in the physics of radiology and radiotherapy, his way of analysing the questions and problems from all sides, and his ability to come up with new ideas over and over again. I am most grateful for their constant encouragement, trust in my abilities and advice on how to work more independently. I express my warmest gratitude to the official reviewers of the thesis, Ossi Korhola, M.D., Ph.D., and Docent Sauli Savolainen, Ph.D., for valuable comments and constructive criticism during the preparation of the final manuscript. I am deeply grateful to all my collaborators, especially to Marja-Liisa Karjalainen-Lindsberg, M.D., Ph.D., for her invaluable efforts and expertise in collecting, preparing and analysing the pathology specimens. I sincerely thank Eva-Maria Elo, M.D., and Professor Pekka Virkkunen, M.D., Ph.D., whose irreplaceable experience in radiographic interpretation as well as effective way of working have impressed me deeply and have been of immeasurable value in accomplishment of this study. Special thanks are due to Alberto Bravin, Ph.D., and Stefan Fiedler, Ph.D., of ID17 for fruitful conversations and valuable cooperation. Many thanks are directed to Manuel Fernández, M.Sc., Aki Kangasmäki, Ph.D., Liisa Porra, M.Sc., and Mika Torkkeli, Ph.D., in particular for computational and experimental help. Without the excellent technical support of Docent Merja Blomberg, Ph.D., Seppo Kousa, M.Sc., Matti Laitinen, M.Sc., Messrs Pauli Engström, Raimo Jouhten and Pekka Pihkala from the Department of Physical Sciences, Mr Mauri Piil from the Department of Oncology, Mrs Pirjo Tuomi from the Central Laboratory of Pathology, HU, and Messrs Thierry Brochard, Christian Nemoz, Ph.D., and Michel Renier from ID17, it would not have been possible to carry out the present work. I owe my thanks to them all. I feel gratitude towards those individuals who, although suffering from breast cancer, nevertheless consented to participate in this study. I am also indebted to the personnel of the Division of X-ray Physics and Central Laboratory of Pathology, HU, departments of 1 Oncology, Pathology and Radiology, HUCH, and Medical Beamline ID17, ESRF, for pleasant cooperation. I wish to thank all my colleagues and friends at HUCH and HU, especially Manuel. It has been a joy to face the challenges of both clinical and scientific work and to share various excitingly inspiring and enjoyable moments with you. You have made our institutes working places in which in- and outdoor activities are almost as important as getting results. In my private life, I have been privileged to have close friends. Aki, Jussi, Marko, Mika, Mikko, Tero, Tuomo, Ville, and the whole team from Joensuun ilmailukerho (The Flying Club of Joensuu), I thank you for sharing with me some of the most important moments of my life. I would like to give my warmest thanks to my parents, Pirjo and Raino, for their care and together with my little sister, Heidi and her family, for their support and confidence in me. I also warmly thank my parents in-law, Kirsti and Seppo, and their whole family for their support all these years. Most importantly, I owe my deepest gratitude to my dear wife Anna-Kaisa, whose love, care and patience have surrounded me all these years. The financial support of the Academy of Finland is gratefully acknowledged. The author of the thesis was a member of the National Graduate School in Informational and Structural Biology. Helsinki, May 17, 2004 Jani Keyriläinen 2 J. Keyriläinen: Diffraction-enhanced X-ray imaging of in vitro breast tumours, University of Helsinki, 2004, 99 pp. + appendices, University of Helsinki, Report Series in Physics, HU-P- D113, ISSN 0356-0961, ISBN 952-10-1655-8, ISBN 952-10-1656-6 (pdf-version). Classification (INSPEC): A6110F, A8760J, A8760M, A8770E Keywords (INSPEC): mammography, diagnostic radiography, X-ray imaging, X-ray diffraction, dosimetry, synchroton radiation Keywords (The RSNA Index to Imaging Literature): breast neoplasms; calcification, CT, experimental studies, breast radiography; comparative studies, phase contrast, technology ABSTRACT The motivation behind this thesis is illustrated by the fact that many breast cancers are missed at X-ray mammography, insufficient contrast being the most important reason. The present thesis considers the diffraction-enhanced imaging (DEI) technique for imaging in vitro breast tumours. DEI is one of the novel methods in which the change in X-ray wavefront phase or propagation direction at the boundaries and interfaces of the object is used for contrast formation. The purpose here was to evaluate the potential of the DEI technique for mammographic imaging. Other issues discussed include X-ray interactions with matter, radiation dose and generic aspects of breast diagnostics. The formation of refraction contrast was studied quantitatively, using well-characterised test objects and incoherent radiation from an X-ray tube. A new type of device for fine rotation of the analyser crystal was designed, constructed and calibrated. Detailed comparison was made between the histopathological sections of 18 excised human breast tumour specimens and radiographic images. Both planar and transaxial images were acquired with the DEI technique using coherent synchrotron radiation, and the same specimens were imaged with screen-film mammography and computed tomography (CT) units at a hospital. Refraction contrast in X-ray imaging was as much as 20 times larger than the absorption contrast. The fine-rotation device proved to be a very stable tool for examining refraction effects with nanoradian angular resolution. The typical morphologic features of lobular carcinoma invasion were evident in the medium-resolution DEI-CTs, while the changes were vague or ambiguous in the CTs. The visibility of microcalcifications and fine structural details was greatly enhanced in the high-resolution DEI images compared with the screen-film mammograms. Regarding the clinical applications, it is essential that refraction contrast prevails with incoherent radiation from the X-ray tube and that small X-ray beam deviations can be revealed with compact instrumentation. Development of compact monochromatic X-ray sources having sufficient flux to allow short exposure times for clinical purposes will remain a challenging task, and the latest developments in this field are discussed. DEI provides improved visibility of early signs of breast abnormalities, which is crucial for detecting tumours at early stages and small sizes, both being the most important prognostic indicators. In addition, lower radiation doses than those currently employed in mammography make DEI a promising method even for breast CT with clinically acceptable doses. However, the factors affecting image formation need to be examined further to yield direct correspondence between the contrast and structure of the object. 3 CONTENTS PREFACE……………..…………………………………………………………………..1 ABSTRACT………………………...……………………………………………………. 3 LIST OF ORIGINAL PUBLICATIONS……..………………………………………….. 6 AUTHOR’S CONTRIBUTIONS…………………………..……………………………..7 ABBREVIATIONS………………………………………………………………………. 8 AIM OF THE THESIS……..………………………….…………………………………. 9 1. INTRODUCTION……………………………………………………………………. 10 1.1 Background…………………...……………………………………………….. 10 1.2 Imaging of the mammary gland……………………………………………….. 11 X-ray mammography…………………………………………………………12 Ultrasonography (US)………………………….………………………….….15 Magnetic resonance imaging