Oncologic and cardiologic PET/CT-diagnosis : an interdisciplinary atlas and manual 9783540740902, 3540740902, 9783540740919, 3540740910

Citation preview

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W. Mohnike · G. Hör · H. R. Schelbert (Eds.) Oncologic and Cardiologic PET/CT-Diagnosis An Interdisciplinary Atlas and Manual

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Wolfgang Mohnike · Gustav Hör Heinrich R. Schelbert (Eds.)

Oncologic and Cardiologic PET/CT-Diagnosis An Interdisciplinary Atlas and Manual With DVD-ROM With contributions by

Thomas Beyer · Konrad Mohnike · Stefan Käpplinger With 909 Figures, 803 in Color and 24 Tables

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Wolfgang Mohnike, MD Professor Diagnostisch Therapeutisches Zentrum am Frankfurter Tor Kadiner Strasse 23 10243 Berlin Germany Gustav Hör, MD Professor Klinik für Nuklearmedizin und Zentrum der Radiologie Klinikum der J. W. Goethe-Universität Theodor-Stern-Kai 7 60950 Frankfurt/Main Germany Heinrich R. Schelbert, MD, PhD Gerorge V. Taplin Professor Department of Molecular and Medical Pharmacology David Greffen School of Medicine at UCLA University of California at Los Angeles 650 Charles E. Young Drive South Los Angeles, CA 90095 USA

ISBN 978-3-540-74090-2

e-ISBN 978-3-540-74091-9

DOI 10.1007 / 978-3-540-74091-9 Library of Congress Control Number: 2008923539 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: Frido Steinen-Broo, eStudio Calamar, Spain Layout: PublishingServices Teichmann, 69256 Mauer, Germany Printed on acid-free paper 9876543210 springer.com

Disclaimer: This eBook does not include the ancillary media that was packaged with the original printed version of the book.

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Foreword

Panels of experts in the USA und Europe agree that positron emission tomography (PET) is the imaging method that has been most rapidly accepted in the last decade. In a review by Beyer and Townsend it was observed that in five years PET/CT has taken the place of coregistration. In institutions equipped with a combined PET/CT tomograph the advantages are increasingly recognised – particularly in pulmonology and thorax surgery. The NNT (number needed to treat) is the standard according to which the number of patients to be successfully treated is measured. Careful diagnosis involving PET/CT with effective treatment can and must reduce the NNT. The simultaneous preparation of fusion images in PET/CT shortens the examination time, spares the patient the time needed for two visits to the doctor and provides nuclear medical specialists and radiologists with anatometabolic images: Anatomy, (surrounding) structure, localisation and molecular biology expand the diagnostic framework. The current trend points towards PET/CT as a standard diagnostic method in oncology. The dynamism of the development process is reflected already in the case studies shown here whose pictorial documentation is based on three generations of apparatus. The case studies document how PET/CT opens up new diagnostic options for the patient when the conventionally established examination methods fail. Decades of experience have taught us that such situations are by no means the exception, even today. This book is intended to help answer the following questions: What are the strengths of PET/CT? What are its current limits, and what is its development potential? On the enclosed DVD you will find a comprehensive overview of additional literature, the entire text in electronic form and several case studies which – when examined with the viewer – give an impression of the three dimensional nature of the studies. Professor Dr. Gustav Hör Specialist in Roentgenology and Radiology Specialist in Nuclear Medicine

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Acknowledgements

The part of this PET/CT Manual that deals with oncology is based on the German PET/CT Atlas by Mohnike and Hör, published in 2006, which has now been updated and expanded. At the same time, the important indication for PET(/CT) in cardiology receives the attention it urgently requires in the form of the important contribution by Prof. H. Schelbert. We thank him for his profound commitment and for taking on this task at short notice, as well as Prof. G. Hör for his European view of cardiological PET(/CT) examination options presented in his customary, esteemed manner. The compilation and publication of an English-language manual was a real challenge for non-native speakers and could not have been achieved without the thorough and highly committed supervision of the journalist Ms S. Thürk M.A. I am also grateful to my son, Konrad Mohnike, and to Dipl.-Phys. S. Käpplinger for their thorough checking of the manuscripts, as well as to Privatdozent Dr. T. Beyer for his careful revision of his contribution. Dr. U. Heilmann, Ms A. Hinze and Ms W. McHugh of Springer-Verlag were also of great assistance to us. Thanks also go to Dr. T. Eberhard, diagnostic radiology specialist, C. Voelkel, radiologist, Prof. J. Schmidt and I. Volkova, nuclear medicine of the Diagnostic Therapeutic Centre (DTZ) in Berlin, my brother, Privatdozent Dr. Klaus Mohnike (Magdeburg University), and Dr. O. Blankenstein (paediatrician at Charité Berlin) for the working up of findings. Special thanks go to Ms K. Stein of Siemens Medical Solutions and Dipl.Math. Mr W. Lauermann for producing the DVD. We would also like to thank Ms B. Engfer and Ms Y. Fobbe, medical radiological technicians, as well as all other staff, at the DTZ. Our thanks also go to Dipl.-Chem. Mr B. Zimontkowski and Mr J. Reinke, who were always ready to assist me with their help and advice. We especially thank Messrs M. Reitermann, Dr. R. Radmanesh, N. Franke, R. Krämer and Dr. F. Anton of Siemens Medical Solutions for their fair and unbureaucratic assistance. Finally, I would like to thank my wife, Bettina, for her constructive advice and patience throughout the project. Professor Wolfgang Mohnike

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Contents

1

Introduction –

3

Positron Emission Tomography: Past and Present

1

1.1 Survey . . . . . . . . . . . . . . . . . . . . . . . . . . Physical and Biochemical Fundamentals . . . . PET in National and International Medical Care Systems. . . . . . . . . . . . . . . . .

1 2

1.2 Technological Variants and Developments . Coincidence PET vs. Dedicated PET . . . . . Differentiated PET Evaluation . . . . . . . . . Radiotherapeutic Tools . . . . . . . . . . . . . PET/CT – a New Key Technology . . . . . . . Influence of PET/CT on PET . . . . . . . . . . Studies Dealing with the Cost Efficiency of PET Alone . . . . . . . . . . . . . . . . . . . . . PET/CT or Comparison of Co-Registered Findings? . . . . . . . . . . . . “Standard” (CARE)-CT and PET/CT . . . . . PET/MRI? . . . . . . . . . . . . . . . . . . . . . American Joint Committee on Cancer . . . . PET Screening in Japan and Taiwan . . . . .

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4 4 4 5 5 5

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6 6 6 7 7

1.3 Increased FDG Uptake Due to Physiological and Technical Factors . . . . . . . . . . . . . . . .

7

1.4 References . . . . . . . . . . . . . . . . . . . . . . .

8

2

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2

Fundamentals Thomas Beyer . . . . . . . . . . . . . . . . . . . . .

11

2.1 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . Positron Emission Tomography (PET) . . . . . . Radioisotopes and PET Tracers . . . . . . . . . . Coincidence Measurement and Quantification . PET Measurement Results and Reconstruction . PET Scanners and Scintillation Detectors . . . .

11 11 12 13 14 16

2.2 Combined PET/CT . . . . . . . . . . . . . . . . . Retrospective Image Fusion . . . . . . . . . . . The PET/CT Prototype . . . . . . . . . . . . . . CT-Based Attenuation Correction . . . . . . . Commercialization of PET/CT . . . . . . . . . . New Technical Developments in PET/CT . . . PET/CT Acquisition Protocols . . . . . . . . . . Sources of Errors and Optimization Options . Radiation Protection Aspects . . . . . . . . . .

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18 18 18 20 21 23 29 30 37

2.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . .

40

2.4 References . . . . . . . . . . . . . . . . . . . . . . .

40

Pneumology

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43

3.1 Bronchial Carcinoma (BC) . . . . . . . . . . . . .

43

3.2 Significance of FDG-PET in Diagnostic and Therapeutic Management . . . . . . . . . . . . . 44 Critical Evaluation of Diagnosis Management . 45 3.3 Guidelines for 18F-FDG-PET Indications . . . .

45

3.4 Technical and Biochemical Factors . . . . . . . Is Coincidence PET Equivalent to Full-Ring PET? . . . . . . . . . . . . . . . . . . . PET as Metabolism and Proliferation Marker . Innovative Radiopharmacy . . . . . . . . . . .

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46 46 46

3.5 Special PET Indications . . . . . . False-Negative PET . . . . . . . . . False-Positive PET . . . . . . . . . . How Useful Is Integrated PET/CT?

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47 47 47 48

3.6 SCLC (Small-Cell Lung Cancer) . . . . . . . . . .

48

3.7 Pleural Processes . . . . . . . . . . . . . . . . . . Malignant Pleural Tumours (Mesothelioma) . . Imaging Methods . . . . . . . . . . . . . . . . . .

48 49 49

3.8 Case Studies . . . . . . . . . . . . . . . . . . . . . Patient 1 Scar Carcinoma of the Lung . . . . . Patient 2 Pneumonia . . . . . . . . . . . . . . . Patient 3 Lymph Node Metastases of a Squamous Cell Carcinoma . . . . . . Patient 4 Metastasized Bronchial Carcinoma . Patient 5 Round Focus in the Lung . . . . . . . Patient 6 Metastasized Bronchial Carcinoma . Patient 7 Metastasized Adenocarcinoma in the Left Lower Lobe of the Lung . . . . . Patient 8 Downstaging of a Squamous Cell Carcinoma of the Lung . . . . . . . . Patient 9 Preoperative Staging of a Bronchial Carcinoma . . . . . . . . . Patient 10 Pleural Carcinosis after Pneumectomy . . . . . . . . . . . . . . Patient 11 Recurrence of a Brain Metastasis . . Patient 12 Pleural Mesothelioma . . . . . . . . . Patient 13 Prevention of Non-Curative Thoracic Surgery . . . . . . . . . . . . Patient 14 Upstaging of a Bronchial Carcinoma . . . . . . . . . Patient 15 Bilateral Metastases of an NSCLC in the Suprarenal Glands . . . . . . .

50 50 52

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3.9 References . . . . . . . . . . . . . . . . . . . . . . .

54 56 58 60 61 62 64 66 69 71 73 76 79 82

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4

Gastroenterology .

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4.1 Introduction . . . . . . . . . . . . . . Molecular Strategy . . . . . . . . . . . Metabolic Influencing Factors . . . . PET Screening? . . . . . . . . . . . . . Incidentally Detected Lesions (IDL)

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86 87 88 88 88

4.2 Oesophageal Carcinoma . . . . . . . . . . . . . . PET in Diagnosis Management of Oesophageal Carcinoma . . . . . . . . . . . . . .

88 88

4.3 Gastric Carcinoma . . . . . . . . . . . . . . . . . . MALT Lymphomas . . . . . . . . . . . . . . . . .

90 90

4.4 Colorectal Carcinomas . . . . . . . Treatment . . . . . . . . . . . . . . . Status of PET . . . . . . . . . . . . . PET/CT as the Optimum . . . . . . PET Indications . . . . . . . . . . . Limitations of PET . . . . . . . . . . Artefacts . . . . . . . . . . . . . . . . FDG-PET . . . . . . . . . . . . . . . Alternative and Adjuvant Markers Synopsis . . . . . . . . . . . . . . . .

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90 91 91 93 93 94 94 94 94 95

4.5 Liver and Biliary Tract Carcinomas . . . . . . .

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4.6 Gastrointestina Stromal Tumours . . . . . . . .

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4.7 Pancreas Carcinomas . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . Curative Treatment . . . . . . . . . . . . . . . New Gene-Based Treatment Strategies . . . . Indications . . . . . . . . . . . . . . . . . . . . DGN Classes, Consequences . . . . . . . . . . Impact of SUVs on Survival Time . . . . . . . False-Negative/-Positive PET Findings . . . . Pancreas NETs (Neuroendocrine Tumours) .

96 96 97 97 97 97 97 97 98

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4.8 Neuroendocrine Tumours (NETs) of the Gastrointestinal Tract . . . . . . . . . . . . Carcinoids . . . . . . . . . . . . . . . . . . . Conventional Diagnostics . . . . . . . . . NET Spectrum . . . . . . . . . . . . . . . . Biochemistry . . . . . . . . . . . . . . . . . High Secretors . . . . . . . . . . . . . . . . Low (Non-)Secretors . . . . . . . . . . . . . Limitations of PET . . . . . . . . . . . . . . 4.9

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85

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98 98 98 99 99 99 99 99

Case Studies . . . . . . . . . . . . . . . . . . . . . . Patient 1 Oesophageal Carcinoma . . . . . . . Patient 2 Lymph Node Metastasis of an Oesophageal Carcinoma . . . . . . . Patient 3 Downstaging of an Oesophageal Carcinoma. . . . . . . . Patient 4 Carcinoma of the Head of the Pancreas . . . . . . . . . . . . . Patient 5 Metastasized Carcinoma of the Head of the Pancreas . . . . . Patient 6 Carcinoma of the Body of the Pancreas . . . . . . . . . . . . .

100 100 103 105 107 110 112

Patient 7 Hepatocellular Carcinoma with Multiple Metastases . . . . . . . . . . Patient 8 Gastric Carcinoma . . . . . . . . . . . Patient 9 Leiomyoma of the Stomach . . . . . . Patient 10 Follow-Up of an Adenocarcinoma of the Stomach . . . . . . . . . . . . . Patient 11 Staging of an Adenocarcinoma of the Stomach . . . . . . . . . . . . . Patient 12 Staging of a Carcinoma of the Corpus of the Stomach . . . . . . . . Patient 13 Lymph Node Metastasis from Gastric Carcinoma . . . . . . . Patient 14 Extended Metastatic Spread to the Liver from Adenocarcinoma of the Stomach . . . . . . . . . . . . . Patient 15 Caecum Carcinoma . . . . . . . . . . Patient 16 Carcinoma of the Colon Ascendens . Patient 17 T1 Carcinoma of the Colon . . . . . . Patient 18 Adenocarcinoma of the Sigmoid Colon. . . . . . . . . . . . . . Patient 19 Liver Metastasis of a Colon Carcinoma . . . . . . . . . . . . Patient 20 Lymphoma Conglomerate Following Colon Carcinoma . . . . . Patient 21 Lung Metastasis Following Colon Carcinoma . . . . . Patient 22 Pulmonary, Hepatic and Lymphogenic Metastatic Spread Following Sigmoid Carcinoma . . . . Patient 23 Metastasized Sigmoid Carcinoma . . Patient 24 Peritoneal Carcinosis and Ascites Following Sigmoid Carcinoma . . . . Patient 25 Lung Metastasis Following Sigmoid Carcinoma . . . . . . . . . . Patient 26 Liver Metastasis Following Sigmoid Carcinoma . . . . . . . . . . Patient 27 Lymph Node Metastasis Following Sigmoid Carcinoma . . . . Patient 28 Metastatic Spread to the Liver Following Rectal Carcinoma . . . . . Patient 29 Liver and Lung Metastases Following Rectal Carcinoma . . . . . Patient 30 Rectal Carcinoma with Lymph Node Metastases . . . . Patient 31 Suprarenal and Lung Metastases Following Rectal Carcinoma . . . . . Patient 32 Lung and Bone Metastases Following Rectal Carcinoma . . . . . Patient 33 Suprarenal Metastasis of a Rectal Carcinoma . . . . . . . . . Patient 34 Restaging of a Rectal Carcinoma . . Patient 35 Suprarenal and Lung Metastases Associated with Rectal Carcinoma . Patient 36 Restaging of a Rectal Carcinoma . . Patient 37 Local Recurrence and Liver Metastases of a Rectal Carcinoma . . Patient 38 Extended Metastatic Spread of a Mesenterial Conglomerate Tumour . Patient 39 GIST Tumour with Liver Involvement . . . . . . . . . . . Patient 40 Malignoma in the Left Epigastric Region . . . . . . . . . . . .

114 117 118 121 123 124 126 128 130 132 134 136 138 140 142 144 146 148 150 153 156 158 160 163 166 168 169 172 174 176 178 181 183 184

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Patient 41 GIST, Metastasis at the Greater Curvature of the Stomach . Patient 42 Tumour Recurrence with Status Post GIST of the Stomach . . Patient 43 Therapy Response Follow-Up Examination Post GIST Resection . Patient 44 Therapy Follow-Up in the Case of GIST . . . . . . . . . . . . .

. 186 . 187 . 189 . 193

4.10 References . . . . . . . . . . . . . . . . . . . . . . . 200

5

Gynaecology .

. . . . . . . . . . . . . . . . . 205

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . 206 The Importance of Nuclear Medical Methods . . . . . . . . . . . . . 206 5.2 Breast Cancers . . . . . . . . . . . . . . . . . . . Mammography . . . . . . . . . . . . . . . . . . . Tumour Markers . . . . . . . . . . . . . . . . . . CT and MRI . . . . . . . . . . . . . . . . . . . . . 18F-Fluoride . . . . . . . . . . . . . . . . . . . . . SPECT . . . . . . . . . . . . . . . . . . . . . . . . Sentinel Node Scintigraphy (SNS) . . . . . . . . Positron Emission Tomography . . . . . . . . . Preoperative Axillary Staging . . . . . . . . . . Extra-Axillary Metastases . . . . . . . . . . . . Treatment Monitoring . . . . . . . . . . . . . . Potentials and Limitations of PET . . . . . . . Special Neuro-Oncological Problems/Pitfalls . PET Screening? . . . . . . . . . . . . . . . . . . . Risk Stratification . . . . . . . . . . . . . . . . . PET/CT . . . . . . . . . . . . . . . . . . . . . . . . Assessment of the Bone Status . . . . . . . . . 18F-Fluoride PET . . . . . . . . . . . . . . . . . . Diagnostic Imaging of the Breast: Indications

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206 207 208 208 209 209 209 209 210 211 211 211 212 212 212 212 212 212 212

5.3 Ovarian Cancer . . . . . . . Tumour Types . . . . . . . Conventional Diagnostics PET . . . . . . . . . . . . . .

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213 213 213 213

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5.4 Peritoneal Cancer (PC) . . . . . . . . . . . . . . . 215 5.5 Cervical Cancer . . . . . . . . . . . . . . . . . . . . 215 PET Diagnostics . . . . . . . . . . . . . . . . . . . 215 5.6 Case Studies . . . . . . . . . . . . . . . . . . . . . . Patient 1 Lymph Node Metastasis with Status Post Carcinoma of the Right Breast and Ovarian Carcinoma on Both Sides . . . . . . . . . . . . . . Patient 2 Inflammatory Breast Cancer . . . . . Patient 3 Breast Cancer with Osseous Metastases . . . . . . . . . . Patient 4 Preoperative Staging of a Breast Cancer . . . . . . . . . . . . . .

216

216 218 220 222

Patient 5 Restaging of a Breast Cancer . . . . . 224 Patient 6 Restaging of a Breast Cancer . . . . . 226 Patient 7 Confirmation of the Diagnosis “Breast Cancer” . . . . . . 228 Patient 8 Psammoma . . . . . . . . . . . . . . . 230 Patient 9 Ovarian Cancer . . . . . . . . . . . . . 232 Patient 10 Restaging of an Ovarian Cancer . . . 234 Patient 11 Therapy Response of a Metastasized Ovarian Cancer . . . . 236 Patient 12 Metastasized Cervical Cancer . . . . 238 Patient 13 Bone Metastasis of a Corpus Uteri Cancer . . . . . . . . . . 240 Patient 14 Trophoblastic Tumour . . . . . . . . . 242 Patient 15 Malignant Ovarian Cyst . . . . . . . 244 Patient 16 Peritoneal Carcinosis Due to Ovarian Cancer . . . . . . . . . . . . . 245 Patient 17 Metastasized Endometrial Carcinoma . . . . . . . . . . . . . . . . 248 Patient 18 Exclusion of Metastatic Spread of an Endometrial Carcinoma . . . . . . . . 250 Patient 19 Therapy Control in Case of Ovarian Carcinoma . . . . . . . . . . 252 Patient 20 Lymph Node and Bone Metastases in Case of Ovarian Carcinoma . . . . . 254 Patient 21 Local Recurrence of Breast Cancer . 256 Patient 22 Restaging of a Breast Cancer after Chemotherapy . . . . . . . . . . . . . 259 Patient 23 Restaging of a Breast Cancer after Rise in Tumour Marker Level . . . . 261 Patient 24 Primary Staging of a Breast Cancer . 262 Patient 25 Restaging of a Breast Cancer after Reduction in Tumour Marker Level . 264 Patient 26 Pre-Therapeutic Staging of a Breast Cance . . . . . . . . . . . . . . . 267 Patient 27 Restaging of a Metastasized Breast Cancer. . . . . . 269 Patient 28 Detection of Metastases by PET/CT with Negative Conventional Imaging 271 Patient 29 Therapy Control of a Metastasized Breast Cancer . . . . . 275 Patient 30 Therapy Control of a Metastasized Breast Cancer . . . . . 276 Patient 31 Evaluation of Radiotherapy Response in Case of Metastasized Breast Cancer . . . . . . . . . . . . . . 279 Patient 32 Restaging of a Breast Cancer . . . . . 283 Patient 33 Restaging of a Breast Cancer Revealing a Fracture Risk in the C6 Vertebral Body . . . . . . . . . . . 285 Patient 34 Restaging of a Breast Cancer with PET/CT Providing Much More Detailed Information . . . . . . . . . 287 Patient 35 Pleural Carcinosis in a Patient with Breast Cancer . . . . . . . . . . . 290 Patient 36 Lung Metastases of a Breast Cancer . 292 Patient 37 Bone Metastases of a Breast Cancer . 294 Patient 38 Male Patient with Metastasized Breast Cancer . . . . . 296 5.7 References . . . . . . . . . . . . . . . . . . . . . . . . 298

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6

Urology .

Patient 26 First Diagnosis of a Prostate Carcinoma . . . . . . . . 361 Patient 27 Response Evaluation of a Prostate Carcinoma . . . . . . . . 362

. . . . . . . . . . . . . . . . . . . . . . 303

6.1 Introduction . . . . . . . . . . . . . . . . . . . . . 303 6.2 Renal Malignancies . . . . . . . . . . . . . . . . . 304 Introduction . . . . . . . . . . . . . . . . . . . . . 304 Diagnostics . . . . . . . . . . . . . . . . . . . . . . 304

6.9 References . . . . . . . . . . . . . . . . . . . . . . . 363

6.3 Adrenal Tumours . . . . . . . . . . . . . . . . . . 305 Imaging Diagnostics . . . . . . . . . . . . . . . . 305

7

Head and Neck Region

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7.1

Head and Neck Tumours 18F-FDG-PET . . . . . . . FDG-PET Pitfalls . . . . . PET Indications . . . . .

. . . .

6.4 Bladder Carcinoma . . . . . . . . . . . . . . . . . 305 Status of PET . . . . . . . . . . . . . . . . . . . . . 306 6.5 Prostate Carcinoma . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . Diagnostics . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . Status of Individual Imaging Methods .

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306 306 306 309 309

6.6 Germ Cell Tumours . . . . . . . . . . . . . . . . . 313 Introduction . . . . . . . . . . . . . . . . . . . . . 313 PET Study Situation . . . . . . . . . . . . . . . . . 314 6.7 Penis Carcinoma . . . . . . . . . . . . . . . . . . . 315 6.8 Case Studies . . . . . . . . . . . . . . . . . . . . . . Patient 1 Malignoma of the Base of the Bladder . Patient 2 Malignoma of the Posterior Wall of the Bladder . . . . . . . . . . . . . . Patient 3 Metastasis in the Suprarenal Gland on the Left Side . . . . . . . . . . . . . Patient 4 Metastasis in the Suprarenal Gland on the Right Side . . . . . . . . . . . . Patient 5 Metastasized Renal Cell Carcinoma . Patient 6 Restaging after Chemotherapy . . . . Patient 7 Restaging after Tumour Nephrectomy . . . . . . . . . Patient 8 Recurrence after Tumour Nephrectomy . . . . . . . . . Patient 9 Metastasized Prostate Carcinoma . . Patient 10 Metastasized Prostate Carcinoma . . Patient 11 Restaging of a Prostate Carcinoma . Patient 12 Lymph Node Metastasis of a Prostate Carcinoma . . . . . . . . Patient 13 First Diagnosis of a Prostate Carcinoma . . . . . . . . Patient 14 Restaging of a Prostate Carcinoma . Patient 15 Restaging of a Prostate Carcinoma . Patient 16 Therapy Control for Metastatized Prostate Carcinoma . . . . . . . . . . Patient 17 Staging of a Prostate Carcinoma . . . Patient 18 Local Recurrence of a Prostate Carcinoma . . . . . . . . Patient 19 Lymph Node Metastasis of a Prostate Carcinoma . . . . . . . . Patient 20 Lymph Node Metastases of a Prostate Carcinoma . . . . . . . . Patient 21 First Diagnosis of a Prostate Carcinoma . . . . . . . . Patient 22 Prostatitis . . . . . . . . . . . . . . . . Patient 23 Prostatitis . . . . . . . . . . . . . . . . Patient 24 Prostatitis . . . . . . . . . . . . . . . . Patient 25 Restaging of a Prostate Carcinoma .

316 316 318 320 322 325 327 330 332 334 336 338 340 342 343 345

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. . . .

369 371 373 373

7.2 Thyroid Carcinomas . . . . . . . . . . . . . . . . . 374 18 F-FDG-PET . . . . . . . . . . . . . . . . . . . . . 375 7.3 Case Studies . . . . . . . . . . . . . . . . . . . . . . 378 Patient 1 CUP Tumour . . . . . . . . . . . . . . 378 Patient 2 Tumour Recurrence of an Atypical Laryngeal Carcinoid . . 380 Patient 3 Restaging of an Oropharyngeal Carcinoma . . . . 381 Patient 4 Hypopharyngeal Carcinoma . . . . . 384 Patient 5 Restaging after Multiple Carcinoma 386 Patient 6 Auricle Carcinoma . . . . . . . . . . . 388 Patient 7 Tonsillar and Laryngeal Carcinoma and Carcinoma of the Base of the Tongue . . . . . . . . . . . . . . 390 Patient 8 Recurrence of a Squamous Cell Carcinoma of the Tongue . . . . 392 Patient 9 Tonsillar Carcinoma . . . . . . . . . . 394 Patient 10 Restaging of a Small-Cell Carcinoma of the Left Principal Nasal Cavity . . 396 Patient 11 Recurrence of a Vocal Cord Carcinoma. . . . . . . . . 400 Patient 12 Cerebral Metastatic Spread of a Bronchial Carcinoma . . . . . . . . . 402 Patient 13 Cystadenocarcinoma of the Lacrimal Sac . . . . . . . . . . . . . . 405 Patient 14 Alzheimer’s Disease . . . . . . . . . . 406 Patient 15 Oligodendroglioma on the Left Side . . . . . . . . . . . . . 408 Patient 16 Low-Malignancy Brain Tumour on the Left Side . . . . . . . . . . . . . 410 Patient 17 Hypophyseal Metastasis . . . . . . . . 413 7.4

References . . . . . . . . . . . . . . . . . . . . . . . 415

8

Dermatology .

347 349 351 352 353 354 355 356 357 359

. . . . . . . . . . . . . . . . . 419

8.1 Malignant Melanoma (MM) Introduction . . . . . . . . . Significance of PET . . . . . Pitfalls PET Indications . . . . . . .

. . . . . . . . . . . . 419 . . . . . . . . . . . . 419 . . . . . . . . . . . . 421 421 . . . . . . . . . . . . 421

8.2 Case Studies . . . . . . . . . . . . . . . . . . . . . . 422 Patient 1 Malignant Melanoma of the Right Thigh . . . . . . . . . . . 422 Patient 2 Recurrent Melanoma . . . . . . . . . 424

xxx

Patient 3 Metastasized Melanoma . . . . . . . 426 Patient 4 Choroidal Melanoma . . . . . . . . . 427 Patient 5 Metastasized Amelanotic Melanoma . . . . . . . . . . . . . . . . 428

11 Paediatric Oncology .

. . . . . . . . . . . 487

11.1 Introduction . . . . . . . . . . . . . . . . . . . . . 487 Changes in the Range of Clinical Indications . . 488

8.3 References . . . . . . . . . . . . . . . . . . . . . . . 433

11.2 Lymphomas in Childhood . . . . . . . . . . . . . 488 Staging, Restaging, Prognosis and Therapy Control . . . . . . . . . . . . . . . . . . . 488

9

11.3 Oncological Orthopaedics in Childhood . . . . . 488

Lymphomas .

. . . . . . . . . . . . . . . . . . 435

11.4 Neuroblastomas . . . . . . . . . . . . . . . . . . . 488 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . 435 9.2 Diagnosis . . . . . . . . . . . . . . . . . . Imaging Methods . . . . . . . . . . . . . FDG-PET . . . . . . . . . . . . . . . . . . Response Evaluation . . . . . . . . . . . Comparison of FDG-PET, 67Ga and CT . Autologous Stem Cell Therapy . . . . . . PET/CT Restaging . . . . . . . . . . . . . Artefacts . . . . . . . . . . . . . . . . . . . Other Problems . . . . . . . . . . . . . . PET Indications . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

9.3 Case Studies . . . . . . . . . . . . . . . . . . . . Patient 1 Follicular Non-Hodgkin’s Lymphoma . . . . . Patient 2 Metastasized Non-Hodgkin’s Lymphoma . . . . . Patient 3 B-Cell Lymphoma in the Hypopharynx . . . . . . . . . . . . . Patient 4 B-Cell Lymphoma . . . . . . . . . . Patient 5 Lymphogranulomatosis, Nodular Sclerosis . . . . . . . . . . . Patient 6 T-Cell Lymphoma of the Cervical Lymph Tract . . . . . . . . Patient 7 B-Cell Lymphoma . . . . . . . . . . Patient 8 Restaging of Hodgkin’s Disease . . Patient 9 Recurrent Hodgkin’s Lymphomas . Patient 10 Chronic Lymphatic Leukaemia . . Patient 11 Restaging of the Multiple Myeloma

. . . . . . . . . .

436 436 437 437 438 438 438 439 439 439

. 440 . 440 . 442 . 444 . 446

. . . . . .

449 451 454 459 461 461

. . . . . . 465

10.1 Introduction . . . . . . . . . . . . . . . . . . . . . 465 10.2 Significance of PET . . . . . . . . . . . . . . . . . 465 PET Tracers . . . . . . . . . . . . . . . . . . . . . . 466 PET Indications . . . . . . . . . . . . . . . . . . . 466 10.3 Case Studies . . . . . . . . . . . . . . . . . . . . Patient 1 Sweat Gland Carcinoma . . . . . . Patient 2 Haemangioendothelioma . . . . . Patient 3 Chondrosarcoma . . . . . . . . . . Patient 4 Medullary Osteosarcoma . . . . . Patient 5 Clear Cell Sarcoma . . . . . . . . . Patient 6 Rhabdomyosarcoma . . . . . . . . Patient 7 Rhabdomyosarcoma of the Left Thigh . . . . . . . . . . Patient 8 Embryonal Rhabdomyosarcoma .

. . . . . . .

11.6 Nesidioblastosis (Congenital Hyperinsulinism) . . . . . . . . . . . 489 11.7 Case Studies . . . . . . . . . . . . . . . . . . . . . Patient 1 Status Post Osteogenous Sarcoma . Patient 2 Status Post Mastitis . . . . . . . . . Patient 3 Embryonal Rhabdomyosarcoma . . Patient 4 Focal Congenital Hyperinsulinism Patient 5 Focal Congenital Hyperinsulinism Patient 6 Focal Congenital Hyperinsulinism Patient 7 Diffuse Congenital Hyperinsulinism . . . . . . . . . . . Patient 8 Focal Congenital Hyperinsulinism Patient 9 Focal Congenital Hyperinsulinism Patient 10 Focal Congenital Hyperinsulinism Patient 11 Langerhans Cell Histiocytosis . . . Patient 12 Langerhans Cell Histiocytosis, Staging and Restaging . . . . . . . .

. . . . . . .

490 490 491 492 494 496 498

. . . . .

500 502 504 506 508

. 510

11.8 References . . . . . . . . . . . . . . . . . . . . . . . . 514

. 448

9.4 References . . . . . . . . . . . . . . . . . . . . . . . 463

10 Oncological Orthopaedics.

11.5 Malignant Melanomas . . . . . . . . . . . . . . . 488

. . . . . . .

467 467 470 473 476 478 480

. . 482 . . 484

10.4 References . . . . . . . . . . . . . . . . . . . . . . . 486

12 CUP Tumours .

. . . . . . . . . . . . . . . . . 515

(Cancer of Unknown Primary)

12.1 Introduction . . . . . . . . . . . . . . . . . . . . . 515 12.2 Significance of PET . . . . . . . . . . . . . . . . . Cancer of Unknown Primary: Indication for PET/CT? . . . . . . . . . . . . . . . Studies Available . . . . . . . . . . . . . . . . . . . Artefacts, Pitfalls and Metabolic Heterogeneity . 12.3 Case Studies . . . . . . . . . . . . . . . . Patient 1 Carcinoma of the Base of the Tongue . . . . . . . . Patient 2 Carcinoma of the Base of the Tongue . . . . . . . . Patient 3 Oropharyngeal Carcinoma Patient 4 Cholangiocarcinoma . . . . Patient 5 Pancreatic Carcinoma . . . Patient 6 Carcinoma of the Head of the Pancreas . . . Patient 7 Mamma Carcinoma . . . . Patient 8 CUP Tumour . . . . . . . . Patient 9 Mamma Carcinoma . . . . Patient 10 Carcinoma of the Base of the Tongue . . . . . . . . Patient 11 Bronchial Carcinoma . . . Patient 12 Bronchial Carcinoma . . .

516 516 516 516

. . . . . . 517 . . . . . . 517 . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

518 520 523 526

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

528 530 533 536

. . . . . . 538 . . . . . . 540 . . . . . . 542

12.4 References . . . . . . . . . . . . . . . . . . . . . . . 544

XIII

XIV

xxxxx

13 Pitfalls

. . . . . . . . . . . . . . . . . . . . . . . 545

14 Radiotherapeutic Aspects .

. . . . . . 625

13.1 Testicular Carcinoma and Other Primary Tumours . . . . . . . . . . . . . . 546 Universal Organ Spectrum of SPT . . . . . . . . 546

14.1 Introduction . . . . . . . . . . . . . . . . . . . . . 625

13.2 Physiological Accumulation of FDG . . . . . . . 547

14.4 Fundamentals Governing the Use of PET/CT Data for Radiotherapy – Bits and Bytes and DICOM . . .626

13.3 False Positive FDG Accumulations in the Oncological Sense . . . . . . . . . . . . . . . . . . 547 13.4 Artefacts Due to Technical Factors . . . . . . . . 547 13.5 False Negative PET Findings . . . . . . . . . . . . 547 13.6 Case Studies Secondary Tumours . . . . . . . . Patient 1 Inflammatory Carcinoma of the Breast and Papillary Carcinoma of the Inner Genital Tract . . . . . . Patient 2 Carcinoma in Situ with Osteoplastic Metastases 10 years later . . . . . . . Patient 3 Recurrence of a Sigmoid Carcinoma, Compression of the Left Ureter . . . Patient 4 Cervical Carcinoma and Rectal Carcinoma . . . . . . . . . . . Patient 5 Mamma Carcinoma and Colon Carcinoma . . . . . . . . . . . . Patient 6 Mamma Carcinoma and Sigmoid Carcinoma . . . . . . . . . . Patient 7 Thymoma . . . . . . . . . . . . . . . . Patient 8 Prostate Carcinoma and Colon Carcinoma . . . . . . . . . . . . Patient 9 Renal Cell and Prostate Carcinoma . Patient 10 Prostate Carcinoma and Colon Carcinoma . . . . . . . . . . . . Patient 11 Carcinoma in Situ of the Rectum and Bronchial Carcinoma . . . . . . . Patient 12 Non-Hodgkin’s Lymphoma and Bronchial Carcinoma . . . . . . . . . Patient 13 Mamma Carcinoma and Bronchial Carcinoma . . . . . . . . . Patient 14 Coecum, Bronchial and Renal Carcinoma . . . . . . . . . . . . Patient 15 Mamma, Cervical and Rectal Carcinoma . . . . . . . . . . . Patient 16 Parotid and Colon Carcinoma . . . .

548 548 551

14.2 PET-Assisted Radiotherapy Planning . . . . . . 625 14.3 Advantages of PET/CT Integration . . . . . . . . 626

14.5 Case Studies . . . . . . . . . . . . . . . . . . . . Patient 1 Prostate Cancer . . . . . . . . . . . Patient 2 Oropharyngeal Cancer . . . . . . Patient 3 Breast Cancer . . . . . . . . . . . . Patient 4 Prostate Cancer . . . . . . . . . . . Patient 5 Squamous Cell Carcinoma of the Oral Cavity . . . . . . . . . . . . . Patient 6 Bronchial Cancer . . . . . . . . . .

. . . . .

. . . . .

630 630 632 634 636

. . 638 . . 640

14.6 References . . . . . . . . . . . . . . . . . . . . . . . 643

554 556 558 560 561

15 Nuclear Cardiology .

. . . . . . . . . . . . 645

– the Situation in Europe

15.1 Introduction . . . . . . . . . . . . . . Development of Nuclear Cardiology and the Present State . . . . . . . . . Molecular Cardiac Imaging . . . . . Fusion Imaging . . . . . . . . . . . . . SPECT and SPECT/CT . . . . . . . . . MRI and PET/MRI . . . . . . . . . . .

. . . . . . . 645 . . . . .

. . . . .

. . . . .

. . . . .

645 647 649 650 652

15.2 Cardiac PET/CT . . . . . . . . . . . . . . . . . Coronary Sclerosis . . . . . . . . . . . . . . . Diabetes Mellitus and Coronary Sclerosis . Plaque Imaging . . . . . . . . . . . . . . . . . Perfusion . . . . . . . . . . . . . . . . . . . . Vitality . . . . . . . . . . . . . . . . . . . . . . Radiation Exposure and Contrast Medium Safety . . . . . . . . . . . Artefacts . . . . . . . . . . . . . . . . . . . . . Invasive Diagnostics, Treatment and Treatment Monitoring . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . Remarks on the Catalogue for Further Training for the Specialization in Nuclear Medicine . . . . . . . . . . . . . . .

. . . . . .

. . . . . .

. . . . . .

652 652 654 655 656 657

. . . 663 . . . 663 . . . 666

13.9 Case Studies Artefacts . . . . . . . . . . . . . . . . . . . . . . . 611 Patient 32–39 . . . . . . . . . . . . . . . . . . . . . 611

15.3 Case Studies . . . . . . . . . . . . . . . . . . . Patient 1 Mild CHD . . . . . . . . . . . . . Patient 2 Status Post Revascularization . Patient 3 Status Post Anterior Infarction and Sextuple Bypass . . . . . . . Patient 4 Surprise Finding of Stem Stenosis. . . . . . . . . .

13.10 References . . . . . . . . . . . . . . . . . . . . . . . 622

15.4 Reference . . . . . . . . . . . . . . . . . . . . . . . 676

564 566 568 570 574 577 579 583 586

13.7 Case Studies Physiologically Increased Uptake . . . . . . . . . 589 Patient 17–21 . . . . . . . . . . . . . . . . . . . . . 589 13.8 Case Studies Non-Oncological Increased Uptake of Inflammatory Genesis . . . . . . . . . . . . . . . 593 Patient 22–31 . . . . . . . . . . . . . . . . . . . . . 593

. . . . .

. . . . .

. . . . .

. . . 657 . . . 658 . . . 658 . . . 661

. . . 661

. . . 668 . . . 672

xxx

16 Cardiac PET and PET/CT .

. . . . . . . . 687

– the Situation in the USA

16.1 Introduction . . . . . . . . . . . . . . . . . . . . . 687 16.2 Coronary Artery Disease . . . . . . . . . . . . . . 687 Imaging with PET . . . . . . . . . . . . . . . . . . 688 Accuracy of PET and PET/CT Stress-Rest Myocardial Perfusion Imaging . . . . . . . . . . 693 Advantages of Myocardial Perfusion Imaging with PET . . . . . . . . . . . . . . . . . . . . . . . . 696 Hybrid PET/CT Myocardial Perfusion Imaging in Coronary Artery Disease . . . . . . . . . . . . 697 16.3 Myocardial Viability . . . . . . . . . . . . . . . . 698 Concepts and Pathophysiology . . . . . . . . . . 699 Assessment of Myocardial Viability . . . . . . . 699 Imaging of Myocardial Perfusion and Metabolism . . . . . . . . . . . . . . . . . . . 701 Clinical Implications of Perfusion Metabolism Imaging . . . . . . . . . . 705 PET/CT vs. Stand-Alone PET . . . . . . . . . . . . 707 Clinical Indications of Perfusion Metabolism Imaging . . . . . . . . . . 708

16.4 Vascular Inflammation and Atherosclerosis . . 709 16.4.1 Large Vessel Vasculitis . . . . . . . . 709 16.4.2 Atherosclerosis and Plaque Imaging 711 16.5 Future Developments . . . . . . . . . . . . . . . . 714 16.6 References . . . . . . . . . . . . . . . . . . . . . . . . 714

17 Future Trends: Molecular PET .

. . . 721

17.1 Technical Potential and Software Optimization . . . . . . . . . . . . . . . 721 17.2 Molecular PET . . . . . . . . . . . . . . . . . . . . 722 Tumour Vitality and Glucose Transporters (GLUT) . . . . . . . . . . . 722 Therapeutic and Diagnostic Potential . . . . . . 722 17.3 Final Remark . . . . . . . . . . . . . . . . . . . . . 723 17.4 References . . . . . . . . . . . . . . . . . . . . . . . 724

Subject Index . . . . . . . . . . . . . . . . . .

727

XV

1.1 Survey

1

Introduction Positron Emission Tomography: Past and Present

CONTENTS 1.1 Survey 1 Physical and Biochemical Fundamentals 2 PET in National and International Medical Care Systems 2 1.2 Technological Variants and Developments 4 Coincidence PET vs. Dedicated PET 4 Differentiated PET Evaluation 4 Radiotherapeutic Tools 5 PET/CT – a New Key Technology 5 Influence of PET/CT on PET 5 Studies Dealing with the Cost Efficiency of PET Alone 6 PET/CT or Comparison of Co-Registered Findings? 6 “Standard” (CARE)-CT and PET/CT 6 PET/MRI? 6 American Joint Committee on Cancer 7 PET Screening in Japan and Taiwan 7 1.3 Increased FDG Uptake Due to Physiological and Technical Factors 7 1.4 References

8

1.1

Survey

Interdisciplinary cooperation, in which nuclear medicine has been involved for more than 50 years, is indispensable to optimize oncological diagnosis and therapy. The processes have developed from tumouraffine radionuclides (with measuring probes), such as 67Ga citrate [35], rectilinear scanners and gamma cameras via marked monoclonal antibodies (immunoscintigraphy [5]) up to high-tech SPECT [14], coincidence imaging (hybrid PET), PET, PET centres (see the references on the DVD [Ö 1.1]) or PET/CT centres. The status report of the “Intersociety Dialogue” in the USA [18] should be mandatory reading for everyone operating PET/CT scanners or arranging PET/CT examinations for clinically proven lesion findings, but particularly for medically trained medical economists. Recommendations issued by interdisciplinary expert committees have a higher competency rating than protocol variants (e.g. options, technical specifications, methodological preferences, clinical application and information on the radiation exposure for the patient and staff as well as the population): For example, the technical staff is exposed to radiation doses amounting to 5.5 mSv [19, 31]. Since the early 1950s, Brownell has reported on positron emitters used to detect brain tumours and till the end of the 1990s on PET cameras and the PET evolution [11, 12, 13]. Among the PET pioneers, Ter-Pogossian also played a major role. Few know that “bone blood flow” with 18F and the positron camera were already described in 1965 [69]. Today, numerous multi-author publications dealing with PET and PET/CT are available. The transfer of new know-how from the scientific level to health policy is usually considerably delayed. Furthermore, the missing adaptation to European standards regarding remuneration by the statutory health insurance companies still remains a restraint for modern di-

1

2

1

Introduction

agnostic standards and a nuisance for well-informed patients and physicians in Germany. The cost efficiency of PET has been discussed since the early 1980s [26], and the question who is to establish the PET/CT findings also has not yet been defi nitely answered. This dispute is absurd: The maximization of information gained for the patient with PET/CT is not seriously criticized [74], and this information is of course fused (as described above) in the interdisciplinary efforts of nuclear medicine physicians and radiologists. Occasionally, the discussion is whether hybrid systems (so-called coincidence PET) and “dedicated PET” can be assessed identically. Finally, the difference concerning the dimension of the detectable lesion size tips the balance in favour of the precision of the full-ring systems (4–6 mm). The same applies to so-called breast dedicated gamma cameras [63]. SPECT methods, multi-detector systems and pinhole SPECT (P-SPECT) have improved the detection of smaller lesions (lymph nodes). P-SPECT has proven useful for navigated SLN biopsy. Offering SPECT/CT as an alternative to PET/CT [62] overshoots the mark. Of course, it can be readily understood that the borders of organs can be better defined with an increased tracer uptake and that the functional relevance of CT lesions can be better characterized, but the precision of PET/CT with regard to functional considerations cannot be achieved. The following restriction applies to PET and PET/CT: Even high-resolution equipment is unable to detect micrometastases. Under the most favourable conditions, the detection limits of SPECT range from 8–10 mm and for PET from 4–6 mm. Micro-PET systems are only suitable for small animal experiments. Detection, localization and molecular vitality diagnosis of tumours and recurrences are postulates with intended differentiation between limited disease and extensive disease. PET has opened the way to this extended framework, and PET/CT has more exactly defined the diagnostic potential.

Physical and Biochemical Fundamentals The discovery of the positron in 1932 by Anderson [1] opened the way for the evolution of PET, which finally led to exclusive PET/CT [48]. Increased glucose consumption as an energy source for the growing tumour cell is the unrivalled metabolic leitmotif

of PET. The Nobel Prize winner Otto Warburg had already published his findings in 1924/25 as a member of the former German Kaiser Wilhelm Institute [78, 77, 79]. Biological experiments with radioactively labeled fluorides were already carried out in 1940 [72], but we had to wait until 18F-FDG could be synthesized in 1977/78 to implement PET in clinical applications [34, 36, 37]. Studies dealing with the biochemical hexokinase composition have been published since 1978 [49]. Differentiated information concerning the factors influencing the uptake of 18F-FDG, a chemical glucose analogue that finally initiated worldwide tumour studies with PET, is available today. PET was first initiated several decades ago [2, 28, 60]. The first information for general practitioners was published in the official journal of the German Medical Association (Deutsches Ärzteblatt) in 1993 [34].

PET in National and International Medical Care Systems PET in the US Medical Care System. The number of PET systems used in North America, particularly in the highly populated regions, is impressive. Statistical investigations reveal that a PET scanner is available to 97% of the US population within a radius of 75 miles [55]. The quick and comparatively unbureaucratic PET allocation in the USA developed in a concerted action of PET physicians (nuclear medicine, radiology, cardiology, oncology, neurology, and psychiatry) and ultimately also in agreement with leading institutions (the NIH, NCI, Academy of Molecular Medicine, Institute of Clinical PET and SNIDD 1), contrary to other countries which, with considerable variations, still maintain a wait-and-see attitude regarding the use of PET. According to a Europe-wide study, Belgium is the leading European country in the field of PET [7]. For all PET indications, the European demand for PET examinations amounts to 2,026 per 1 million inhabitants. More than 1,000 positron emission tomographs are already available in the USA (> 500 PET/ CT). Recurrent tumours and therapy control have long since been accepted indications for at least six tumours in the USA [17], and applications have been made for seven further entities (see below). 1

Society of Nuclear Imaging and Drug Development

1.1 Survey

 Accepted: diagnosis, staging and restaging of NSCLC (non-small-cell lung cancer), colorectal and oesophageal cancer, head and neck cancer, lymphoma and melanoma.  Applied for: pancreas, brain, small-cell lung cancer, cervix, ovary, multiple myeloma, testicles (petition submitted to the Secretary of Health, signed by 37 US senators).  Present situation: Since the beginning of 2005, the US health insurance programme Medicare has borne all costs associated with PET examinations: PET(-CT) is nowadays used to diagnose all types of cancer, and a PET database has been established [cooperation of the National Cancer Institute (NCI), the Society of Oncology and patient representatives. More detailed information is available from these institutions]. In Germany, PET(-CT) is still a subject of political discussion. Three symposiums about PET/CT took place in Berlin on 5 May 2004, 9 December 2004 and 1 June 2005 [44]. These meetings gave further impetus to encourage compensation for doctors for PET examinations and for technical upkeep [6, 8]. The precarious situation of the social security systems resulting from high unemployment rates and demographic changes as well as medical progress with the corresponding increase in financial turnover in the health care sector has led to the predominance of economics. The administrations of the legal health insurances treat this like a doctrine, emphasizing primarily financial benefits, especially when considering the introduction of new medical procedures. This approach is often short-sighted, and the costs that actually have to be paid per patient, including the therapy resulting from the diagnosis, are neglected. Using the example of NSCLC, Oberender [50] discussed attainable objectives of economical nuclear medicine, taking into account the relevant literature (see also Chap. Pneumology). Representative documents were also established in Cologne. The supplementary volume edited by Czernin (2004) is a compilation of state-of-the-art essays [20]. Paediatric oncology has only been using PET and PET/CT moderately to date [32]. Tidal Wave of Costs for Cancer Patients. The National Cancer Institute (NCI) in the USA registers an escalation in health care costs (amounting to several billion [109] dollars), the sum of which covers more

than 10% of the total medical costs, whereby more than 50% have to be paid for the treatment of carcinomas of the breast, the bronchial system and the prostate, as well as other tumours. Tabular data are available for PET regarding the sensitivity, specificity, accuracy, impact on management and therapy of more than 18,000 patients [30] and of more than 7,000 patients according to the selection rules established by evidence-based medicine [59]. In cost-benefit analyses, the so-called net benefit can be calculated by deducting the investment costs from the savings [50]. The clinical classification of the PET evaluation is continually updated by expert commissions. Many PET priorities are classified into class 1a and 1b. These can nowadays be categorized as PET core competencies. Due to the lack of legal provisions regulating doctors’ remunerations for PET examinations, Germany lags behind in Europe [48] – regardless of the innovative potential of German scientists and clinical physicians who have taken an active part in the worldwide progress of modern PET diagnosis. Paradoxically, Germany is in fact the leading European country with 80–100 positron emission tomographs (in hospitals and practices), with one PET scanner per 1 million inhabitants. However, this equipment is only available to those who can afford the high costs of PET examinations, mainly because their private health insurance covers these costs. The allowance procedure established for PET compensation in cases of lung cancer is a first step towards achieving world standards. Beyond this, agreements with individual health insurance companies in the fields of bronchial carcinoma, breast carcinoma and malignant lymphoma have, in addition to their practical contribution towards patient care, the responsibility to improve the analysis of data. This development shows that views have changed, also in Germany. Arguments blocking discussion are no longer acceptable, particularly with regard to a decision taken by the German Federal Constitutional Court on 6 December 2005, according to which every patient is entitled to be treated with state-of-the-art equipment and methods. However, the PET problem is just another example of the actually existing deficiencies in the medical care system. Nonetheless, the first positive steps have been taken. In the field of basic research, especially in the development of medicines, even big centres (and also industry/university associations) are not able

3

4

1

Introduction

to make use of molecular PET and micro-PET studies. We cite a modified quotation from Immanuel Kant that perfectly captures the situation, asking: How long will it still take until the “immanent logic of truth” has made its way? PET Centres in the Federal Republic of Germany. Pilot institutions were installed in the early 1980s, with the first PET centres established in Hannover, Heidelberg and Jülich. Frankfurt was one of the late entrants, first installing a PET system in 1994. From 1994 to 1999, PET scanners were increasingly used and helped to diagnose more than 3,000 patients; in 2005, the number rose to more than 6,000 patients. However, the PET/CT scanners used have not yet been fully developed with regard to technological and clinical aspects. Since then, it has become obvious that “PET alone” is in fact able to meet the expected general requirements, but PET/CT nevertheless provides an even more differentiated standard with regard to the required indications. Among others, a PET/CT scanner was installed in the Diagnostic Therapeutic Centre (DTZ) in Berlin in October 2003. Non-invasive heart examinations can also be carried out using the new generation of PET/CT equipment (PET/CT high resolution or Biograph 64, respectively). In the meantime, the expansion of PET/CT equipment with high-definition measurement technology has taken place. Currently, over 5,000 patients have been examined in the Diagnostic Therapeutic Centre (DTZ) (December 2007).

1.2

Technological Variants and Developments

A detailed survey of PET and PET/CT technology is given in Chapter 2, “Fundamentals”. We will at this point only present selected notes from a PET physician’s view.

Coincidence PET vs. Dedicated PET Even the stages of the lowest technological development of PET have unquestionably proven useful in practice. Using the example of breast cancer, it can

be clearly shown that a resolution of about 2 cm is inferior to classical full-ring PET. Even more, coincidence PET cannot compete with the high-tech variant PET/CT. New approaches were proposed to improve the SUV, such as attenuation correction, patient positioning aids and fusion images in case of PET/CT.

Differentiated PET Evaluation Since 1980, pioneer studies have dealt with regional tissue perfusions and myocardial, brain and tumour metabolism (with 15O, 11C and 18F) as well as with graphical analyses and flux constants, linear regression analyses and neuronal networks associated with dementias. Cerebral studies marked the beginning of multimodal (comparative) diagnosis with PET, CT and MR [47, 56, 57]. Aids are quantitative parameters (in the simplest case SUV) and – in the field of research – more expensive measurements (PATLAK analysis). Reconstruction and attenuation correction tools have been improved, and socalled navigation tools have been developed. In this context, we have to distinguish between expensive methods that are unaffordable in clinical routine use and simpler score-based and index-based semiquantitative evaluation concepts. SUV (Standardized Uptake Value). The SUV has been criticized for being an impermissible simplification and defined as having “silly useless value” [42]. Too many factors influencing the result are taken into account in this calculation so that a great inter-institutional and also a great inter-patient variance are observed. The “lean body mass” was described as a correct reference parameter. In summary, the following SUV modifications should be mentioned: dual-phase early/ late PET, SUV time quotient, and so-called total lesion indices that are score-based. In the meantime, several teams have postulated a SUV bonus for follow-up and therapy control [9, 42, 67]. The most acceptable approach (which is nevertheless not unproblematic) is the intra-individual comparison of the FDG uptake values prior to and after therapy. Compartment analyses determining the influx and transflux constants yield more precise results, but are not practicable. Meanwhile,

1.2

controversially positive data are available, too. More expansive kinetic analyses (PATLAK) are only eligible for studies [53, 54]. The benefit that can be achieved with the dual-time technique (PET scans after 90 min and 1–4 h later) is being discussed [24]. Prognostic Evaluation with SUV. Follow-up observation of the SUV must be evaluated cautiously. For example, what does it mean to the patient if a longer survival time is postulated in case of lower SUVs than for higher values if a difference of just a few weeks is not statistically significant?

Radiotherapeutic Tools In addition to the above-mentioned software and navigation techniques, the following approaches are being further investigated for PET applications in radiotherapy (see also Chap. “Radiotherapy”):  fully integrated PET/CT simulators,  image segmentation and  delimitation of the biological target volume. Neuronuclear medical and neuroradiologic procedures used to image brain tumours will not be taken into account in this survey [57].

PET/CT – a New Key Technology Specific impulses are due to PET/CT technology, which has now reached the milestone of the 3D version. Stage classification (“overall TNM stage”) has become more precise: 77% vs. 54% (MR), T-stage 80% (PET/CT) vs. 52% (MRI), N-stage 93% vs. 79% with MRI, while PET und MRI yield similar results according to the Essener Study (published by the University Hospital of Essen, Germany). Townsend [15, 68] notes (“PET/CT today/tomorrow”) that this already plays an evident role based on the improved acceptance and preliminary results of studies. Five years after PET/CT was developed [15, 39, 46], clinical integration of this new imaging method made unexpectedly quick progress, although only a minority sees the necessity of fused images in approximately 7% of all cases (see below).

Technological Variants and Developments

Schulthess [73] has published documentation of the experience gained in Zurich, Switzerland, which meets its match only in a few German institutions (e.g. Essen, Ulm). Recently, a rather comprehensive report dealing with the latest progress in the field of PET and PET/CT was published in a book edited by Baum [6]. PET/CT should be available to all insured patients, but this is not the case in Germany yet [17]. Nevertheless, the number of installations in Germany since the first edition of this book has virtually trebled. We are expecting a continuation of this dynamic development in the next few years. More than 5,000 patients (as of December 2007) have been examined solely in Berlin. In other expert centres in Germany, the number of examinations probably exceeds 10,000.

Influence of PET/CT on PET In Johns Hopkins Medical Institutions in Baltimore, the frequency of PET examinations has increased by 900% (!) in the 3 years since PET/CT was introduced [75, 76]. This does not mean that PET alone is absolutely outdated. But optimized protocols and new navigation tools eliminate problems and help to give answers to open questions regarding the necessity of a “standard care CT” with or without oral/IV contrast agents and to prevent PET artefacts. A study published by the University Hospital of Ulm, Germany, in 2004 confirms that PET/CT detects at least 13% of those tumour recurrences that would not have been detected with PET or CT alone [43]. The discussion on the necessity of RCT (“randomized clinical trials”) has given rise to certain doubts (“about errors with probabilities” [80]). Shortfalls of CT alone are:  the tumour vitality cannot be evaluated;  the lymph node malignancy around/below 1 cm cannot be interpreted;  the solitary foci of the lung depend on a waitand-see strategy;  the response classification after therapy is inadequate;  the change of the morphological tumour load (mass) after therapy is not decisive;  there is no information about the metabolic activity and proliferation of DNA synthesis;

5

6

1

Introduction

 hypoxia potential of the tumour environment?  tumour-specific receptors?  little experience with “functional genomics/proteomics (reporter gene, reporter probe)”. Shortfalls of PET alone are:  morphology, the invasion into neighbouring organs cannot be displayed;  the exact level of the lymph nodes (e.g. in the ENT area) cannot be localized by the surgeon;  tumours/metastases in the chest wall/pleura cannot be separated;  mislocations of liver metastases in the lung (respiratory artefacts);  mislocations of infraclavicular foci and apical foci;  bone/soft tissue and brain metastases can be better diagnosed by CT.

PET/CT or Comparison of Co-Registered Findings?

Studies Dealing with the Cost Efficiency of PET Alone

“Standard” (CARE)-CT and PET/CT

Pertinent studies must be completed by economic follow-up studies dealing with PET/CT to determine precisely the reduction factor due to management cost minimization. Fused PET/CT images compensate the shortfalls: This imaging method  perfects the anatomo-metabolic/molecular (nano) diagnosis,  favours an improved therapy strategy and response control,  reduces incorrect staging,  optimizes molecular radiotherapy,  localizes metabolic, molecular genetic (gene transfer) mechanisms and receptor-controlled signal transduction,  implements stem cell research,  provides, for example, repair control after acute myocardial infarction, migration kinetics of progenetor cells [65, 23]. PET/CT avoids the problems arising from separate co-registrations with subsequent image fusion: Errors during mathematical adjustment of the algorithms, mislocation of lesions and interval events (differences in hydration, intestinal fi lling, defecation artefacts). Lesions were incidentally detected by PET in the gastrointestinal tract only in 3% of the cases, however with an essential risk of precancerous lesions [41].

Reports published by the University of Aachen, Germany, were irritating [58]: According to these reports, essential supplementary information was only made available in 6.7% of all cases. Experts from Zürich contradicted this minority opinion [74]. From a critical point of view, some kind of combined acquisition of PET and CT data is necessary in almost 50–67% of all cases to localize lesions precisely. In Berlin, a majority tactic is based on the triad: image fusion, separate evaluation of CT (radiologist) and PET (nuclear medicine physician), with concerted expertise of the PET/CT team for definite medical co-evaluation.

At present, this decision is made by the radiologist [3]. If a standard, contrast-enhanced CT is already available before the PET/CT examination is carried out, it must be clarified whether – for example, in case of an ametabolic or hypometabolic FDG constellation – active metastases are present or not (metastatic conversion in case of an FDG-positive primary tumour). An exclusion of false-positive PET might increase the need for contrast-enhanced CT (CE-CT). The intestinal wall and abdominal lymph nodes may be a problem in native CT. Oral contrast agents are usually applied in case of gastrointestinal tumours; in case of bolus passages, an FDG uptake that is not due to a tumour must under all circumstances be excluded, e.g. with a two-phase PET (see above, [24]). A diagnostic CT is considered obligatory within the scope of radiotherapy planning and to prepare for surgical procedures, but not for PET- and PET/CTbased chemotherapy and radiotherapy control.

PET/MRI? Tumour detection with magnetic resonance imaging (MRI alone) was first reported by Damadian [21]. A continuing competitive argument about the authorship was provoked by the award of the Nobel Prize to Mansfield in 2003. In any case, MRI has a

1.3

Increased FDG Uptake Due to Physiological and Technical Factors

competent morphologically based status today [71]. Initial steps towards the development of PET/MRI (“fusion image”) and a back-up following the rules of the current medical state are taking place [61].

American Joint Committee on Cancer The basic categories of the tumour classifications were developed in 1997 [29]. In principle, these categories can also be used for PET and PET/CT:  T (tumour size, extent),  N (regional lymph nodes, the number of infi ltrated lymph nodes determines the expected survival time),  M (distant metastases). A current revision of the lymph node imaging concept developed by Massachusetts General Hospital, Boston (2004), deals with new approaches regarding multimodal imaging, for example, in the field of risk stratification of prostate patients [16] and breast cancer patients [81], also taking into account problems related to false-negative intraoperative explorations [22].

tic strategies (surgery, radiochemotherapy as primary option) [66, 27, 38]. PET Experiments in Japan. Within 10 years, 40,000 asymptomatic test persons were examined (“most cancers” – 3/5 in males, 4/5 in females – were PETpositive); five persons obtained unnecessary surgical interventions. In 1.14% of all cases PET could detect a tumour (3,165 persons). PET Experiments in Taiwan. A total of 3,631 patients underwent a PET examination, and a tumour was found in 1.05% of all cases (in 24 cases falsepositive findings were detected). Both PET teams defended their PET motives with incomprehensible arguments. They will have to answer the following critical questions:  How many carcinomas were not detected?  Were quality-of-life indicators taken into account?  Which inclusion/exclusion criteria were used?  Which methods were used as the gold standard, and which results did they yield?  Were the studies prospectively randomized?  How was the radiation exposure justified vis-àvis the (above all the young) test persons? Were they informed of the exposure?  How was carcinoma prevalence distributed?  What about the costs and cost efficiency?

PET Screening in Japan and Taiwan A majority of all PET experts worldwide agree that a (clinically not indicated) search in oncology is untenable, and even less acceptable in healthy persons. Mass screenings are only conducted in two countries, Japan and Taiwan. After this approach had been controversially discussed in Germany, Silverman (UCLA/USA) extensively criticised this concept [64]. Impetus was given by articles from Japan and Taiwan. In the meantime, the rejection is accounted for by the majority vote being negative. However, no objection could be raised against the observance of (unexpected) chance findings. Nuclear medicine and radiology have already been working on this problem for decades [52, 70, 40]. This is detailed in the chapters on organs. (Pre-)malignant lesions can be discovered incidentally. The possible early detection of recurrent carcinomas is also worth mentioning as the course setter towards altering the diagnostic and therapeu-

It is in fact interesting that computed tomography is concerned by this screening problem in spite of the experience gained over a long period of time.

1.3 Increased FDG Uptake Due to Physiological and Technical Factors The physicians evaluating the PET images must be properly informed of artefacts and pitfalls (due to physiological and technical factors), and also of the reasons for potentially positive PET findings in case of benign processes, such as autoimmune lymphoproliferative syndrome (ALPS), WAT (white adipose tissue) and BAT (“brown adipose tissue”) [33, 51, 82], for which radio-iodine-labeled MIBG seems to be useful.

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Introduction

Atherosclerotic plaques with high macrophage potential accumulate FDG and other radiolabeled components (e.g. MCP-1, matrix metal proteinases) and are being tested at present. In the area of larger vessels (aorta, carotids, experimentally also in the area of the coronary vessels), an increased macrophage capacity indicates plaque instability. Increased glucose levels impair the PET result [44]. The multitude of causes ranges from inflammation/infection with consecutive false-positive PET findings up to septic bone surgery/orthopaedics. It is important to know more than 100 (!) causes of benign processes in 37 organs [4] with focal or diffuse hypometabolic FDG uptake.

1.4 References 1. Anderson CD (1932) Foundations of nuclear physics–The positive electron. Beyer RT (ed). Dover Publishing, New York 1949, 76:238 2. Anger HO, van Dyke DC (1964) Human bone marrow distribution shown in vivo by iron-52 and the positron scintillation camera. Science 144:1587–1589 3. Antoch G, Forsting M (2004) Wieviel CT braucht die PET/ CT? Nuklearmedizin 43:141–2 4. Bakheet SM, Powe J (1998) Benign causes of 18FDG uptake on whole body imaging. Semin Nucl Med 28:352–358 5. Baum RP (1999) At the crossroads: From cancer imaging and therapy using radiolabeled monoclonal antibodies to metabolic tumour imaging with positron emission tomography (PET). Ind J Nucl Med 14:51–66 6. Baum RP (2004) PET in der Onkologie-aktueller Stand. Thieme, Stuttgart 217–334 7. Bedford M, Maisey MN (2004) Requirements for clinical PET: comparisons within Europe. Eur J Nucl Med Mol Imaging 31:208–221 8. Beyer T (2004) Kombinierte Positronen-EmissionsTomographie/Computertomographie (PET/CT) für die klinische Onkologie: Technische Grundlagen und Akquisitionsprotokolle. Der Nuklearmediziner 27:236–245 9. Boellaard R, Krak NC, Hoekstra O, Lammertsma AA (2004) Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values. J Nucl Med 45:1519–1527 10. Bos R, van Der Hoeven J, van Der Wall E et al (2002) Biological correlates of 18F fluordeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 20:379–387 11. Brownell GL (1999) A History of positron imaging. http:// www.mit.edu/glb/alb.html 12. Brownell GL, Ackerman RH, Strauss HW et al (1980) Preliminary imaging with 18F-FDG. J Comp Ass Tomogr, 4:473–477 13. Brownell GL, Kairento AL, Swartz M, Elmaleh DR (1985) Positron emission tomography in oncology – The Mas-

sachusetts General Hospital Experience. Semin Nucl Med 15:201–209 14. Budinger TF, Derenzo SE, Gullberg GT, Greenberg WL, Huesman RH (1977) Emission computer assisted tomography with single-photon and positron annihilation photon emitters. J Comp Assisted Tomogr 1:131–145 15. Charron M, Beyer Th, Bohnen NN et al. (2000) Image analysis in patients with cancer studied with a combined PET and CT scanner. Lippincott Williams & Wilkins 25:905–910 16. Cheng L, Zincke H, Blute ML et al. (2001) Risk of prostate carcinoma death in patients with lymph node metastases. Cancer 91:66–73 17. Coleman RE (2003) Accepted PET indications in the United States. Mol Imaging and Biol 5:174 18. Coleman RE, Delbeke D, Guiberteau MJ et al. (2005) Concurrent PET/CT with an integrated imaging system: Intersociety dialogue from the joint working group of the American College of Radiology the Society of Nuclear Medicine, and the Society of Computed Body Tomography and Magnetic Resonance. J Nucl Med 46:1225–1239 19. Cronin BF, Marsden PK, O’Doherty MJ (1999) Are restrictions to behaviour of patients required following (18)-FDG PET studies? Eur J Nucl Med 26:121–128 20. Czernin J, Weber W (2004) Translational molecular imaging (editorial). Mol Imaging Biol 6:183–187 21. Damadian R (1971) Tumour detection by nuclear magnetic resonance. Science 171:1151–1153 22. Davis GL (1995) Sensitivity of frozen section examination of pelvic lymph nodes for metastatic prostate carcinoma. Cancer 76:661–668 23. Döbert N, Britten M, Assmus B et al. (2004) Transplantation of progenitor cells after reperfused acute myocardial infarction: evalution of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur J Nucl Med Mol Imaging 31:1146–51 24. Döbert N, Hamscho N, Menzel C et al. (2004) Limitations of dual time point FDG-PET imaging in the evaluation of focal abdominal lesions. Nuklearmedizin 43:43–49 25. Edwards D, Hayes RL (1969) Tumour scanning with 67Ga Citrate. J Nucl Med 10:103–105 26. Evens RG, Siegel BA, Welch MJ (1983) Cost analysis of positron emission tomography for clinical use. Am J Roentgenol 141:1073–1076 27. Even-Sapir E, Lerman H, Gutman M et al. (2006) The presentation of malignant tumours and pre-malignant lesions incidentally found on PET/CT. J Nucl Med 47:541–552 28. Feinendegen LE, Shreeve WW, Eckelman WC, Bahk YW, Wagner HN Jr (2003) Molecular nuclear medicine (The challenge of genomics and proteomics to clinical practice). Springer, Berlin Heidelberg New York Tokyo 29. Fleming ID, Cooper JS, Henson DE et al (1997) American Joint Committee on Cancer/American College of Surgeons: Cancer Staging Manual, 5th edn. American Joint Committee on Cancer, Philadelphia 30. Gambhir SS, Czernin J, Schwimmer J et al (2001) A tabulated summary of the FDG PET literature. J Nucl Med (Suppl) 42:1–93 31. Hacker M, Schnell-Inderst P, Nosske D et al (2005) Radiation exposure of patients undergoing nuclear medicine procedures in Germany between 1996–2000. Nuklearmedizin 44:119–130

1.4 32. Hahn K, Pfluger Th (2004) Has PET become an important clinical tool in pediatric imaging? Eur J Nucl Med 31:615–621 33. Hany ThF, Gharehpapagh E, Kamel EM et al (2002) Brown adipose tissue: a factor to consider in symmetrical tacer uptake in the neck and upper chest region. Eur J Nucl Med 29:1393–1398 34. Hör G (1993) Positronen-Emissions-Tomographie (PET) – Von der Forschung zur Klinik. Dtsch Ärztebl. 25/26:A11883–A11891 35. Hör G, Glaubitt D, Grebe SF et al (1972) Gallium-67 Erste Europäische Multizenterstudie (Hannover 1970). FK Schattauer, Stuttgart pp 318–332 36. Hör G, Mantaka P (1998) Application of PET in clinical oncology. Limouris GS, Shukla SK, Bender HF, Biersack HJ (eds) Radionuclides for oncology. Mediterra Publishers, Athens, pp 107–111 37. Ido T, Wan CN, Fowler JS, Wolf AP (1977) Fluorination with F2-2. A convenient synthesis of 2-FDG. J Org Chem 42:2341–2342 38. Israel O, Kuten A (2007) Early detection of cancer recurrence: 18FDG PET/CT can make a difference in diagnosis and patient care. J Nucl Med (Suppl 1) 46:28–35 39. Jaroff L (2000) Medical science invention of the year. Time Magazine 4: 40. Kamel EM, Thumshirn M, Truninger K et al (2004) Significance of incidental 18F-FDG accumulations in the gastrointestinal tract on PET/CT: Correlation with endoscopic and histopathological results. J Nucl Med 45:1804–1810 41. Kamel EM, Thumshirn M, Truninger K et al (2004) Significance of incidental 18F-FDG accumulations in the gastrointestinal tract on PET/CT: Correlation with endoscopic and histopathological results. J Nucl Med 45:1804–1810 42. Keyes JW (1995) SUV: Standard uptake or silly useless value? J Nucl Med 36:1836–1839 43. Krause BJ, Blumstein NM, Schäfer S et al (2004) Evaluation of F-18 FDG PET/CT in patients suspected of local recurrence of colorectal cancer introduced to external conformal radiotherapy (Abstr. 348). Eur J Nucl Med Mol Imyaging 31:S285 44. Langen KJ, Braun U, Kops ER et al. (1993) The influence of plasma glucose levels on fluorine-18-fluorodeoxyglucose uptake in bronchial carcinomas. J Nucl Med 34:355–359 45. Martin GV, Caldwell JH (1992) PET imaging of carbon-11S-adenosyhomocystein: A measure of myocardial energy balance? J Nucl Med 33:2144–2146 46. Martinelli M, Townsend D, Meltzer C et al (2000) Survey of results of whole body imaging using PET/CT at the University of Pittsburgh Medical Center Facility. Clin Positron Imaging 3:167–179 47. Meyer E (1989) Simltaneous correction for tracer arrival delay and dispersion in CBF measurement by the H-2 15O autoradiographic method and dynamic PET. J Nucl Med 30:1069–1078 48. Mohnike W (2004) Erste Erfahrungen mit PET/CT im niedergelassenen Bereich, Klinische Highlights, ökonomische Daten. Diagnostisch-Therapeutisches Zentrum, Berlin und BDN:p 22 49. Monakhov NK, Neistadt EL, Shavlovski M et al (1978) Physicochemical properties and isoenzyme composition of hexokinase from normal and malignant human tissues. J Natl Cancer Inst 61:27

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50. Oberender P (2004) Kosten-Nutzen-Analyse der PET- und PET/CT-Diagnostik am Beispiel des nicht-kleinzelligen Bronchialkarzinoms (NSCLC). Diagnostisch-Therapeutisches Zentrum und BDN, p 5 51. Okuyama Ch, Sakane N, Yoshida T et al (2002) 123I-or 125 I-metaiodobenzylguanidine visualization of brown adipose tissue. J Nucl Med 43:1234–1240 52. Park CHH, Glassman LM, Thompson L N L, Malo JS (1973) Reliability of renal imaging obtained incidentally in 99mTcpolyphosphate bone scan. J Nucl Med 14:534–536 53. Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cerbral Blood Flow Metab 5:584–590 54. Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood to brain tranfer constants from multiple time uptake data. J Cerebral Blood Flow Metab 3:1–7 55. Patterson II JC, Mosley ML (2005) How available is positron emission tomography in the United States? Mol Imaging Biol 7:197–200 56. Pietrzyk U, Herholz K, Fink G, Jacobs A, Mielke R, Slansky I, Würker M, Heiss W-D (1994) An interactive technique for three-dimensional image registration: validation for PET, SPECT, MRI and CT brain studies. J Nucl Med 35:2011–2018 57. Pöpperl G (2004) PET (und PET/CT) – Stellenwert in der Diagnostik von primären Hirntumouren. Der Nuklearmediziner 27:246–254 58. Reinartz P, Wieres FJ, Schneider W et al (2004) Side-byside reading of PET and CT scans in oncology: which patients might profit from integrated PET/CT? Eur J Nucl Med Mol Imaging 31:1456–1461 59. Reske S, Kotzerke J (2001) FDG-PET for clinical use (Results of the 3rd German Interdisciplinary Consensus Conference, “Onko-PET III”, 21 July and 19 September 2000). Eur J Nucl Med 28:1707–1723 60. Robertson JA, Marr RB, Rosenblum M et al (1973) Thrity-two crystal positron transverse section detector. In: Freedman GS (ed) Tomographic imaging in nuclear medicine. The Society of Nuclear Medicine, New York, pp 142–153 61. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes RB (2000) Evidence-based medicine: How to practice and teach EBM, Churchill Livingstone, Edinburgh 62. Schillaci O (2004) SPECT-CT as an alternative to PET/ CT (Abstr. 273a). Eur J Nucl Med Mol Imaging, (Suppl 2) 31:S269 63. Schillaci O, Buscombe JR (2004) Breast scintigraphy today:indications and limitations. Eur J Nucl Med Mol Imaging, (Suppl 1) 31:35–45 64. Silverman DHS (2005) Screening 18F-FDG whole-body scanning: AWESOM-PET or FALSEPOS-PET. J Nucl Med 46:717 65. Strauer BE, Brehm M, Zeus T et al (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918 66. Tatlidil R, Jadvar H, Bading JR, Conti PS (2002) Incidental colonic fluorodeoxyglucose uptake: Correlation with colonoscopic and histopathologic findings. Radiology 224:783–787

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67. Thie JA (2004) Understanding the standardized uptake value, its methods, and implications for usage. J Nucl Med 45:1431–34 68. Townsend DW, Carney JPJ, Yap JTP, Hall NC (2004) PET/ CT today and tomorrow. J Nucl Med (Suppl) 1:4S–14S 69. van Dyke D, Anger HO, Yano Y, Bozzini C (1965) Bone blood flow shown with 18F and the positron camera. Amer J Phys 209:65–70 70. Vieras F, Boyd CHM (1975) Diagnostic value of renal imaging incidental to bone scintigraphy with 99mTcphosphate compounds. J Nucl Med 16:1109–1114 71. Vogl Th J (1995) MR-Angiographie und MR-Tomographie des Gefässsystems – Klinische Diagnostik. Springer, Berlin Heidelberg New York Tokyo 72. Volker JF, Hodgke HC, Wilson HJ et al (1940) The absorption of fluorides by enamel, dentin, bone, and hydroxyapatite as shown by the radioactive isotope. J Biol Chem 134:543–48 73. von Schulthess GK (2003) Clinical molecular anatomic imaging PET, PET/CT and SPECT/CT. Lippincott Williams and Wilkins, Philadelphia 74. von Schulthess GK (2004) Maximizing the benefit of integrated PET/CT: the road ahead. Eur J Nucl Med Mol Imaging 31:1462–1463

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2.1

2

Preface

Fundamentals Thomas Beyer

CONTENTS

2.1 Preface 11 Positron Emission Tomography (PET) 11 Radioisotopes and PET Tracers 12 Coincidence Measurement and Quantification 13 PET Measurement Results and Reconstruction 14 PET Scanners and Scintillation Detectors 16 2.2 Combined PET/CT 18 Retrospective Image Fusion 18 The PET/CT Prototype 18 CT-Based Attenuation Correction 20 Commercialization of PET/CT 21 New Technical Developments in PET/CT 23 PET/CT Acquisition Protocols 29 Sources of Errors and Optimization Options 30 Radiation Protection Aspects 37 2.3 Conclusion

40

2.4 References

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2.1

Preface

The focus in the field of diagnostic imaging in oncology is shifting more and more from CT-controlled anatomical imaging to molecular/functional imaging with positron emission tomography (PET). Both imaging methods developed in parallel for the past 25 years before they were combined for the first time in one unit at the end of the 1990s. As a diagnostic method PET/CT has numerous advantages over PET and CT alone, which will be discussed below with regard to the equipment used and described from a medical point of view by taking into account exemplary cases in the main part of this book.

Positron Emission Tomography (PET)

T. Beyer, PhD Timaq medical imaging Inc., Technopark Luzern, D4 Platz 4, 6039-Root, Switzerland

Tracer Principle. Contrary to radiological or morphological examination methods, nuclear-medical imaging methods show the functionality of the organism with in-vivo studies by means of emission measurements. With this method, a tracer is brought into the body, and the radiation emitted by this tracer, consisting of a carrier molecule (e.g. glucose) coupled with a radioactive isotope (e.g. 18F), is detected from outside the body (Fig. 2.1). The tracer principle was introduced by George de Hevesy in the 1920s [39]. This idea is based on the fact that the system (i.e. the patient) is not to be disturbed during the examination. The biological function (metabolism) can then be examined with minute quantities of a substance (tracer) that cannot be distinguished from conventional substances available in the body and involved in selected metabolism processes. This can be achieved by radioactive labeling of the tracer. This is done by replacing special ion groups of the original molecule in the

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Fundamentals

Tracer X-ray tube

Detector ring

Detector

a

c

b

Fig. 2.1a–c. Oncological imaging. a CT transmission measurement. b Emission measurement with PET. c PET/CT as equipment combination consisting of both PET and CT with the possibility to perform both examinations quasi-simultaneously

tracer molecule by radioactive isotopes or groups; in this way, the chemical properties of the molecule are not modified, or at least not in such a way that they are not involved in the first metabolism steps in the body. The radiation emitted by the tracer then allows the localization of the distribution of the tracer and the tracking of its metabolism in vivo. The choice and production of a radioactively labeled tracer used for diagnostic imaging depends on the physiological and biochemical metabolic processes (e.g. blood flow, metabolism, receptor binding) that are to be observed and on the properties of the radioisotopes (half-life, radiation protection) as well. The tracer development process starts with the selection of the radioisotope (for PET or SPECT). Isotopes that are not available on the market must be produced “onsite”.

Radioisotopes and PET Tracers If we consider the multitude of artificially produced radioisotopes, we see that positron emitters (E+) have several advantages over photon emitters [66]. The distribution of the E+ emitters may be tracked from the outside by a coincidence measurement, which is a better measurement method than the acquisition of single gamma rays (“single photon emitter”). During the coincidence measurement, pairs of 511 keV annihilation photons created after the emission of a positron and its crossing with an electron are measured and used to localize the radiotracer and then also for attenuation correction (Fig. 2.2). Although a rather expensive infrastructure with both a cyclotron and a radiochemical laboratory must be available in the vicinity of the PET scanner to produce short-lived

2.1 PET detector ring

I(x)

511 keV Patient

CH2

HO

D2

β+

e–

H

p→n + β+ + ne

Preface

I0

O

OH

H OH

HO

Annihilation

H

H

511 keV H D1

18

TX

F

Fig. 2.2. Electronic coincidence measurement with PET. A tracer (for example FDG [18F]-fluorodesoxyglucose) is injected. A positron is emitted through radioactive decay of 18F (E+-emitter), which attracts an electron and then decays into two 511 keV annihilation photons emitted 180 degrees apart. The straight line on which the decay took place can be clearly identified by the detection of the two annihilation photons in opposite detectors D1 and D2. The emission activity is underestimated due to self-absorption [I(x) < I0]. The absorption coefficients (μ) for each possible detector combination Di–Dj can be ascertained with a transmission source (TX) rotating around the patient

isotopes such as 15O (2-min half-life), these short-lived isotopes are very useful in studies dealing with metabolic processes, which only last a few seconds or minutes and thus require repetitive short measurements. However, authentic labeling of the biomolecule is impossible in many cases. This is the reason why analogue biogenic isotopes must be used to ensure that the biological activity and thus the metabolic process to be observed are maintained after the tracer molecule has been labeled. Table 2.1 lists the most frequently used PET isotopes. As the half-life of the four most important PET isotopes (11C, 13N, 15O and 18F) is rather short (20.4 min, 10 min, 2 min and 109 min), high doses must be produced with short labeling processes. An external production and delivery to PET installations without a cyclotron are presently only established for 18F-labeled tracers. Generally the labeling position of the biomolecule with the positron emitter is chosen according to the metabolic process to be observed as well as the stabilization of the biological activity. Steric and electronic effects may considerably modify the physiological properties of the labeled molecules. It is therefore often difficult to prognosticate the behaviour of newly developed tracers, so the scientists developing such new tracers need to have comprehensive experience (with regard to both chemical and biological features). But in many cases the molecule and its metabolic properties are in fact known and may therefore be more reliably used to visualize selected physiological processes.

Table 2.1. Most commonly used PET isotopes, radioactive half-life T½, maximum emission energy Emax and average free path length in water (soft tissue) Isotope

T1/2 (min)

Emax (MeV)

Rp (mm)

15O

2.05

1.72

0.7

13N

9.9

1.19

0.5

11C

20.4

0.97

0.3

18F

109.7

0.64

0.2

62Cu

9.74

2.93

14.3

68Ga

68.0

1.9

9

82Rb

1.25

3.36

16.5

124 I

6019.2

2.13

10.2

Coincidence Measurement and Quantification The measuring principle of PET is based on two assumptions (Fig. 2.2):  the positron was located on the straight line defined by the two detected annihilation photons and  the annihilation photons are emitted 180 degrees apart. In practice, the two assumptions are just approximations. Strictly speaking, the positron is emitted

13

14

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Fundamentals

with an energy whose amount depends on the isotope concerned (see Table 2.1); thus, that the location of the emission process cannot be fi xed on a straight line. Furthermore, the annihilation photons are not emitted exactly 180 degrees apart. Both processes must be taken into account for an exact description of the spatial resolution of a PET scanner. The advantage of coincidence measurement of PET is that the localization and quantification of the tracer distribution do not depend on the spatial distribution of the tracer. Contrary to SPECT (single photon emission tomography) based on the detection of single photons, the PET signal does not depend on the depth of the tracer in the tissue, and it may always be unequivocally assigned to a connection line (or connection volume) according to the coincidence measurement. The measured coincidence rate only depends on the total attenuation along the line connecting the detectors (Fig. 2.3). The true intensity of the tracer distribution may then be determined if the attenuation along these connection lines is known, regardless of the position along this line (or the depth in the tissue).

PET Measurement Results and Reconstruction A detected PET event is valid if the following requirements are met:  the two annihilation photons were detected within a certain time window (coincidence window, e.g. 12 ns),  the line connecting the two detectors that have registered the event is within a pre-defined acceptance angle and  both annihilation photons are detected within a predefined energy window (typically 350–650 keV). Figure 2.4 shows schematically possible events detected during a PET scan. Individual photons are called singles, and two singles meeting the above requirements form a coincidence event, also called a prompt event. Prompts summarize true coincidences (trues), random coincidences (randoms) and scattered events (scatters). All events, except the trues, contribute to a falsification of the true tracer distribution and have to be corrected to guarantee an absolutely reliable quantification. All PET (and PET/

Emission scan

Transmission scan

L = exp { – ∫ μ (x, 511keV) dx} I 0

L I = I0 exp { – ∫ μ (x, 511keV) dx} 0

Transmission

Emission

I0

AC-PET

Fig. 2.3. The measured emission signal I is smaller than the true signal I0, because some annihilation photons (511 keV) cannot reach the detector due to self-absorption. Due to the coincidence principle of PET, the attenuation along all lines connecting the detector elements can be measured by performing an external transmission measurement and using a transmission source of known intensity, and the attenuation correction factor can then be calculated by dividing the known by the measured transmission intensity. The lower row shows the attenuation information (transmission), the uncorrected emission distribution (emission) and the PET image after attenuation correction (AC-PET) by using the example of a patient with a 3-cm large hamartoma. The tumour would not have been detected on an uncorrected emission image (material made available by Paul E. Kinahan, PhD, Seattle, WA)

2.1

Preface

700 Tr [kcps]

S A S

Ra

NEC Trues

Randoms

Scatter 0

20

[kBq/ml]

Fig. 2.4. Measurement events in PET are called prompts. Such a coincidence consists of two singles (S) and has to meet the requirements stipulated in the text. Pairs of unscattered singles produced by a single annihilation event are called true coincidences (trues). If these pairs were produced during different annihilation events, they are called random coincidences (randoms). Among other factors, the share of randoms directly depends on the coincidence time window width. Coincidences with one or more scatter event(s) (green) are called scattered coincidences (scatters). The number of scatters depends on the object and not of the count rate. The straight line on which the positron was detected is mispositioned due to both the randoms and scatters so that the tracer distribution is finally not correctly displayed. The graph on the right shows count rates (Tr trues, Ra randoms, NEC noise equivalent counts) for a full-ring PET with the 3D imaging mode

CT) scanners available on the market are able to correct randoms and scatters. The randoms are usually estimated by means of a staggered electronic time window and subtracted from the prompts [21]. With the use of new detector materials enabling shorter coincidence windows [48], the random rate may be minimized prospectively. The rate of scattered events is usually determined by taking into account simulated scatter distribution patterns and estimations regarding the tracer distribution, and the result is also subtracted from the prompts. In this context, the possibilities related to an improved energy resolution of the detectors are also taken into consideration to distinguish prospectively between the true and scattered coincidences by taking into account the energy to which the detector has been exposed. All PET events are documented in so-called sinograms, i.e. in a kind of polar coordinate system in which the distance and the rotation angle of a certain coincidence line (connecting two activated detectors) is registered with reference to the centre of the detector ring (Fig. 2.5). A line in a sinogram represents, for example, a parallel projection of a certain projection angle where the individual projection points include the sum of all prompts along a parallel detector combination. After completion of the scan, the sinograms are used to reconstruct PET images reflecting the distribution of the tracer in the area examined. The sinograms must previously be multiplied with the attenuation correction factors to obtain quantitative PET

images. PET image reconstruction was originally governed by the fi ltered backprojection based on the approaches proposed by the Austrian Johann Radon who was the first to show how one can determine an object function from its line integrals in 1917. In the context of PET, one can draw conclusions regarding the original tracer distribution (object function) by taking into account the projections of the emission signals (sinograms) and projecting them back from the directions I. In this context, supplementary efforts by CORMAC and others in the 1950s and 1960s led to mathematical concepts of image reconstruction from projections, which are known today as fi ltered backprojection [19]. In 1975 Ter-Pogossian, Phelps and Hoffman were the first to describe a PET scanner with implemented FBP reconstruction [54, 60]. During the FBP reconstruction, the line integrals are convoluted with a fi lter (ramp fi lter) prior to backprojection in order to eliminate blurring during the backprojection. A ramp fi lter has negative sidebands suppressing marginal blurring of the projections outside the object function during the backprojection. Due to the inadequacies of FBP in case of poor count rates (because of short scan times or low activity applied), alternative image reconstruction algorithms have been greatly elaborated for PET scanners during the past years. Iterative reconstruction approaches have meanwhile been established that, contrary to FBP, are also able to take into account tracer distribution models (i.e. first estimations) and

15

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Fundamentals

may thus improve the reconstruction of the true tracer distribution [26]. Figure 2.5 shows such an example of an iterative, attenuation-weighted image reconstruction for a FDG whole-body scan.

PET Scanners and Scintillation Detectors PET scans are based on the concept of scintillation detectors coupled to a photomultiplier (PMT). By arranging the detectors around the patient (Fig. 2.3) or by rotating partial detector rings around the main axis of the patient and connecting opposite detector pairs in a coincidence detection circuit, it is possible to register the tracer distribution in vivo and

then to quantify and reconstruct this distribution as discussed above. Since the first coincidence measurements, PET measurements have been mainly based on the use of inorganic scintillators. In addition to NaI (Tl), which was originally used as the standard material, in the 1980s BGO (Bi4Ge3O12) was considered because of its higher density and atomic mass number and BaF2 because of its short decay time; in fact, BGO soon became the standard detector material in commercial PET scanners. Other scintillators, such as CsF, CsI and GSO (Gd 2SiO5), have comparable decay times and light yields, but only GSO is still used in whole-body PET scanners today. Table 2.2 provides a survey of the current PET scintillators with their most important physical properties.

x z f

z p(s,f) s Sinogram

PET scanner

3DRP

1994

FORE + AWOSEM

Reconstructed image

2001

Fig. 2.5. Single measurement events are sorted in sinograms in the PET. A straight line in a sinogram [p (s, f)] corresponds to a parallel projection with a defi ned projection angle in the scanner. The sinograms are used to reconstruct the emission images (right side). The reconstruction techniques have become increasingly sophisticated over the past years. A comparison with the same data set is shown below: the image on the left side was reconstructed with algorithms used in 1994 and on the one on the right side was reconstructed with algorithms used in 2001 with iterative and attenuation-weighted approaches. (Materials made available by David W. Townsend, PhD, UT Knoxville, TN, and Paul E. Kinahan, PhD, Seattle, WA)

2.1 Table 2.2. Physical properties of the PET detector materials Property

NaI(Tl)

BGO

LSO

GSO

Density [g/ml]

3.67

7.13

7.4

6.7

Effective Z

51

74

66

61

Decay time [ns]

230

300

35–45

30–60

Photons/MeV

38.000

8.200

28.000

10.000

Light yield [% NaI]

100

15

75

25

Hygroscopic

Yes

No

No

No

A PET detector must be able to detect the single events (singles) with  a high efficiency,  a high spatial resolution,  short dead times and  a high time and energy resolution. Furthermore, the material must not be too expensive because otherwise the voluminous detectors would no longer be affordable [49]. The selection of a PET detector depends on a multitude of physical and other parameters that are differently weighted by the different suppliers. At present, three crystal materials are being used in PET (and PET/CT) scanners: BGO, GSO and LSO (for more detailed information, refer to [52] and [41]). In general, PET detector materials coupled to a photomultiplier (PMT) should

    

Preface

have a short attenuation length (< 1.5 cm), induce a high photoelectric effect (> 0.3), have a short decay time (< 100 ns), be available at low cost (< $ 20 per ml) and have a high light yield (> 8,000 photons per MeV).

All of these requirements influence the count rate behaviour of a PET scanner. However, Table 2.2 also shows that actually none of these current PET detector materials meets all these requirements perfectly, so the selection of the detector is always a compromise between cost and benefits. PET scanners typically consist of a row of several detector rings arranged side-by-side and covering an axial examination length of at least 15 cm altogether. Longer areas (torso, whole body) are thus examined by scanning these areas with several staggered PET positions, i.e. by moving the patient discontinuously through the PET scanner. Figure 2.6 shows currently used detector modules and arrangements in modern PET scanners that may be divided into partial-ring and full-ring scanners for whole-body examinations. In addition, some PET systems are equipped with so-called septa, i.e. partial discs that may be placed between the detector rings and thus, for example, minimize the scattered events among the different detector rings, but also limit the absolute sensitivity.

Detector

a

b

c

PMT

d

Block detector

e

Segment detector

f

Detector block

Fig 2.6a–e. Diagrams of currently used PET scanners: a rotating partial ring, b full ring and c full ring consisting of segments. The designs a and b are based on so-called block detectors (d,f), whereas (e) is the basic component for design (c). In all cases several single crystals are coupled to a photomultiplier. The activated detector element can be unequivocally localized by means of special matching processes

17

18

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Fundamentals

If the septa are placed in the PET field of view, we are talking about a 2D PET scan; if they are parked outside the field of view and the detectors are ready to detect cross-ring coincidences, then we are talking about 3D PET scans. The advantages and disadvantages of the 2D and 3D acquisition modes are discussed in detail by Cox [24].

2.2 Combined PET/CT As a technological extension of PET, combined PET/ CT is a non-invasive imaging method used to display anatomical and molecular correlations by a quasisimultaneous examination. Since the first PET/CT prototypes were introduced in 1998, this imaging technology has developed at a rapid pace. Due to the use of fast PET detector materials in PET/CT scanners and the use of CT for attenuation correction, oncological whole-body scans can today be completed in less than 20 min. PET/CT also has a logistical advantage for the patient and the clinician since both examinations – as far as justified by clinical findings – may be acquired quasi-simultaneously and only a single, integrated diagnosis must be elaborated. Nevertheless, there are numerous methodical sources of error, mainly due to the use of CT-based attenuation correction, which can be compensated for or minimized by using optimized acquisition protocols. With these improvements, PET/CT may be successfully used as a component of modern diagnostic imaging.

Retrospective Image Fusion The first serious tests trying to register and fuse image data of different complementary – mostly neurological – studies (CT and PET, MRI and PET) were run in the 1990s [55, 56, 64, 65]. These approaches were based on linear registration approaches that put the image volumes in spatial congruence. For the brain, which may be interpreted as a rigid organ, a linear registration approach is a realistic assumption. However, this does not apply to extra-cranial regions to be examined where a spatial image reg-

istration may also be useful from a clinical point of view, because on the one hand the individual organs may not be considered as being rigid, and on the other hand the movement between the individual examinations may be considered as being linear. An image fusion of different and complementary image volumes of the thorax or abdomen must therefore be based on non-linear registration approaches that may often just be partly automated or not automated at all, the registration accuracy of which may not be reviewed by standardized methods yet and that are not used in clinical routine yet due to their complexity. Although software-controlled retrospective image fusion has considerably contributed to the acceptance of multimodal imaging, particularly due to the successful application in the field of neurological research, the corresponding approaches could not really make their way in clinical practice for applications outside the brain. As PET and CT scanners were generally accepted and largely available in the 1990s, the development engineers then tried to fuse the PET/CT hardware to provide a diagnostic instrument that might be used for non-invasive anatomic-metabolic imaging in the clinical routine and is efficient for both therapy planning and follow-up. Prospective image registration with fused hardware will become indispensable in future, all the more since PET examinations with highly specific tracers, whose PET images will no longer contain anatomical background information, will presumably become increasingly important.

The PET/CT Prototype The fi rst PET/CT scanner was installed in May 1998 at the University of Pittsburgh Medical Center (USA) and was in operation until July 2001 (Fig. 2.7a). The PET/CT prototype still represents the best possible integration of the hardware components today. The CT and PET components were installed on the front and back side of a common aluminium rack rotating with 30 rpm. The exterior gantry was 168 cm high and 170 cm wide with a tunnel length of 110 cm. The transversal opening of the gantry had the same size as the opening of the PET, i.e. 60 cm. The CT and PET components were arranged at a distance of 60 cm from each other along the axial scan direction [5].

2.2 Combined PET/CT

CT CT PET

PET/CT

Fig. 2.7. a PET and CT hardware was for the fi rst time integrated in the PET/CT prototype. However, a PET/CT scan was still performed with two rather independent consoles. b FDG-PET/ CT (prototype) used for follow-up of a patient suffering from a progressive ENT tumour after several surgical interventions

PET Patient bed

CT images

PET images

CT console

Image fusion

a

b

pre

A common patient handling system was installed in front of the gantry. The coaxial scan length used for the acquisition of complementary CT and PET data was 100 cm, i.e. a little bit shorter than the length of a dedicated PET or CT scanner. During the design phase of the prototype, the acquisition and reconstruction consoles (computers) were not integrated. The CT and the PET component were controlled by separate computers, but attenuation correction and reconstruction of the PET data were handled by a common computer. Adapted visualization software was used to display the fused PET/CT

PET console

post I

post II

data and to evaluate (localize and quantify) supplementary PET accumulations. More than 300 cancer patients were examined during the 3 years of the clinical test run (Fig. 2.7b). The first clinical studies [19] indicated a modification of the clinical information in 30% of the cases with PET/CT, compared with CT and PET alone [22]. In studies performed later with newer PET/CT scanners and by experts who were more experienced in PET/CT, the percentage of the case descriptions modified by PET/CT was reduced to approximately 10% [4, 67].

19

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Fundamentals

CT-Based Attenuation Correction In addition to the intrinsic image fusion of the CT and PET data sets acquired during a combined PET/CT scan, the CT transmission images may also be used for attenuation and scatter correction (Figs. 2.3 and 2.4) of the emission data. Figure 2.8 compares the acquisition protocols including transmission measurement for a PET and a PET/CT whole-body examination. This comparison shows that the PET transmission scan is deleted or completely replaced by the CT scan if the patient is examined with PET/CT. With conventional PET transmission scans, a typical whole-body examination was time-consuming, taking 10 to 20 min. As the transmission data were usually acquired in the post-injection mode, i.e. while the tracer had already been injected, the transmission scans were contaminated by the events detected from the emission activity. The most frequently used PET transmission sources were rod sources filled with 68Ge and rotating around the patient (cf. Fig. 2.8a) so that

the attenuation along all detector combinations registered during the emission scan could be computed. As 68Ga has a half-life of 268 days, this was an expensive solution since these rod sources had to be replaced at regular intervals, i.e. almost once a year. The use of the CT transmission instead of conventional PET transmission scans has therefore a series of methodical advantages. One of these advantages is that the total scan time may be reduced by 40% because a whole-body CT is acquired within approximately 1 min, i.e. within a small fraction of the PET scan time [58]. On the other hand, the equivalent source intensity is six times higher on the scale, so that contamination caused by patient activity during the CT transmission measurement can be excluded. Figure 2.9 shows the CT-based attenuation correction schematically. As the X-ray tube corresponds to a polychromatic radiation source with up to 140 kVp, the attenuation coefficients have to be transformed to the values obtained with 511 keV (PET) [43]. CT-based attenuation correction is based

Axial scan area PET

Patient table

Gantry

Transmission

Emission

Corrected emission

Emission

Corrected emission

a

CT CT PET

Topogram b

CT

Fig. 2.8a,b. Whole-body scan with PET (a) and PET/CT (b). a The patient undergoes a transmission (TX) and an emission scan, which are both performed with a table feed with stepwise overlap. The TX scan is performed with 68Ge rod sources or 137Cs point sources. The whole scan time for the marked axial scan area amounts to ~1 h. b In the PET/CT the axial scan area is defi ned after a tomogram has been acquired. The TX scan is replaced by the CT scan with continuous table feed (spiral CT). The emission scan is performed similar to the PET. Due to the shorter CT scan time, the whole examination only takes less than 40 min. Furthermore, PET/CT makes available intrinsically correlated CT images that can be evaluated

2.2 Combined PET/CT

on the assumptions that CT scanners are operated with an effective energy and that only the Compton effect (scatter) makes a decisive contribution to the interaction of the X-radiation with the tissue, so that the attenuation values for another energy (e.g. 511 keV for PET) may be scaled. Linear scaling is a valid method if soft tissue and bones can be distinguished. Due to the high concentration of calcium, the CT energy attenuation coefficient of bones considerably differs from the coefficient for the soft tissue (cf. Fig. 2.9), so another scaling factor must be used [43]. However, soft tissue and bones can be properly separated and segmented on the CT images, and by means of a resulting bilinear scaling model for both fractions one can elaborate a corresponding attenuation pattern for 511 keV (Fig. 2.9) that will then be used for attenuation correction [44].

The CT-based attenuation correction is today the standard method used in all PET/CT scanners, and attenuation-corrected (and thus quantitative) PET data are thus today generally accepted in oncology, which was not the case in all clinical centres as long as dedicated PET scanners were used.

Commercialization of PET/CT The interest in a commercial distribution of PET/ CT scanners grew with immediate clinical interest in intrinsically fused PET and CT images (Fig. 2.10) and in a routinely available low-noise attenuation correction. While the individual components of the prototype PET/CT were sufficient for an evaluation of the concept of a combined PET/CT scanner,

Soft tissue Bone

CT: 2

106

GBq

μ/ρ [cm2/g]

0.3 0.2 Se 0.1

Soft tissue CT

0 a

Sk

PET μ Image 511 keV

CT image 0

100 200 300 400 500 [keV]

Bone

b

CT (Eeff ) P35

P35 Standard PET: 0.1-1GBq

Scaled 511 keV c

P41 Beam source

P41 Segmented

d

Fig. 2.9. a If CT is used as TX, then the CT attenuation values (μ) must be transformed from 30–140 keV to the energy of PET (511 keV). b For this purpose, the CT image must be segmented into soft tissue and bones. The μ-values of each pixel group are transformed with their own scaling factor (Sk) into μ-coefficients with 511 keV (c). As the source intensity of CT considerably exceeds the intensity of conventional transmission sources, the transmission image quality is improved and image noise is reduced (d)

21

22

2

Fundamentals

shortly after their introduction they were no longer state of the art and did not meet the required standards that in the meantime had come to be expected by the potential PET/CT users with regard to a possible combination of CT and PET. Table 2.3 provides a summary of the limitations of the first PET/CT scanner in prognostic deployment in clinical routine with high patient throughput.

Fig. 2.10. PET/CT example of an oesophageal carcinoma (image-of-the-year prize awarded during the Society of Nuclear Medicine Conference 1999, Toronto, Canada)

For a revised design of a PET/CT scanner, it was particularly necessary to redesign the patient handling system to provide a reproducible and exact handling system (Fig. 2.11). Due to the axial offset of the CT and PET components in a combined design (Figs. 2.7 and 2.8), the patient handling system should be designed such that there are no vertical misregistrations with an increasing examination length as was the case with the PET/ CT prototype. Such a patient handling system may for example consist of a movable post mounted to a rail system in the main axis of the gantry (Fig. 2.11c). Alternatively, a conventional patient bed (CT or PET) can be moved on a rail system by the distance between the CT and PET components (Fig. 2.11d), or a supplementary support system can be installed inside the gantry to prevent vertical deflection (Fig. 2.11e). With the prototype PET/CT, a whole-body examination from the head/neck region to the symphysis took about 1 h (topogram, CT, PET). The long duration of this examination is due to the cooling periods required for the X-ray tube while it travels over extended areas to be scanned. The CT component used corresponded to the fi rst generation of a spiral CT and was not yet designed for high-resolution CT examinations of extended scan areas. Furthermore, the count rates of the PET module used – a partial

Table 2.3. Properties and limitations of the prototype PET/CT. Conclusions for PET/CT successor models Prototype design

Consequence (Oncology)

PET/CT Design Goals

Partial-ring PET (ECAT ART)

Limited efficiency, long scan time (t1 h for whole-body scans)

High efficiency, high resolution

Single-row spiral CT (90s technology)

Low tube capacity, cooling periods required

High tube capacity for quick, continuous scans

PET and CT rotate with 2 s rotation time

CT scans with IV contrast agent are limited

Rotation time < 1 s

The transversal field of view of CT is smaller than for PET

Image artefacts in case of large patient’s girth, falsified attenuation correction

Adaptation of the CT field of view to PET

100 cm coaxial scan length

“Whole-body examinations” are limited from head to thigh

200 cm scan length for whole-body examination

Non-fixed patient pallet

Relative vertical deflection between CT and PET is possible

No further deflection of the pallet after the patient has been positioned

Independent console

Acquisition protocol not integrated

One integrated acquisition, integrated evaluation

Restricted access for service staff

Service difficulties

Unrestricted access to the service staff

2.2 Combined PET/CT

CT

PET

CT

PET

Position A B

Position A B a c

b d

e

Fig. 2.11a–e. In commercial PET/CT scanners, the PET and CT components are installed one after another. If only the patient pallet is moved, then a relative vertical offset of the CT and PET data cannot be avoided (a). This problem can be coped with by moving the patient into the scanner together with the whole patient table (b). c–e Examples of patient positioning systems in commercial PET/CT scanners

ring scanner (ECAT ART [61, 62]) – were not sufficiently high to achieve emission measuring times of clearly less than 5 min per bed position. The performance parameters of the CT and PET entities thus had to be considerably improved to match the state of the art in the field of CT and PET (Table 2.3). Another limitation of the prototype PET/CT regarding the use as a planning instrument for radiotherapy with different positioning aids was the insufficient diameter of the gantry opening (60 cm) and the measured maximum field of view of the CT scanner (45 cm), which was thus 15 cm smaller than the corresponding field of view of the PET scanner. The patients could therefore not be positioned with their positioning aids (vacuum cushion, arm rests, reference markers) because the gantry diameter was too small. On the other hand, the reconstructed CT image for very tall patients was limited in that truncation artefacts arose, which resulted in an incorrectly reconstructed PET activity if the CT images were used for attenuation correction; these artefacts will be discussed below. The design goals summarized in Table 2.3 were for the first time implemented in a design presented by the vendors Siemens Medical Solutions and CPS Innovations who presented the first commercial PET/

CT scanner (biograph-BGO) at the Society of Nuclear Medicine Meeting in 2000 in St. Louis, MO. In the same year, GE Medical introduced their version of the PET/CT, the Discovery LS, at the Radiology Society of North America Conference in Chicago. One year later, Philips Medical presented their PET/CT scanner, the Gemini. Table 2.4 gives a survey of the different PET/CT designs.

New Technical Developments in PET/CT With the introduction of PET/CT scanners in the market in 2000, the interest in this combined imaging method has grown rapidly. Since then, new designs have been particularly presented during the annual meetings of nuclear-medical and radiological societies that not only refer to the technological aspects, but also to new acquisition and evaluation software. The scanners listed in Table 2.4 illustrate the third generation of PET/CT scanners, which are mainly characterized by the selection of the PET detector materials and the CT complexity (number of detector lines, X-ray tube). However, all designs combine a spiral CT and a full-ring PET.

23

24

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Fundamentals

Table 2.4. Development of PET/CT scanners with main features of CT, PET and applications. Most PET/CT scanners are operated with 3D mode (without septa). The detector materials used for PET are BGO (standard), LSO and GSO. Conventional PET transmission sources (PET-TX) are available optionally. The total scan times may vary with the different installations Prototype

Second Generation (2000–2003)

SMART

Discovery LS

Biograph Classic

N=2,4; spiral 80 cm in 30–80 s

Full ring BGO-2D/3D PET-TX sources WB in ~30 min

Third Generation (2003 and later)

SMART

Gemini XL

Discovery ST

Biograph Sensation 16, 64

N=1,2; spiral

N=1, spiral 80 cm in 240 s

N=8, 64, spiral

N=8,16, 64; spiral 80 cm in 20–30 s

N=6,16, 64; spiral

Full ring BGO/LSO-3D GK in ~30 min

Partial ring BGO-3D PET-TX sources WB in 50 min

Full ring GSO-3D PET-TX sources WB in ~20 min

Full ring BGO-2D/3D PET-TX sources WB in 10 ng/ml skeletal scintigraphy, and with >50 ng/ml a CT or MRI of the spine (AWMF Guidelines, Guidelines of the German Radiological Society for Imaging Diagnostics, registry no. 039/075). The sensitivity of the biochemical PSA recurrences – given in the literature as 59% – is termed unsatisfactory [96]. After reviewing the case histories of 915 patients, the PSA value alone was not conclusive; the doubling time after 3 months (PSAD), however, was more informative. Although determination of the PSA level is not a regular part of statutory cancer screening, this test is still – despite its inherent defects – highly regarded according to expert urological reports. ANNA methods (artificial neuronal network analyses) come in third place after PSA and punch biopsies if the urologist is still undecided after clinical examination, even with TRUS. MRI [109] and quite certainly nuclear medicine are currently methods of the “last resort”. Current methods, such as 18F-choline, do not receive sufficient attention [83]. Under specified conditions (20 mAs, 140 kv, 512×512 matrix) in a hitherto still limited patient collective, a group in Berlin [31] verified correct-negative PET results (13/28, SUV 4–14) and false-positive 18F-choline data (8/21, SUV 3.3–4.7) in acute and chronic prostatitis with a ROC-SUV cut-off value of 3.3 (ben/mal), an SUV sensitivity of 70% and an SUV specificity of 57%. The qualitative evaluation yielded a sensitivity of 86%, a specificity of 61%, a positivepredictive value of 80%, a negative-predictive value of 72% and an accuracy of 77.6%. Historically, 18F-FDG-PET has proved inadequate for slowly growing tumours and permitted reliable information only for far-advanced disease (FAD). The use of 18F-fluoroacetate (FAC) was based on the biochemical knowledge of increased lipid synthesis, similar to other cell membrane precursors (choline) [143, 144, 26]. FAC can be obtained by means of an automatic synthesizer system [127]. Objections that have already been raised concerning 11C-acetate (superimposition of tumour and inflammation, lymph

6.5

nodes, bladder activity) require further clarification [103, 99]. 18 F-choline recently yielded favourable results in the differentiation of malignant and benign lesions [52, 7]. As regards the detection of pelvic lymph nodes, recent results point to a superiority of PET/ CT, at least in aggressively growing primary carcinomas [119, 78, 140, 74, 108].

Prostate Carcinoma

into account here [12]. The Memorial Sloan Kettering Cancer Centre (MSKCC) in New York is one of the world’s longest-standing oncology centres. In 1995, Schwartz [117] commented on the tumour marker status for common entities.

Status of Individual Imaging Methods Follow-up after Prostatectomy and Radiotherapy. This is performed at first by PSA determination and DRE, with an increasing finding also by TRUS and if necessary an MRI of the small pelvis. In case of very high PSA levels, a CT of the abdomen and pelvis as well as a skeletal scintigraphy and a thorax X-ray should be carried out in order to exclude distant metastases. After radiotherapy, a TRUS-based biopsy also comes into consideration instead of this (AWMF Guidelines, Guidelines of the German Radiological Society for Imaging Diagnostics, registry no. 039/075). In treatment monitoring – e.g. after brachytherapy [126] – no attention is paid to PET (or to nuclear medicine in general) either in locally limited carcinoma with a low risk or in case of moderate to high risk.

Treatment Depending on the age and tumour stage of the patient, radical prostatectomy, local or locoregional radiotherapy alone, or the combination of a surgical procedure and additive or adjuvant radiotherapy come into consideration as curative treatments. As palliative treatment of the incurable patient particularly hormone treatment rather than chemotherapy has proved useful (AWMF Guidelines, registry no. 052/003, German Society for Radiooncology). The interstitial brachytherapy of the prostate carcinoma in the form of permanent implants (I-125, Pd-103) or as combined HDR brachytherapy and percutaneous radiotherapy also forms part of the curative therapy options (AWMF Guidelines, registry no. 052/012, Guidelines in Radiooncology). Astonishingly, it has until now not been included in a PET scenario on a validated study basis as far as we know. From the urological point of view, percutaneous radiotherapy after radical prostatectomy is offered as possibly the only curative treatment approach if the PSA level persists above zero. Other premises must be taken

Bone Scintigraphy. In the year 2004 nuclear medicine still played a minor role – after ultrasound, CT and MRI – in imaging diagnostics of prostate carcinoma. Bone scintigraphy has proved to be a highly sensitive method for 30 years now. It is used as a stratification variable for the evaluation of the treatment response and – with low specificity – for the detection of metastases and has been rather too hastily classed as completely replaceable by PSA [20]. Older studies have shown that after prostatectomy, the PSA level is highly sensitive, and bone scintigram (with negative PSA of little informative value) is valuable in case of a PSA rise between 10 and 20 ng/ml and in case of symptoms [123, 124]. Bone pain, however, is not a reliable indicator of treatment response. Scintigraphy has no informative diagnostic value in case of sclerotic/lytic metastases and should be supplemented by other markers (hydroxyproline). In case of inconclusive SPECT scintigrams, 18F-fluoride PET and PET/CT can be of further help [34]. Experiences in Erlangen [110] attest that SPECT/CT (hybrid technique) yields a more accurate differentiation between spondyloarthrosis and malignant lesions [73, 72, 110]. Sentinel Node Diagnostics. Sentinel node lymphoscintigraphy (SNL) registers the first regional lymph node to be affected (sentinel lymph node). Once again, the goal is to reduce the radicalism of exploratory pelvic surgery. Preoperative lymphoscintigraphy with 99mTc-nanocolloids has been used in a large number of patients [30, 135, 136]: 70% of the nodal-positive findings were detectable only with SNL. Earlier initiatives using ileopelvic lymph node scintigraphy for the early detection of metastasis-infested lymph nodes and after intralymphatic injection of labeled monoclonal antibodies shifted the weighting mostly to an already advanced tumour stage. One may ask, who needs lymph node dissection [17]? The interdisciplinarily involved practitioner of nuclear medicine should be informed about clinical problems.

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Occult lymph node metastases are, if clinically justified, accessible for PET or PET/CT [49]. Reference must be made here to the “metabolic flare” (elevated tracer uptake) after use of successful treatments, whereas the “biochemical flare” (PSA increase) need not conform to this. It must be analyzed in greater detail in studies (preferably with PET/CT) on the basis of weighted SUV index determinations whether the recommendations of the EORTC (positive signal 1 to 2 weeks after start of treatment) generally apply [134, 128, 45]. Immunoscintigraphy. No success was achieved in earlier studies with labeled monoclonal antibodies [5, 44, 54, 77, 102]. The US multicentre study with over 2,000 cases stands out: Pelvic and extrapelvic metastases with lower Gleason indices were also detectable [122]. After incomplete prostatectomy, the 111In-labeled monoclonal antibody – in addition to PSA – was described as helpful for the prognosis. 1 The method has, however, still not been included in clinical practice. A fusion image (immunoscintigram/MRI) became a much cited highlight. The objective is to identify the patient collective that can be spared diagnostic lymph node dissection [17]. The Guidelines of the German Society for Urology provide procedure instructions. Radiopeptide receptor diagnostics. Radiopeptide receptor diagnostics (68-Ga-Dotabom = bombesin analog) and treatment tested with PSA levels of 7–24 ng/ml (smallest detected tumour 5 mm) are a source of hope [119]. Molecular genetic diagnostics with PET and consecutive gene therapy have been investigated in the experimental stage [2, 100]. Suicide gene therapy is an excellent example of the future prospects for immuno-PET in prostate carcinomas. The use of monoclonal antibodies against the extracellular domain of PSMA takes another route in case of the metastatic prostate carcinoma. In-vitro Molecular Markers. DNA microassays, gene chips, triple novel imaging (fluorescence, bioluminescence, PET reporter genes), gene and reporter probe – the p53-tumour suppressor gene [86], methods that will gain significance in the future, should also be mentioned.

1

Thomas CT, Bradshaw PT, Pollock BH et al (2003) J Clin Oncol 22:1715–1721

Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy. Expert centres in the USA accord MRI (and MRS) a decisive adjuvant role in prostate carcinoma [23, 62, 112]: in case of postoperative PSA increase, with the 3D-MRS also metabolically for the determination of localization and penetration. This enables the modification of the treatment stratification. In a retrospective analysis MRI offered a greater sensitivity (83%, PPV 50%) than DRE (33/67%) and TRUS (33/57%). MRI has an “incremental value” in extracapsular extension of the tumour. The method has, however, not yet become standard practice everywhere. The endorectal technique has promoted the imaging diagnostics of recurrences. In treatment monitoring (e.g. after cryoablation), uncertainty remains as to whether, in the absence of gadolinium enhancement, vital or avital residual tissue is present 6 months after prostatectomy [9, 29]. Lymphotropic, superparamagnetic nanoparticles are being tested for the verification of lymph node metastases when lymph nodes have achieved connection to the interstitial lymph transport. H-MRS (proton resonance spectroscopy) aims for the imaging of the transitional zone of the prostate carcinoma and 19F for metabolic studies. PET and MRI. If it can be further confirmed that (incipient) capsule perforation can be detected on time with MRI or an organ-specific process proven, an adjuvant role of PET will probably have to be researched again. In the intermodal comparison of a study limited, however, to 20 patients, 11C-choline did better (100% detection of primary tumours) than MRI and magnetic resonance spectroscopy (MRS) (60/65%) with, however, a low correlation of maximal SUV (standardized uptake value) and PSA levels [140]. Receptor PET (FDHT) and molecular in-vitro/in-vivo methods (gene PET) will probably also gain importance [80, 145]. How Can PET be Made More Precise? If we trust optimistic figures (PPV up to 98%), no further imaging diagnostics would be needed. However, the bimodal combination (PET/CT) has already shown that additions are extremely beneficial for the method. Prostate carcinoma is characterized by morphological heterogeneity, multifocality and genome instability. The future presumably belongs to different, subtype-specific metabolic markers in

6.5

keeping with individual, patient-specific decisions (Abstract [58]). The quantification by means of SUV corresponds to the lowest level. On the other hand, costly and complex methods (e.g. compartment analysis, PATLAK) are not practical on a routine basis. In metastasis diagnostics, the soft tissue sector can be assessed more subtly with PET (PET/CT) than the bone status. 18F-fluoride – described already 30 years ago – is the bone marker that has proven superior in terms of quality and safety. If one combines the advantages of multimodal procedures, specificity, sensitivity and early in-vitro diagnostics can further optimize the information potential. The combined technique (FDG/fluoride) suggested in Freiburg requires a study exploration on a multicentre basis [55] in order to evaluate the differentiability of soft tissue and juxtaposed bone metastases. Studies with 11C, 18F-labeled fluoroputrescines were inefficient [63, 82]. Several teams have opted for multimetabolic PET imaging since there are (also) tumours in prostate carcinoma that prefer, e.g. the utilization of 11C-methionine, others 18F-FDG (known as the PET-only collective) or 18Fdihydrotestosterone [80]. A study comparing multimetabolic PET with MRS would be useful. NUNEZ et al. [94] analyzed different PET metabolics, including 11C-methionine: 20% of the hormone-resistant prostate carcinomas can be classed as PET-only (FDG-positive) [141]. 18F-dihydrotestosterone (FDHT) and thymidine derivatives in androgen-(in)dependent prostate carcinomas are among the compounds undergoing initial studies. Dosimetric studies have always been a prerequisite for the clinical testing of new radiopharmaceuticals. For F-FDHT, a maximum administered activity of 331 MBq 5 cGy/(0.0151 cGy/MBq) was determined [145]. Therapeutic approaches have been researched by means of radioiodine therapy mediated by the hNIS (human sodium iodide symporter). PET Markers. 18F-FDG-PET. Owing to their short half-life, routine diagnosis with 11C-compounds (pilot studies published since 1985 [59, 88, 137]) is not possible in practices and hospitals without a cyclotron. After initial reports about FDG-PET in prostate carcinoma, also from Aachen [32, 57, 121], other groups have described FDG as being of no value [56].

Prostate Carcinoma

Relative indications for FDG-PET are:  aggressively growing prostate carcinoma–local recurrences, metastases  “far advanced stages” (Sloan Kettering Cancer Institute, New York [79]): “total lesion index” = sum of all metabolically active lesions  treatment monitoring  hormone-resistant bone metastases accumulate FDG in 20% [141]  evaluations of (anti-)androgen therapy (deprivation) [96] 1,  prognosis [97] 11C-acetate

PET. Local recurrences and lesions were detected in 83%, bone metastases in 100% (50% specificity). Primaries and N-staging are named as preferences, always subject to inclusion of a PSA rise [39, 70, 71, 95, 98]. False-positive acetate PET in case of prostatitis and hyperplasia must be taken into account. Discussions are dominated by the pros and cons of the application. 11C-choline, 18F-choline. The metabolite, phosphorylcholine, can be detected in the cells of most tumours to a markedly increased extent owing to a high choline kinase activity. This enables the tumour cell to retain choline in a trapping mechanism analogous to FDG, but with a specifically different enzyme reaction. Phosphatidylcholine is incorporated into the tumour cell membrane as a function of the duplication rate of the tumour. 11C-choline is characterized by its kinetics and relatively simple production, and displays practically no accumulation in the efferent urinary tract. De Jong et al. demonstrated [24] that 11C-choline is sensitive and accurate in the preoperative staging of the pelvic lymph nodes. An advantage of 18F-fluorocholine is, however, its longer half-life. Choline, as a partial metabolite of the phospholipid membrane metabolism, was also tested for its suitability for (other) oncological studies with PET [46, 47]. 11C-choline is accorded preference from the point of view of radiation hygiene. A high uptake in prostate carcinomas has been proven for fluoromethylcholine, also for fluoroethylcholine and 11C-choline. In the study with free 18F-fluoroethylcholine, a certain advantage in image quality was observed in comparison with 11C-choline. A 1

After androgen ablation FDG utilization in the primary tumours and metastases is suppressed

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further practical advantage is its longer half-life, whereby 11C-choline achieves high SUVs with very rapid flooding after a short time and practically does not accumulate in the bladder. For the preoperative staging of pelvic lymph nodes, a sensitivity of 80%, a specificity of 96% and a diagnostic accuracy of 93% were demonstrated for 11C-choline in 67 patients. PET analyses in 77 patients with local recurrences and elevated PSA levels correlated with negative results for conventional diagnostics. The Bologna PET/CT data yielded 39 negative and 38 positive results, pathological bone scintigrams in 13 out of 38 patients, pelvic, iliac and lumboaortal metastases in 49%, with the result that an additive value of PET/ CT was observed both in local recurrences as well as in distant metastases [35]. In Ulm all recurrences in 116 patients were detected, also in case of PSA progress after brachytherapy with 125I [90]. The PET-based evaluation of the inclusion of the prostate base into the radiation planning appears relevant for the radiotherapist. PET/CT study results with 18F-choline (presented on the occasion of the “Baseler Tagung” conference in 2005) were:  PSA levels over 6 (doubling time = PSAV) are PET-positive  Positive PET/CT is also possible with PSA values below 5 ng/ml  Prostatitis and benign prostatic hypertrophy (BPH) may yield false-positive results, for which reason other protocols also use the combination of 11C-choline and MRS. Choline can detect a slowly growing tumour in an early stage better than FDG:  Primary tumour assessment:  preoperative staging of pelvic lymph nodes with a tumour diameter of less than 1.5 cm  as a supplementary indicator to ultrasound and MRI before prostate biopsy [24, 47, 46, 69].  Problems shared by acetate and choline:  decision as to whether the prostate bed alone is defined as the target volume of the radiotherapy or is expanded to include the lymph drainage pathways  bowel activity varies between patients, not between the two tracers  lymph nodes of less than 5 mm and microscopic infestation cannot be reliably detected

 detection of osteoblastic metastases (18F-fluoride)  normal prostate and BPH, as well as prostatitis, accumulate acetate  local recurrences can be localized [14, 65, 70, 95], validated study results for the proven differentiability of prostatitis and small carcinoma are lacking. Receptor PET. PET provides insights into receptor kinetics in initial clinical experimental studies after androgen ablation. Here, as in aggressive forms of prostate carcinoma, 18F-FDHT can characterize the course of the treatment in greater detail. Data from New York show that between 4 weeks and 5 months after androgen therapy, androgen receptors (18FFDHT) show a metabolic signal of successful androgen ablation in agreement with the CT and the PSA drop [80]. Importance of PET/CT. This key technology 1 combines a dual nuclear medical radiological strategy as a replacement for the previously necessary succedaneous intermodal coregistration of PET and CT and the time-consuming manipulation of the technique of subsequent fusion. Patient throughput thus can be maximized by 25% and is made more accurately determinable, particularly if more recent navigation techniques are included. Local recurrences, lymph node infestation and bone involvement are seen as promising indications for PET/CT with 18F-fluorocholine [115]. PET/CT-based examinations  increase patient capacity  reduce false-positive and false-negative results  spare the patient the redundancy of double examinations  are less time-consuming for patient and doctor  are cost-effective Further preferences from the doctor’s point of view are:  localization of molecular malfunction  improved differentiation of borderline normal findings of intermodal imaging diagnostics  change of stage and treatment, depending on the type of cancer, in at least 20–30% 1

Bockisch A et al. (2006) PET/CT-Evolution oder Revolution in der onkologischen Diagnostik? Dtsch Ärztebl 103(5):A249–254

6.6 Germ Cell Tumours

 more precise evaluations of the treatment response  assistance of the diagnostics of primary tumours in metastases of unknown origin (CUP syndrome = cancer of unknown primary)  precise staging (in 20–30% in malignancies of the lungs, breast, large intestine)  navigation systems capable of development, planning and optimization of radiotherapy, e.g. intensity-modulated radiotherapy (IMRI)  interdisciplinary basis PET/CT interpretation – the preserve of doctors? A dispute over priorities as to who should evaluate PET/CT images is not helpful: The patient profits most if – initially independently of one another – an experienced specialist in nuclear medicine interprets the PET information, a radiology expert analyzes the CT and then both arrive at a joint consensus in assessing the PET/CT. In the interdisciplinary consultation of all doctors involved in diagnosis and treatment, the findings should be integrated into the overall design [36, 139]. Changed investment strategy. In the USA 60% of the investment for new PET apparatuses already goes into PET/CT. There are some 1,000 of these devices worldwide and 24 in Germany – new DUO/ PICO type – only few(!) equipped with multislice CT (16-liners), which are also suitable for functions at the heart; no (university) hospital in Hesse has PET/CT – an additional deficit on top of the lack of PET centres. Tasks for the future  The potential of diagnostic imaging of tumour and metastasis, particularly for prostate carcinoma, is pursued on separate levels instead of on the certainly more informative synoptic (study) basis.  The in-vitro methods of molecular biology (such as signal transduction inhibitors–EGF receptors), metalloproteinase inhibitors and angiogenesis inhibitors must be involved.  Diagnostic and therapeutic studies are to be coordinated more intensively in the context of “theranostics”, for which gene/genome/proteome research is exemplary [45].  PET and PET/CT must be classed according to stage and combined at the multicentre level in

order to update valid classification and indication schemata. Updatable criteria catalogues, e.g. those of Kent and Larson are helpful [66].

6.6

Germ Cell Tumours

Introduction Germ cell tumours are among the less important applications of PET. Despite their minimal incidence (1% of urological tumours), the diagnosis requires a particular differentiation for manifold reasons:  prevalence of young age of the persons affected  high rate of new cases in Germany  chances of healing even in metastasizing (disseminated) stages The urgency of surgical intervention in case of suspected recurrence does not necessarily rule out redundant interventions [25]. Shortcomings of tumour markers, CT and MRI in comparison with PET lie in the inability to objectify the chemotherapy monitoring and the lack of delimitation from residual-vital and avital-necrotic (fibrotic) tissue portions [138] since anatomical neoformation and posttherapeutic persistence of tumour-like lesions do not reflect the degree of residual tumour tissue that is still metabolically active. Empirically, before the PET era, bodies of experts had decided that a tumour is suspected at a size above 1.5 cm. Since the tumour size alone, however, is not an adequate characteristic, it was hoped that the immune and metabolic status would yield an information gain above and beyond tumour size. Immunoscintigraphy with 99mTc-anti-AFP, however, was not a sweeping success, and although (soft tissue) skeletal scintigraphy was–with 99mTcPYP according to anecdotal reports–focally positive in extragenital seminomas [5, 4, 48, 54], only FDG-PET yielded a real gain as a method this side of biopsy, exploratory laparotomy and histology. Preferred metastasis pathways are the para-aortal lymph nodes, in approximately 22% of seminomas also iliac and inguinal metastasis pathways, in 40% of non-seminomas, with approximately 15% displaying pulmonary metastasis.

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Epidemiology. Germ cell tumours (GCT) are diseases of young men. The predominant age for the disease is 15–35 years. The predisposing factor is undescended testes, even after corrective surgery. The prognosis depends on the stage, but the healing rate is over 90%. In about 20% of the patients metastases can be removed by means of retroperitoneal lymph node dissection. Pathogenesis. The pathogenesis was recently discussed on the basis of molecular and epigenetic considerations [118]. Even today, it has not been conclusively clarified; many factors come into consideration, primordial germ cells or spermatocytes as starting cells, chromosome aberrations, apoptosis deficiencies and p53-inactivation. The “multistage theory” has experimental foundations.

larged, and the status of recurrences and residual tumours as benign or malignant is not identifiable. The evaluation of function curves of “late enhancement” (after administration of contrast medium) and MRS sets a new emphasis. As far as surgery is concerned, an inguinal orchiectomy is performed – if possible – while the bulky disease, with encirclement of renal vessels and aortic bifurcation, is left to radiotherapy. Ga-67-citrate and, in PET studies, C-11-compounds such as tyrosine are no longer relevant for practice in case of non-seminoma tumours.

PET Study Situation 11C-compounds

Diagnosis, treatment and prognosis. This starts with tumour marker determinations, AFP and β-HCG [120] parallel to the clinical examinations and ultrasound. If all the examinations are normal, the status is defined as stage I (approximately 60–70%). However, recurrences are to be expected in some 30%. Alpha-fetoprotein (AFP; normal below 7 ng/ml) and human chorionic gonadotropin (E-HCG; normal below 5 ng/ml) are elevated possibly 100 to 1,000 times in case of metastases. Retroperitoneal metastases may present a metabolism different to that of the primary tumour. After treatment the morphological tumour burden revealed by computer tomography may be unchanged, reduced in size or – in case of metabolic inactivity – may be unapparent. Approximately 85% of non-seminoma germ cell tumours, but only about 20% of seminoma tumours, are accompanied by elevated tumour marker levels (AFP, beta-HCG, occasionally also LDH). Teratomatous primary tumours that have been verified intraoperatively make chemotherapy mandatory. A drop in the tumour markers offers after all no certainty as to the existing residual vitality of the tissue residues, and immunohistochemical studies offer no in-vivo imaging metabolic diagnostics. Patients having undergone adjuvant chemotherapy in case of vascular tumour invasion (large primary tumours or dominant embryonal carcinoma) are at risk of recurrence. Some 40% of non-seminoma testicular carcinomas are associated with retroperitoneal metastases. In computer tomography the metastasis volumes are unchanged in some cases, occasionally even en-

fail outside of classical PET centres in the allocation of (ultra-)short-lived PET nuclides. Amino acids (tyrosine) offer no proven competition [68]. In PET practice 18F-FDG remains the target molecule of choice. Compared to other PET indications, the international PET data pool is smaller, but displays noteworthy peculiarities in favour of PET. Study designs were introduced with reference to the individual stage, with hitherto unforeseeable success [25]. 18F-FDG-PET.

In a study published by a Danish research group, sensitivity, specificity and accuracy were 70, 100 and 93%, respectively. In case of smaller retroperitoneal metastases, however, a loss of sensitivity of up to 88% was observed. The NPV and PPV were 92 and 100%, respectively, in contrast to an NPV of 78% obtained with standard diagnostic procedures [70]. Of patients with non-seminoma tumours, 30% are at risk of recurrence (1 year after orchiectomy). The detectability of a PET focus depends not so much on the size of the lesion as on the extent of the glycolytic activity of the tumour cells [81]: Small retroperitoneal metastases were nevertheless detected in 88% with a general sensitivity of 70%. The specificity was 100%, the diagnostic accuracy 93% in 46 patients examined. It remains to be clarified whether the data obtained with larger patient contingents confirm this high level. The Aachen group has supplied systematic experiences [21, 22]. PET is superior to CT in the differentiation of vital tumour residues 14 days after completed chemotherapy with prior loss of PET sensitivity. Histologically different tumours respond

6.7

differently to FDG-PET. Mixed types of seminomas and teratocarcinomas remain a problem group for FDG-PET. Early tumour stages and lymph nodes were viewed as attractive targets for PET. Limitations of PET. As has already been suggested, pathobiological PET characteristics differ from one subtype of germ cell tumour to the other with the result that the value decisive for treatment as the result of PET is not always positive. This can be explained by the histological differences mentioned. It must be evaluated on the basis of the standard of the retroperitoneal lymphadenectomy whether the indicators of metastasis (angioinvasion, embryonalcarcinomatous tissue portions) relevant for CT are (ever) achieved with PET with the reliability postulated by urologists. It is regarded, also in the interest of a best possible treatment of the patient, as the most reliable approach route in non-seminoma stage-I tumours. SUV Determinations. What applies for PET applies also for the higher evaluation level of the SUV-based checks that can probably be regarded as objective orientation markers:  7 to approximately 14 (seminomas)  1–3 (teratocarcinomas, mixed types)  3.5–5 (embryonal and chorionic carcinomas) According to our knowledge, there are no sound study collectives with PET/CT as yet. Advantages/Predominant Indications for PET  Metabolic trapping [40]  The further to be evaluated differentiation by means of quantification of FDG uptake  Early stages I/II (treatable tumour foci)  Prognosis indicator (SEMPET study) 1  Treatment monitoring (residues of vital tumours)  Optimisable staging (M-status)  Long-term observation of intercurrent chemotherapy in FAD stages (far advanced disease)  Retroperitoneal lymph node infestation with inconclusive CT and MRI  Negative biopsy finding  Tumour marker rise 1

Becherer A et al. (2003) J Nucl Med Suppl 5, 174P

Penis Carcinoma

The PET impact manifests itself in the stage correction (22%) and change in treatment management.

6.7

Penis Carcinoma

Only few PET studies with figures on a casuistic level exist on the incidence of this rare tumour: PET examinations were performed in 13 patients with suspected primary carcinomas or recurrences. PET was correct-positive in 6 out of 8 (75%), and falsepositive in 1 out of 13. Given the high sensitivity/ specificity (94/100%) and a similarly small sample size of the results analyzed by PET/CT, the quality of the data cannot be seriously discussed [51, 46a, 113].

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6.8

Case Studies

Patient 1 Malignoma of the Base of the Bladder Clinical history: A 69-year-old male status post anterior rectal resection and regional lymphadenectomy 3 years ago due to a tubulopapillary adenocarcinoma in the rectosigmoidal transition. A bladder tumour was diagnosed 1 year later. Pain in the right groin and the right testicle. Prostate hypertrophy. PET/CT indication: Tumour staging of the bladder tumour with PET/CT as well as propagation diagnosis and metastatic spread.

Findings: A 3.7 × 4.5 × 3.1-cm-large tumour on the left base of the bladder with glucose metabolic activity consistent with malignancy. Two other small tumours were found on the right lateral and dorsal bladder base wall with glucose utilization consistent with malignancy. Unsuspicious pattern in the anastomosis area of the resected carcinoma in the rectosigmoidal transition. No other evidence for distant metastases. Teaching points: In spite of the concurrent increased uptake of the activity eliminated via the urogenital system, the increased uptake in the carcinomas can be readily delineated.

Fig. 6.1.1. MIP as well as transaxial, sagittal and coronal slices on which a larger tracer accumulating area can be delineated in the area of the base of the bladder and further minor activity accumulation indicated by the MIP projection

6.8 Case Studies

Fig. 6.1.2. Transaxial PET/CT slice showing the activity in the larger tumour in the area of the base of the urinary bladder and of another small tumour dorsally

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Patient 2 Malignoma of the Posterior Wall of the Bladder Clinical history: A 76-year-old male status post GIST of the stomach with en-bloc resection of the tumour and the posterior stomach wall. Status post prostate surgery approximately 2 years ago. PET/CT indication: Evidence for residual tumour or metastatic spread in the whole body? Findings: Focus in the area of the posterior wall of the urinary bladder consistent with malignancy, close to the ostium on the right side as an incidental finding consistent with malignancy. No evidence for recurrence with regard to the GIST tumour. Teaching points: The whole-body scan incidentally detected a urinary bladder malignoma.

Fig. 6.2.1. Non-corrected PET images in all three slice planes and in the MIP image. A markedly increased uptake in the area of the posterior wall of the uninary bladder is readily visible

6.8 Case Studies

Fig. 6.2.2. Corrected PET/CT images in all three slice planes and in the MIP image showing increased uptake consistent with malignancy in the area of the posterior wall of the urinary bladder

Fig. 6.2.3. Transaxial slice showing the extent of the malignoma in the area of the urinary bladder

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Patient 3 Metastasis in the Suprarenal Gland on the Left Side Clinical history: A 66-year-old male with squamous cell carcinoma of the left main bronchus with telectasis of the entire left lobe associated with pleural effusion. PET/CT indication: Tumour staging for further therapy planning. Findings: Markedly increased uptake of the bronchial carcinoma in the completely collapsed left lung lobe with further increased uptake in the area of

atelectasis. Metabolic activity consistent with malignancy in the lower left abdominal region along the descending colon. Metastatic involvement of the left suprarenal gland. Bone metastasis in the T2 vertebral body. Teaching points: The patient exhibited metastatic involvement of the left suprarenal gland, which is often detected in patients with bronchial carcinoma. CT only shows moderate dilatation, whereas PET detects markedly increased uptake. The whole-body scan is able to perform staging and to detect the metastasis in the subrenal gland with a single examination.

Fig. 6.3.1. Series of PET slices with marked left bronchial carcinoma. Furthermore, PET detects a mild, diffuse increased uptake in the left lung

6.8 Case Studies

Fig. 6.3.2. Series of coronal PET/CT slices showing the bronchial carcinoma as well as a diffuse increased uptake in the pleura carcinomatous lymphangiosis

Fig. 6.3.3. Transaxial PET/CT slice showing a metastasis in the left suprarenal gland

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Patient 4 Metastasis in the Suprarenal Gland on the Right Side Clinical history: A 71-year-old male status post adenocarcinoma of the rectosigmoidal transition with extended anterior rectum-sigma resection, anastonomosis 17 cm from the anus. Adjuvant chemotherapy. Resection of a pulmonary metastasis in segment III on the right side. Eight chemotherapy cycles. Six months after surgical intervention, increase of the CEA values up to 6 ng/ml at present. PET/CT indication: Restaging. Is there any evidence for recurrent tumour or metastases, respectively, revealed by the whole-body scan?

Findings: Detection of a tumour of the right suprarenal gland with glucose metabolic activity consistent with malignancy sized 4.6 × 5.0 × 4.7 cm, which probably mainly indicates metastatic spread with status post-colorectal carcinoma. No other tumouror metastasis-suspicious foci. Teaching points: The PET/CT whole body scan is able to detect a so far unknown metastasis in the right suprarenal gland and to exclude the presence of another metastasis, which should be decisive for further therapy [see Metser U et al. (2006) J Nucl Med 47:32–37].

Fig. 6.4.1. Series of coronal PET slices that clearly show an increased uptake in the right abdominal region as projection onto the suprarenal gland region

6.8 Case Studies

Fig. 6.4.2. The MIP image as well as the transaxial, sagittal and coronal slice show a left suprarenal gland tumour that is readily visible both morphologically due to a considerably increased suprarenal gland and on the PET image showing markedly increased glucose metabolic activity

 Fig. 6.4.3. Series of coronal PET/CT slices showing a metastasis in the right suprarenal gland

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Fig. 6.4.4. Late enhancement image as transaxial PET/CT slice showing a metastasis in the right suprarenal gland: multifocal FDG-avid foci, central and multiple marginal ametabolic regions (avital tumour necroses)

6.8 Case Studies

Patient 5 Metastasized Renal Cell Carcinoma Clinical history: A 75-year-old male status post tumour nephrectomy on the right side due to a renal cell carcinoma. Status post deep resection of the rectosigmoid 5 years later due to malign polyps. Status post hemithyroidectomy on the left side and resection of the thrombosed jugular vein due to an intrathyroidal metastasis of the renal cell carcinoma another 12 months later. At present, a new cervical metastasis was detected that infi ltrates into the pharynx, the base of the tongue, the larynx and the entrance of the oesophagus. A resective surgical intervention is planned. Findings: The known large cervical metastasis exhibited a glucose metabolic activity consistent with

malignancy with the highest uptake found in the medial tumour area adjoining the larynx region. Furthermore, it must be assumed that four metastases are present in the area of the right niche of the kidney and beside this area. Furthermore, there is another area consistent with malignancy in the area of the upper splenic pole more laterally on the left side, which is classified as a spleen metastasis. Teaching points: In addition to the already known large cervical metastasis, the whole-body PET/CT scan detected a multilocular metastatic spread in the area of the right niche of the kidney. Furthermore, a so far unknown spleen metastasis was detected. The advantage of the whole-body examination technique is particularly highlighted in this case.

 Fig. 6.5.1. PET/CT detects a left cervical metastasis in all three slice planes and in the MIP image

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Fig. 6.5.2. Metastasis in the right niche of the kidney shown on the early enhancement image, with clear increase in metabolic activity in the late enhancement image, indicating metabolic activity consistent with malignancy

6.8 Case Studies

Patient 6 Restaging after Chemotherapy Clinical history: A 76-year-old female status post anterior resection of a rectum carcinoma. Left hemihepatectomy due to solitary liver metastasis as well as simultaneous cholecystectomy and revision of the bile ducts due to cholescystitis. Last chemotherapy cycle completed right before the examination. PET/CT indication: Restaging after chemotherapy.

Findings: The lesion regressed considerably during chemotherapy with regard to both size and metabolic activity in the area of the above-mentioned lung metastasis, the lymph node metastasis at the level of the celiac artery and the suprarenal gland metastasis on the left side. No evidence for new organ or lymph node metastases. Teaching points: PET/CT is well suited for evaluating the therapy progress during chemotherapy.

 Fig. 6.6.1. Scan prior to chemotherapy: Lung metastasis, metastasis at the level of the celiac artery and metastasis in the left suprarenal gland in all three slice planes and in the MIP image

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Fig. 6.6.2. Lymph node metastasis at the level of the celiac artery after therapy. Here, clearly reduced metabolic activity with an SUV value inconsistent with malignancy (therapy effect)

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Fig. 6.6.3a,b. Metastasis in the left suprarenal gland, a prior to therapy, b after therapy on a transaxial PET/CT slice. This example documents the reduction in size of the tumour and the reduction of the metabolic activity under therapy

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Fig. 6.6.4a,b. Metastasis in the left lung a prior to and b after therapy. A significant reduction of the metabolic activity and a discernible reduction in size are also visible here

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Patient 7 Restaging after Tumour Nephrectomy Clinical history: A 67-year-old male status post right tumour nephrectomy due to carcinoma. Five years later partial nephrectomy due to left-sided kidney tumour. In addition, partial pancreatectomy as well as splenectomy. Secondary healing. One year later suspicion of recurrent tumour of the left kidney as well as evidence for lymph nodes and a suprarenal gland metastasis. The suspicion of recurrent tumour of the left kidney was initially not confirmed. In addition, lymphadenectomy, removal of 13 lymph nodes that were tumour-free. PET/CT indication: Can PET/CT detect tumour activity in the enlarged paraaortal lymph node and in the left suprarenal gland tumour? Tumour propagation? Further metastases?

Findings: Small subcapsular recurrent tumour in the area of the ventrolateral portions of the remaining kidney on the left side. Furthermore, locoregional paraaortal lymph node fi liae as well as suprarenal gland metastasis, always with evident glucose metabolic activity consistent with malignancy. Teaching points: PET/CT unequivocally classifies the suspicious region in the area of the remaining kidney on the left side as a recurrent malignoma. Furthermore, there was evaluation of the lymph node metastasis and suprarenal gland metastasis as malignomas.

Fig. 6.7.1. A round focus of increased uptake consistent with malignancy is revealed in the subcapsular area of the remaining left kidney

Fig. 6.7.2. The series of late enhancement images shows increased uptake in the area of the remaining left kidney

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Fig. 6.7.3. Left-sided paraaortal left lymph in a transaxial PET/ CT slice

Fig. 6.7.4. Transaxial PET/CT slice showing a metastasis in the suprarenal gland with increased glucose metabolic activity consistent with malignancy

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Patient 8 Recurrence after Tumour Nephrectomy Clinical history: A 62-year-old male status post right tumour nephrectomy followed by radiotherapy. Further multiple surgical interventions with removal of metastases, lymph node dissection, middle lobe resection, suprarenal gland resection. Three years after surgery revision due to recurrent tumour in the right retroperitoneal space, tumour excision as well as splenectomy. The last CT scan performed 2 years later revealed progressive loculation as well as border enhancement and solid parts in the border area of the upper pole of the left kidney. Surgical exploration without sufficient mobilizability of the recurrent tumour. PET/CT indication: Propagation diagnosis. Infi ltration into neighbouring areas? Distant metastases?

Findings: Glucose metabolic activity consistent with malignancy in the area of the retroperitoneal recurrent tumour in the left epigastric region and in the area of the capsule of a postoperative residual hematoseroma. Unequivocal tumour infi ltration into the left crus of the diaphragm seems rather improbable because neither glucose metabolism nor pleural effusion could be observed. Further tumours could not be localized. Teaching points: PET/CT could delineate the recurrent tumour in the left epigastric region in the area of the capsule of the postoperative residual hematoseroma. The following resection confirmed the PET findings so that the patient could be curatively operated.

Fig. 6.8.1. Recurrent tumour in all three slice planes and in the MIP projection. The slice clearly depicts a tumour superposed to the kidney with metabolic activity particularly in its border areas

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Fig. 6.8.2. Series of transaxial PET/CT slices showing the recurrent tumour. These slices also clearly depict the concentration of metabolic activity in the border regions

Fig. 6.8.3. Single transaxial PET/CT slice depicting the extent of the recurrent tumour

Fig. 6.8.4. Coronal PET/CT slice showing the recurrent tumour superposed onto the left kidney

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Patient 9 Metastasized Prostate Carcinoma Clinical history: A 50-year-old male with newly detected proven prostate carcinoma. PET/CT indication: Does the whole-body scan reveal evidence for metastatic spread? Findings: Proven glucose metabolic activity consistent with malignancy in the area of the prostate with focal accentuation on the left side. Furthermore, slightly increased tracer uptake in the area of the left ischium indicates beginning metastatic spread into the bone. No further evidence of metabolic activity consistent with malignancy. Teaching points: Although glucose markers are more and more supplanted by radiolabeled choline or acetate markers for prostate examinations, glucose markers may be useful for staging prostate carcinoma. An interesting aspect of this case is the marked representation of the carcinoma in the area of the prostate and in the area of the left ischium. Fig. 6.9.1. Increased uptake in the area of the left prostate lobe in the three slice planes and in the MIP image

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Fig. 6.9.2. Transaxial PET/ CT slice with marked glucose metabolic activity consistent with malignancy in the left prostate lobe

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Fig. 6.9.3a,b. Round focus of decently increased uptake in the left ischium indicating beginning metastatic spread in the sagittal and transaxial PET/CT slice

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Patient 10 Metastasized Prostate Carcinoma Clinical history: A 60-year-old male status post radical prostatovesiculectomy as well as lymph node dissection. Casodex therapy. The skeleton scintigram shows increased uptake in the area of the ninth right dorsal rib, which is suspicious for metastases. Eight months later suspicious presacral mass detected during a PET pre-examination. No evidence for lymphoma in supplementary CT and MRI examinations, no rise in PSA. PET/CT indication: Verification of the presacral mass as well as propagation diagnosis.

Findings: Glucose metabolic activity consistent with malignancy in the minor pelvis presacrally, projecting onto the rectosigmoidal transition. Further diagnosis by colonoscopy is recommended. Detection of osseous metastases in the ventral portion of the T9 vertebral body, no fracture hazard. Teaching points: Incidental finding of a malignoma in the rectosigmoidal transition classified as a secondary tumour as well as detection of a bone metastasis in the T9 vertebral body.

Fig. 6.10.1. Tumour-suspicious increased uptake is shown in the three slice planes and in the MIP image in the area of the presacral rectosigmoidal transition

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Fig. 6.10.2. Tumour in the area of the presacral restosigmoidal transition

Fig. 6.10.3. Sagittal PET/CT slice in the bone window with regionally increased bone metabolism indicating a bone metastasis

Fig. 6.10.4. Bone metastasis in the transaxial slice, left-accentuated in the ventral region

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Patient 11 Restaging of a Prostate Carcinoma Clinical history: A 81-year-old male with a history of a histology-proven prostate carcinoma. No glucose metabolic activity consistent with malignancy found during a pre-examination performed as a whole-body PET/CT scan and particularly in the area of the prostate. Therapy with Casodex and Zometa with PSA levels ranging from 0.1 to 0.3. Therapy was stopped due to side effects such as gynecomasty, hyperhydrosis and bad general state of health shortly after the PET/CT scan was completed. Two months later increase in PSA level up to 1.5. MRI diagnosed an capsular invasion on the left side of the prostate. PET/CT indication: Restaging of the prostate and the whole body.

Findings: Glucose metabolic activity consistent with malignancy in the area of the left prostate, which was not detected as such during the pre-examination and corresponds to the capsular invasion diagnosed by MRI. No further evidence for metastases. Teaching points: PET/CT is suited for follow-up observation of malignomas; particularly rising tumour marker levels or PSA levels, respectively, can be taken into account.

Fig. 6.11.1. Series of coronal PET/CT slices showing a circumscribed increased uptake consistent with malignancy projected onto the left prostate lobe

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Fig. 6.11.2. Transaxial PET/CT slice showing tumour 12 mm in diameter in the left prostate lobe with increased metabolic activity consistent with malignancy

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Patient 12 Lymph Node Metastasis of a Prostate Carcinoma Clinical history: A 73-year-old male status post prostate carcinoma following radical prostatectomy pT3, G3, NO. Seven years later rapid rise in PSA from 0.9 to 8.09 ng/ml. Metastasis T5/6 vertebral bodies – rather due to degenerative changes according to CT. Decrease in PSA level under Zoladex therapy down to 0.1 ng/ml. Another 5 years later again increase in PSA level up to 4.1 ng/ml. In addition to Zoladex therapy, also Casodex and mistletoe therapy. At present the PSA level is 1.3 ng/ml. PET/CT indication: Evidence for recurrent tumour or metastatic spread especially in the area of the right upper abdominal region due to complaints.

Findings: Detection of a glucose metabolic activity consistent with malignancy in the area of the T5 vertebral body with only minor CT correlation, indicating a fracture hazard. Furthermore, glucose metabolic activity consistent with malignancy with a lymphoma in the area of the minor pelvis on the right side. Further focal lesions typical of metastasis were not detected, particularly no detection of liver metastases. Teaching points: In spite of the just moderately high PSA level of 1.3 ng/ml, a lesion could be detected in the T5 vertebral body and in a lymph node.

Fig. 6.12.1. Coronal PET/CT slice showing a lymph node with changes consistent with malignancy in the minor pelvis on the right side

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Fig. 6.12.2. The same lymph node in the minor pelvis on the right side in a transaxial PET/ CT slice

Fig. 6.12.3. Bone metastasis in the transaxial PET/CT slice (in the bone window) in the area of the T5 vertebral body

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Patient 13 First Diagnosis of a Prostate Carcinoma Clinical history: A 65-year-old male with suspected prostate carcinoma with a rise in PSA level from 3.5 approximately 2 years ago to 9.0 today. Several biopsies performed during this period were negative. PET/CT indication: Can a focus consistent with malignancy be detected in the prostate or in the whole body by means of choline PET/CT? Findings: Metabolic activity consistent with malignancy in the area of the right anterior prostatic lobe. No other evidence for further neoplastic activity in the whole body. Teaching points: PET/CT using choline-based tracers is able to localize a hypermetabolic focus in the right prostatic lobe that could later be verified by biopsy.

Fig. 6.13.1. Sagittal PET/CT slice showing a focus in the prostate with significantly increased SUV

Fig. 6.13.2. Series of transaxial PET/CT slices showing a right-sided prostate focus with its maximum in the right anterior region

6.8 Case Studies

Patient 14 Restaging of a Prostate Carcinoma Clinical history: A 71-year-old male status post prostate carcinoma after prostatectomy (PSA 9.2 at that time) as well as orchyectomy. Three years later PSA level 3.05 ng/ml. Radiation therapy with 70 Gy. Then decrease in PSA level. At present, again increase in PSA to 14.2. CT of the abdomen was suspicious of a local recurrence. PET/CT indication: PET/CT with choline-based tracers for further therapy planning, whereby it should be clarified whether there is only a recurrent tumour or general metastatic spread. Findings: Detection of multifocal metabolic activity consistent with malignancy in the area of multiple osseous lesions as correlation for the present rise in PSA. Furthermore, retroperitoneal lymph node metastases. Further organ or lymph node metastases could not be detected. Teaching points: PET/CT with choline-based tracers is able to detect osseous metastatic spread as well as lymph node metastases. A recurrent tumour in the area of the prostate bed cannot be detected. Fig. 6.14.1. Sagittal PET/CT slice with multiple bone metastases in the area of the cervical spine, the thoracic spine and the upper lumbar spine in the area of the vertebral bodies and in the area of one vertebral arch



Fig. 6.14.2. Transaxial PET/CT slice in the bone window with isolated bone involvement in the right hip joint

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Fig. 6.14.3. Series of transaxial PET/CT slices with multilocular lymph node involvement, particularly in the paraaortal region

Fig. 6.14.4. Isolated lymph node involvement in the minor pelvis on the right side

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Patient 15 Restaging of a Prostate Carcinoma Clinical history: A 77-year-old male status post prostate carcinoma receiving hormone therapy with Trenantone, Turisteron and Casodex. Seven years later, supplementary ambulant radiotherapy due to rising PSA. Decrease of the PSA value from 9.0 to 2.56. At present, re-increase in PSA level up to 13.0. PET/CT indication: Search for metastases.

Findings: Regression of metabolic activity consistent with malignancy in the area of the prostate and the prostate bed. However, intensive metastatic spread into the retroperitoneal, paraaortal and paracaval lymph nodes as well as along the iliac vessels could be detected. No evidence of metastatic spread to the organs detected in the whole-body scan. Teaching points: Choline PET/CT is able to stage metastatic spread reliably. Furthermore, reduction in metabolic activity in the area of the prostate, i.e. regression of the primary tumour, can be proven.

 Fig. 6.15.1a,b. Transaxial slice depicting a multilocular manifestation of lymphomas in the area of the vena cava, but also in the paraaortal region and underneath the hilum of the kidney c,d

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Fig. 6.15.1a–d. Transaxial slice depicting a multilocular manifestation of lymphomas in the area of the vena cava, but also in the paraaortal region and underneath the hilum of the kidney

6.8 Case Studies

Patient 16 Therapy Control for Metastatized Prostate Carcinoma Clinical history: A 56-year-old male with metastatic spread of prostate carcinoma into the bones and lymph nodes. Status post radical prostatectomy followed by hormone therapy (Flutamid). Two years later, osseous metastatic spread as well as extensive spread into the cervical and retroperitoneal lymph nodes. Administration of bicalutamide combined with bisphosphonate therapy. With this treatment regression of metastases, decrease of the PSA value. Discrete increase in PSA level as well as new biopsy specimen from the area of the operation scar with verification of a local recurrence. PET/CT indication: Propagation diagnosis. Metastatic spread? Findings: Choline metabolism consistent with malignancy in the area of a focal local recurrence of

the prostate carcinoma bulging towards the posterior wall of the bladder and resembling a pine cone in shape. Furthermore, metabolic activity consistent with malignancy in the area of cervical lymphomas. In addition, extended lymphomas in the right mediastinal, pretracheal area as well as the left paratracheal space, confluent in this area. Metabolic activity consistent with malignancy also in the area of retroperitoneal lymphomas with bundle-like structure. Diffuse osseous metastatic spread, particularly in the spine of the C7 vertebral body and in the T2 vertebral body. Increased accumulation of contrast medium consistent with malignancy in the area of the pelvic skeleton. Furthermore, metabolic activity consistent with malignancy in the right ischium and the right proximal femur. Teaching points: Choline PET/CT allows wholebody restaging of the prostate carcinoma with a single scan.



Fig. 6.16.1. Marked local recurrence in the area of the operated prostate bed. A bone metastasis is also revealed in the area of the pubis and the right ischium in the transaxial PET/CT slice and bone window

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Fig. 6.16.2. Isolated metastasis in the spine of the C7 vertebral body in the transaxial PET/CT slice and the bone window

Fig. 6.16.3. Marked bone metastasis in the T2 vertebral body more pronounced on the right side as well as one smaller metastasis more pronounced on the left side shown on the transaxial slice and the bone window of the CT parameters

Fig. 6.16.4. Bone marrow metastasis in the proximal right femur

6.8 Case Studies

Patient 17 Staging of a Prostate Carcinoma Clinical history: A 65-year-old male first diagnosed with prostate carcinoma with suspicion of an isolated bone metastasis in the T12 vertebral body. Bone metastasis diagnosed within the scope of the primary diagnosis 5 years ago could not be detected any more. Last tumour staging without any evidence of skeletal metastases. However, suspicion of tumour growth extending beyond the capsule and beginning infi ltration in the urinary bladder. Therapy at present: Trenantone as well as Zometa. PET/CT indication: Do we have to deal with a locally delimited prostate carcinoma? Can pelvic or paraaortal lymph node metastasis be detected? Evidence of osseous metastases?

Findings: Multifocal choline metabolism consistent with malignancy in the area of the prostate, but no evidence of tumour growth extending beyond the capsule. No detection of seminal vesicle infi ltration. Furthermore, no proof of locoregional lymph node metastases and retroperitoneal lymphomas. Bone metastasis in the T12 vertebral body. Teaching points: Choline PET/CT is useful to evaluate the prostate situation with exclusion of locoregional lymph nodes and, with the same scan, to evaluate the skeletal system with detection of an isolated metastasis in the T12 vertebral body.

 Fig. 6.17.1. Transaxial PET/CT slice through the prostate region reveals two foci consistent with malignancy

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Fig. 6.17.2. Series of transaxial PET/CT slices showing multilocular increased uptake in the area of the prostate

Fig. 6.17.3. Sagittal PET/CT slice in the bone window showing an isolated circumscribed metastasis in the T12 vertebral body

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Patient 18 Local Recurrence of a Prostate Carcinoma Clinical history: A 65-year-old male status post anterior resection of a sigma carcinoma. Six months later, status post left tumour nephrectomy due to a bifocal clear cell renal cell carcinoma. Then radiotherapy for 3 months due to a biopsy-proven prostate carcinoma. Laparascopic lymphadenectomy. Six months later increase in PSA. PET/CT indication: Is there any evidence of a local recurrence or metastatic spread, respectively? Findings: Detection of a small local recurrence in the area of the left prostate lobe. In addition, exclusion of further lesions or metastatic spread. Teaching points: The tumour recurrence, which is responsible for the PSA rise, is found in the left prostate lobe by F18 choline PET/CT.

Fig. 6.18.1. Image of a circumscribed lesion in the left prostate lobe indicating a recurrent tumour

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Patient 19 Lymph Node Metastasis of a Prostate Carcinoma Clinical history: A 72-year-old male with histologically proven prostate carcinoma (medium-differentiated glandular adenocarcinoma). After histological verification of the diagnosis, pelvic lymphadenectomy, temporary anti-androgenic therapy. Prostate bed radiotherapy with 63 Gy. At present, biochemical recurrence with increase in PSA level to 3.6 ng/ ml.

PET/CT indication: Is there any evidence of a local recurrence? Metastatic spread? Findings: Choline accumulation consistent with malignancy in lymph nodes of the iliac internal and external as well as obturatory lymph node chain on the right side. No evidence of a local recurrent tumour in the area of the prostate bed. Teaching points: F-18 choline PET/CT is able to detect affected lymph nodes and thus to clarify the causes of the PSA increase. Exclusion of a local recurrence.

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Fig. 6.19.1a–c. Transaxial, coronal as well as sagittal PET/CT slices show lymph node involvement in the right pelvis

6.8 Case Studies

Patient 20 Lymph Node Metastases of a Prostate Carcinoma Clinical history: A 72-year-old male status post adenocarcinoma of the prostate with radical prostatectomy and pelvic lymphadenectomy on both sides 15 years ago. Now continuous rise in PSA level up to 0.92 ng/ml at present. Continued Casodex therapy. Status post stent-graft placement in an infrarenal aortic aneurysm (stent aortobiiliacal).

Findings: No evidence of a local recurrence, however detection of metabolic activity consistent with malignancy in the area of paraaortic and retroaortic lymphomas at the level of the abdominal aorta. Secondary finding: Imaging of the stent placed in the area of the infrarenal aortic aneurysm. Teaching points: PET/CT is able to detect paraaortic and retroaortic lymphomas at the level of the distal abdominal aorta.

Fig. 6.20.1. Retroaortal lymphoma on the left side. Secondary fi ndings: image of stent-graft placed due to an aortic aneurysm

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Patient 21 First Diagnosis of a Prostate Carcinoma Clinical history: Continuous increase in PSA level recently up to 16.4 ng/ml with known prostate hyperplasy. Findings: Detection of bifocal metabolic activity consistent with malignancy, accentuated in the left and less intense in the right basal prostate lobe. No evidence of locoregional lymph nodes metastases. Teaching points: Imaging showed accumulations consistent with malignancy in the prostate with F18 choline and exclusion of further spread, indicating lymphomas or bone metastases (Fig. 6.21.1).

Fig. 6.21.1. Transaxial PET/CT slice showing a large focus in the left prostate lobe and slightly increased uptake in the right prostate lobe

6.8 Case Studies

Patient 22 Prostatitis Clinical history: A 57-year-old male with fluctuating, slightly increased PSA levels ranging from 4.3 ng/ml to 4.6 ng/ml. Fine-needle biopsy ruled out pathological findings. PET/CT indication: Can additional tracer accumulations consistent with malignancy be found in the area of the prostate and in other areas?

Fig. 6.22.1. Transaxial PET/ CT slice with diffuse, moderately increased uptake in both prostate lobes

Fig. 6.22.1. The late enhancement image also shows an essentially diffuse uptake without any evidence of malignant growth

Findings: No evidence of metabolic activity consistent with malignancy in the area of the prostate and the prostate-related lymph drain paths. However, there is a diffuse accumulation of radioactivity in the area of the prostate, which may indicate prostatitis. Teaching points: F18 choline PET/CT is able to exclude focal accumulation of radioactivity consistent with malignancy in the prostate area and in the neighbouring tissue.

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Patient 23 Prostatitis Clinical history: A 70-year-old male with known benign prostate hyperplasy with progressive micturition difficulties. Fluctuating PSA levels, finally increasing up to 15.9. Several biopsies did not reveal any evidence of malignancy. PET/CT indication: Can evidence of malignancy be revealed in the area of the prostate or in other areas?

Findings: PET/CT does not reveal any evidence of metabolic activity consistent with malignancy in the area of the prostate and the prostate-related lymph drain paths. There is a moderate, diffuse accumulation of radioactivity in the area of the prostate, which is consistent with prostatitis. Teaching points: Exclusion of an accumulation consistent with malignancy by means of F18 choline PET/ CT in the whole body and in the area of the prostate.

Fig. 6.23.2. Transaxial PET/ CT slice with diffuse increased uptake

Fig. 6.23.1. Series of transaxial PET/CT slices showing a diffuse, moderately increased tracer uptake in the prostate

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Patient 24 Prostatitis Clinical history: A 61-year-old male status post urethroplasty 25 years ago due to urethral stenosis. First increase in PSA level 6 months ago. Biopsy ruled out pathological findings. Increase in PSA level up to 15.0 ng/ml as a result of prostatitis. At present the PSA level amounts to 4.5 ng/ml. PET/CT indication: Evaluation of the metabolic situation by means of F18 choline PET/CT prior to a new biopsy. Findings: No evidence of metabolic activity suspicious for or consistent with malignancy. The almost homogeneous accumulation in the prostate area presumably indicates prostatitis. Teaching points: Exclusion of hypermetabolic activity typical of prostate cancer by means of F18 choline PET/CT.



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b Fig. 6.24a,b. Early and late enhancement image of increased choline uptake in the area of the prostate. Neither the early nor the late enhancement image show foci of increased uptake

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Patient 25 Restaging of a Prostate Carcinoma Clinical history: A 65-year-old male with prostate carcinoma proven for 7 years. Histology revealed a highly differentiated light-cell adenocarcinoma with an initial PSA level of 11.3 ng/ml. Then four times TUR-laser resection of the prostate resulting in a decrease in PSA level to 3.2 ng/ml 7 years ago. Then antihormone therapy resulted in a further decrease in PSA level. Since then, again an increase in PSA level, which was counteracted by laser therapy and again by antihormone therapy. At present, considerable increase in PSA level up to 14.68 ng/ml.

This examination is intended to clarify propagation diagnosis, taking into account the unsuspicious skeleton scintigram. Findings: Metastatic spread into the paraaortal and paracaval lymph nodes at the level of the L2 vertebral body and medial to the psoas at the level of the L2 and S1 vertebral body.  No evidence of local recurrence.  No evidence of bone metastases. Teaching point: Safe exclusion was made of a local recurrence and localization of the lymph node metastases with whole-body PET/CT.



Fig. 6.25.1. Known prostate carcinoma for 7 years, lymph node metastasis ventrally to the right psoas

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Fig. 6.25.2. Known prostate carcinoma for 7 years, lymph node metastasis in the right paracaval area

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Patient 26 First Diagnosis of a Prostate Carcinoma Clinical history: A 66-year-old male with PSA levels increasing from 3.0 to 10.3 ng/ml over the past 1½ years. Two punch biopsies did not reveal the presence of a prostate carcinoma. Decrease in PSA level to 2.3–3.0 ng/ml after antibiotic therapy, then another increase. This PET/CT scan is intended to answer the differential diagnostic question whether the patient suffers from prostate carcinoma or prostatitis. Findings: Choline PET/CT reveals metabolic criteria indicating the presence of a prostate carcinoma in the craniodorsal region of the left prostatic lobe, with a focus sized 1.0×2.0 cm. Teaching point: In a given case, PET/CT can be used for primary diagnosis if the punch biopsy was not successful.

Fig. 6.26.1. First diagnosis of prostate carcinoma in the left prostatic lobe

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Patient 27 Response Evaluation of a Prostate Carcinoma Clinical history: A 56-year-old male with biopsyproven prostate carcinoma 1 year ago with a PSA level of 24.8 ng/ml. Decrease in PSA level to 0.47 ng/ml due to chemotherapy administered until 9 months ago. Now another increase in PSA level up to 15.28 ng/ml. Computed tomography detects multiple osteoplastic bone metastases. Then therapy with Casodex and Zometa. Therapy led to a decrease in PSA value to 0.67 ng/ml. This examination is intended to evaluate the metabolic activity locally and in the whole body.

Findings: A metabolically active focus with an SUV of 7.1 is detected in the area of the right prostate lobe (with known prostate carcinoma) in spite of the therapeutic efforts. However, no evidence of metabolic activity in the metastases in the whole skeleton region and particularly in the area of the T12 vertebral body, which is most affected according to the CT. Teaching point: The metabolic response of the prostate carcinoma and its metastases can be well evaluated.

Fig. 6.27.1. Detection of significantly increased choline uptake in the prostate

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6.9 References 1. Albertsen PC, Hanley JA, Fine J et al (2005) Twenty-year outcomes following conservative management of clinically localized prostate cancer. J Am Med Ass (JAMA) 293:2095–2101 2. Bander NH, Trabulsi EJ, Kostakoglu L et al (2003) Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J Urol 170:1717–1721 3. Bastian PJ, Waha A, Müller StC, von Rücker A (2004) Epigenetische Veränderungen in der Karzinogenese des Prostatakarzinoms. Dtsch Ärztebl 101:A1981–1985 4. Baum RP, Hertel A, Baew-Christow T et al (1991) First clinical results with a Tc-99m labeled monoclonal anti-AFP antibody in germ cell and liver tumours (FP-2G3-5). Eur J Nucl Med 18:535 5. Baum RP, Hertel A, Baew-Christow T, Boeckmann W, Hör G, Goldenberg DM (1991) Initial clinical results with a Tc-99m labeled anti-AFP monoclonal antibody fragment in germ cell and liver tumours (Abstr. 613 ). J Nucl Med 32:1053 6. Baum RP, Hör G (1996) Renal tumour imaging. In: Pabst HW, Adam WE, Hör G, Kriegel H, Schwaiger M (eds) Handbook of nuclear medicine. Gustav Fischer, Stuttgart, pp 180–190 7. Beheshdi M, Vali R, Langsteger W (2007) 18F-fluorocholine PET/CT in the assessment of bone metastases in prostate cancer (Letter to the editor) Eur J Nucl Med Mol Imaging 34:1316–17 8. Belitsky PH, Ghose T, Aquino J, Tai J (1978) Radionuclide imaging of renal cell carcinoma by 131-labeled antitumour antibody. Radiology 126:515 9. Beyersdorff D, Taupitz M, Winkelmann B et al (2002) Patients with a history of elevated prostate-specific antigen levels and negative transrectal US-guided quadrant or sextant biopsy results: Value of MR imaging. Radiology 224:701–706 10. Blumstein NM, Finsterbusch FM, Penner S et al (2005) Präoperative C-11- Cholin-PET/CT der Prostata und histopathologische 3-D-Korrelation. Nuklearmedizin 44:V85 11. Blumstein NM, Reske SN (2004) PET/CT zur Diagnostik des Prostatakarzinomes. Der Nuklearmediziner 27:304–314 12. Bottke D, Wiegel Th, Müller M et al (2004) Strahlentherapie nach radikaler Prostatektomie (Vorgehen bei PSAAnstieg oder -Persistenz ohne histologische Sicherung eines Lokalrezidivs). Dtsch Ärztebl 101:A2255–2259 13. Bourguet P, Group de Travail SOR (2003) Standards, options and recommendations for the use of PET-FDG in cancerology. Results in urologic cancers. Bull Cancer 90:S80–87 14. Breeuwsma AJ, Pruim J, Jongen MM et al (2005) In vivo uptake of 11C-cholin does not correlate with cell proliferation in human prostate cancer. Eur J Nucl Med Mol Imaging 32:668–673 15. Breul J, Zimmermann F, Dettmar P, Paul R (2003) Prostatakarzinom/Manual urogenitale Tumoren. Zuckschwerdt, Munich, pp 1–42

References

16. Bruwer G, Heyns CF, Allen FJ (1999) Influence of local tumour stage and grade on reliability of serum prostate-specific antigen in predicting skeletal metastases in patients with adenocarcinoma of the prostate. Eur Urol 35:223–227 17. Burkhard FC, Bader P, Fischer B et al (2000) Who needs lymph node dissection as a staging procedure in prostate cancer? J Urol 163:190 18. Chae EJ, Kim JK, Bae SJ, Cho K (2005) Renal cell carcinoma: Analysis of postoperative recurrence patterns. Radiology 234:189–196 19. Choudhri AH, Patel PR, Cunningham DA (1987) Uptake of 99mTc-DTPA by a renal oncocytoma. Eur J Nucl Med 13:311–312 20. Chybowski FM, Bergstralh EJ, Oesterling JE (1992) The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study. J Urol 148:83–86 21. Cremerius U, Effert PJ, Adam Get et al (1998) FDG PET for detection and therapy control of metastatic germ cell tumours. J Nucl Med 39:815–22 22. Cremerius U, Wildberger J, Borchers H et al (1999) Does positron emission tomography using 18 fluoro-deoxy2-deoxyglucose improve clinical staging of testicular cancer? Results of a study in 50 patients. Urology 54:900–9004 23. Davis BJ, Pisansky TM, Wilson TM et al (2000) Extent of extracapsular extension in localized prostate cancer. Urology 55:382–386 24. de Jong IJ, Pruim J, Elsinga PhH et al (2003) Preoperative staging of pelvic lymphnodes in prostate cancer by C-11-choline PET. J Nucl Med 44:331–335 25. de Wit M, Heicapell R, Bares R (2001) PET zur Stadieneinteilung und Therapiekontrolle bei Keimzelltumouren. Dtsch Ärztebl 98:C2710 26. DeGrado TR, Baldwin StW, Wang S et al (2001) Synthesis and evaluation of 18F-labeled choline analogs as oncologic tracers. J Nucl Med 42:1805–1814 27. Demas BE, Hricak H (1992) The kidneys. In: Higgins CHB, Hricak H, Helms CA (eds) Magnetic resonance imaging of the body, 2nd edn. Raven Press, New York, pp 785–816 28. Dhingsa R, Qayyum A, Coakley VF et al (2004) Prostate cancer localization with endorectal MR imaging and MR spectroscopic imaging: effect of clinical data on reader accuracy. Radiology 230:215–220 29. Donnelly SE, Donnelly BJ, Saliken JC et al (2004) Prostate cancer: Gadolinium-enhanced MR imaging at 3 weeks compared with needle biopsy at 6 months after cryoablation. Radiology 231:published online 30. Dorn R et al (2003) Lymphoscintigraphy and sentinel lymph node (SLN) identification in prostate cancer: Results from 350 patients (Abstr. 15). Eur J Nucl Med Molecular Imaging 30:153 31. Dresel ST (2007) Wertigkeit der C-11 Cholin PET und PET/CT bei Patienten mit Verdacht auf Prostatakarzinom. Nuklearmedizin/Informationen, BBGN, Berlin 22:1–16 32. Effert PJ, Bares R, Handt S, Wolff JM, Büll U, Jakse G (1996) Metabolic imaging of untreated prostate cancer by positron emission tomography with 18-fluorinelabeled deoxyglucose. J Urology 155:994–998 33. El Helou, Hör G (1979) 99mTc-methylene diphosphonate uptake in a primary Wilms’ tumour. Therapiewoche 29:7785–7795

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34. Even-Sapir E, Metser U, Meshani E et al (2006) The detection of bone metastases in patients with high-risk prostate cancer: 99mTc- MDP planar bone scintigraphy, single- and multi-field-of view SPECT, 18F-fluoride , and 18F-fluoride PET/CT. J Nucl Med 47:287–297 35. Farsad M, Castellucci P, Nanni C et al (2004) 11C-choline PET/CT imaging for localization of recurrent prostate cancer (Abstr. 204). Eur J Nucl Med Mol Imaging, Suppl 2, 31:S252 36. Fischman AJ, Thrall JH (2003) Who should read and interpret 18F-FDG PET studies? J Nucl Med 44:1197–1199 37. Flamen P, Bossuyt A, De Greve J, Pipeleers-Marichal M, Keuppens F, Somers G (1993) Imaging of renal cell cancer with radiolabeled octreotide. Nucl Med Comm 14:873–877 38. Fornara P (2003) PSA-Test-Gesellschaft für Urologie. Dtsch Ärztebl 100:C2117 39. Fricke E, Machtens S, Hofmann M et al (2003) Positron emission tomography with 11C-acetate and 18F-FDG in prostate cancer patients. Eur J Nucl Med 30:607–611 40. Gallagher BM, Fowler JS, Gutterson NI et al (1978) Metabolic trapping as a principle of radiopharmaceutical design: some factors responsible for the biodistribution of (18F)-deoxy-2 fluoro-D-glucose. J Nucl Med 19:1154 41. Gann PH, Han M (2005) The natural history of clinically localized prostate cancer. J Am Med Ass (JAMA) 293:2149–51 42. Garcia Fifueiras R, Martin CV, Isidro IRE (2007) MRI, CT offer answers to renal mass queries. Diag Imag Europe June/July:9–12 43. Garnick MB, Fair WR (1996) Prostate cancer: Emerging concepts (part I). Ann Intern 125:118–125 44. Goldenberg DM, De Land FH, Bennett SJ et al. (1983) Radioimmunodetection of prostatic cancer. In vivo use of radioactive antibodies against prostatic acid phosphatase for diagnosis and detection of prostate cancer by nuclear imaging. JAMA 250:630–635 45. Grosu AL, Krause BJ, Nestle U (2006) PET/CT in der Strahlentherapieplanung. Der Nuklearmediziner 29:151–58 46. Hara T (2002) 11C-Choline and 2-deoxy-2-(18) fluoroD-glucose in tumour imaging with positron emission tomography. Molecular Imaging Biol 4:267–273 47. Hara T, Kosaka N, Kishi H (2002) Development of 18F-fluoroethylcholine for cancer imaging with PET: Synthesis, biochemistry, and prostate cancer imaging. J Nucl Med 43:187–199 48. Hardy JG, Anderson GS, Newble GM (1976) Uptake of 99mTc-pyrophospate by metastatic extragenital seminoma. J Nucl Med 17:105–106 49. Harisinghani MG, Barentsz J, Hahn PF et al (2003) Noninvasive detection of clinically occult lymphnode metastases in prostate cancer. N Engl J Med 348:2491–2499 50. Harrison J, Ali A, Bonomi Ph, Prinz R (2000) The role of positron emission tomography in selecting patients with metastatic cancer for adrenalectomy. Am Surgeon 66:432–437 51. Hautzele H, Müller-Mattheis V, Reinhardt MJ et al (2005) Validierung von F-18-FDG-PET und CT im Vergleich zur Histologie beim Peniskarzinom. Nuklearmedizin 44:V90

52. Heinisch M, Loidl W, Haim S et al (2005) PET/CT mit F18 Fluorcholin zum Restaging von Patienten mit Prostatakarzinom: Sinnvoll bei PSA 6) [43]. Operated patients had a longer disease-free survival time. In case of high FDG uptake resection was recommended rather than applying other therapy methods (followed by radiotherapy with or without chemotherapy). Radiotherapy Planning. In the past, the planning concept was incorrect in 5%–30% of all cases [1]. Immuno-SPECT reduces uncertainty (by broadening or narrowing the borders of radiated areas to prevent healthy tissue from being harmed during radiation). Intensity-modulated radiotherapy (IMRI) and 3D conformal radiotherapy focusing on the target volume offered completely new perspectives for PET and PET/CT with respect to more precise molecular radiotherapy [60]. PET, PET/CT, SLN, Intraoperative Gamma Probes. According to our knowledge, validated intermodal (multicentre) studies are not available. Radioisotope surgery [29] was already proposed in the 1960s. Since then, classification of lymphatic drainage and the problems related to sentinel nodes have been critically commented on in numerous symposia and consensus conferences. SUV Optimization. SUV evaluation may be optimized with a relativizing approach (the sensitivity is increased to 75%) or by determining the metabolic FDG rate (sensitivity 86%). An earlier study performed in Frankfurt, Germany [77], was able to verify that sensitivity of 18F-FDG PET (compared with the pathological findings) after neck dissection (ND) was consistent in only 70% in case of negative nodal findings. Even in patients who had undergone prophylactic neck dissection, microscopic infi ltrates could still be found in 30% of the cases [6, 73, 63].

Therapy progress of ENT tumours cannot only be evaluated visually and empirically. The significance of PET and PET/CT evaluation is increased if the SUV is taken into account [9]. Therapy response may obviously be determined more precisely in PET radiopharmacy centers with 11C-thymidine [86, 74]. Unrevealed (but suspicious) foci and synchronous (second) malignomas are better detected than with conventional diagnostic approaches [83]. Data analyses performed in 2004 assume a sensitivity of 87% and a specificity of 80%–93% [71]. Artefacts mentioned earlier (BAT, brown adipose tissue) can be dramatically reduced by PET/CT. The complex anatomy of the ENT region with multiple compartments and the disturbing effects of BAT producing artefacts indicate that PET/CT might be useful to complement diagnostic imaging. Under certain conditions, patients presenting with laryngeal oedemas after radiotherapy had to undergo unwanted larynx biopsy to exclude necroses or recurrent tumours or vital tumour residues. PET/ CT reduces the rate of false negative findings and may be considered as a gatekeeper [33]. PET/CT is sensitive, for example, to laryngeal recurrences in 92% of cases and management consequences arise in up to 59% (up to 100% for distant metastases). PET/CT can image lymph node metastases undetected by CT alone or MRI and are thus falsely classified as N0 stage [68]. Prevalence was estimated to be 20% in these stages. False positive findings (in cases of laryngitis and lymphadenitis) occur, but micrometastases can neither be proven nor excluded even with the most sophisticated fusion technology. One team directly compared different methods and stated: PET/CT, CT and PET yielded comparable accuracy for the T- and M-stage in 20 newly diagnosed cancers [17], but for restaging PET/CT was superior to PET alone (95% vs. 83%). PET/CT. PET/CT complements therapy strategies used in the past because it perfectly combines anatomical features and the metabolic tumour volume and thus acts as a viability marker. Both in-vitro markers and technical modifications can help to distinguish tumours from inflammations. Like bronchial carcinomas [32, 46], head-neck tumours are among the indications for which PET and PET/CT scanners are preferably used:

7.1

   

Sensitivity and specificity are higher T- and N-staging 1 yield more precise results CUP can be better differentiated Prevention of malposition/reposition artefacts arising if the images of separate PET and CT scans are fused [44]  Lymph nodes can be more exactly evaluated with respect to their appearance (e.g. jugulodigastric nodes), the base of the tongue and the floor of the mouth, and encasement of muscles and vessels.

Weak points of CT and MRI, e.g. scars, oedemas and smaller recurrent tumours, can be minimized with PET/CT. A significant advantage of PET/CT over PET alone is also illustrated in a study performed in 2005 [15], which showed a sensitivity of 98%, specificity of 92%, accuracy of 94%. Improvement of Diagnostic Accuracy by Multimodal Imaging. The cervical status of a squamous cell carcinoma of the oral cavity must be carefully analyzed. In a study performed in Taiwan, 124 patients were examined multimodally (histological gold standard [59]):  Accuracy identifying the primary tumour: 98.5%, 87.1% (FDG-PET, CT/MRI, respectively)  Sensitivity identifying lymph node metastases (on a level-by-level basis): 74.7%, 52.6% (FDGPET, CT/MRI, respectively)  Specificity: 93.0%, 94.5% (FDG-PET, CT/MRI, respectively) This study is noteworthy for the following reason: ROC analysis revealed a significant advantage of FDG-PET over CT/MRI – if objectively compared with the visual evaluation – as long as total nodal detection was taken into consideration. A purely visual interpretation of the modalities merely revealed FDG/PET and CT/MRI to be moderately superior to PET alone, i.e. this approach is not precise enough to abstain from staging by neck dissection.

Head and Neck Tumours

FDG-PET Pitfalls Physiological Uptake Patterns. Increased uptake due to physiological features may lead to misinterpretation [56]:  “Hypermetabolic phenomena” in the tongue, palate, salivary glands (variable here), vocal cords. These phenomena can be mitigated by instructing the patient not to talk or swallow and to abstain from doing anything that might stimulate salivary secretion immediately prior to FDG injection.  In addition to physiological artefacts reported in the past (WAT, BAT – adipose tissue – supraclavicular, supradiaphragmatic, see below) it has since been revealed that there are also infradiaphragmatic FDG deposits [11], mainly in young patients (perirenal, paracolic and parahepatic)  In case of cervical FDG foci (with/without proven ENT primary tumours) a certain importance is attributed to SUV-based quantification, mainly with respect to prognosis. According to clinical examinations (including panendoscopy, sentinel node biopsy) PET and MRI are useful in case of suspicious, recurrent, (a)symptomatic constellations. Inflammation, Benign Processes, Absence of FDG Uptake  No or only one hypometabolic FDG uptake of normal size, but mainly in reactively enlarged lymph nodes which can refer to inflammatory genesis or tumour necroses with concomitant infection of a metastatic process [25, 32, 31, 44]. The differential diagnosis “tumour/inflammation” is facilitated by quantitative PET.  In older patients, FDG foci in the carotid region may (in chain-like formation) correspond to atheromas, less frequently also to vasculitides [14, 22].

PET Indications

1

Mediastinal lymph nodes, differential diagnosis N1/N2, spinal staging, N1 LN distally to the medial or visceral pleura, N2 LN in the medial pleura, (prognosis)

 CUP syndrome [23]  Localization of the primary tumour, early stage of the laryngeal carcinoma [42, 48]  Propagation of the primary tumour, infi ltration

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 Selection of the puncture site in case of rebiopsy after unclear findings  Distant metastatic spread in case of suspected false negative CT and MRI (and sonography)  Identification of lesion malignancy by modified (quantitative) PET evaluation  Detection of recurrent tumour [5, 47]  Nodal staging,  Residual tumour foci after therapy (oedemas, fibroses, scars, subchronic infections)  Therapeutic strategy (change of management in approximately 30%)  Follow-up with quantitative PET  PET/CT and MRI, detection and depth of invasion [36]  Radiotherapy planning IMRI, conformal 3D radiotherapy.

   

Functional parameters of the thyroid gland Two-plane X-ray of the thorax Vocal cord mobility Serum calcium

Fine needle puncture, serum calcitonin, CEA, neck lymph node extirpation, clarification of MENII (multiple endocrine neoplasia) syndrome (suprarenal gland? parathyroid gland?), MRI or CT without contrast agent, barium swallow, thoracic-inlet-view if invasive growth is suspected and, somewhat vague, diagnosis to exclude distant metastases (PET?) are considered to be useful examinations in individual cases.

Diagnosis. According to the AWMF guidelines 2 the following examinations should be performed prior to primary intervention:  Anamnesis and clinical examination  Neck sonography  99mTc scintigraphy

Therapy. Primary therapy consists of total thyroidectomy with lymph node dissection, the extent of which depends on the fi ndings and the tumour type, while neighbouring structures (oesophagus, trachea, vessels) are resected if the tumour has invaded these regions and R0 resection is intended. After 3 weeks of hormone withdrawal [or alternatively after IV injection of hTSH (human thyreoidea-stimulating hormone)], it will be established whether radiolabeled iodine can be stored, as in 50%–60% of all cases [50, 69] 3, and – usually in case of follicular and papillary thyroid carcinomas – radiolabeled iodine therapy is performed to remove residual thyroid tissue and to detect/ exclude/treat accumulating lymph nodes or distant metastases. Percutaneous radiotherapy is indicated after anaplastic carcinomas post thyroidectomy assuming they are limited to the thyroid gland, and in case of differentiated carcinomas after R1 or R2 resection if surgical revision and/or radioiodine therapy is not possible. Distant metastases are treated with radioiodine therapy if iodine is stored, or with percutaneous radiotherapy in case of insufficient uptake. In case of diffuse metastatic spread therapeutic approaches may include monochemotherapy, polychemotherapy or radiochemotherapy 4.

1

3

7.2 Thyroid Carcinomas Epidemiology and Etiology. Thyroid carcinomas originating either from follicular epithelial cells or from C cells are relatively rare malignomas with an incidence of approximately 2 per 100,000 inhabitants in Germany. The proportion of different carcinoma types (follicular, papillary, medullary, anaplastic carcinoma) varies considerably from one region to another. In a large number of cases, hereditary medullary thyroid carcinoma occurs more frequently due to somatic mutation of the c-ret-oncogene (multiple endocrine neoplasia, type II). Furthermore, radiation exposure of thyroid gland is a proven cause of thyroid carcinoma 1.

2

See also Riede and Schaefer (1999) Allgemeine und Spezielle Pathologie. Thieme, Stuttgart) German Cancer Society: Kurzgefaßte Interdisziplinäre Leitlinien (Concise Interdisciplinary Guidelines) 2002, 3rd edition 2002

4

Guidelines established by the German Society for Nuclear Medicine (DGN), ablative radio-iodine therapy German Cancer Society: Kurzgefaßte Interdisziplinäre Leitlinien (Concise Interdisciplinary Guidelines) 2002, 3rd edition 2002

7.2 18

F-FDG-PET

Numerous efforts have aimed at imaging metastases without radioiodine metabolic activity using tumour-affine radionuclides, e.g. with 201thallium [40]. PET fi lled a gap also here, with a precision no other tracer could hitherto afford. Despite the rather low incidence of this tumour, the number of PET publications is surprisingly high. The main indication for 18F-FDG-PET is the search for 131I-negative foci in case of GLUT-1 and GLUT-3 increase. The aggressivity of the biological behaviour is correlated with the overexpression of GLUT-1. The previous view that PET scans (only) provide positive results if the thyroglobulin level is about 100 μg/ml or higher must be relativized. Therapy consequences would be important if the degree of resistance of FDG-avid thyroid carcinoma metastases actually determined the treatment mode of high-dose radiotherapy. In the DGN classification “Onko-PET III” [65] evidence level 1a was assigned to the restaging of radioiodine-negative carcinomas and evidence level 1b to radioiodine-positive tumours. Indications for 18F-FDG-PET  hTG (thyroglobulin) rise, but no radioiodineaccumulating foci  Detection of supplementary FDG-positive foci (see below)  Occult metastatic spread of a thyroid carcinoma [3]  Radiation dosimetry ([61] u. S.). NIS (sodium iodide symporter) rise presumably indicates 131I-utilizing, and GLUT transporter rise indicates 18F-FDG-utilizing metastases (see also [18, 19, 37, 38, 51, 70]). 131I and 18F-FDG positive metastases may occur simultaneously. This is an important finding regarding the clinical application of PET and PET/CT. In this context the authors would like to refer to NET-PET and SPECT used in gastroenterology with a comparable gain in competence by means of molecular PET. Physiological Kinetics. A Nagoya study [41] compared the detection of skeletal metastases by means of FDG-PET and 99mTc compounds with the following results:

Thyroid Carcinomas

Sensitivity FDG-PET 84.7 % versus 99mTc tracer 78 % Specificity FDG-PET 99.6 % versus 99mTc tracer 91.4 % The basic data incidence of bone metastases in patients suffering from thyroid carcinoma totalled 38%. Primary options for PET (and PET/CT) include stage classification in case of 131I-negative (but optional in case of 131I-positive) patients in the control group after total thyroidectomy and radioiodine therapy (RIT). A non-specific increase in FDG uptake is observed in cases of chronic lymphocytic thyroiditis [85, 41]. Medullary thyroid carcinomas classified as residual, recurrent or metastasizing tumours of this class could not be detected with calcitonin levels under 1,000 pg/ml with tenable sensitivity (78%). Under 500 pg this statement was considered to be of limited importance. 68Ga-DOTA-Tyr3-Octreotide increases the detection rate significantly [28]. The healthy thyroid gland can utilize 18F-FDG and be imaged in up to 30% of all cases on PET scan. Both autonomous adenomas and focal thyroiditis also display regional hypermetabolic foci. Incidentally diagnosed solitary nodes are clarified in detail in the Diagnostic-Therapeutical Center (DTZ) by ultrasound-guided fine-needle biopsy. Histology and FDG Uptake. Histology determines the degree of FDG utilization:  Papillary, follicular carcinomas are FDG-PEThyper-avid  Medullary carcinomas: somatostatin analogues, in most cases with SPECT tracers. This experience was confirmed in Frankfurt and elsewhere [2, 4, 8]. 18F-DOPA can be used for PETbased imaging. Medullary carcinomas are classified as outliers in which neuroendocrine receptor scintigraphy 1 is helpful. Determination of serum calcitonin is an initial test performed in the laboratory. According to our initial experience gained in Frankfurt, 24 locoregional lymph node metastases could be detected using whole-body PET scan which were neither manifested by conventional tumour markers nor by somatostatin receptor expression. 1 111In-SMS

analogues [69], 123I-MIBG, 99mTc-Penta-DMSA, somatostatin = growth hormone)

68Ga-DOTATOC

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PET/CT. PET/CT studies for recurrent tumours confirm that there could be benefits in the after-care which exceed the customary diagnosis, as emphasized by Mazzaferi [49]. Magnetic resonance imaging (MRI) is presently only practicable as a coregistering imaging method with secondary fusion, but not as an integrated simultaneous combined PET/MRI imaging system 1.

than 125 ml, but only 18% survived with volumes of more than 125 ml [82]. In fact, such a summary limit seems to be arbitrary, but none of the 66 patients with FDG-negative PET died even though distant metastases were found in some patients at the end of the observation period, while approximately 70% (of 59 patients) with positive FDG-PET died during the same follow-up period.

Indications for PET and PET/CT. Reasons why PET/ CT may also be superior to other imaging methods with respect to thyroid malignomas:  CT is not able to distinguish vital (residual, recurrent tumour) tissue from postoperative scare formations.  Despite a sensitivity of 93%, FDG-PET is not able to evaluate/separate anatomical neighbouring organs (e.g. parotid gland, etc.).  PET/CT dual imaging modality (DM) is an ideal complementary method compensating the inadequacies related to date to PET alone: Recurrent tumours could be detected in the head-neck region in 4 of 8 patients examined: 75% of the resected foci were malignant.

124I-PET.

Taking PET/CT scan results into account the surgeon is able to localize and demarcate the vital tissue of the recurrent tumour, including metabolically vital/involved regional lymph nodes, i.e. making is possible to:  Delineate the borders of the mass to be resected  Reduce surgical radicality  Alter multimodal therapy before and after surgical intervention  Benefit from the interaction of TSH and insulin and from other molecular methods (mRNA [66]). Cost/efficiency studies are also noteworthy [27]. The significance of PET/CT was recently described in a more detailed publication by Rosenbaum et al. [67]. According to these authors, this method can be used for differentiated (18F-FDG, 124I), medullary and anaplastic carcinomas. Three-Year Survival Rates Depending on FDG Metabolic Activity? In all, 96% of the patients survived if (FDG-avid) metabolic tumour volume was less 1

Gracioso et al (2005) IEE Puerto Rico, Abs M01

This PET tracer has been investigated in PET centres since 1987 and routinely recommended prior to radioiodine therapy and for response control, e.g. in case of hyperthyreosis [27, 61]. Corresponding studies with 124I-PET relating to dosimetry, radiation exposure, therapy differentiation and detection of so-called malignant microadenomas and mediastinal micrometastases should be given increased attention, maybe as a contribution to early diagnosis in the future. Mediastinal micrometastases may be detected by combining PET/CT and 124iodine. Anti-CEA antibodies and diabodies are discussed by Sundaresan et al. [78]. Molecular Nuclear Medicine and Molecular Endocrinology. This special branch is also governed by the principle: Monopolic thinking with respect to the best possible method must be replaced by a strategic cooperation between internists/endocrinologists and nuclear medicine physicians [72] (see also Table 7.1). The combination of both methods also increases the prognostic significance and will soon be integrated in clinical routine regarding presurgical search for and identification of recurrent cervical lymph node metastases if test biopsy was unable to provide clear results. Molecular PET and Tg mRNA amplification seem to be a promising and useful combination (see “reverse transcription polymerase chain reaction”, RTPCR). What Can One Expect From Sodium Iodide Symporter (NIS)? Translational research deals with studies on gene therapy using NIS. NIS [18] was cloned and characterized in 1996 [21]. Transporter gene imaging offers a subtle insight into transcription and translation – in case of NIS into the molecular medicine of the thyroid gland, e.g. in patients with nodular hyperplasia. NIS

7.2

expression is directly correlated with the degree of differentiation, and indirectly with GLUT-1. Combination of molecular PET and molecular in vitro methods (e.g. quantitative determination of reverse transcriptase, PCR) [66] offers a tool which can be perfectly combined with other tools. NIS-PET could improve therapy decisions. Targeted expression of NIS could become the foundation for molecular radionuclide gene therapy. The NIS gene transferred to other cells may increase iodine uptake 100-fold. If we succeed in developing tissue-specific promoters (maximization of cyto-direction correlated with a minimization of side effects) it might also be possible to initiate a gene-based radionuclide therapy of prostate carcinoma.

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PET/CT indication: Is there any evidence of recurrent tumour or local recurrence?

7.3 Case Studies Patient 1 CUP Tumour

Findings: New glucose metabolic activity consistent with malignancy in the area of the pharynx or the tonsillar region on the right side as indication of the primary tumour.

Clinical history: A 54-year-old male post extirpation of a lymph node metastasis in the right cervical region. The metastasis was histologically identified as a lymph node metastasis of a moderately differentiated cornified squamous cell carcinoma.

Teaching points: PET/CT is able to identify a focus in the right cervical area which might be the primary tumour. The next step is the examination of the area by an ENT specialist followed by surgical treatment.

Fig. 7.1.1. Projection in the head-neck region reveals focally increased uptake

7.3 Case Studies Fig. 7.1.2. Transaxial PET slice with a hypermetabolic focus in the area of the right oropharynx, with a diameter of approximately 2 cm

Fig. 7.1.3. Follow-up examination yielding transaxial PET/CT slices showing an increase in SUV for the region described

Fig. 7.1.4. MIP image as well as transaxial, sagittal and coronal PET/ CT slices

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Patient 2 Tumour Recurrence of an Atypical Laryngeal Carcinoid Clinical history:. A 53-year-old male post neuroendocrine tumour of the left side of the larynx (atypical carcinoid). The tumour was first diagnosed 3 years previously. Status post partial laryngeal resection on the left side, neck dissection on both sides. Suspicion of recurrent tumour with biopsy-proven recurrent tumour of the vocal cords.

Findings: Detection of glucose metabolic activity consistent with malignancy in the area of the recurrent tumour on the left side, invading the hypopharynx from the larynx. Slightly extended pleural effusion on the right side which is partially degenerating, as well as discrete subcapsular ascites of the liver without suspicious PET correlate. Teaching point: PET/CT is able to evaluate the extent of the recurrent tumour and to exclude further metastatic spread in the whole body.

Fig. 7.2.1. Tumour recurrence of an atypical laryngeal carcinoid on the left side invading the hypopharynx

7.3 Case Studies

Patient 3 Restaging of an Oropharyngeal Carcinoma Clinical history: A 64-year-old male post oropharyngeal carcinoma on the right side. Tumour first diagnosed 2 years previously. The patient then underwent radiochemotherapy. Locoregional metastases in the buccal mucous membrane and in the retrolingual region were resected. A further recurrent tumour in the area of the right buccal mucous membrane and the lip was operated 6 months previously. New tumour recurrence now seen in the area of the retrolingual region on the right side. Furthermore, squamous cell carcinoma metastasis in the right lobe of the thyroid gland with partial resection a few months previously. Pulmonary metastases were detected during the last PET/CT pre-examination. The patient subsequently underwent radiotherapy. PET/CT indication: Restaging for further therapy planning.

381

Findings: Regression of tracer uptake and partial reduction in size after radiotherapy. Nevertheless, persistent metabolic activity consistent with malignancy in the foci in the area of the palate and the retrolingual region. Furthermore, evidence of slightly reduced metabolic activity in the pulmonary metastases described above; however, also detection of new pulmonary metastases. No further metastases detected during the examinations. Teaching point: Precise description of metastatic spread by PET/CT.

Fig. 7.3.1. Oropharyngeal carcinoma on the right side, coronal slice



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Fig. 7.3.2. Top, recurrent oropharyngeal carcinoma on the right side. Bottom, further growth of the recurrent tumour in spite of radiochemotherapy 3 months later

Fig. 7.3.3. Lymph node metastasis of the oropharyngeal carcinoma on the right side

7.3 Case Studies

Fig. 7.3.4. Lung metastasis of the oropharyngeal carcinoma

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Patient 4 Hypopharyngeal Carcinoma Clinical history: A 56-year-old male post maxillary inflammation approximately 10 weeks previously. In this context, suspiciously swollen lymph node in the left cervical region. Resection and biopsy 14 days previously. Surprisingly, histology-proven carcinoma. Long-term history of nicotine and alcohol abuse. PET/CT indication: Is there any evidence for glucose metabolic activity consistent with malignancy in the hypopharyngeal region and also in the whole body?

Findings: Detection of glucose metabolic activity consistent with malignancy in the area of the left anterior wall of the oro- and hypopharynx as seat of the primary tumour with metastasis in the lymph nodes on the left side of the neck. No evidence of further organ or lymph node metastases in the rest of the whole-body scan. Teaching point: PET/CT is able to detect a primary tumour in the oro- or hypopharynx, and to exclude further metastatic spread in the whole body.

Fig. 7.4.1. Oro-/hypopharyngeal carcinoma on the left side shown with three slice planes

7.3 Case Studies

Fig. 7.4.2. Late enhancement image of an oro-/hypopharyngeal carcinoma on the left side

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Patient 5 Restaging after Multiple Carcinoma Clinical history: A 67-year-old male with a history of excision of the floor of the mouth and partial resection of the tongue due to a squamous cell carcinoma 13 years previously. Neck dissection 5 years later. The following year, resection of the left upper lobe of the lung due to an adenocarcinoma. Thoracoabdominal oesophagus resection and interposition of the stomach due to an adenocarcinoma of the oesophagus at the base of a Barrett’s mucosa 2 years later. Further surgical treatment due to a recurrent tumour of the tongue 2 years later. Surgical therapy of a tumour in the right auricle due to a highly differentiated focally cornifying squamous cell carcinoma invading the stroma 11 months later. Gastroscopy without any

evidence of malignant growth in the oesophagogastric anastomosis region 2 months previously. PET/CT indication: Restaging of the tumour diseases described above. Findings: PET/CT detects glucose metabolic activity consistent with malignancy in the area of a polypoidal mass next to the ventral outer wall of the upper anastomotic region at the level of the T9 vertebral body. No other evidence of further malignant growth in the whole body. Teaching points: PET/CT is a particularly useful restaging method in case of long-term history of malignant growth. A polypoid tumour could be detected in the right thoracic region by whole-body scan. The markedly hypermetabolic polypoid process is clearly visible in the area of the ventral outer wall.

Fig. 7.5.1. Coronal PET/CT slice with glucose metabolic activity consistent with malignancy in the area of the ventral exterior wall of the upper anastomotic region of the operated adenocarcinoma of the oesophagus

7.3 Case Studies

Fig. 7.5.2. Tumourous process shown on a sagittal PET/CT slice with lung window setting for the CT scan

Fig. 7.5.3. Transaxial PET/ CT slice showing the tumouraffected anastomotic region of the operated oesophageal carci-

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Patient 6 Auricle Carcinoma Clinical history: A 65-year-old male post rectal carcinoma with abdominosacral rectum amputation. Adjuvant radiochemotherapy. Radiotherapy to the right acetabulum with 50 Gy. Bisphosphonate therapy. Auricle carcinoma on the right side, 2 years later ablation of the right auricle and selective neck dissection on the right side. Radiotherapy with up to 68 Gy. Second re-resection with resection of the external auditory meatus including cartilaginous support structures on the right side, as well as third re-resection for petrosectomy and plastic surgery a further 2 months later. New local recurrence at present. PET/CT indication: Distant metastases? Propagation diagnosis for therapy planning.

Findings: Glucose metabolic activity consistent with malignancy in the area of the clinically detected local recurrence. In addition, an approximately 18-mm smaller subcutaneous node located in the caudal retromandibular region on the right side with glucose metabolic activity consistent with malignancy can be detected. Despite status post radiotherapy to the right acetabulum there is still focally increased glucose metabolic activity at the border of the acetabulum and in the area of the acetabulum convexity without discernibly invasive tumour or evidence of pathological fracture or fracture risk.

Teaching points: Restaging of the carcinoma of the right auricle revealed a clear extension of the hypermetabolic area, but distant metastases could be excluded.

Fig. 7.6.1. Sequence of transaxial PET/CT slices showing an extended tumour area with increased metabolic activity

7.3 Case Studies Fig. 7.6.2. Coronal PET/CT slice showing an approximately 3-cm large area with glucose metabolic activity consistent with malignancy

Fig. 7.6.3. Transaxial PET/CT slice showing the auricle carcinoma

Fig. 7.6.4. The same region in a late enhancement image with significant increase in metabolic activity

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Patient 7 Tonsillar and Laryngeal Carcinoma and Carcinoma of the Base of the Tongue Clinical history: A 55-year-old male post left tonsillar carcinoma with subsequent radiochemotherapy. Larynx carcinoma 2 years later. Resection of a carcinoma in the left retrolingual region 4 years later. Chemotherapy, cycles I and II have been completed. The patient is examined while chemotherapy is ongoing. PET/CT indication: Restaging

Findings: In comparison with the results obtained during pre-examination under chemotherapy, the glucose metabolic activity consistent with malignancy is increased in the left retrolingual region. However, there is still no evidence of locoregional lymphomas. Lymph node in the left axillary area requires observation. Teaching points: Compared with the preceding examination an increasing SUV value is verified in spite of the ongoing chemotherapy, which indicates inadequate therapy success. In this case, PET/CT can be used to assess therapeutic effectiveness.

Fig. 7.7.1. Image of a tumour in the retrolingual region and in the area of the floor of the mouth on the left side

Fig. 7.7.2. The same region on a transaxial slice with slightly regressive SUVs

7.3 Case Studies

Fig. 7.7.3. Contrary to the pre-examination under continued chemotherapy PET/CT now reveals increasing glucose metabolic activity consistent with malignancy in the area of the left retrolingual region

Fig. 7.7.4. Late enhancement image of the follow-up examination with continuing increase in glucose metabolic activity such that a local recurrence must be diagnosed

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Patient 8 Recurrence of a Squamous Cell Carcinoma of the Tongue Clinical history: A 61-year-old female suffering from squamous cell carcinoma of the right border of the tongue which was first diagnosed 4 years previously. Status post laser resection and suprahyoidal lymph node resection on the right side. First tumour recurrence in the area of the right buccal mucous membrane 3 years after surgical intervention. Second tumour recurrence in the plica pterygomandibularis on the right side 3.5 years after surgical intervention. In both cases the patient underwent local chemotherapy with bleomycin combined with electrosurgery. Pronounced trismus due to scar formation is now present. Therapy consisted of cicatricotomy and excision as well as interposition of a fasciocutaneous lobe from the left forearm. Histology also revealed cells of a moderately differentiated, cornifying squamous cell carcinoma in the excised material. PET/CT indication: Tumour staging

Findings: Extended tumour recurrence in the area of the right facial part of the skull extending from the ventral base of the scull to the right lower jaw which has also invaded into cervical lymph nodes located caudally to the right. Lymph node metastases are also found in the left cervical region. No further evidence of distant metastases in the rest of the whole body. Teaching points: PET reveals an extended tumour recurrence in the skull which would be difficult to evaluate using other imaging methods due to multiple adhesions.

Fig. 7.8.1. Sagittal and coronal PET image showing extended tumour masses in the right facial part of the skull

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7.3 Case Studies Fig. 7.8.2a–c. Consecutive sequence of transaxial PET/CT slices demonstrating the extent of the recurrent tumour

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Patient 9 Tonsillar Carcinoma Clinical history: A 44-year-old male with CUP syndrome, with lymph node metastasis in the neck from a slightly cornifying squamous cell carcinoma on the left side. Tumour first diagnosed 10 days previously. Functional neck dissection on the left side with second surgical hemostasis to control post-operative bleeding. Status post panendoscopy and test excision. The primary tumour could not be detected as yet. History of nicotine and alcohol abuse. PET/CT indication: Search for primary tumour as well as staging for further therapy planning.

Findings: Detection of glucose metabolic activity consistent with malignancy in the area of the left tonsillar bed, i.e. PET/CT findings provide evidence of a tonsillar carcinoma being the primary tumour. The rest of the whole-body scan does not provide any evidence of further organ or lymph node metastases or tumourous processes. Teaching point: Primary tumour diagnosis as well as staging with a single scan.

Fig. 7.9.1. Tonsillar carcinoma on the left side with three slice planes

7.3 Case Studies

Fig. 7.9.2. Tonsillar carcinoma on the left side, late enhancement images with three slice planes

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Patient 10 Restaging of a Small-Cell Carcinoma of the Left Principal Nasal Cavity

PET/CT indication: Restaging after radiochemotherapy in comparison with the PET/CT pre-examination?

Clinical history: A 42-year-old male post small-cell carcinoma of the principal nasal cavity on the left side with infi ltrations into the orbita and the base of the skull. Status post transfrontal operation with intra- and extracranial tumourectomy, fat graft and closure of the internal table of the bone defect 1 year previously. Post-operative radiochemotherapy. Visual impairment due to cataract.

Findings: Status post surgical intervention in the area of principal nasal cavity on the left side and radiochemotherapy with considerable locoregional improvement with regression tendency of the residual PET findings. Complete regression of a lymphoma in the angle of the left mandible. However, diffuse metastatic spread into the liver with multiple focal lesions ranging in size from a few millimeters up to 2.5 cm was diagnosed

Fig. 7.10.1. PET image taken before radiochemotherapy with significantly increased tracer uptake in the area of the principal nasal cavity on the left side

7.3 Case Studies

for the first time. Furthermore, glucose metabolic activity consistent with malignancy diagnosed for the first time in the area of the T4 and T7 vertebral bodies with suspicion of early osseous metastatic spread.

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Teaching points: Comparative examination before and after radiochemotherapy indicates good therapeutic effect which can only be properly evaluated by PET, while morphological changes cannot be delineated by CT. However, the whole-body scan reveals that, despite good local results following radiochemotherapy, further metastatic spread into the liver has considerably complicated and aggravated disease progression.



Fig. 7.10.2. CT image of a tumourous change in the area of the principal nasal cavity on the left side

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Fig. 7.10.3. Sequence of transaxial, sagittal and coronal PET/CT slices as well as MIP image. The images clearly show a markedly increased tracer uptake with a projection to the principal nasal cavity on the left side, whereby the tissue growth determined during the CT scan is congruous with the markedly increased tracer uptake detected during the PET scan

Fig. 7.10.4. Transaxial PET/CT slice showing a markedly increased glucose metabolic activity in connection with a swollen region in the area of the principal nasal cavity on the left side before combined radiochemotherapy

7.3 Case Studies

Fig. 7.10.5. PET/CT fi ndings after combined radiotherapy with significant reduction in SUV but without marked changes in the morphological fi ndings

Fig. 7.10.6. Metastatic spread into several areas of the liver diagnosed for the fi rst time after radiochemotherapy

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Patient 11 Recurrence of a Vocal Cord Carcinoma Clinical history: A 70-year-old male post vocal cord carcinoma with laser therapy to the right vocal cord 3 years previously. The patient suffers from squamous cell cancer. At present, histological verification of a superficial local recurrence in the area of the right vocal cord with suspicion of a local recurrence of the carcinoma. PET/CT indication: Further propagation diagnosis as well as clarification of metastatic spread of the vocal cord carcinoma.

Findings: A proven vocal cord carcinoma is associated with locoregional glucose metabolic activity consistent with malignancy in the right ventral region. Evidence of lymph node or organ metastases could be found neither in the area of the locoregional lymph node stations nor in the remaining whole body. Teaching point: PET/CT is able to exclude further metastatic spread. The extent of the activity consistent with malignancy corresponding to a recurrence of the vocal cord tumour on the right side can be described with its metabolic pattern. An additional resection is thus indicated.

Fig. 7.11.1. Local recurrence of a vocal cord tumour on the right ventral side

7.3 Case Studies

Fig. 7.11.2. MIP image of a vocal cord carcinoma on the right ventral side with otherwise unsuspicious metabolic activity in the whole body

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Patient 12 Cerebral Metastatic Spread of a Bronchial Carcinoma Clinical history: A 71-year-old male with adenocarcinoma of the right upper lobe of the lung. Tumour first diagnosed 2 years previously. Neoadjuvant chemotherapy, surgical revision 20 months previously followed by radiotherapy. 15 months previously, a carcinoma in situ in the vocal cord was operated. 1 year later, resection of a large brain metastasis on the right front side with abscess formation later. After successful treatment of the abscess, radiotherapy up until 12 months previously. At present, persistent cephalgias. PET/CT indication: Restaging for further therapy planning.

Findings: Glucose metabolic activity consistent with malignancy in the area of a residual or recurrent tumour, in the right frontobasal as well as right and left parietal region, in terms of multilocular cerebral metastatic spread. No additional evidence of further tumour propagation. Teaching point: Reliable statement regarding the propagation of the active tumour tissue by PET.

Fig. 7.12.1. Adenocarcinoma of the right upper lobe of the lung

7.3 Case Studies

Fig. 7.12.2. Lymph node metastasis in the right cervical region

Fig. 7.12.3. Brain metastasis in the right frontobasal region demonstrated by three slide planes

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Fig. 7.12.4. Brain metastasis in the right frontobasal region shown on a sequence of transaxial slices; recurrent tumour after neurosurgical intervention

7.3 Case Studies

Patient 13 Cystadenocarcinoma of the Lacrimal Sac Clinical history: A 36-year-old female following extirpation of a cystadenocarcinoma of the right lacrimal sac 2 months previously. PET/CT indication: The presence of residual tumour tissue and further tumour propagation are to be evaluated with PET/CT to assist decision-making with regard to further therapy.

Fig. 7.13.1. Tumour recurrence after extirpation of a cystadenocarcinoma of the right lacrimal sac, coronal slice

Fig. 7.13.2. Tumour recurrence after extirpation of a cystadenocarcinoma of the right lacrimal sac, sagittal slice

Findings: A clearly enlarged soft tissue mass is detected in the lateral border of the right orbit. Increased glucose metabolic activity which is even more increased in the late enhancement image is detected in an area sized 5 × 9 mm. The criteria indicating the presence of residual malignant growth are thus met. The anterior part of the musculus rectus cannot be separated from this soft tissue mass. Teaching point: With the use of a PET scanner to evaluate metabolic activity it is possible to detect hypermetabolic residual tissue such that the patient will have to undergo radiotherapy.

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Patient 14 Alzheimer’s Disease Clinical history: Reduction of brain performance PET/CT indication: Exclusion of Alzheimer’s disease

Restricted glucose metabolic activity, particularly in the parieto-temporo-occipital region, particularly pronounced on the left side, with reduced total glucose metabolic activity similar to early Alzheimer’s disease. Teaching point: Differentiation between a general CVI and changes typical of Alzheimer’s disease.

Findings: Internally pronounced atrophy as well as reduced densities of the cerebral medulla indicating a CVI. No evidence of an expanding or infi ltrating focal process.

a Fig. 7.14.1a–c. Internally pronounced atrophy as well as decrease in the density of the bone marrow indicating a CVI, restricted glucose metabolic activity, particularly in the parieto-temporo-occipital region similar to Alzheimer’s disease

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7.3 Case Studies

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Patient 15 Oligodendroglioma on the Left Side Clinical history: A 58-year-old male with oligodendroglioma in the left frontotemporal region and symptomatic epilepsy. Surgical revision 1 year previously with discontinuous faradization of the cortex (while the patient was awake) with permanent neurophysiological monitoring and examination for aphasia, apraxia and body image disturbances during analgesic sedation. Partial resection of 80%–90% of the tumour. The patient has been mostly free of complaints since then. Newly appearing convulsions 4 weeks previously. No evidence of areas with increased metabolic activity detected during a PET examination performed at another institution. PET/CT indication: Can FET-PET provide evidence of tumour recurrence or growth of the residual tumour? Propagation diagnosis.

Findings: The FET-PET/CT image shows a relatively pronounced frontotemporal tumour (oligodendroglioma) with moderately extended perifocal oedema as well as slight consecutive midline displacement and compression of the left lateral ventricle. Teaching point: Detection of tumour recurrence by FET-PET.

Fig. 7.15.1. Tumour recurrence of an oligodendroglioma in the left frontotemporal region and symptomatic epilepsy

7.3 Case Studies

Fig. 7.15.2. Transaxial sequence of PET/CT slices showing a recurrent oligodendroglioma in the left frontotemporal region

Fig. 7.15.3. PET/CT slices showing a recurrent oligodendroglioma with three slice planes

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Patient 16 Low-Malignancy Brain Tumour on the Left Side

PET/CT indication: Differential diagnostic clarification of whether the patient suffers from ischemia or a low malignancy tumour with FET-PET/CT.

Clinical history: A 51-year-old male post transitory aphasia and perceptual disorder in terms of TIA (recovery after 7–8 min). MR tomography reveals an oedema in the left parieto-occipital region and a mass with shortened posterior horn of the left lateral ventricle, DD ischemia, e.g. low-grade malignant lymphoma. SPECT reveals hyperperfusion.

Findings: Increased FET uptake in the area of the clinically as well as visually suspicious left parietooccipital region, mainly in the subcortical parts with a maximum size of 2.0 × 2.5 × 4.0 cm (W × D × H) and a peak activity of SUV 2.6. SUV rises to 3.7 in the series of control slices. Compared with the results of the pre-examination performed 4 weeks previously, the CT scan reveals a focal mass densification in the subcortical parts.

Fig. 7.16.1. Status post transitory aphasia; SPECT: local hyperperfusion in the left parieto-occipital region; MRI: oedema and mass in this region. Glucose PET: regional hypometabolism in the left parieto-occipital region

7.3 Case Studies

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Apart from that, the scan still shows a moderately expanding oedema with almost unchanged shortened posterior horn of the left lateral ventricle. Teaching point: In summary, the FET-PET/CT scan reveals a low-malignancy tumour in the left parietooccipital region. PET finally reveals glucose hypometabolism in this region.

Fig. 7.16.2. FET-PET: increased FET uptake in the left parieto-occipital region. Diagnosis: low-malignancy brain tumour with extended perifocal oedema



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Fig. 7.16.3. Regional hypometabolism in the left parieto-occipital region detected with F18-FDG-PET

Fig. 7.16.4. Increased uptake in the left parieto-occipital region detected by MF 18FET-PET

7.3 Case Studies

Patient 17 Hypophyseal Metastasis Clinical history: A 58-year-old female with inoperable carcinoma of the left breast. Tumour fi rst diagnosed 6 years previously. Firstly, seven chemotherapy cycles, followed by radiotherapy. Chemotherapy again 4 years previously due to tumour recurrence. New tumour recurrence or exulceration of the tumour, 6 months previously. Spontaneous pathological fracture of the left humerus due to a bone metastasis with following resection of the osteolysis and surgical treatment 4 months previously. Then chemotherapy again. Right mastectomy 1 month previously.

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Findings: Detection of glucose metabolic activity consistent with malignancy in the whole body indicating generalized metastatic spread into bones, liver, mediastinal, hilar and left axillary lymph nodes, multiple pulmonary metastases and suspicion of early metastatic spread into the brain with proven hypophyseal metastasis. Fracture risk mainly in the area of the C7 vertebral body and in the area of the mid-thoracic spine. NB. Transverse lesion symptoms. Teaching point: Taking into account the long-lasting tumour history, the whole-body PET/CT examination proves to be a particularly useful imaging method in determining the extent of metastatic spread so as to facilitate further therapy planning.

 Fig. 7.17.1. Metastatic spread of breast carcinoma, hypophyseal metastasis

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Fig. 7.17.2. Metastatic spread of breast carcinoma, bone metastasis in the os petrosum on the left side

Fig. 7.17.3. Metastatic spread of breast carcinoma, multilocular osseous metastatic spread, particularly metastasis at C7 with risk of transverse lesion symptoms

7.4

7.4 References 1. Adamietz IA, Schemmann F, Baum RP, Knecht R, Saran F, Mose S, Thilmann C, Hör G, Böttcher HD (1995) Wertigkeit der SPECT-Immunszintigraphie für die Bestrahlungsplanung bei Patienten mit Plattenepithelkarzinomen im HNO-Bereich. Strahlenther Onkol 171:278–283 2. Adams S, Acker P, Lorenz M, Staib-Sebler E, Hör G (2001) Radioisotope-guided surgery in patients with pheochromocytoma and recurrent medullary thyroid carcinoma. Cancer 92:263–270 3. Adams S, Baum RP, Hertel A, Schumm-Dräger PM, Usadel KH, Hör G (1996) Ganzkörper Fluor-18-Fluordeoxyglucose (FDG)-PET zum Nachweis okkulter metastasierter Schilddrüsenkarzinome. In: Reichwein D, Weinheimer B (Hrsg) De Gryter, pp 520–526 4. Adams S, Baum RP, Hertel A, Schumm-Dräger PM, Usadel KH, Hör G (1998) Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings. Eur J Nucl Med 25:1277–1283 5. Adams S, Baum RP, Knecht R, Hör G (2001) Staging und Rezidivdiagnostik von Tumouren im Kopf-Hals.Bereich. Der Nuklearmediziner 24:47–54 6. Adams S, Baum RP, Stuckensen T, Bitter K, Hör G (1998) Prospective comparison of FDG PET with conventional imaging modalities CT, MRI, US in lymph node staging of head and neck cancer. Eur J Nucl Med 25:1255–1260 7. Adams S, Baum RP, Stuckensen T, Bitter K, Hör G (1998) Prospective comparison of FDG PET with conventional imaging modalities CT, MRI, US in lymph node staging of head and neck cancer. Eur. J. Nucl. Med., 9, 25:1255–1260 8. Adams S, Nickel E, Hör G (2000) Differentialdiagnostische Problematik bei der Beurteilung von mediastinalen und pulmonalen Herden mittels F-18-FDG (Kasuistik). Nuklearmedizin 5:N83–84 9. Allal AS, Dulguerov P, Allaoua M, al (2002) Standardized uptake value of 2-(18F) fluoro-2-deoxyglucose in predicting outcome in head and neck carcinomas treated by radiotherapy with or without chemotherapy. J Clin Oncol 42:1398–1404 10. Avril N, Dose J, Jänicke F, Ziegler S et al. (1996) Assessment of axillary lymphnode involvement in breast cancer patients with positron emission tomography using radiolabeled 2-(fluorine-18)-fluoro-2-deoxyglucose. J. Natl. Cancer Inst. 88:1204–1209 11. Bar-Shalom R, Gaitini D, Keidar Z, Israel O (2004) Nonmalignant FDG uptake in infradiaphragmatic adipose tissue: a new site of physiological tracer biodistribution charcterized by PET/CT. Eur J Nucl Med Mol Imaging 31:1105–1113 12. Baum RP, Söldner J, Schmücking M, Niesen A (2004) Peptidrezeptorvermittelte Radiotherapie (PRRT) neuroendokriner Tumouren(Klinische Indikationen und Erfahrung mit 90Yttrium-markierten Somatostatinanaloga). Onkologe 10:1098–1110 13. Behr TM, Gratz S, Herrmann A et al. (1997) Anti-CEAAntikörper versus Somatostatin-Analoga zur Detektion metastasierter medullärer Schilddrüsen-Karzinome:

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most PET of lung and head neck cancer will be PET/CT. J Nucl Med [Suppl 1]45:66S–71S 33. Gordin A, Daitzchman M, Doweck I et al. (2006) Fluordeoxyglucose positron emission tomography/computed tomography imaging in patients with carcinoma of the larynx: diagnostic accuracy and impact on clinical management. Laryngoscope 116:273–278 34. Grünwald F, Kälicke Th, Feine U, Lietzenmayer Ret al. (1999) Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicenter study. Eur J Nucl Med 26:1547–52 35. Haberkorn U, Strauss LG, Reisser Chet al. (1991) Glucose uptake, perfusion, and cell proliferation in head and neck tumours: relation of positron emission tomography to flow cytometry. J Nucl Med 32:1548–1555 36. Hauth E, Antoch G, Freudenberg LS et al. (2003) Einsatz der PET-CT und Ganzkörper-MRI bei Patienten mit Karzinom ohne gesicherten Primärtumor (CUP-Syndrom). Fortschr Röntgenstr: http://wwwthieme.de/roefo/abs. 37. Heath JR, Phelps ME, Hood L (2003) Nano systems biology. Mol Imaging Biol 5:312–325 38. Heufelder AE, Joba W (2001) Der Natrium-Jodid-Symporter in der Diagnostik und Therapie von Schilddrüsenerkrankungen. Der Nuklearmediziner 24:117–127 39. Hör G (1993) Positronen-Emissions-Tomografie (PET) – von der Forschung zur Klinik. Dtsch Ärztebl 90:1883–1892 40. Hör G, Maul FD, Standke R, Munz D (1981) Scintigraphy in oncology-review on present, outlook on further possibilities: 201 TlCl. IAEA, Vienna, pp 487–495 41. Ito S, Kato K, Ikeda M et al. (2007) Comparison of 18F-FDG PET and bone scintigraphy in detection of bone metastases of thyroid cancer. J Nucl Med 48:889–885 42. Kim H, Boyd J, Dunphy F, Lowe V (1998) F-18 FDG PET scan after radiotherapy for early stage larynx cancer. Clin Nucl Med 11:750–752 43. Kim SY, Roh J, Kim M et al. (2007) Use of 18F-FDG for primary treatment strategy in patients with squamous cell carcinoma of the oropharynx. J Nucl Med 48:752–57 44. Kluetz PG, Meltzer C.C, Villemagne VL et al. (2000) Combined PET/CT imaging in oncology: impact on patient management. Clin Positron Imag 3:223–230 45. Kouvaraki MA, Shapiro SE, Fornage BD et al. (2003) Role of preoperative ultrasonography in surgical management of patients with thyroid cancer. Surgery 134:946–954 46. Lardinois D, Weder W, Hany ThF et al. (2003) Staging of non-small cell lung cancer with integrated positron emission tomography and computed tomography. N Engl J Med 348:2500–2507 47. Lowe VJ, Boyd JH, Dunohy FR et al. (2000) Surveillance for recurrent head and neck cancer using positron emission tomography. J Clin Oncol 18:651–658 48. Lowe VJ, Kim H, Boyd JH et al. (1999) Primary and recurrent early stage laryngeal cancer: preliminary results of 2-(fluorine 18) fluoro-2 deoxy-D glucose PET imaging. Radiology 212:799–802 49. Mazzaferri EL (2005) Empirically treating high serum thyreoglobulin levels. J Nucl Med 46:1079–1088 50. Mazzaferri EL, Kloos RT (2002) Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 87:1490–1498

51. Miehel K, Paschke R (2004) Molekulargenetik und molekulare Diagnostik bei Schilddrüsenerkankungen. Nuklearmediiziner 27:120–122 52. Minn H, Paul R, Ahonen A (1988) Evaluation of treatment response to radiotherapy in head and neck cancer with 18 Fluorodeoxyglucose. J. Nucl. Med. 29:1521–1525 53. Muhle C, Brenner W, Südmeyer M et al. (2004) CT-guided lymphoscintigraphy in patients with squamous cell carcinoma of the head and neck: a feasibility study. Eur J Nucl Med Molec Imaging 31:940–944 54. Munz DL (2001) The sentinel lymph node concept in oncology. Zuckschwerdt, München 55. Munz DL, Maza S, Ivancevic V, Geworski L (2000) Classification of the lymphatic drainage status of a primary tumour: a proposal. Nuklearmedizin 39:88–91 56. Nakamoto Y, Tatsumi M, Hammoud D et al. (2005) Normal FDG distribution pattern in head and neck: PET/ CT evaluation. Radiology 234:879–885 57. Newman JS, Francis IR, Kaminski MS, Wahl RL (1994) Imaging of lymphoma with PET with 2-(F-18)-fluoro2-deoxy-D-glucose: Correlation with CT. Radiology 190:111–116 58. Ng S, Chang JT, Chan S et al. (2004) Nodal metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET. Eur J Nucl Med Mol Imaging 31:1073–1180 59. Ng SH, Yen TC, Liao ChT et al. (2005) 18F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med 46:1136–1143 60. Oehler W, Baum RP (2004) Aktueller Beitrag der PET und PET/CT zur Zielvolumenmodulation für die biologischmedizinische Planung im Rahmen der intensitätsmodulierten Strahlentherapie (IMRI). Der Nuklearmediziner 27:324–329 61. Ott RJ, Batty V, Webb S, Flower MA et al. (1987) Measurement of radiation dose to the thyroid using positron emission tomography. J Radiol 60:245–251 62. Pauleit D, Zimmermann A, Stoffels G et al. (2006) 18F-FET PET compared with 18F FDG PET and CT in patients with head and neck cancer. J Nucl Med 47:256–261 63. Paulus P, Sambon A, Vivegnis D et al. (1998) 18F-FDG PET for the assessment of primary head and neck tumours: clinical, computed tomography , and histopathological correlation in 38 patients. Laryngoscope 108:578–583 64. Regelink G, Brouwer J, de Bree R et al. (2002) Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDGPET versus conventional modalities. Eur J Nucl Med 29:1024–1030 65. Reske S, Kotzerke J (2001) FDG-PET for clinical use (Results of the 3rd German Interdisciplinary Consensus Conference, “Onko-PET III”, 21st July and 19th September 2000). Eur J Nucl Med 28:1707–1723 66. Ringel MD, Balducci-Silano PL, Anderson JS et al. (1999) Quantitative reverse transcription-polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma. J Clin Endocrinol Metabol 84:4037–42 67. Rosenbaum S, Freudenberg L, Pink R et al. (2004) PET/CT-Stellenwert beim Schilddrüsenkarzinom. Der Nuklearmediziner 27:272–277 68. Schoder H, Carlson DL, Kraus DH et al. (2006) 18F-FDG

7.4 PET/CT for detecting nodal metastases in patients with oral cancer staged NO by clinical examination and CT/ MRI. J Nucl Med 47:755–762 69. Schlüter B, Bohuslavizki KH, Beyer W, et al. (2001) Impact of FDG PET on patients with differentiated thyroid cancer who present with elevated thyreoglobulin and negative 131I scan. J Nucl Med 42:71–76 70. Schmidt D, Herzog H, Langen KJ, Müller-Gärtner HW (1994) Glucose metabolism in thyroid cancer metastases. Exp Clin Endocrinol 102:51–54 71. Schoder H, Yeung HW. (2004) Positron emission of head and neck cancer, including thyroid carcinoma. Semin Nucl Med 34:180–197 72. Schonberger J, Ruschoff J, Grimm D et al. (2002) Glucose transporter I gene expression is related to thyroid neoplasms with an unfavorable prognosis: an immunohistochemical study. Thyroid 12:747–754 73. Shah JP (1990) Patterns of cervical lymphnode metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg 160:405–409 74. Shields A, Mankoff D, Link J, Graham M, Eary J, Kozawa S, Zheng M et al. (1998) Carbon 11 Thymidine and FDG to measure therapy response. J Nucl Med 39:1757–1762 75. Shu-Hang Ng, Chang Tung-Chieh J, Sheng-Chieh Ch et al. (2004) Clinical usefulness of 18F-FDG PET in nasopharyngeal carcinoma patients with questionable MRI findings for recurrence. J Nucl Med 45:1669–1676 76. Steinkamp HJ, Hosten N, Langer R, Mathe F, Ehritt C, Felix R (1992) Halslymphknotenmetastasen. Sonographischer Malignitätsnachweis. Fortschr Röntgenstr 156:135–141 77. Stuckensen T, Kovacs AF, Adams ST, Baum RP. (2000) Staging of the neck in patients with oral cavity squamous cell carcinoma: a prospective comparison of PET, ultrasound, CT and MRI. J Craniomaxillofac 28:319–324

References

78. Sundaresan G, Yazaki PJ, Shively JE et al. (2003) 124I-labeled engineered anti-CEA minibodies and diabodies allow high-contrast, antigen-specific small animal PET imaging of xenografts in athymic mice. J Nucl Med 44:1962–1969 79. Torabi M, Aquino SL, Harisinghani M (2004) Current concepts in lymph node imaging. J Nucl Med 45:1509– 1518 80. Vogl T, Mees K, Muhlig M, Lissner J (1987) Magnetic resonance imaging in diagnosing diseases of the neck. Hospimedica 5:1–2, 17 81. Vogl TJ, Grevers G, Lissner J (1992) Die Magnetresonanzverfahren für die Tumordiagnostik in der Kopf-HalsRegion. Dt Ärztebl 89:B-2539-B-2546 82. Wang W, Larson SM, Tuttle RM et al. (2001) Resistance of (18F-) fluorodeoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioiodine. Thyroid 11:1169–1176 83. Wax MK, L Myers L, Gubulski EC et al. (2002) Positron emission tomography in the evaluation of synchronous lung lesions in patients with untreated head and neck cancer. Arch Otolaryngol Head Neck Surg 28:703–7 84. Weissleder R, Elizondo G, Wittenberg J et al. (1990) Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 175:489–493 85. Yasuda S, Shotsu A, Ide M et al. (2007) Chronic thyreoiditis: diffuse uptake of FDG at PET. Radiology :775–778 86. Yau K, Price P, Pillai RG, Aboagye E (2006) Elevation of radiolabeled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidilate synthase inhibitors. Eur J Nucl Med Mole Imaging 33:981–987 87. Reiser M, Kuhn F-P, Debus J (eds) (2004) Radiologie. Thieme-Verlag Stuttgart

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8

Dermatology

CONTENTS 8.1 Malignant Melanoma (MM) Introduction 419 Significance of PET 421 Pitfalls 421 PET Indications 421

8.1 Malignant Melanoma (MM) 419

8.2 Case Studies 422 Patient 1 Malignant Melanoma of the Right Thigh 422 Patient 2 Recurrent Melanoma 424 Patient 3 Metastasized Melanoma 426 Patient 4 Choroidal Melanoma 427 Patient 5 Metastasized Amelanotic Melanoma 428 8.3 References

Malignant Melanoma (MM)

433

Introduction Not only in the field of PET have dermatologists and nuclear medicine physicians in Frankfurt, Germany, traditionally co-operated well [13, 14, 15]. Even before the PET era, and in addition to skeletal scintigraphy (e.g. for rheumatoid arthritis, psoriatic osteopathy), scintigraphic methods were already available, comprising primarily 67Ga citrate scintigraphy and immunoscintigraphy, used in particular in cases of lymph node metastases with 99mTc-labeled monoclonal antibody Fab fragments and which demonstrated higher sensitivity (93%) than radiological methods (73%). However, since the former method is somewhat unspecific and the tracer accumulates due to inflammatory and AIDSassociated processes and the latter method displays a relatively high unspecific accumulation in the liver, kidney and intestines, oncological 18F-FDG-PET has prevailed, initially within the scope of pilot projects dealing with high-risk MM (in Zurich, Frankfurt and Tübingen). The sensitivity values ranged from 74% up to almost 100% if the number of metastatic sites was higher than 5. Some teams (Hamburg, Baltimore) made deliberate restrictions with regard to PET in sentinel node biopsy (SNB=24%–49% sensitivity, PET=16.7%, PPV=50%, SNB=100%), but PET was nevertheless evaluated as influencing the staging accuracy favourably (40% upstaging, 11% downstaging) [17, 27]. A cumulative evaluation of PET/CT was performed in Stanford on 106 patients with advanced stage cancers (III and IV) [16]. An earlier prospective PET study on 100 patients was disregarded [23], as were other European/Swiss guidelines which were already available [8]. Different procedures are

419

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recommended, depending on stage classification. CT and PET are only recommended if the Breslow thickness is >4 mm and/or lymph node metastases are found [11]. A direct comparison of PET/CT and PET alone in the same patient cannot be ethically justified; the use of PET (and PET/CT at an earlier stage) must be, in our opinion, revised on an individual basis [16]. Epidemiology, Incidence and Etiology. The incidence is increasing worldwide in the Caucasian population (with a slightly pigmented light skin); 59,580 new cases were expected in the US in 2005, i.e. approx. 4% of all expected cancer cases. At particularly high risk are red-haired individuals with light skin and numerous nevi, as well as patients with pre-stages of melanoma similar to dysplastic nevus syndrome. There is a direct correlation with exposure to the sun, including excessive single exposures during childhood. So-called polygenic hereditary factors favour MM formation. The majority of malignant melanomas develop from preexisting nevi. The age-standardized incidence rate estimated by the German Robert-Koch-Institut (www.rki.de) for the year 2000 amounted to 11.9 (men) and 12.1 (women)/year per 100,000 inhabitants. In Australia, with its extreme solar radiation and high proportion of light-skinned and frequently red-haired people, the estimates total 30–60 new cases/year per 100,000 inhabitants. MM patients bear the risk of a second disease related to the malignant melanoma. Distant metastases (CNS, lung, spleen) considerably impair the chance of recovery. The highest survival rate is registered for stage I with more than 90% after 5 years and approximately 80% after 10 years; a low survival rate is achieved with stage IV (less than 10%) [18]. Diagnosis and Aftercare. Clinical evaluation of pigment lesions is governed by the A-B-C-D rule:  Asymmetry of the mole or birthmark  Border, irregular  Color (or discoloration) is not the same all over  Diameter (more than 6 mm) Most malignant melanomas are due to epidermal melanocyte proliferation. We distinguish between superficial spreading melanoma (more than 50%), nodular melanoma, lentigo-malignant melanoma, acral lentiginous melanoma and non-classifiable melanoma. The most important prognostic fac-

tors are the vertical tumour thickness according to Breslow, ulceration, depth of invasion according to Clark, detection of micrometastatic spread, gender (men have a poorer prognosis) and tumour localization. Important diagnostic features include clinical examinations, laboratory examinations, chest Xray (CXR), ultrasound examinations and – optionally for high risk MM to exclude metastatic spread – skull CT/MRI and skeletal scintigraphy. Scintigraphic mapping of lymphatic drainage – as developed by Munz 1 – is today part of the coordinated expertise of the DGN expert committees [25]. The need for sentinel node in-transit lymphatic outflow scintigraphy and the related problems with intrasurgical control are described in the relevant literature [7, 26]. Scintigraphic documentation using 99mTc-interleukin-2 was successful as a cell activation signal. Expression of the CD25 T lymphocyte cluster (IL2R as receptor) against melanoma cells might still be proven during the pre-stage of FDG signal incisiveness [24]. Therapy. For patients with stage I/II cancer, therapy consists of tumour excision; in case of inoperability or non-R0-resection, lymph node, skin and bone metastases therapy consists of (adjuvant) radiotherapy, also in combination with hyperthermal treatment; and in case of increased risk of metastatic spread, adjuvant immunotherapy with interferon-alpha-2a or 2b. Under certain conditions, inoperable recurrent tumours, inoperable regional metastases, as well as distant metastases (stage IV) are indications for systemic chemotherapy. Several experimental immunotherapies are scheduled for trials (peptide immunization, vaccination with dendritic cells, hybrid vaccines, etc., see guidelines issued by the German Cancer Society and the German Society of Dermatology, German Association of Scientific Medical Societies (AWMF) guideline register 032/024). Patients diagnosed with stage I and II, as well as 20% of patients with lymph node metastases (without distant metastases), can be cured by surgery; for patients diagnosed with stage IV and M1 only palliative treatment can be considered.

1

Munz DL (2001) The sentinel lymph node concept in oncology. Zuckschwerdt, München

8.1

Significance of PET For high-risk melanomas the conclusions cited in the first pilot study [4, 5, 21, 26] are still valid: Earlier stages (micrometastases, stages I and II) can be best detected by combined FDG-PET and sentinel node biopsy; the differentiation of stage I/II with PET alone was classified as being inadequate [5], since only 14% of the nodally positive lymph nodes were detected by the FDG-PET scan. Other proliferation markers such as 18F-FLT should be mentioned in this context since their successful application has been mentioned with respect to numerous tumours (breast, larynx, soft tissue tumours). In case of melanomas, attempts to determine the point in time at which melanocytes are transformed into malignant melanoma cells failed (to date). With regard to expected therapeutic outcome, FDG-PET can also be recommended for patients suffering from advanced-stage melanoma (sensitivity 92%, specificity 88%, accuracy 91%). Initial results are also reported in patients with high-risk melanomas. Small tumours and micrometastases remain problematic [12, 22, 23]. FDG-PET. The first results of the prospective study performed in Frankfurt, Germany, with primary diagnosis correlated with follow-up scans or biopsy [23] was encouraging: sensitivity 100%, specificity 94%, diagnostic accuracy 95% compared with 68% accuracy achieved by conventional diagnosis. Overall data are not particularly useful with a sensitivity ranging from 22% to 100%. Correlations referring to volume/stage factors are more valid [19, 20]: According to this approach, the detection threshold for lymph node metastases is above a volume of 70 mm3 (sensitivity 90%, for smaller volumes 14%) [20]. Tumours with a volume of 80 mm3 can be classified as stages III–IV. Crippa et al. also demonstrated a stage-dependent sensitivity of 95% for stage III, for stage II they evaluated PET as being the “second best method” after sentinel node biopsy. PET is not the best choice for small-volume disease. Only 23% of large foci up to 5 mm are detected with PET, while PET detects 83% of all foci larger than 5 mm and 100% of those larger than 10 mm [6]. PET is best suited to stage III disease for the detection of regional lymph node involvement as well as

Malignant Melanoma (MM)

distant metastases in organs (e.g. spleen, according to our own experience) and thus for therapy management as well as in studies testing new treatment methods (immunotherapy, interferon). Therapy strategies for patients with favourable reports are altered following FDG-PET scan in up to 53% of all cases, 26% of 283 patients [10].

Pitfalls False-positive PET findings are due to inflammation and artefacts, e.g. as a result of muscle activity, while false-negative findings are due to lesions 38°C (Pel-Ebstein fever), night sweats, weight loss of more than 10% of the body weight over the previous 6 months], reduced vitality and, in some cases, also pruritus. Among other diagnostic methods, HL and NHL are diagnosed as follows:  Lymph node biopsy, bone marrow biopsy, immunohistochemistry  Laboratory examinations such as haemogram, clotting, liver enzymes, LDH, creatinine, a2-microglobulin  Electrophoresis, determination of the lymphocyte subpopulations (CD4+, CD8+)  Cytogenic examinations in case of chronic lymphatic leucemia (CLL) for prognosis evaluation  Serology: HIV, hepatitis B and C, CMV, EBV

thorax/abdomen performed for propagation diagnosis, in rare cases also MRI, and possibly also cerebrospinal puncture. In case of clinical suspicion of bone involvement, skeletal scintigraphy may be useful; PET is considered as being an optional solution. PET and PET/CT have proved to be relevant for diagnosing malignant lymphomas, but of varying relevance with respect to Hodgkin’s and nonHodgkin’s lymphomas. Except for stages characterized by microdissemination, PET scans are also recommended for early stages of HL. However, an established spectrum of diagnostic approaches is available to oncological internists dealing with identification, localization and expansion, i.e. the preconditions for appropriate therapy [7, 16]. Hodgkin’s Disease. Subgroups: nodular sclerosis (approximately 60%–70%), mixed cellularity (approximately 25%, in older patients), more rarely lymphocyte-rich and lymphocyte-depleted (“poor”) forms. Subclassifications (CD20, CD45) have not been systematically compared with FDG-PET as yet. Since the central European Hodgkin’s study centre in Cologne, Germany, has been given formal status, we can expect competent guidelines similar to the approach established in Leipzig for PET lymphoma classification in childhood (Table 9.1). Non-Hodgkin’s Lymphomas. With regard to NHL [e.g. (B, T) lymphoblastic lymphoma, CLL, Burkitt’s lymphoma, MALT lymphoma, cutaneous T-cell lymphomas] we have to distinguish between precursor cells and mature B-cell or T-cell lymphomas, according to the WHO classification.

Table 9.1. Ann Arbor classification (also applies to NHL) Stage I

Involvement of a lymph node region (I/N) or an extranodal focus (I/E)

Stage II

Two or more affected lymph nodes, homolateral diaphragm (II/N) or localized extranodal foci with involvement of one or several lymph nodes on one side of the diaphragm (IIE)

Stage III Like stage II, however on both sides of the diaphragm (III/N, III/E)

Imaging Methods Radiological imaging methods include, for example, chest X-ray, sonography and CT scan of the neck/

Stage IV Disseminated involvement of one or several extralymphatic organs In addition, the letters A and B denote absence and presence of general symptoms respectively(B symptoms, cf. above)

9.2

According to our knowledge the relatively comprehensive data pool does not contain any separately classified studies dealing with the above-mentioned or other subpopulations. Secondary tumours detected after chemotherapy are (marginal) indications for PET.

FDG-PET Dominant strengths of PET are primary staging, secondary staging and therapy monitoring of malignant Hodgkin’s and non-Hodgkin’s lymphomas. Comprehensive data is available for HL, while less data is available for NHL [11, 12, 30]. In 1970 a group of patients suffering from lymphoma was presented for the first time in the first European multicentre study 1 with 67gallium citrate; this study was later compared with 67Ga-PET and 201Tl and – until recently – with 99mTc compounds [24, 29, 42]. Today, the majority of experts hold the opinion that there is no doubt about the superiority of FDG-PET. First PET studies were performed with 11C components [22, 23, 28] to make a metabolic differentiation between high-grade and low-grade lymphomas. Since the 1990s 18F-FDG has been used for clinical applications since it is better suited to this end and yields comparably accurate results [44]: sensitivity, specificity, positive and negative predictive value were rated at up to 100% in favourable expert opinions (CT: 20, 83, 50, 56%). The following data were gathered in Ulm [3]: sensitivity, 86% – for restaging 100%; specificity, 96%; PPV, 75%; NPV, 98%; diagnostic accuracy, 95%. The consensus conference “Onko-PET III” classified staging and therapy monitoring for Hodgkin’s disease as 1b (probable clinical benefit), and highly malignant NHL as 1b (staging) or 1a (therapy control, proven clinical benefit). At that time (July 2000), low-malignancy NHL were classified as unevaluable because the required data was not yet available [30]. Depending on the histological parameters, metabolic activity of lymphomas may be classified according to a high, low or absent degree of FDG avidity which – similar to other malignomas – may correlate with the activity/expression of the glucose transporter (GLUT 1) and special constellations of the genome (see “functional genomics and proteomics”). 1

See [31a], p. 9

Diagnosis

PET is preferably suited to (large-cell) malignant lymphomas which are in general characterized by higher differentiation; small-cell, cystic, low-malignancy lymphomas can not, or barely, be evaluated with PET. A registration of early stages would be desirable, e.g. supradiaphragmatic lesions, stages I (and II), since short cycles of chemotherapy and local radiotherapy are adequate in these cases, while more intensive therapy is required for stages III and IV. The prognostic significance of PET and the impact on therapeutic strategy to be used during early stages are unchallenged [27, 34]. If different studies use different classifications (WHO, REAL – Revised European American [9]), it is somewhat difficult to compare stages – and this objection applies not only to PET but to all intermodal diagnostic imaging methods. In 172 patients with various lymphomas the sensitivity of PET-supported metabolic diagnosis was 100% for large B-cell lymphomas, 98% for HL, and less than 60% for small lymphocytic forms [32]. MALT Lymphomas. In contrast, extranodal B-cell lymphomas of the MALT type were not classified as being PET-differentiable. An appropriate PET contribution is being discussed [36]. PET in Childhood Hodgkin’s Disease. The number of adults who have undergone PET examination by far exceeds the number of children diagnosed using this imaging method [14, 20, 21, 39]. Comprehensive results are available in the PET study presented in Leipzig [39]. A wide range of derivable indications are already identifiable today with respect to staging, restaging, prognosis and therapy monitoring. In the patient population of the Leipzig study, which comprised children suffering from Hodgkin’s disease, 1743 regions were analyzed by directly comparing PET with conventional methods [21]: Negative concordant results were found in 69.7%, positive concordant results in 22.3%, while in 5.5% bone involvement could be verified with PET only.

Response Evaluation The mode of therapy response criteria has been recently modified. More objective precision was assigned to FDG-PET; some authors call for a new definition [1, 40].

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Lymphomas

The basic consensus is that a nuclear medicine physician should meet the following requirements as stipulated by an oncologist: “minimize treatment for local response lesions, maximize in far-advanced disease (FAD), avoid over-/undertreatment”. A struggle for the best possible PET strategy is currently on-going [19]. Vital lymphomas following six HOP cycles (probably) indicate therapy resistance. CT criteria alone show no grounds to believe that an alternative chemotherapeutic substance would be advantageous. Additional radiotherapy is not unproblematic with regard to late toxicity – especially in case of bulky and limited stage disease. In this context, PET/ CT can reduce the doubts which were so far related to the decision of whether the tumour is resistant to chemotherapy and/or radiotherapy, and the risk of radiotherapy can be reduced. Salvage radiation performed less than 1 year after chemotherapy in case of recurrent Hodgkin’s lymphomas was not deemed to be useful in the past [10]. This opinion can be modified today due to progress in the field of bone marrow transplantation, the efficiency of which can be controlled with PET/CT [6, 34, 33]. In case of aggressive lymphomas this also applies to high-dose chemotherapy which some teams consider as a justifiable indication for PET/CT [19]. After completion of therapy the nuclear medicine physician should also take an oncological evaluation into account. CR = “complete remission”, PR = “partial remission”, PR = “progression”, RD = “residual disease”. According to the IOWA study [17] CR was most reliably evaluated with PET/CT (92%). For aggressive NHL, PET/CT-based therapy response evaluation was declared to be a new and the best possible standard [34, 35, 43]. Quantitative PET (SUV, input function) – with simplified handling features – is recommended for therapy monitoring. Positive PET means a shortened progression-free interval. The – even critically evaluated – SUV value decreases according to experience gained by some teams: A therapy response reaction can be registered already after the fi rst chemotherapy cycle. PET and PET/CT are superior to CT alone and MRI. Therapy response and failure are amongst the most urgent PET matters of concern and proven strengths which in case of child related lymphomas have fulfi lled certain expectations in wider studies [20]. In particular, for patients suffering from aggressive HL the earliest discernible

response rate after the first (!) therapy cycle would bring enormous benefits [27]. From a total of 407 patients, management was changed in 21%, staging for tumours diagnosed for the first time in 5% and for recurrent tumours in 10% of all cases [32].

Comparison of FDG-PET, 67Ga and CT According to Wirth et al. [42] the “case positivity” was 90% using conventional methods, 67% with gallium and 98% with PET. With a combination of all methods detection reliability was increased to 100% [29, 36, 42].

Autologous Stem Cell Therapy Autologous stem cell therapy is incorporated in the strategy deployed by oncological internal medicine and is thus also a new indication for PET. Aggressive lymphomas prior to and after autologous stem cell transplantation were reviewed within the scope of preliminary PET studies – but initially only at the preclinical stage.

PET/CT Restaging Some studies confirmed that dual imaging yields the most favourable degree of safety for all parameters reviewed. The following values were achieved for a patient population of n = 135. Sensitivity 96%, specificity 99%, PPV 96%, NPV 99%, diagnostic accuracy 99% [11]. Taking into account the different patients, these values were identical to the values registered for conventional PET and CT examinations, but they were better than for PET alone and CT alone, with the latter yielding comparatively poor results. “To Enhance or Not to Enhance?” This question was also discussed by the group working in Essen (although in a different context). A study performed in Zürich, Switzerland, on Hodgkin’s lymphomas and 18 patients suffering from high-grade non-Hodgkin’s lymphomas came to the conclusion that PET/ CT with non-enhanced CT is more sensitive and

9.2

more specific than a contrast-enhanced evaluation of the lymph node and organ involvement [32]. PET/CT thus play a leading role in (re-)staging methods and this fact should be taken into account for future competent guidelines. Their contribution in terms of staging (upstaging, downstaging) and impact on therapy design are of consistently high quality and importance. The German Radiation Protection Commission expressed its opinion in this regard in 2004 [2] (Table 9.2). The response classification which is already favourable with PET alone, even for NHL [17, 35], becomes increasingly relevant with PET/CT. The differentiation between vital residual and non-vital residual tumour masses will be a determining factor for therapy. The question of how PET, once it is integrated in clinical routine, can influence survival times must be answered within the scope of longitudinal studies. Table 9.2. Advantages and disadvantages of PET/CT Advantages of PET/CT

Disadvantages, pitfalls

Biopsy can be guided more precisely Tumour stages can be defined more exactly Strategy modification

Costs

Reduction of false positive and false negative findings Response classification (after tumour therapy) Regional nodal staging Extranodal staging Distant metastases Radiotherapy planning with dose reduction, extratumoural Exacter borders (mediastinal/lung) Artefact reduction

Tumour vital (residual) components (radiological masses) Mislocation avoidable (liver/diaphragm/lung base) Prognosis Cost efficiency and remuneration

Low-grade tumours Radiation exposure for unfavourable case max. 60 mSv Artefacts (cf. this chapter)

MSCT (16 lines, 25 s scans) Respiratory gating? Respiratory mid-position? Contrasting agent, yes or no? Standard care CT?

Infectuous foci Atheromatomous plaques (aorta, carotids, coronary vessels) Infected vascular grafts

Artefacts Misevaluations occur when – following chemotherapy – residual inflammations with activated neutrophilic granulocytes/macrophages manifest false positive FDG foci. The proportion of BAT is relatively high for phaeochromocytomes (catecholamine excess). 18F dopamine can be used to visualize local sympathetic innervation. With dopamine, BAT was visible in 18% of 67 patients, with FDG in 19% of 83 patients [13]. The following artefacts can occur:  Muscle, fat (WAT, BAT)  Kidney/urinary tract  Contrast agent  Gastro-intestinal tract  Metal implants  Respiration (respiratory gating)  Hibernoma (lipoma)  Pneumonias  APS (autoimmune proliferative syndrome) [37]

Other Problems Autoimmune proliferative diseases may display metabolic patterns similar to the patterns of HL/ NHL [37], which can only be distinguished from one other by clinical/bioptic examinations. The morphological analysis performed to predict the metastatic tumour load [38] is generally superior to PET because it is well known that PET cannot detect microdisseminations (up to 5 mm). Isolated spleen involvement and initially solitary pulmonary manifestations are also problematic. FDG-PET cannot be used for differential diagnosis of malignant SPN. Furthermore, occult multiple myelomas and hibernomas should be mentioned.

PET Indications Thymus artefacts in children

Diagnosis

    

Staging Restaging Recurrent tumours Prognosis Therapy monitoring/follow-up

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9.3 Case Studies Patient 1 Follicular Non-Hodgkin’s Lymphoma Clinical history: A 67-year-old patient with a history of follicular Non-Hodgkin’s lymphoma. Status post hemilaminectomy T8 vertebral body on the right and radiation therapy T6 to T9 vertebral body. Status post extirpation of the mandibular lymph node on the left side with subsequent percutaneous radiation therapy. Lymph node manifestation in the right inguinal region 8 weeks later. Status post percutaneous radiation therapy T9 to T12 vertebral body due to a recurrence 4 years after the first manifestation. Intraspinal mass on the right side in the lumbocaudal region 4.5 years later. A further recurrence in the area of the 7th, 8th and 9th thoracic vertebral body on the right with massive infi ltration of the adjoining pleura on the right at the level of the 10th rib. PET/ CT showed an almost complete regression of the activity in the whole body scan after completion of the therapy except a small metabolically active area paravertebrally on the right side of T10 vertebral body and in the paravertebral rib area of the 9th rib on the right 6 months previously. PET/CT indication: restaging.

Findings: Once again, progressive course of the follicular Non-Hodgkin’s lymphoma with manifestation on the right side paravertebrally to T7, T9 and T10 vertebral body with involvement of the adjoining pleura region. In addition, several small hilar and mediastinal lymph nodes, as well as several lymph nodes in the area of the right groin and at least one lymph node in the left groin, were found with increased glucose metabolic activity such that another manifestation of the lymphoma must also be assumed here. Teaching points: The fourth PET/CT follow-up examination performed after several therapeutic interventions provides a very good overview of the actual tumour spread and can reliably distinguish hypermetabolic tissue from non-suspicious lymph nodes.

Fig. 9.1.1. Sagittal PET/CT slice showing thoracic spine involvement

Fig. 9.1.2. Marked involvement in the area of the T10 vertebral body with involvement of the adjoining pleura

9.3 Case Studies

Fig. 9.1.3. Pleural involvement in the transaxial PET/CT slice

Fig. 9.1.4. Right inguinal lymphoma on the transaxial PET/CT slice

Fig. 9.1.5. Small abdominal lymphoma on the right side, in front of the right hip joint, in the transaxial PET/CT image

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Patient 2 Metastasized Non-Hodgkin’s Lymphoma Clinical history: A 74-year old male with lymphoma of the left groin, meanwhile diagnosed as a NonHodgkin’s lymphoma. Chemotherapy for 6 months. The patient then underwent radiotherapy to the left groin and the testicle with a total dose of 39 Gy. Subsequent development of considerable oedema in the suprapubic region, the scrotum, the penis and, to a minor extent, also the proximal femur. PET/CT indication: Propagation diagnosis of the Non-Hodgkin’s lymphoma. Findings: Multiple involvement of the skeleton in the area of the right middle humerus shaft, the right humeral head, as well as the right clavicle and the left acromion. Involvement of the left 8th and right 9th lateral rib, as well as the left transverse process and the adjoining muscles of the T8 vertebral body.

Further involvement is found in the area of the proximal femur shaft on the right side and of the middle femur shaft on the left side. A large lymphoma parabasally on the right side at the level of the socket base of the hip bone and in the left groin area, as well as paracavally at the level of the base of L1. Massive abdominal wall oedema in the suprapubic region, also involving the scrotum and penis. Due to the remarkably high glucose metabolic activity this area is suspicious for carcinomatous lymphangiosis. Teaching points: The considerable metastatic involvement of the skeletal system, lymph nodes and also of the soft tissue related to the Non-Hodgkin’s lymphoma could be verified by the PET-CT wholebody scan. The critically ill patient could be spared the originally planned “curative” therapy.

Fig. 9.2.1. Coronal sequence of slices acquired with PET with the increased glucose metabolic activity particularly demonstrated in the area of the pelvis and exterior genital organs

9.3 Case Studies

Fig. 9.2.2. MIP and three slice planes with considerably increased glucose uptake mainly in the pelvic region

Fig. 9.2.3. Sequence of transaxial PET/CT slices with the highest activity in the scrotum and the penis. Furthermore, lymphomas with increased metabolic activity in the left groin and a focus in the bone marrow of the right femur

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Patient 3 B-Cell Lymphoma in the Hypopharynx Clinical history: A 56-year-old male with a 15-year history of multiple sclerosis, 1-year history of dysphagias. First sign of trachyphonia 3 months previously. MRI-detected mass in the hypopharynx. Histological verification of a B-cell lymphoma 1 month previously. Start of the first chemotherapy cycle 1 day before the scan was performed. PET/CT indication: Propagation diagnosis for further therapy planning.

Findings: High-grade malignoma-typical metabolism in the area of a lymphoma conglomerate in the larynx/hypopharynx area on the left side. No evidence of further lymphoma infi ltrates detected in the whole-body scan. Teaching point: Confirmation of the local findings. Exclusion of further metastasis.

Fig. 9.3.1. B-cell lymphoma, lymphoma conglomerate in the larynx and hypopharynx on the left side, otherwise unsuspicious whole-body scan

9.3 Case Studies

Fig. 9.3.2. B-cell lymphoma in the larynx/hypopharynx, transaxial slice

Fig. 9.3.3. B-cell lymphoma in the larynx/hypopharynx, transaxial slice sequence

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Patient 4 B-Cell Lymphoma Clinical history: A 50-year-old male with a history of B-cell lymphoma post combined radio-chemotherapy. Status post viral infection. Palpable lymph node in the left groin as well as axillary. PET/CT indication: Propagation diagnosis. Lymphoma involvement? Findings: Increased glucose metabolic activity in the area of a lymphoma conglomerate in the left inguinal area. In addition, also pathologic glucose metabolic activity in a row of lymph nodes in the left parailiacal region from the right aortic bifurcation to the paravesical region. No suspicious glucose utilization in the axillary region with lymph nodes increased to borderline values. Teaching points: PET/CT was able to exclude involvement of the axillary lymph nodes. Furthermore, increased metabolic activity could be confirmed in the area of the inguinal lymph nodes.

Fig. 9.4.1. Sequence of coronal slices acquired with PET/CT showing inguinal as well as left parailiacal lymphomas which must be classified as pathologic masses with regard to both the glucose metabolic activity and their size

9.3 Case Studies

Fig. 9.4.2. MIP representation as well as PET/CT slices in three planes with documentation of inguinal and left parailiacal lymphomas

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Patient 5 Lymphogranulomatosis, Nodular Sclerosis Clinical history: An 18-year-old female patient with lymphogranulomatosis of the nodular sclerosis subtype, initial stage IIa. Status post application of six therapy cycles. Partial remission. Residual mediastinal lymph nodes found in the last follow-up CT.

Findings: Detection of glucose metabolic activity in the area of multiple lymphomas in the anterior mediastinum, subcarinally, as well as in the left hilar region and also in the right cervical region typical of malignoma. No other structures suspected of lymphomas and no other suspicious manifestations. Teaching points: PET/CT enables a metabolically correct classification of the remaining lymphomas such that, owing to residual activity, the patient will have to undergo appropriate therapy.

a

b

Fig. 9.5.1.a–c. Transaxial PET/CT slice with lymphomas, the metabolic activity of which is documented by the corresponding SUV values

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9.3 Case Studies

Patient 6 T-Cell Lymphoma of the Cervical Lymph Tract Clinical history: A 39-year-old female patient with a proven T-cell lymphoma. Diagnosis for the first time 4 weeks previously (biopsy proven). Primary compact swelling in the supraclavicular area or at the base of the neck 8 weeks previously. Further mediastinal lymph nodes detected by CT. PET/CT indication: Further propagation diagnosis for therapy planning. Detection of further lymphoma infi ltrates. Organ manifestation?

Findings: The clinically proven T-cell lymphoma shows glucose metabolic activity typical of malignant growth in the area of a lymphoma conglomerate in the lower lymph tract on the left side of the neck and in the area of a mediastinal lymphoma retrosternally on the right side. No further lymphomas detected by whole-body scan. Teaching point: Reliable staging with the PET/CT whole-body scan.



Fig. 9.6.1. T-cell lymphoma conglomerate in the lower lymph tract on the left side of the neck in the three slice planes

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Fig. 9.6.2. T-cell lymphoma conglomerate, transaxial slice of the lower lymph tract of the neck

9.3 Case Studies

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Patient 7 B-Cell Lymphoma Clinical history: A 76-year-old female patient with highly malignant Non-Hodgkin’s lymphoma of the B-cell type with axillary lymphomas post therapy followed by immunotherapy. PET/CT indication: Follow-up for preliminary examination as well as propagation diagnosis. Findings: Glucose metabolic activity typical of malignant growth with tumour and lymphoma progress with considerable increase in size of the spleen permeated by lymphoma. Also detectable lymphomas in the splenic hilum as well as growing lymphoma inguinally on the right side. It can not be reliably excluded that the lymphoma has infi ltrated into the stomach wall. Teaching points: The course of the disease can be reliably evaluated during therapy with PET/CT follow-up.



Fig. 9.7.1. Sequence of coronal PET slices in which the manifestation in the projection to the spleen is particularly striking

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Fig. 9.7.2. MIP representation as well as PET/CT representation in all three slice planes. The lesion is readily visible in the area of the right groin and in the area of the spleen

Fig. 9.7.3. Transaxial PET/ CT slice with considerable lymphoma infi ltration of the spleen

9.3 Case Studies

Fig. 9.7.4. Lymphoma manifestation in the area of the splenic hilum

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Patient 8 Restaging of Hodgkin’s Disease Clinical history: A 41-year-old female patient with Hodgkin’s disease stage IIa. Tumour first diagnosed 1 year previously with supraclavicular and mediastinal localization. The patient underwent chemotherapy 1 year previously, with partial remission. The patient underwent radiotherapy in the mediastinal and supraclavicular area 2 months later. Restaging CT/MRI performed 4 weeks previously detected a lymphoma in the right axilla and further suspected lymphomas in the spleen/hilar area, as well as a mass in the upper splenic pole.

Known follicular nodular hyperplasia foci (FNH) in the liver segments V, VI and VII, as well as liver hemangiomas in segment V or VIII. PET/CT indication: Does PET/CT provide evidence of a recurrent metabolic disease? Propagation diagnosis and restaging. Findings: PET/CT localizes glucose metabolic activity typical of malignant growth in the area of right axillary lymphomas and in the diffusely and multifocally infi ltrated spleen. Furthermore, detection of lymphomas in the splenic hilum and in the area of the dorsal gastric wall, also in the area of an osseous lesion of the os sacrum, the pelvic and thoracic skeleton. Teaching point: Considerably improved therapyrelevant findings with PET/CT.

Fig. 9.8.1. Hodgkin’s disease IIa, post radiotherapy and chemotherapy with partial remission, recurrence in the right axilla

9.3 Case Studies

Fig. 9.8.2. Recurrence of Hodgkin’s disease, multilocular spleen involvement. Known FNH of the liver

Fig. 9.8.3. Osseous involvement in Hodgkin’s disease

Fig. 9.8.4. Osseous involvement in Hodgkin’s disease

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Patient 9 Recurrent Hodgkin’s Lymphomas Clinical history: A 51-year-old male with third recurrence of Hodgkin’s disease. Tumour fi rst diagnosed 16 years previously. Recently irradiated regional lymph nodes of the left hilum of the kidney following non-local PET findings. Last CT: Lung metastasis as well as abdominal lymphomas. Findings: Glucose metabolic activity typical of malignant growth associated with disseminated small foci of pulmonal metastasis. Detection of mediastinal lymphomas as well as axillary lymphomas on both sides, more on the right than on the left. In addition, mesenterial and retroperitoneal lymphomas. Furthermore, detection of a multilocular hepatic metastasis. Diffuse osseous or bone marrow metastases, no acute fracture hazard at present. Teaching points: Documentation of the multilocular manifestation of the Hodgkin’s lymphoma with the PET/CT (Figs. 9.5.1–9.5.6).

Fig. 9.9.1. Sequence of coronal and sagittal PET slices showing involvement of the pulmonary region, liver and osseous structures

9.3 Case Studies

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Fig. 9.9.2. Transaxial PET/ CT slice in the lung window showing disseminated small foci of pulmonal metastasis

Fig. 9.9.3. Multiple mediastinal lymphomas in the transaxial PET/CT image

Fig. 9.9.4. Right and left axillary lymphomas in the transaxial PET/CT image



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Fig. 9.9.5. Transaxial PET/CT image with proven mesenterial and retroperitoneal lymphomas

Fig. 9.9.6. Multilocular hepatic metastasis in a transaxial PET/ CT image

9.3 Case Studies

Patient 10 Chronic Lymphatic Leukaemia Clinical history: A 65-year-old female patient with chronic lymphatic leukaemia of 14 years’ duration. Chemotherapy during the previous 2 years which had to be interrupted due to poor tolerance by the patient. Radiotherapy of the whole lumbar spine 3 months previously. Impact of family history (father intestinal cancer, mother also leukaemia). An osseous involvement of the L1 and L2 vertebral body, as well as the L5 vertebral body with paraosseous soft tissue infi ltration is known. PET/CT indication: Restaging.

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Findings: Increased activity in the right dorsal middle lung field and the right ventral lower lung field are manifestations of lymphatic disease. Another manifestation of malignant growth in the left upper renal pole. In addition, osseous manifestations in L1, L2 and L5 as well as in the dorsal ilium. Teaching points: PET/CT detects new pulmonary lesions as well as involvement of the upper left kidney area.

 Fig. 9.10.1. MIP representation as well as PET/CT representation in three slice planes. The images mainly highlight the osseous lesions due to their high metabolic activity as well as the slightly increased manifestations in the area of the lung

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Fig. 9.10.3a,b. The pictures document osseous manifestations in the area of the lumbar spine and the ilium on the left side

9.3 Case Studies

Patient 11 Restaging of the Multiple Myeloma Clinical history: A 62-year-old male first diagnosed with multiple myeloma with diffuse involvement of the whole spine 2 years previously. Three cycles of induction therapy completed 1.5 years previously, as well as mobilization therapy with cyclophosphamide and successful stem cell apheresis. In spite of therapy further diffuse involvement of the marrow of the whole spine detected during an MRI scan. Radiotherapy to C7 to T6 vertebral body 6 months previously. First high-dose therapy using melphalan and autologous stem cell transplantation 3 months previously. At present, MRI finds plasmacytoma foci less

461

than 10 mm in size in the area of the T12 vertebral body, as well as in the pedicle of the L2 and L3 vertebral body and the vertebral bodies of L3 up to S1. PET/CT indication: Restaging and evaluation of metabolic findings by PET/CT. Findings: The examination reveals metabolic activity of the still active plasmacytoma involvement mainly in the area of T11 to S1 vertebrae. Signs of instability are not displayed at present. Glucose metabolic activity suspected as malignant growth is now detected in the area of the left hip socket. No signs of metabolic activity in the other areas of the spinal column. Teaching point: Clear extension of the metabolically active plasmacytoma foci beyond MRI findings.



Fig. 9.11.1. Multiple myeloma with diffuse involvement of the whole spine. Lesion also in the left ilium, coronal slice

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Fig. 9.11.2. Multiple myeloma, diffuse involvement of the whole spine, sagittal slice

Fig. 9.11.3. Multiple myeloma with diffuse spine involvement, increase in metabolic activity during late enhancement imaging

9.4

9.4

References

1. Academy of Molecular Imaging (2005) Molecular imaging and biology (Scientific Abstracts of the 2005 Annual Conference of the Academy of Molecular Imaging, Orlando, Florida). Springer, Heidelberg, pp 79–180 2. Deutsche Gesellschaft für Nuklearmedizin (2004) Empfehlungen der Strahlenschutzkommission (Anwendung der Positronenemissionstomographie (PET) als effizientes dosissparendes Diagnoseverfahren). Nuklearmedizin PET 3:N35–N36 3. Bangerter M, Kotzerke J, Grieshammer M et al. (1999) Positron emission tomography with 18F-fluorodeoxyglucose in the staging and follow-up of lymphoma in the chest. Acta Oncol 38:799–804 4. Baum RP, Niesen A, Hertel A, Adams S, Kojouharoff B, Goldenberg DM, Hör G (1994) Initial clinical results with Tc99m labeled LL2 monoclonal antibody fragment in the radioimmunodetection of B-cell lymphomas. Cancer 73:896–899 5. Cremerius U, Fabry U, Neuerburg J et al. Positron emission tomography with FDG detect residual disease after therapy of malignant lymphoma. Nucl Med Comm 19:1055–1063 6. Cremerius U, Fabry U, Wildberger JE et al. (2006) Pretransplant positron emission tomography (PET) using fluorine-18-fluoro-deoxyglucose (FDG) predicts outcome in patients treated with high-dose chemotherapy and autologous stem cell transplantation. Bone Marrow Transplant 30:103–111 7. DeVita VT, Canellos GP (1999) The lymphomas. Semin Hematol 36:84–94 8. Eary JF et al (1990) Imaging and treatment of B-cell lymphoma. J Nucl Med 31:1257–68 9. Elstrom R, Guan L, Baker G et al. (2003) Utility of FDG PET scanning in lymphoma by WHO classification. Blood 101:3875–6 10. Fox KA., Lippman SM, Cassady JR et al. (1987) Radiation therapy salvage of Hodgkin`s disease following chemotherapy failure. J Clin Oncol 5:38–45 11. Freudenberg LS, Antoch G, Schütt P et al. (2004) FDGPET/CT in restaging of patients with lymphoma. Eur J Nucl Med Molec Imaging 31:325–329 12. Gambhir SS, Czernin J, Schwimmer J et al. (2001) A tabulated summary of the FDG PET literature. J Nucl Med [Suppl] 42:1–93 13. Hadi M, Chen CC, Whatley M et al. (2007) Brown fat imaging with 18F-6-fluorodopamine PET/CT, 18F-FDG PET/CT, and 123I-MIBG SPECTA study of patients being evaluated for pheochromcytoma. Eur J Nucl Med Mol Imaging 48:1077–1083 14. Hahn K, Pfluger Th (2004) Has PET become an important clinical tool in pediatric imaging? Eur J Nucl Med 31:615–621 15. Herrmann S, Wormanns D, Pixberg M et al. (2005) Staging in childhood lymphoma (differences between FDGPET and CT). Nuklearmedizin 44:1–7 16. Hoskin PJ (2003) PET in lymphoma:what are the oncologists needs? Eur J Nucl Med 30 [Suppl 1]:37–41 17. Juweid ME, Wiseman G, Mendal Y et al. (2004) Integrated positron emission tomography/computed tomography-

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34. Spaepen K, Stroobants S, Dupont P et al. (2001) Prognostic value of positron emssion tomography (PET) with fluorine-18 fluorodeoxyglucose(18F-FDG) after first-line chemotherapy in non-Hodgkin`s lymphoma: is PET a valid alternative to conventional diagnostic methods? J Clin Oncol 19:414–419 35. Spaepen K, Stroobants S, Dupont P et al. (2002) Early restaging positron emission tomography with 18F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 13:1356–63 36. Sun S, Kao Ch (2001) Negative results of 18F-FDG and 67 Ga-citrate scintigraphy in gastric MALT lymphoma. Ann Nucl Med Sci 14:183–186 37. Tartar M, Kipper MS (2004) Positron emission tomography scan findings of autoimmun lymphoproliferative syndrome. Mol Imaging Biol 6:124–125 38. Tatsumi M, Kitayama H, Sugahara H et al. (2001) Wholebody hybrid PET with 18FDG in the staging of non-Hdgkin’s lymphoma. J Nucl Med 42:601–608 39. Voelker T, Denecke T, Amthauer H et al. (2004) The use of FDG PET for primary staging in pediatric Hodgkin’s lym-

phoma: comparison with conventional imaging modalities (Abstr. 275). Eur J Nucl Med Mol Imaging [Suppl] 2 31:S270 40. Walter WA Forget about RECIST 1: Towards molecular imaging based treatment planning (zit. b. [1] Abstr. 67) 218 41. Weidmann E, Baican B, Hertel A et al. (1999) Positron emission tomography (PET) for staging and evaluation of response to treatment in patients with Hodgkin’s disease. Leukemia and Lymphoma 34:545–551 42. Wirth A, Seymour JF, Hicks RJ et al. (2002) Fluorine F-18 fluorodeoxyglucose positron emission tomography, gallium-67 scintigraphy and conventional staging for Hodgkin`s disease and non-Hodgkin’s lymphoma. Am J Med 112:262–268 43. Yamane T, Daimaru O, Ito S et al. (2004) Decreased 18 F-FDG uptake 1 day after initiation of chemotherapy for malignant lymphoma. J Nucl Med 45:1838–1842 44. Young CS, Young BL, Smith SM (1998) Staging Hodgkin disease with 18FDG-PET comparsion with CT and sugery. Clin Pos Imaging 1:161–164

1

RECIST = Defi nition, WHO “response-evaluation criteria in imaging staging”

10.1

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Oncological Orthopaedics

CONTENTS 10.1

Introduction

10.2

Significance of PET 465 PET Tracers 466 PET Indications 466

10.3

Case Studies 467 Patient 1 Sweat Gland Carcinoma 467 Patient 2 Haemangioendothelioma 470 Patient 3 Chondrosarcoma 473 Patient 4 Medullary Osteosarcoma 476 Patient 5 Clear Cell Sarcoma 478 Patient 6 Rhabdomyosarcoma 480 Patient 7 Rhabdomyosarcoma of the Left Thigh 482 Patient 8 Embryonal Rhabdomyosarcoma

10.4

References

Introduction

10.1 Introduction

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For more than 40 years bone scintigraphy has been one of the most frequently used examination methods in the field of nuclear medicine, although CT and to an even greater extent MRI have contributed to a reduction of the number of bone scintigraphy examinations (see the references on the DVD [Ö 10.1]). This was counteracted by the development of SPECT. Bone tumours, fever of unclear genesis, infectious and inflammatory diseases whose causes cannot be clarified are potential indications for scintigraphic examinations with 99mTc-labeled antigranulocytic antibodies (immunoscintigraphy).

10.2 Significance of PET PET centres have useful supplementary options at their disposal if they have to deal with bone tumours (recurrent tumours, prognosis, therapeutic decision [7, 13, 10, 25]) and inflammatory bone processes [6, 26]. PET/CT also turned out to be an advantageous imaging method in this context to make better diagnostic use of anatometabolic and molecular information [8], e.g. in case of:  osteosarcomas, chondrosarcomas and soft tissue sarcomas, as far as they display an adequate degree of FDG utilization;  scintigraphically invisible bone metastases;  soft tissue and bone metastases in juxtaposed regions can be subjected to a more differentiated evaluation due to the proposal of the Freiburg group [17]: 18F-FDG and 18F fluoride combination.

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PET Tracers With 18F-FDG (macrophage PET) and 18F sodium fluoride (osteoplastic-fluoroplastic reaction), PET has made new and reliable principles for metabolic osseous diagnosis available. Long before PET technology was developed (early and mid-1970s) and before PET scanners were implemented in clinical practice (initially in 1976 in UCLA), studies dealing with 18F fluoride had been published. Innovative approaches were directed towards PET studies comparing the histological degree of bone and soft tissue sarcomas with proliferation markers (Ki 67) and other molecular markers such as p53 [9]: These studies could not yet prove that such markers can be used to prognosticate the outcome of the disease independent of PET. Contrarily, the multimodal consensus model with imaging (also including PET) and molecular methods are considered as a safe standard. If a tumour is diagnosed for the fi rst time with 18F-fluoride PET, qualitative evaluation is usually performed, whereas the SUV value is used for therapy control and differential diagnosis to distinguish malignant from benign lesions. In fact, SUV is assumed to be strictly correlated with nonlinear regression (Patlak analysis), but it is not really significant for processes with low metabolic activity [5]. The potential applications of PET were comprehensively explored in Münster, Germany [13, 10, 11, 12, 14, 15]. First clinical examinations with 18F-FDG were then performed, and examining the bones with a PET scanner was recommended if the conventional skeleton scintigraphy yielded negative results – provided that such an examination seemed to be justified due to clinical findings as well as therapy-determining and prognostic indications [24]. A team working in Freiburg, Germany [17], proposed combining FDG-PET (soft tissue metastases) and 18F-fluoride PET (separation of bone metastases from superposed soft tissue metastases, e.g. vertebral bodies/lung) – “a feasible two-in-one-approach to cancer imaging”. A classification into grade I, II and III yielded an incremental SUV value (3.3 vs. 5.4 vs. 7.1) [4]: The sensitivity (detection of recurrent tumours), specificity, PPV and NPV amounted to 90, 76, 64 and 94%, respectively, with a cut-off SUV of 4. A standard

publication on septic bone surgery takes immunoscintigraphy and FDG-PET into account [2, 20]. Inflammatory bone processes have been diagnosed for more than 40 years by scintigraphy using bone-affinity radionuclides [18, 19]. Today, a fused PET/CT image is virtually a compulsory requirement to localize active foci in their anatomical environment [16]: sensitivity 94%, specificity 87% and accuracy 91%. Whether PET/MRI (instead of PET/CT) can further improve precision (soft tissue, oedema, fibrotic compartments) is still being discussed. Several generations would be occupied with experimental studies dealing with micro-PET [3] in order to analyze numerous (osseous) PET tracers during pre-clinical stages. It would be useful to establish score-based criteria catalogues similar to those used in radiology (for example, [1]), but that take an innovative radiopharmacy into account (18Ffluoride, -FLT, gene-based). For patients with Ewing’s sarcoma, the latest results obtained with PET/CT regarding sensitivity and specificity have proven to be more convincing than PET [22]. PET/CT has thus proven to be the better method, particularly with respect to highly differentiated sarcomas [21]. Tracers used in the past, such as 201Tl and 67Ga, are obsolete.

PET Indications  Bone metastases, if the conventional diagnosis cannot provide reliable results, and clinical consequences must be expected,  malignant bone tumours (pre-/postoperative, radiotherapy, recurrent tumours),  Ewing sarcoma metastases, osteosarcoma,  chemotherapy response,  differentiation of bone/soft tissue metastases (combined 18F-fluoride and 18F-FDG),  recurrent tumours, also in case of sarcomas in childhood and adolescence,  prognosis (osteosarcomas),  loosening of endoprothesis: mechanical, inflammatory, abrasion of polyethylene [6],  bone infi ltration in case of malignant lymphomas (generally superior to MRI),  graft viability after hip revision arthroplasty [23],  autologous femoral head graft.

10.3

10.3 Case Studies Patient 1 Sweat Gland Carcinoma Clinical history: A 91-year-old male status post mucinous multilocular sweat gland carcinoma. Progressive hypostenia for the past months. Multiple lung foci were found during the pre-examination; histological verification is not available yet. History of gunshot fracture of the right upper arm as well as through-and-through wound in the right lung. PET/CT indication: Malignancy of the pulmonary foci. Propagation diagnosis. Findings: PET/CT detects glucose metabolic activity consistent with malignancy in the area of the pleuropulmonary foci on the right side. The findings ultimately indicate a pleural carcinosis. The suspi-

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ciously increased glucose metabolic activity in the area of the pleuritis calcaria thoracica in the right anterior upper area is presumably due to a chronic inflammation. The rest of the whole-body scan does not reveal any evidence for further foci suspicious of or consistent with malignancy, and particularly no evidence of abdominal metastases. Teaching points: The detection of a pronounced pleural carcinosis clearly illustrates the complementary information gained by combined PET and CT. The pleural foci could not have been unequivocally classified without CT.

 Fig. 10.1.1. Sequence of coronal PET slices showing several foci in the thoracic region.

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Fig. 10.1.2. Sequence of transaxial PET/CT slices with the lung window setting. Multiple pleural and pulmonary lesions on both sides

Fig. 10.1.3. Sequence of transaxial PET/CT slices. These slices clearly illustrate a significant pleural apposition with both increased glucose metabolic activity and CT correlation

10.2 Fig. 10.1.4. Transaxial PET/ CT slice with the lung window setting. Mainly the increased glucose metabolic activities in the parietal region of both lungs are suspected of being pleuritis carcinomatosa

Fig. 10.1.5. Transaxial PET/CT slice with soft tissue window setting. Extended uptake consistent with malignancy in the left thoracic region

Fig. 10.1.6. Transaxial PET/CT slice with soft tissue window setting showing an apposition consistent with malignancy on the right ventral side in the area of the pleura

Fig. 10.1.7. Late enhancement image of the same lesion in the right thoracic region with an increase in activity consistent with malignancy

Significance of PET

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Patient 2 Haemangioendothelioma Clinical history: A 77-year-old female status post resection of a haemangioendothelioma from the right proximal thigh 2 years ago, then chemotherapy. Six months later, multiple liver metastases as well as diffuse metastatic spread into the lung. At present, the patient refuses to continue chemotherapy. PET/CT indication: Staging of metastases after chemotherapy. Findings: Generalized metastatic spread of the known epitheloid haemangioendothelioma particularly in the skeleton system. The vertebral body in the area of L3 is broken and might thus become instable. Furthermore, multilocular involvement of the spine and the osseous pelvis. With respect to instability, the situation in the area of C1 should be

specially monitored. Disseminated liver metastases. Generalized metastatic spread into the pulmonary region with mediastinal lymph node metastases. Teaching points: With a single scan PET/CT is able to evaluate the propagation of the malignant growth in the whole body, particularly in the skeletal area. Co-registration with CT allowed the evaluation of the instability risk with a single scan (Figs. 10.2.1–10.2.6).

Fig. 10.2.1. Sequence of coronal and sagittal slices with increased tracer uptake consistent with metastatic spread in the area of the cervical spine, the thoracic spine and the lumbar spine. The images also clearly illustrate pulmonary lesions. Metastatic spread into the liver is less pronounced

10.3

Fig. 10.2.2. MIP image as well as sequence of PET slices with the 3 slice planes with markedly increased uptake in the skeleton system as well as just slightly increased uptake in the liver

Fig. 10.2.3. Sagittal PET/CT slice with bone window setting showing considerable metastatic spread in the area of the thoracic spine and the lumbar spine as well as less pronounced spread in the cervical spine and in the sternum

Case Studies

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Fig. 10.2.4. MIP projection of the lower extremities as well as PET/CT slices with the 3 planes. Particularly the MIP projection of the right leg clearly shows increased uptake in the right thigh consistent with malignancy

Fig. 10.2.5. Sequence of coronal slices showing an approx. 6 mm large lesion in the section of the femur close to the knee joint

Fig. 10.2.6. Transaxial PET/CT slice of the liver showing 2 metastases

10.3

Patient 3 Chondrosarcoma Clinical history: A 44-year-old male with chondrosarcoma in the area of the left shoulder under ongoing chemotherapy. Tumour diagnosis for the first time 12 weeks ago. Primary pain in the left shoulder. Significantly progressive tumour growth, approximately 10.0×10.0×15.0 cm found at the last measurement. Findings: Glucose metabolic activity consistent with malignancy in the area of the proven chondrosarcoma of the left proximal humerus. Taking into account the existing semicircular sheathing of the proximal humerus and the shoulder area as well as an extended tumour matrix calcification and a tumour extending almost to the shaft of the humerus, a beginning cortical infi ltration cannot be safely excluded, but a circumscribed cortical destruction or infi ltration into the myeloma can in fact be excluded. No evidence for metastatic spread into the lymph node or organs found in the wholebody scan.

Case Studies

Teaching points: The co-registered PET/CT image has the advantage that, on the one hand, PET can unequivocally classify the metabolically active tissue, contrary to CT, which cannot ensure such a reliable classification, but on the other hand CT can clearly assign the increased metabolic activity to the anatomical region involved, so that further therapy is facilitated.

 Fig. 10.3.1. Sequence of coronal PET slices showing a markedly increased uptake in the projection to the left shoulder joint

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Fig. 10.3.2. Coronal PET/CT slice with significant hypermetabolic activity in the soft tissue of the left shoulder

Fig. 10.3.3. Transaxial slice plane with increased uptake in the left shoulder joint consistent with malignancy

10.3

Case Studies

Fig. 10.3.5. Transaxial PET/CT slice with markedly increased metabolic activity in the left shoulder

Fig. 10.3.4. Increase in activity in the left shoulder shown with the 3 slice planes and on the MIP image during late phase of enhancement

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Patient 4 Medullary Osteosarcoma Clinical history: An 11-year-old girl status post amputation of the left lower extremity due to a medullary osteosarcoma of the distal femur with status post accidental radiation exposure. Preoperative and postoperative chemotherapy with seven cycles. Metastatic spread could not be detected in the initial CT image of the thorax; however, masses suspicious of metastatic spread were found in the following images. PET/CT indication: Metastatic tumour staging by PET/CT.

Teaching points: PET/CT allows a more detailed classification of the CT findings suspicious for metastatic spread by taking into account the evaluation of the glucose metabolic activity. Malignant growth is particularly confirmed by the increased activity detected in the late enhancement image.

Findings: In the area of the suspicious focus in segment 2 of the right lobe of the lung, PET/CT detects a moderately increased glucose metabolic activity illustrating the presence of a metastasis, which is still rising from the early to the late enhancement image. In addition, metabolic activity in the medullary space of the amputation stump of the left lower extremity. Fig. 10.4.1. Sequence of coronal slices with a moderately increased glucose metabolic activity in the amputation stump which must be classified as being suspicious for malignancy

10.3

Case Studies

Fig. 10.4.2. Transaxial PET/CT slice showing increased glucose metabolic activity in the medullary space of the amputation stump which is suspicious for malignancy

Fig. 10.4.3. Transaxial PET/CT slice with lung window setting revealing moderately increased glucose metabolic activity in the area of the lesion examined in segment 2

Fig. 10.4.4. The same lesion during late phase of enhancement with increasing glucose metabolic activity

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Patient 5 Clear Cell Sarcoma Clinical history: A 65-year-old female status post amputation of the right lower leg due to a clear cell sarcoma in the area of the right ankle joint 2½ years ago. Endoprosthesis of the left knee joint. Muscle dystrophy of type Becker-Kiener. Now suspicion of recurrent metastasis in the area of the right groin.

Teaching points: In this case, the PET/CT image not only shows the lymph node with changes consistent with malignancy in the right groin, but PET/ CT also detects a lymph node metastasis in the right intestinal region as well as a bone metastasis at the level of L4.

Findings: Approximately 2.8-cm-large round lymph node metastasis in the right medial groin area with status post amputation of the lower leg due to a clear cell sarcoma. Furthermore, detection of intestinal lymph node metastases in the area of the ileum on the right side. Still suspicion of beginning osseous metastatic spread at the level of L4.

Fig. 10.5.1. Sequence of coronal PET slices of the lower extremities showing both the lymph node metastasis in the right groin and an unspecifically increased uptake in the area of the endoprosthesis of the knee joint

10.3 Fig. 10.5.2. Coronal PET/CT slice with tumour-specific increased glucose metabolic activity in the area of the enlarged lymph node in the right groin

Fig. 10.5.3. Transaxial PET/CT slice clearly revealing the lymph node with changes consistent with malignancy in the right groin

Fig. 10.5.4. Tumour-typical increased uptake in a lymph node in the right intestinal region with both the glucose metabolic activity revealed by PET and the increase in size shown on the CT image being suspicious for malignant growth

Case Studies

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Patient 6 Rhabdomyosarcoma Clinical history: The 6-year-old girl was complaining of double vision and gait disturbances in the sense of ataxy for 8 weeks. MRI reveals multiple focal hyperintense lesions with disseminated distribution pattern, mainly on both sides of the cerebellum and in the whole myeloma. Furthermore, also large masses in several areas of both lobes of the lung. Puncture biopsy of two foci in the lung mainly revealed necrosis with smaller cell assemblies that could not be assigned to a tumour type. Increase in unspecific tumour marker for soft tissue tumour (NSE). Unknown primary tumour. PET/CT indication: Search for the primary tumour. Findings: Disseminated tumour spread in the area of both lobes of the lung and in the cerebrum, mainly in both cerebellar hemispheres, and along the myeloma from C1 to L1 with increased glucose metabolic activity consistent with malignancy. Furthermore, increased glucose metabolic activity

consistent with malignancy in the area of the right dorsal diaphragmatic angle, which is suspected to be the primary tumour with respect to a rhabdomyosarcoma of the diaphragm. Teaching points: PET/CT allows reliable classification of the lesion as malignant growth and determination of the propagation pattern, mainly in the myeloma, and it also detects tumour-specific increased glucose metabolic activity consistent with malignancy in the area of the dorsal diaphragmatic angle on the right side, which is suspected of being the primary tumour.

Fig. 10.6.1. Sequence of transaxial PET/CT slices with lung window setting showing malignant growth in numerous areas of the two lungs

10.3

Fig. 10.6.2. Sagittal PET/CT slice imaging considerably increased uptake in the myeloma, particularly pronounced in the area of the cervical spine and the upper region of the thoracic spine

Fig. 10.6.3. Increased uptake in the area of the right dorsal diaphragmatic angle which can be fairly well delineated and is suspicious for the presence of a rhabdomyosarcoma

Case Studies

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Patient 7 Rhabdomyosarcoma of the Left Thigh Clinical history: A 51-year-old male with a mass in the left thigh that could be reliably classified as a rhabdomyosarcoma. Status post muscle fibre rupture 20 years ago. Since that time, swelling in the thigh area. Aggravation of the focal lesion with recent sonographically suspicious findings. PET/CT indication: Propagation diagnosis. Metastatic spread? Findings: Detection of metabolic activity consistent with malignancy in the area of the partly necrotized rhabdomyosarcoma of the thigh. No additional evidence for further increased activity consistent with malignancy. Teaching point: Unequivocal staging with PET/CT.

Fig. 10.7.1. Partly necrotized rhabdomyosarcoma of the left thigh, sagittal slice

10.3

Case Studies

Fig. 10.7.2. Partly necrotized rhabdomyosarcoma of the left thigh, transaxial slice

Fig. 10.7.3. Partly necrotized rhabdomyosarcoma of the left thigh, sequence of transaxial slices

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Patient 8 Embryonal Rhabdomyosarcoma Clinical history: An 8-year-old girl with embryonal rhabdomyosarcoma of the right fossa pterygopalatina with infiltration into the middle cranial fossa. Tumour first diagnosed 1 year ago. The patient then underwent chemotherapy resulting in a complete regression of the visible swelling and considerable regression of the mass.

Fig. 10.8.1. Recurrent tumour of an embryonal rhabdomyosarcoma of the right fossa pterygopalatina. PET on the left upper side. CT on the right upper side. Lower right side showing the CNS

Then radiotherapy with 44 Gy because the residual tumour could not be completely removed. A PET/CT scan performed 1 year ago showed a residual tumour with an unchanged extension, but without any metabolic activity. Then maintenance chemotherapy. Recurrent tumour growth since 1 week. PET/CT indication: Evaluation of the activity of the process. Metastatic spread?

10.3

Findings: The metabolic activity in the area of the cerebrum and the cerebellum shows an extended recurrent tumour in the area of the fossa pterygopalatina on the right side sized 2.7×2.9×3.5 cm (W×D×H) and parietally pronounced metabolic activity consistent with malignancy with an SUV value of 5.4.

Fig. 10.8.2. Recurrent tumour of an embryonal rhabdomyosarcoma of the right fossa pterygopalatina, transaxial, sagittal and coronal

Case Studies

The postoperative osseous concomitant defect still has a smooth contour without any evidence of erosion or tumour infi ltration. Teaching point: A reliable evaluation of the tumour activity would not have been possible without a measurement of the metabolic activity by PET.

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10.4 References 1. Abella HA (2005) Report-Musculoskeletal. diagnosticimaging.com. Diagn Imag Eur 3:35–37 2. Adams S, Hör G (2004) Nuklearmedizinische Diagnostik von Knochenentzündungen. In: Schnettler R, Steinau HU (eds ) Septische Knochenchirurgie. Thieme, Stuttgart, pp 57–74 3. Berger F, Lee YPLoening AM et al (2002) Whole body skeletal imaging in mice utilizing micro-PET: optimization of reproducibility and applications in animal models of bone disease. Eur J Nucl Med Mol Imaging 29:1225–1236 4. Brenner W, Conrad EU, Eary JF (2004) FDG PET imaging for grading and prediction of outcome in chrondrosarcoma patients. Eur J Nucl Med Mol Imaging 31:189–195 5. Brenner W, Vernon Ch, Muzi M et al (2004) Comparison of different quantitative approaches to 18F-fluoride PET scans. J Nucl Med 45:1493–1500 6. Cremerius U, Mumme T, Reinartz P et al (2003) Analyse des 18F-FDG Speichermusters in der PET zur Diagnostik von septischer und aseptischer Lockerung bei Totalendoprothesen des Hüftgelenks. Nuklearmedizin 42:234–239 7. Even-Sapir E (2005) Imaging of malignant bone involvement by morphologicalscintigraphic and hybrid modalities. J Nucl Med 46:1356–1367 8. Even-Sapir E, Metser U, Flusser G et al (2004) Assessment of malignant skeletal disease: Initial experience with 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl Med 45:272–278 9. Folpe AL, Lyles RH, Sprouse JT et al (2000) (F-18) fluordeoxyglucose positron emission tomography as a predictor of pathological grade and other prognostic variables in bone and soft tissue sarcoma. Clin Cancer Res 6:12379–12387 10. Francius C, Bielack St, Flege S et al (2002) Prognostic significance of 18F-FDG and 99mTc-methylene diphosphonate uptake in primary osteosarcoma. J Nucl Med 43:1012–1017 11. Francius C, Daldrup-Link HE, Sciuk J et al (2001) FDGPET for detection of pulmonary metastases from malignant primary bone tumours: Comparison with spiral CT. Ann Oncol 12:479–486 12. Francius C, Daldrup-Link HE, Wagner-Bohn A et al (2002) FDG-PET for detection of recurrences from malignant primary bone tumours: comparison with conventional imaging. Ann Oncol 13:157–160 13. Francius C, Sciuk J (2000) Positronenemissionstomographie mit F-18-Fluordesoxyglukose (FDG PET) im Kindes-

und Jugendalter (Erfahrungen an über 500 pädiatrischen Patienten). Der Nuklearmediziner 23:287–295 14. Francius C, Sciuk J, Brinkschmidt C et al (2000) Evaluation of chemotherapy response in primary bone tumours with F18 FDG positron emission tomography compared with histologically assessed tumour necrosis. Clin Nucl Med 25:874–881 15. Francius C, Sciuk J, Daldrup-Link HE et al (2000) FDGPET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 27:1305–1311 16. Hartmann A, Eid K, Dora C et al (2007) Diagnostic value of 18 F-FDG PET/CT in trauma patients with suspected chronic osteomyelitis. Eur J Nucl Med Mol Imaging 34:704–714 17. Hoegerle S, Juengling F, Otte A et al (1998) Combined FDG and F-18-fluoride whole body PET: a feasible two-in-oneapproach to cancer imaging. Radiology 209:253–258 18. Hör G, Frey KW, Keyl W, Hertel E (1969) Vergleich von Szintigraphie und Röntgendiagnostik bei Osteomyelitis. Fortschr Röntgenstr 110:708–716 19. Hör G, Keyl W, Langhammer H, Herzog M, Pabst HW (1975) Ergebnisvergleich der 99mTc-PolyphosphatKamera (Sequenz- Funktions-) Szintigraphie der 85Sr-, 87mSr-Scannerszintigraphie und radiologischer Methoden in der Orthopädie. Nuklearmedizin 14:37–45 20. Hsu WK, T B, Feely, Krenek L et al (2007) The use of 18F-fluoride and 18F-FDG PET scans to assess fracture healing in a rat femur model. Eur J Nucl Med Mol Imaging 34:1291–1301 21. Lodge MA, Lucas JD, Marsden PK et al (1999) A PET study of 18FDG uptake in soft tissue masses. Eur J Nucl Med 26:22–30 22. Mullerad M, Eisenberg DP, Akhurst TJ et al (2006) Use of positron emission tomography to target prostate cancer gene therapy by oncolytic herpes simplex virus. Mol Imaging Biol 8:30–35 23. Piert M, Winter E, Becker GA, Bilger K et al (1999) Allogenic bone graft viability after hip revision arthroplasty assessed by dynamic (18F)fluoride ion positron emission tomography. Eur J Nucl Med 26:615–624 24. Sasaki M, Ichiya Y, Kuwabara Y, Otsuka M, Fukumura T, Kawai Y, Koga H, Masuda K (1993) Fluorine-18-fluorodeoxyglucose positron emission tomography in technetium-99m-hydroxymethylenediphosphate negative bone tumours. J Nucl Med 34:288–290 25. Schirrmeister H, Glatting G, Hetzel J et al (2001) Prospective evaluation of the clinical value of planar bone scans, SPECT, and 18F-labeled NAF PET in newly diagnosed lung cancer. J Nucl Med 42:1800–1804 26. Zhuang H, Duarte PS, Pourdehnad M et al (2001) The promising role of 18F-FDG PET in detecting infected lower limb prosthesis implants. J Nucl Med 42:44–48

11.1 Introduction

11

Paediatric Oncology

CONTENTS 11.1

11.1

Introduction 487 Changes in the Range of Clinical Indications 488

11.2 Lymphomas in Childhood 488 Staging, Restaging, Prognosis and Therapy Control 488 11.3 Oncological Orthopaedics in Childhood 11.4

Neuroblastomas

488

11.5 Malignant Melanomas 11.6 11.7

488

488

Nesidioblastosis (Congenital Hyperinsulinism)

489

Case Studies 490 Patient 1 Status Post Osteogenous Sarcoma 490 Patient 2 Status Post Mastitis 491 Patient 3 Embryonal Rhabdomyosarcoma 492 Patient 4 Focal Congenital Hyperinsulinism 494 Patient 5 Focal Congenital Hyperinsulinism 496 Patient 6 Focal Congenital Hyperinsulinism 498 Patient 7 Diffuse Congenital Hyperinsulinism 500 Patient 8 Focal Congenital Hyperinsulinism 502 Patient 9 Focal Congenital Hyperinsulinism 504 Patient 10 Focal Congenital Hyperinsulinism 506 Patient 11 Langerhans Cell Histiocytosis 508 Patient 12 Langerhans Cell Histiocytosis, Staging and Restaging 510

11.8 References

514

Introduction

Paediatric nuclear medicine initially was not practiced in Germany because of the radiation exposure (of 131I); de Rudder placed a ban on it in 1954 (personal communication, T. Hellbrügge, Munich). This attitude changed when quickly decaying tracers became available for SPECT and PET or PET/ CT, respectively [6, 9, 12]. Exposition data are available, even for (necessary) PET scans performed in infancy [22]. For adults, 18F-FDG is considered to be a labeled central molecule, regardless of the relative lack of specificity. Specific metabolic substances, e.g. noradrenaline, DOPA analogues, fluorides and thymidine, are subjects of research projects. Only a few publications deal with PET/CT examinations in childhood. Data collected from 146 infantile tumours (age range, 2 months to 18 years) with an eight-line PET/CT scanner were published. Important tumour types detected with the above examinations were lymphomas, sarcomas, neuroblastomas, Wilms’ tumours and brain tumours [1, 13]. Taking into account the high radiation doses to which the children are exposed, a differentiated examination is recommended. Misinterpretations may impair the evaluation if performed by inexperienced staff. Hypermetabolic foci, such as the thymus display, increase uptake due to physiological features and must thus be distinguished from lesions consistent with malignancy. PET/CT can also clarify certain unclear aspects in this context because CT takes into account the anatomical features [27, 4, 7, 23, 2, 25].

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Changes in the Range of Clinical Indications Lymphomas, Ewing’s sarcomas and other malignant bone tumours, high-risk neuroblastomas and malignant melanomas are today the main focus of PET examinations for children [4, 8, 27].

11.2

Lymphomas in Childhood

Comprehensive documentation is available in two outstanding PET studies [15, 26]. A range of relevant indications is already discernible today.

Staging, Restaging, Prognosis and Therapy Control Positive PET means a shortened progression-free interval. A therapy response reaction can already be registered after the fi rst chemotherapy cycle. PET and PET/CT are superior to CT and MRI alone. In a study established in Leipzig that took into account children suffering from Hodgkin’s disease, 1,743 regions were analyzed by directly comparing PET with conventional methods: Negative concordant results were found in 69.7%, positive concordant results in 22.3%, and bone involvement could be verified in 5.5% by PET only. More than 90% of the children and adolescents suffering from Hodgkin’s disease can be cured today. In early stages with complete remission and negative FDG-PET after chemotherapy, radiotherapy can be omitted, whereby PET can help to minimize the risk. The earlier the therapy response occurs, the more favourable the prognosis. The economic benefit is already very highly placed today. SPECT tracers become less important [14]. However, not unexpectedly, contrary results are being reported, according to which staging of lymphomas in children can yield divergent findings with FDG-PET and CT (in 6 of 25 patients, 470 nodal and 192 extranodal regions, which encourages validated studies [10]).

11.3

Oncological Orthopaedics in Childhood

Noteworthy data regarding the primary tumour (staging), stage classification (M-staging) and detection of recurrent tumours were, for example, made available by teams working in Muenster and London [6, 27]. The PET result influenced the management in 24% and was useful even in 75%. According to the above studies, spiral CT can detect lung metastases of bone tumours better than other imaging methods. It is expected that the use of combined PET/CT scanners will thus further improve the results.

11.4

Neuroblastomas

Rather comprehensive data are already available for 123,131I-MIBG (see also the results of the Frankfurt study [11]); for FDG-PET, e.g. in case of MIBGnegative and CT-positive lesions [16, 24], indications are foreseeable for high-risk patients [11]. 124I-MIBG-PET has made a foray into the molecular level with technological and metabolic advantages [3]. In patients suffering from high-risk neuroblastomas, PET obviously detects more tumour lesions before therapy than MIBG scintigraphy, and after treatment the extent of the residual disease can be more exactly assessed for MIBG-negative fi ndings. Artefact problems (FDG accumulation in the thymus) as well as FDG depots in muscles, the thyroid gland and in case of paravenous injection must be taken into consideration.

11.5

Malignant Melanomas

The indications are the same as those described for adults, cf. in this chapter.

11.6 Nesidioblastosis (Congenital Hyperinsulinism)

11.6

Nesidioblastosis (Congenital Hyperinsulinism)

Congenital hyperinsulinism is a special domain of PET. This severe congenital disease, which is also called nesidioblastosis, occurs rather seldom (approximately 15–20 patients per year in Germany). It is most prevalent in case of newborns and infants. This disease is due to a disturbed regulation of insulin secretion, which frequently cannot be corrected by medications. Severe persistent hypoglycaemias result in permanent mental disorders. This unfavourable prognosis can be avoided if the patients are treated with high-dose glucose infusions and if surgical intervention is performed in time. Until now, subtotal pancreatectomy has been recommended to prevent severe cerebral injuries. The patients then frequently suffered from diabetes. Circumscribed foci could be identified in approximately 30–40% of the patients. These regions used

to be identified by selective percutaneous pancreatic vein catheterization and determination of the insulin level. L-DOPA PET was developed as a milder alternative to localization diagnosis. L-DOPA is absorbed by neuroendocrine cells and pancreas islet cells and metabolized into dopamine [17, 18]. Beta cells of the pancreas possess dopamine receptors [21]. The uptake of (18F-)DOPA is considerably increased in foci with high insulin synthesis rates [19, 20]. More than 100 examinations have been performed worldwide since 2003. For the operated patients in which the diagnosis was proven by clinical and histological examinations, a sensitivity of 94% was calculated for 18F-DOPA-PET, combined with a specificity of 100%. 18F-DOPA-PET (or integrated PET/CT) is the most precise method used to differentiate between the focal and diffuse form of congenital hyperinsulinism. Once the focus has been localized with L-DOPA PET, the borders of the section to be resected can be exactly determined. Subtotal pancreatectomy can thus be avoided in early babyhood.

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11.7 Case Studies Patient 1 Status Post Osteogenous Sarcoma Clinical history: A 17-year-old girl status post osteogenous sarcoma. The patient first underwent chemotherapy, then received a right knee joint endoprosthesis that had to be removed due to infection. Then arthrodesis by plate osteosynthesis. Status post resection of an isolated lung metastasis 2 years ago. Persistent/chronic infection in the right thigh with fistulation in several areas on the lateral side of the thigh. Now suspicion of recurrent 8-mm-large lung metastasis in the dorsobasal region in the ninth segment of the right lower lobe of the lung. PET/CT indication: Evaluation of the malignancy of the round focus in the ninth segment of the right lung. Is there any further tumour spread in the right lower extremity?

Findings: No evidence for glucose metabolic activity suspicious for or consistent with malignancy in the area of the ninth segment of the right lung. The regions in which increased glucose metabolic activity were revealed in the area of the right thigh, and the lower leg must be classified as inflammatory regions if we take into account the clinical finding, the clinical history and the findings of the examinations performed. Teaching points: Taking into account the PET/CT findings, we are able to evaluate the malignancy of the lesions in both the area of the lung and the area of the right lower extremity, so that the best possible therapy can be performed.

Fig. 11.1.1. Circumscribed regions with increased uptake in the operating area of the right lower extremity which must be evaluated as being due to inflammation

11.7 Case Studies

Patient 2 Status Post Mastitis Clinical history: A 17-year-old girl status post mastitis on the left side 1 year ago. A painful tumour in the left breast was perceived 5 months later. Test excision did not furnish any evidence in support of malignant growth. Due to persistent complaints with respect to the left breast, a PET/CT scan will be performed to exclude malignant lesions.

Fig. 11.2.1. Transmissioncorrected sagittal PET image. The image shows a small round focus with increased uptake which is under the limit considered as being consistent with malignancy

Fig. 11.2.2. Transaxial PET/CT slice with unsuspicious tracer uptake

Findings: PET/CT does not furnish any evidence for malignant tumour in the area of both mammary glands. The whole-body scan does not furnish any evidence for glucose metabolic activity suspicious for or consistent with malignancy either. Teaching points: Taking into account the PET/CT findings, it is possible to exclude malignant growth in both the breast and in the whole body.

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Patient 3 Embryonal Rhabdomyosarcoma Clinical history: A 4-year-old girl with abdominal embryonal rhabdomyosarcoma, IRS 1-stage III. Tumour first diagnosed 1 year ago. Status post R1 resection 11 months ago, ovariopexy on both sides and adhesiolysis of the small and large intestine 6 months ago with biopsy taken. Status post antineoblastic chemotherapy according to IRS protocol. Last chemotherapy 4 weeks before the first PET/CT scan was performed, and the results were unsuspicious. A controlled PET/CT scan was performed 7 months after the first PET/CT scan.

1

Findings: Detection of a precaval 13-mm-large soft tissue focus, probably indicating a recurrence of the known and proven rhabdomyosarcoma. The relatively low SUV value indicates that the therapy was partly successful and should thus continue. No additional evidence for further focal lesions with glucose metabolic activity consistent with malignancy in the whole body. Teaching points: Although the morphological findings of the ultrasonic, CT and MRI examinations remain unchanged, PET/CT follow-up examination now detects a recurrent tumour in the operating area so that continuation of the chemotherapy is indicated as a result of the PET/CT findings.

IntergroupRabdomyosarcoma Study

Fig. 11.3.1. Sagittal PET/CT slice detecting a moderately increased uptake in an abdominal prevertebral soft tissue lesion

11.7 Case Studies

Fig. 11.3.2. Coronal slice showing the same round focus with increased uptake in the abdominal region indicating a recurrent tumour of the treated rhabdomyosarcoma

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Patient 4 Focal Congenital Hyperinsulinism Clinical history: A 6-week-old male baby with spontaneous hypoglycaemia after birth. Taking into account the clinical findings and the laboratory value, the patient was suspected of suffering from nesidioblastosis. The patient was examined to consider whether a focal nesidioblastosis existed to determine if the patient should undergo curative surgical intervention. The examination was performed in accordance with the Berlin Protocol 20, 30, 40 and 60 min after 18F-DOPA had been injected. Findings: The examination of the pancreas region and of the abdominal region revealed a round focus of increased uptake approximately 5 mm in diameter at the transition from the tail of the pancreas to the

body of the pancreas dorsally in the neighbourhood of the vena lienalis, which was also revealed on the contract-enhanced CT images as a separate lobular structure that is nevertheless part of the pancreas. Rising SUV values were registered from 20 to 60 min after injection, and considerable tracer uptake was revealed during the above period. The distance to the aorta and the inferior vena cava could be determined with computed tomography as an important parameter for the planned surgical intervention. Teaching points: The focal nesidioblastosis could be reliably localized with 18F-DOPA-PET/CT. The patient underwent surgical treatment 2 days after the examination. The tumour could be found in the area localized during the examination, and the blood sugar level returned to normal after the operation.

Fig. 11.4.1a–d. Transaxial PET/ CT slices showing the round focus with increased tracer uptake in the pancreas region

a

11.7 Case Studies

b

c

d

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Patient 5 Focal Congenital Hyperinsulinism Clinical history: A 7-week-old female baby with hypoglycaemia appearing immediately after birth, which gave rise to the suspicion that the girl suffers from nesidioblastosis. Further laboratory findings also confirmed this suspicion so that the patient was examined with 18F-DOPA-PET/CT to clarify whether surgical intervention would be justified to remove a tumour.

Findings: The 18F-DOPA-PET/CT detects a 7-mmlarge focus with increased uptake in the ventral region at the body of the pancreas. In the rest of the pancreas, PET/CT showed a homogeneous tracer distribution. A focal nesidioblastosis must thus be assumed. Teaching points: As PET/CT could confirm a focal form of nesidioblastosis, the patient could undergo surgical therapy. Blood sugar and insulin level returned to normal after the operation.

Fig. 11.5.1a–d. Tracer uptake 20, 30 and 45 min after injection. The images clearly show an oval focus with increased uptake in the pancreas

a

b



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c

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Patient 6 Focal Congenital Hyperinsulinism Clinical history: A 6-week-old female baby with hypoglycaemia appearing immediately after birth, which gave rise to the suspicion that she suffers from nesidioblastosis due to the intensity of the symptoms and further laboratory values. The physicians in charge had to answer the question whether they have to cope with a focal form indicating curative surgical treatment.

Findings: Focally increased uptake of 18F-DOPA in the area of the head of the pancreas, which can be particularly well delineated in the 3D image. Slightly increased uptake is also detected in the tail of the pancreas, however, without a focus that can be delineated. Teaching points: This patient also underwent surgical therapy, but the situation did not completely return to normal. Subsequent evaluation revealed that this child suffers from a mixed form of nesidioblastosis so that curative therapy can only be partially successful.

Fig. 11.6.1. The transaxial PET/ CT slice shows increased uptake in the head of the pancreas the margins of which can not be sharply delineated

11.7 Case Studies

Fig. 11.6.2. The left part consists of transaxial PET/CT slices with different colour scales and dynamic range and the lower right part shows a coronal slice demonstrating a slightly increased uptake in the area of the body of the pancreas up to the tail of the pancreas. The image illustrates the increased tracer uptake the focus of which is not really sharply delineated

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Patient 7 Diffuse Congenital Hyperinsulinism Clinical history: A 12-month-old female infant with hypoglycaemia, the question being whether the physicians have to deal with a focal lesion of diffuse involvement and if surgical treatment might thus be successful.

Fig. 11.7.1. Transaxial PET/CT slice 28 min after injection. This slice reveals a strongly increased tracer uptake in the area of the head of the pancreas

Fig. 11.7.2. The transaxial image taken 28 min after injection shows the increased uptake in the area of the body and the tail of the pancreas with another transaxial slice plane

Findings: The examinations performed 28, 38 and 60 min after injection revealed a diffuse involvement of the whole pancreas area so that a focal form cannot be confirmed by the findings of this PET/CT scan, and the patient will have to undergo drug therapy. Teaching points: As a focal lesion could be excluded, the child is spared the operation, and the health insurance company does not have to pay the costs for such an operation.

11.7 Case Studies

Fig. 11.7.3. Four transaxial PET/CT slices taken 38 min after injection and documenting a diffuse involvement of the pancreas

Fig. 11.7.4. The image taken 60 min after injection still shows diffuse involvement, particularly pronounced in the upper left transaxial PET/CT slice

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Patient 8 Focal Congenital Hyperinsulinism Clinical history: A 4-month-old male baby with congenital hyperinsulinism. PET/CT indication: Localization diagnosis or clarification of a potential focal localization. Findings: The examination with F18-DOPA reveals a focal hyperinsulinism in the body of the pancreas. The focus size is approximately 4–5 mm and directly adjoins the upper ventral border of the confluent in the dorsal region of the adjoining body of the pancreas. Teaching point: Reliable diagnosis of a focal lesion that could be clearly delineated and confirmed during the operation.

Fig. 11.8.1. Focal congenital hyperinsulinism in the body of the pancreas, sequence of transaxial slices

11.7 Case Studies

Fig. 11.8.2. Focal congenital hyperinsulinism in the body of the pancreas, sagittal slice

Fig. 11.8.3. Focal congenital hyperinsulinism in the body of the pancreas, fused with CT angiography image

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Patient 9 Focal Congenital Hyperinsulinism Clinical history: A 17-month-old infant with suspicion of congenital hyperinsulinism. PET/CT indication: Does PET/CT reveal any evidence for a diffuse or focal form of CHI in the pancreas? Findings: The examination with F18-DOPA reveals a focus at the upper ventral border of the pancreas body with a transverse diameter of 5 mm and a vertical diameter of 9 mm. The ductus pancreaticus is not involved. A focus rich in blood vessels must be assumed. Teaching point: Reliable diagnosis and localization with PET/CT.

Fig. 11.9.1. Focal congenital hyperinsulinism, images in all 3 slice planes

11.7 Case Studies

Fig. 11.9.2. CT, PET and PET/CT images of focal hyperinsulinism, contrast-enhanced CT image clearly shows hypervascularization in the focal region

Fig. 11.9.3. CT, PET and PET/CT showing focal congenital hyperinsulinism. The increased F18DOPA uptake is consistent with increased uptake of contrast agent on the CT image indicating hyperperfusion

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Patient 10 Focal Congenital Hyperinsulinism Clinical history: Suspicion of congenital hyperinsulinism (CHI). PET/CT indication: Does PET/CT reveal any evidence for a diffuse or focal form of CHI in the pancreas? Findings: The examination with F18-DOPA reveals a focus in the sense of focal congenital hyperinsulinism.

The focus is located at the ventral border of the upper area of the pancreatic body, and its size is approximately 7 mm, with the maximum tracer uptake being registered over a length of 3 mm. Involvement of the ductus pancreaticus is not shown. Teaching point: Reliable diagnosis of a focal lesion and precise localization. The patient was operated on and has in the meantime returned to a euglycemic condition.

Fig. 11.10.1. Focal congenital hyperinsulinism in the body of the pancreas, in all three slice planes

11.7 Case Studies

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Fig. 11.10.2a–c. Focal congenital hyperinsulinism in the body of the pancreas fused with CT volume rendering technique

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Patient 11 Langerhans Cell Histiocytosis Clinical history: A 16-year-old boy with a 6-year history of Langerhans cell histiocytosis with recurrent reactivations in different regions. Status post several therapy schemes, cytostatics used to treat several foci, surgical interventions, local administration of corticoids and radiotherapy in the area of some foci. At present, reactivation in the upper and lower jaw. Radiotherapy with 8 Gy in this region. Now pain in the right lower leg and knee region. PET/CT indication: Is there any evidence for glucose metabolic activity consistent with malignancy in the whole body, especially in the area of the lower extremities? Findings: Detection of active and reactivated focal osseous lesions with the whole-body scan, particularly on both sides of the upper parietal area of the scull cap, at the sternal attachment point of the

right clavicula, at the ventral right hemithorax, in the ilium on both sides, in the ischium on the left side, in the right proximal femur and mainly in the right distal femur shaft. No increased tracer uptake in the area of the knee joints on both sides or in the proximal lower leg. Secondary findings: pneumothorax on both sides, much more on the right than on the left side as well as extended exudative-alveolar infi ltrates and evidence for beginning fibrosis on both sides. Teaching points: The whole-body PET/CT scan enables a very differentiated evaluation of the propagation of the malignant growth, and, in addition, the CT images also show the pulmonary lesions.

Fig. 11.11.1. The MIP projection and the transaxial, sagittal and coronal PET/CT slices show increased uptake in the area of the scull cap and at the sternal attachment point of the right clavicula, in the ilium on both sides, in the ischium on the left side and in the proximal femur

11.7 Case Studies

a

b Fig. 11.11.2a,b. Coronal and sagittal PET slices showing increased uptake. The images clearly reveal round foci of increased tracer uptake in the area of the skull cap, in the area of the pelvis and the femur. Also note the diffusely increased uptake in both lungs. The images clearly show the partial pneumothorax on both sides, more pronounced on the right than on the left side

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Patient 12 Langerhans Cell Histiocytosis, Staging and Restaging Clinical history: A 14-year-old boy with Langerhans cell histiocytosis. The disease was histologically proven in the anterior mediastinum during the first year of life. The patient then underwent chemotherapy. Then reactivation in the area of the ear with radical operation and further chemotherapy cycles. After completion of the chemotherapy, multiple reactivation of the disease treated with chemotherapy, whereby mainly the ear, the pelvis on the right side and the right femur head as well as the lateral wall of the orbit were involved. It should also be mentioned that the patient has an identical twin and that his brother also suffers from Langerhans cell histiocytosis. The first PET/CT scan was performed to clarify the propagation diagnosis and to localize the regions involved.

Findings: Glucose metabolic activity consistent with malignancy in the area of extended tumour osteolyses in S1, in the right proximal femur up to the neck of the femur with pathological fracture or infraction as well as in the os occipitale on the left side with slight warping of the soft tissue tumour towards the cerebellar region. Furthermore, small osteolysis of the sternum with glucose metabolic activity consistent with malignancy. Slightly increased uptake in the os ischii on the right side, but without CT correlation. Inguinal lymphoma on the right side. Further organ or lymph node metastases could not be detected with the wholebody scan. The patient presented 6 months later after he had again undergone chemotherapy. The PET/CT scan that was then performed did not reveal any evidence for focally increased tracer uptake consistent with malignancy in the area of the lesions described as a result of the pre-examination.

Fig. 11.12.1. MIP image as well as transaxial, sagittal and coronal slices demonstrating increased uptake in several regions, with strongly increased uptake in the os sacrum and the right femur

11.7 Case Studies

Fig. 11.12.2. Increased uptake in the left occipital region of the skull cap with slight displacement of the cerebellum shown an a transaxial PET/CT slice

Fig. 11.12.3. Transaxial PET/CT slice showing increased uptake on the right side in the sternum

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Fig. 11.12.4. Coronal slice showing increased uptake in the os ilium and the right femur regions

Fig. 11.12.5. Transaxial PET/CT slice with right inguinal lymphoma

11.7 Case Studies

Fig. 11.12.6. Follow-up CT performed 6 months after the fi rst examination showed complete regression of the lesions described above after chemotherapy

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11.8 References 1. Abouzied MM, Al-sugair A, Meer H et al. (2007) 18F-FDG PET/CT in children: One year experience in a tertiary care setting (Abstr. 400). J Nucl Med (Suppl 2) 48:289 2. Bar-Shalom R, Gaitini D, Keidar Z, Israel O (2004) Nonmalignant FDG uptake in infradiaphragmatic adipose tissue:a new site of physiological tracer biodistribution characterized by PET/CT. Eur J Nucl Med Mol Imaging 31:1105–1113 3. Bockisch A, Freudenberg L, Rosenbaum S, Jentzen W (2006) 124I in PET imaging: impact on quantification, radiophamaceutical development and distribution. Eur J Nucl Med Mol Imaging 33:1247–1248 4. Depas G, De Barsy C, Jerusalem G et al. (2005) 18F-FDG in children with lymphomas. Eur J Nucl Med Mol Imaging 32:31–38 5. Fekete CN, De Lonlay P, Jaubert F, Rahier J, Brunelle F, Saudubray JM (2004) The surgical management of congenital hyperinsulinemic hypoglycemia in infancy. J Ped Surg 39:267–269 6. Franzius C, Lang K, Wormanns D et al. (2004) PET/CT und PET-Einsatz in der pädiatrischen Onkologie. Der Nuklearmediziner 27:315–323 7. Franzius Ch, Schober O, Juergens KU, Hahn K, Pfluger T (2006) Is PET/CT necessary in paediatric oncology? (For/ against). Eur J Nucl Med Mol Imaging 33:960–968 8. Gritters LS, Francis IR, Zasadny KR, Wahl RL (1993) Initial assessment of positron emission tomography using 2-fluorine-18-fluoro-2-deoxy-d-glucose in the imaging of malignant melanoma. J Nucl Med 34:1420–1427 9. Hahn K, Pfluger Th. (2004) Has PET become an important clinical tool in pediatric imaging? Eur J Nucl Med 31:615–621 10. Herrmann S, Wormanns D, Pixberg M et al. (2005) Staging in childhood lymphoma (differences between FDGPET and CT). Nuklearmedizin 44:1–7 11. Hör G, Maul FD, Kornhuber B et al. (1991) Outcome of I-131- meta-iodo-benzylguanidine therapy of neuroblastoma: 7 years after. J Nucl Biol Med 35:207–215 12. James L, Rosenthall AE, Wagner HN, Cooke RE (1974) Gastrointestinal imaging: Imaging the liver in pediatrics. In: Wagner HN et al. (eds) Pediatric nuclear medicine. Saunders, Philadelphia, pp 277ff 13. Kabickova E, Sumerauer D, Cumlivska E et al. (2006) Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin`s disease. Eur J Nucl Med Mol Imaging 33:1025–1031

14. Kapucu LÖ, Akyüz C, Vural G, Oguz A, Atasever T et al. (1997) Evaluation of therapy response in children with untreated malignant lymphomas using technetium-99msestamibi. J Nucl Med 38:243–247 15. Krausse A, Kluge R, Mauz-Koerholz C et al. (2004) Initial staging of Hodgkin’s disease (HD) in children by 18F-FDG PET vs CT/MRI/US (abstr 350). Eur J Nucl Med Mol Imaging (Suppl 2) 31:285–286 16. Kushner BH, Yeung HWD, Larson StM et al. (2001) Extending positron emission tomography scan utility to high risk neuroblastoma: Fluorine-18 f luordeoxyglucoe positron emission tomograpgy as sole imaging modalilty in follow-up of patients. J Clin Oncol 19:3397–3405 17. Lindstrom P (1986) Aromatic-L-amino-acid decarboxylase activity in mouse pancreatic islets. Biochim Biophys Acta 884:276–281 18. Oei HK, Gazdar AF, Minna JD, Weir GC, Baylin SB (1983) Clonal analysis of insulin and somatostatin secretion and L-DOPA decarboxylase expression by a rat islet cell tumour. Endocrinology 112:1070–1075 19. Otonkoski T, Nänto-Salonen K, Seppänen M et al. (2006) Noninvasive diagnosis of focal hyperinsulinism of infancy with 18F-fluoro-DOPA positron emission tomography. Diabetes 55:13–18 20. Ribeiro MJ, De Lonlay P, Delzescaux T et al. (2005) Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-L-DOPA. J Nucl Med 46:560–566 21. Rubi B, Ljubicic S, Pournourmohammadi S et al. (2005) Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem 280:36824–36832 22. Ruotsalainen U, Suhonen-Polvi H, Eronen E et al. (1996) Estimated radiation dose to the newborn in FDG-PET studies. J Nucl Med 37:387–393 23. Shreve PD, Anzai Y, Wahl RL (1999) Pitfalls in oncological diagnosis with FDG-PET imaging:physiolgic and benign variants. Radiographics 19:61–77 24. Shulkin BL (1997) PET applications in pediatrics. Q J Nucl Med 4:281–291 25. Sironi S, Buda A, Picchio M et al. (2005) Lymph node metastasis in patients with clinical early-stage cervical cancer. Radiology Nov, on-line: radiol. 2381041799 26. Voelker T, Denecke T, Amthauer H et al. (2004) The use of FDG PET for primary staging in pediatric Hodgkin’s lymphoma: comparison with conventional imaging modalities (Abstr. 275). Eur J Nucl Med Mol Imaging (Suppl 2) 31:S270 27. Wegner EA, Barrington SF, Kingston JE et al. (2005) The impact of PET scanning on management of paediatric oncology patients. Eur J Nucl Med Mol Imaging 32:23–30

12.1 Introduction

12

CUP Tumours (Cancer of Unknown Primary)

CONTENTS 12.1

12.1 Introduction

Introduction 515

12.2 Significance of PET 516 Cancer of Unknown Primary: Indication for PET/CT? 516 Studies Available 516 Artefacts, Pitfalls and Metabolic Heterogeneity 516 12.3 Case Studies 517 Patient 1 Carcinoma of the Base of the Tongue 517 Patient 2 Carcinoma of the Base of the Tongue 518 Patient 3 Oropharyngeal Carcinoma 520 Patient 4 Cholangiocarcinoma 523 Patient 5 Pancreatic Carcinoma 526 Patient 6 Carcinoma of the Head of the Pancreas 528 Patient 7 Mamma Carcinoma 530 Patient 8 CUP Tumour 533 Patient 9 Mamma Carcinoma 536 Patient 10 Carcinoma of the Base of the Tongue 538 Patient 11 Bronchial Carcinoma 540 Patient 12 Bronchial Carcinoma 542 12.4 References 544

Cancer of unknown primary (CUP) (or metastases of unknown origin, MUO) characterizes a tumour disease in which the primary tumour is (initially) not known and is finally detected during autopsy in spite of comprehensive diagnostic examinations [2, 8, 16]. In case of tumours of the neck/nape area, cervical lymph nodes may initially be the only symptom. Sensitivity and specificity (100% and 94%, respectively) are better for PET than for conventional diagnostic methods (92%/76%) [18]. This tumour type accounts for 5%–10% of all carcinomas. Dominant locations of metastases are the mediastinum (12%–20%) and retroperitoneum, lung (13%), lymph nodes and liver. In 1267 patients diagnosed (during life or at autopsy) with MUO syndrome the primary tumour was located in the pancreas (23%), lung (22%) and colon/rectum (10%) [10]. Symptomatic manifestations occur in the abdominal region in one third of all cases, in the lungs (approximately 20%), as lymphadenopathy (20%), in the area of the skeleton (16%) and in the neurological system. Oestrogen receptors cast suspicion on undetected mamma carcinomas, but according to statistical findings breast tumours are only responsible for the lethal outcome of the MUO in 3% of cases. Due to perfected diagnostic examinations, prostate and colon carcinomas are found to be the unknown primary only in rare cases. Ovarial and peritoneal carcinoses might be the unknown primary in case of isolated pleural effusion, while bronchial carcinomas account for 30%–50% of all bone metastases, but only for 5% in case of MUO, whereas this metastatic location accounts for 30% in case of MUO. Pancreas and liver carcinomas only account for 5%–10% of all primary tumours. Lung and liver metastases are less frequently due to a prostate carcinoma.

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The earlier the primary tumour is detected and treated, the fewer metastases are found or the more metastases can be resected, and thus the better the survival prognosis.

12.2 Significance of PET Cancer of Unknown Primary: Indication for PET/CT? The fact that approximately 75% of all malignomas are found underneath the diaphragm is a further argument supporting the strategy predicted by Wahl [21]. The question is not whether but why almost all tumours of the abdominal region will probably be examined with PET/CT in the future (see also [9, 13]). This also applies to occult recurrent ovarial carcinomas [3].

Studies Available UCLA CUP PET Study. Primary tumours were detected in 27% by whole-body PET and conventional imaging (CI) , in 53% by PET alone, in 20% by CT alone with a total cost amounting to $ 62,278 (CI algorithm) and $ 31,656 (for PET and additive methods). The small number of patients only allowed guarded conclusions [20]. CUP PET Study established in Frankfurt/Germany. A total of 76 lesions in 29 patients were classified as:  0 Negative PET  I Positive PET with multiple foci without PT identification  II Positive PET with tumour identification  IIa Proven  IIB Probable The detection probability is proportional to the number of lesions (in 12 patients with 63 PET foci) [12, 17]. Management was changed in 30%–50% [7]. The different data collected with PET alone, e.g. [1, 17, 11], have in the meantime been differentiated by meta-analyses [6] and with PET/CT in Essen/Germany, where 45 patients with cervical metastases were

examined [9]: one third of the primary tumours could be identified. PET alone could verify the primary tumour in only 24% of all cases. In this context the author would like to refer to the Danish cohort study [14] and contributions from Zürich/Switzerland [22]. Inclusion criteria, localization of the CUP and a determined probability certainly influence the results of the studies. In 2003, Delgado et al. published a meta-analysis taking into account 15 studies dealing with 298 patients with UPT 1. 18F-FDG PET detected the primary tumour in 43% with a sensitivity and specificity of 87% (95% CI, 81%–92%) and 71% (95% CI, 64%–78%), respectively (see the references on the DVD [Ö 12.1). However, it must be assumed that further and extended UPT studies with PET/CT will confi rm the superiority of this method over PET alone. Recent PET studies – without PET/CT – were false positive in 10% (primary tumour located in the distal region), in 42% the primary tumour could not be identified, but in 38% of all cases therapy was changed. If studies are dealing with ENT patients (see this chapter), a thorough understanding and analysis of normal FDG uptake variants is indispensable to make available clinically useful PET fi ndings, an exemplary atlas which is kept up-to-date [4, 19].

Artefacts, Pitfalls and Metabolic Heterogeneity The primary tumour and metastases display different spectra with respect to histology and molecular biology so that metabolic heterogeneity must also be assumed even if identical or similar histological and morphological parameters are detected. The number of identified primary tumours (conventionally 10%–20%) may be increased with PET and PET/CT if multimetabolic imaging can be implemented. Known artefacts are, for example, increased uptake levels in the BAT (brown adipose tissue) and there are also casuistic reports describing PET-positive lipomas [15]. Randomized controlled studies are not known.

1 Unknown primary tumour. This analysis mainly dealt with

cervical and supraclavicular, axillary and other lymph nodes, bone, lung, liver and skin lesions and disseminated metastatic spread.

12.3

12.3 Case Studies Patient 1 Carcinoma of the Base of the Tongue Clinical history: A 55-year-old male post resection of a choroidal melanoma in the area of the left eye 13 years previously. Status post neck dissection on the left side due to lymph node metastases of a squamous cell carcinoma of unknown primary in the left cervical region 2 years previously. Left clavicular fracture of uncertain pathological origin. PET/CT indication: Search for primary tumour.

Case Studies

Findings: Increased uptake consistent with malignancy at the left base of the tongue measuring approximately 1.6–2.0 cm. Taking into consideration status post extirpation of a lymph node metastasis of a cornifying squamous cell carcinoma of the neck region 2.5 years previously it must be assumed that this was the primary tumour. According to both the PET and CT findings, as well as the fused images, the known clavicular fracture in the left medial region must be classified as a pathological fracture due to metastatic spread. Teaching points: PET/CT could detect the primary tumour at the left base of the tongue and new lesions could be subsequently diagnosed so that adequate therapeutic steps could be taken.

Fig. 12.1.1. Corrected coronal PET slice showing 2 lymph node metastases in the left cervical region as status post therapy of the primary tumour

Fig. 12.1.2. Transaxial PET/CT slice with tumour-specific increased tracer uptake in the ventral area of the floor of the mouth. It must be assumed that the tumour has grown in this area whereas tumourous tissue could not be found in the area where the malignant growth was originally detected

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Patient 2 Carcinoma of the Base of the Tongue Clinical history: A 50-year-old female post biopsy of a right cervical lymph node 4 weeks previously. The histological examination revealed a squamous cell carcinoma. Further enlarged lymph nodes were found on both sides of the cervical region. The primary tumour is not known. PET/CT indication: CUP syndrome. Localization of the primary tumour.

Furthermore, PET/CT detects a cervical lymph node metastasis in the area of the angle of the right mandible and, in addition, two lymph node metastases in the area of the angle of the left mandible, i.e. at the level of the lower border of the left ear. Teaching point: Detection of the primary tumour and of two other so far unknown lymph node metastases by PET/CT.

Findings: The images show a string-shaped area of activity which is not symmetrical with the left side in the area of the right base of the tongue above the throat level which is assumed to be the unknown primary tumour.

Fig. 12.2.1. Cervical metastases of unknown primary (CUP) on both sides

12.3

Fig. 12.2.2. The sought after primary tumour is detected at the base of the tongue on the right side, increased tracer uptake only in the late enhancement image

Case Studies

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Patient 3 Oropharyngeal Carcinoma Clinical history: The 59-year-old male suffered from a neck lymphoma on the right side classified as a metastasis of an undifferentiated large-cell carcinoma. PET/CT indication: Search for the primary tumour as well as further propagation diagnosis. Findings: Detection of a 5.7 × 5.0 × 7.2-cm large tumour in the area of the cervical lymph tract with extended necrotized areas in the centre and with SUV values consistent with malignancy in its perimeter

area. Furthermore, detection of a lymphoma in the angle of the right mandible measuring 1.0 × 2.0 cm which also displays glucose metabolic activity consistent with malignancy. A mass displaying increased tracer uptake in the area of the oropharynx or the upper hypopharynx on the right side is suspected of being the primary tumour. Teaching points: PET/CT could localize the primary tumour in the oropharynx. Propagation diagnosis revealed both the known cervical lymphoma and another lymphoma in the area of the angle of the right mandible.

Fig. 12.3.1. The MIP image depicts an annular area with increased uptake on the right side of the neck. The PET/CT images document the cervical lymphoma with three slice planes

12.3

Fig. 12.3.2. Transaxial PET/CT slice showing a considerably increased cervical lymphoma in the right cervical region which has already displaced the soft tissue in the neck area. The image illustrates the increased tracer uptake in the marginal area as well as reduced tumour activity in the centre

Case Studies

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 Fig. 12.3.3. Sequence of coronal slices with significantly increased glucose metabolic activity in the area of the cervical lymphoma

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Fig. 12.3.4. Another lymphoma in the right cervical region which displaces the soft tissue in the neck area

Fig. 12.3.5. Increased uptake in the area of the primary tumour in the right oropharynx

12.3

Patient 4 Cholangiocarcinoma

Case Studies

Clinical history: A 57-year-old female with multiple liver metastases of unknown primary. The histological examination revealed a medium-differentiated adenocarcinoma. Generalized metastatic spread in the lung as well as lymph node conglomerates in the liver hilus were detected by CT. PET/CT indication: Localization of the primary tumour by PET/CT.

lymph nodes and the known histology of an adenocarcinoma. In addition to the known metastatic spread in the area of the liver hilus and both lobes of the lung revealed during the CT pre-examination, the latest scan reveals ascites, pleural effusion on the right side as well as metastases in the left suprarenal gland. Furthermore, osteolytic metastases in the right humeral head, the right 4th rib laterally, the manubrium sterni, the right pedicle and the left transverse process of the T7 vertebral body as well as the lower right ala of the sacrum.

Findings: The tracer distribution pattern is in the first place characteristic of a cholangiocarcinoma. This assumption is supported by the accumulation pattern of the glucose metabolic activity consistent with malignancy and the morphological propagation pattern of the liver lesion. It is also in line with the pronounced regional metastatic spread into the

Teaching points: The distribution pattern revealed by PET/CT characterizes the primary tumour as a cholangiocarcinoma. In addition, the whole-body scan provides much more detailed information, the main findings being the pleural effusion and ascites as well as the metastasis in the left suprarenal gland and the bone metastases.

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Fig. 12.4.1. Sequence of attenuation-corrected coronal PET images. The most important fi nding is the considerable metastatic spread into the liver. There is also slight evidence for lung metastases

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Fig. 12.4.2. MIP image and PET/ CT slice planes. The images show liver metastases, the metastasis in the sacrum as well as the metastasis in the left suprarenal gland

Fig. 12.4.3. Coronal PET/CT slice showing metastatic spread to the liver and the metastasis in the left suprarenal gland

12.3

Case Studies

Fig. 12.4.4. Transaxial PET/CT slice with lung window setting, with extended metastatic spread to the pulmonary region

Fig. 12.4.5. Sequence of 3 sagittal PET/CT slices. The most striking fi ndings in these images are the bone metastases in the spine and the liver metastases

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Patient 5 Pancreatic Carcinoma Clinical history: A 75-year-old female patient. Liver changes were fi rst diagnosed during a routine examination. A poorly differentiated adenocarcinoma which might have its origin in the biliary tract was tentatively diagnosed. From a differential-diagnostic point of view, an extrahepatic primary tumour had to be taken into consideration (e.g. of the pancreas). A primary pancreatic tumour is not as yet reliably localized. Tumour (3.5 cm in diameter) extirpation with segment V resection and cholecystectomy 1.5 years previously. Considerable postoperative rise in tumour marker. Meanwhile, detection of new focal liver lesions in the segments VI/VII and VIII according to the results of an MRI scan.

PET/CT indication: Recurrent tumour in the liver? Another primary tumour? Metastatic spread? Further propagation diagnosis. Findings: With status post segment V resection, tumour-free resection margins. No evidence for local recurrence. Detection of at least six liver metastases in both lobes of the liver. Subcutaneous metastases in the area of the navel. The multiple hepatic metastases are probably due to a relatively extended tumour in the area of the body of the pancreas. Mesenterial lymphoma below the cecal pole. No further evidence for metastatic spread. No ascites. No pleural effusion. Teaching point: The primary tumour, i.e. a pancreatic carcinoma, can be diagnosed with PET/CT and the metastatic spread can also be precisely evaluated.

Fig. 12.5.1. MIP image with liver metastases as well as strongly increased tracer uptake in the epigastric region projective over the pancreatic area. Furthermore, the PET/CT slice with the different slice planes. Metastases in the liver and in the pancreas region in the MIP image and the PET/CT slice planes

12.3

Fig. 12.5.2. Transaxial PET/ CT slice showing the primary tumour in the area of the body of the pancreas as well as liver metastases

Fig. 12.5.3. Subcutaneous metastasis in the area of the navel

Fig. 12.5.4. Transaxial slice showing a mesenterial lymphoma

Case Studies

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Patient 6 Carcinoma of the Head of the Pancreas Clinical history: A 66-year-old female patient post ERCP revealing strong suspicion of a carcinoma of the head of the pancreas with fi liform DHC stenosis in the middle third. Status post insertion of a 10-F stent. Both the CT scan and the sonographic scan revealed masses suspicious of metastatic spread in the left lobe of the liver. Increased tumour marker level. PET/CT indication: Confirmation of the diagnosis of a carcinoma of the head of the pancreas by PET/CT as well as further propagation diagnosis for therapy planning.

Findings: Carcinoma of the head of the pancreas which must be considered the cause of the stenosis of the hepatocholedochus duct. Furthermore, detection of a metastasis in the left lobe of the liver with a maximum diameter of 3.6 cm, necrotized in the centre. No further evidence for distant metastases. Teaching points: Reliable diagnosis of the carcinoma of the head of the pancreas being classified as the primary tumour. Furthermore, detection of a liver metastasis and exclusion of further metastases.

Fig. 12.6.1. The MIP image shows a lesion in the projection onto the left lobe of the liver as well as another lesion in the epigastric region. The standard PET/CT slices illustrate malignant growth in the pancreas

12.3

Fig. 12.6.2. Transaxial PET/CT slice showing a focus in the head of the pancreas consistent with malignancy

Fig. 12.6.3. Transaxial PET/CT slice of a liver metastasis in the left lobe of the liver ventrally with glucose metabolic activity consistent with malignancy

Fig. 12.6.4. Coronal PET/CT slice showing the metastasis with markedly increased uptake in the centre

Case Studies

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Patient 7 Mamma Carcinoma Clinical history: A 76-year-old female with a lymph node metastasis of an adenocarcinoma in the right axillary region. Cancer of unknown primary. PET/CT indication: Search for the primary tumour. Findings: Detection of right axillary lymphomas as well as diffuse metastatic spread into the skeleton. The bifocally slightly increased glucose metabolic activity in the area of the right breast is classified as a developing carcinoma considered to be the unknown primary tumour. Teaching points: Despite relatively extended metastatic spread, the primary tumour displays only slightly increased glucose metabolic activity. It is not unusual to find an apparent discrepancy between an only slightly conspicuous primary tumour and extensive hypermetabolic metastases.

Fig. 12.7.1. Transaxial, coronal and sagittal PET/CT images of a partial body scan of a patient laying on her abdomen, showing bifocally increased glucose metabolic activity in the right breast

12.3

Fig. 12.7.2. Sequence of transaxial PET/CT slices with 2 lymph nodes in the right axillar region displaying markedly increased tracer uptake

Case Studies

 Fig. 12.7.3. Sequence of transaxial PET/CT slices with bone window setting showing increased uptake levels in the area of several bone lesions

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Fig. 12.7.4. Transaxial PET/CT slice with bone window setting showing a metastasis in a vertebral body as well as one metastasis in the spine of a vertebral body

Fig. 12.7.5. Sagittal PET/CT slice with bone window setting in the area of the lumbar spine and the middle thoracic spine

12.3

Patient 8 CUP Tumour Clinical history: A 64-year-old male patient post resection of two brain metastases. Status post operation of the right lung due to malignant growth detected 4 weeks later. Radiotherapy to another brain metastasis diagnosed 3 months later. At present, the patient suffers from speech disorders and motor restrictions of the upper and lower left extremities. The primary tumour is not known. PET/CT indication: Search for the primary tumour with PET/CT as well as further staging of metastases. Findings: At least 11 metastases in the right and left lobe of the liver. Furthermore, a large brain metasta-

Case Studies

533

sis in the area of the right temporal lobe beside two smaller brain metastases on the left side, adjoining the median line and in the left occipital region. In the cerebral area PET/CT detects increased uptake on the ventral side in the region where the metastasis has been removed which must be interpreted as indicating that the metastasis could not be completely excised. The primary tumour could not as yet be localized. Teaching points: The search for the primary tumour may be successful in varying degrees, depending on the statistical method used. Although absolutely indicated from a curative perspective, this approach is only successful in approximately 40% of all cases. In spite of extended metastatic spread, a primary tumour could not be detected in this case.



Fig. 12.8.1. Brain metastasis in the right temporal region shown with the different PET/CT slice planes and in the MIP image

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12 CUP Tumours

Fig. 12.8.2. Transaxial PET/CT slice showing the right temporal brain metastasis

Fig. 12.8.3. Sequence of transaxial PET/CT slices showing pronounced metastatic spread to the liver

12.3

Fig. 12.8.4. Transaxial PET/CT slice documenting the metastases in the left lobe of the liver

Case Studies

535

536

12 CUP Tumours

Patient 9 Mamma Carcinoma Clinical history: A 74-year-old female patient post radiotherapy to a tumour of the right breast wall with a total dose of 45 Gy. From a differentialdiagnostic point of view we are dealing with an adenocarcinoma with metastasis of unknown primary. Now nodal infi ltration of the right breast of unclear genesis. PET/CT indication: Tumour propagation? Where is the primary tumour? Metastatic spread? Findings: The PET/CT images reveal significant improvement or regression of the soft tissue tumour in

the chest wall on the right side after radiotherapy, but they also reveal a new nodal infi ltration of the right breast with glucose metabolic activity consistent with malignancy. Extended locoregional lymph node infi ltration in the lower cervical lymph tract and in the supraclavicular region persists. New liver metastasis. Furthermore, newly detected ascites as well as bilateral pleural effusions. Teaching points: Classification of the nodal changes in the area of the right breast as being consistent with malignancy. In addition, significant broadening of the findings, i.e. detection of ascites diagnosed for the first time, of pleural effusions as well as metastatic spread into the liver.

Fig. 12.9.1. MIP image as well as transaxial, coronal and sagittal slices illustrating markedly increased uptake in the area of the right breast

12.3 Fig. 12.9.2. Transaxial PET/CT slice with markedly increased uptake in the right breast

Fig. 12.9.3. Transaxial PET/CT slice with liver metastasis

Case Studies

537

538

12 CUP Tumours

Patient 10 Carcinoma of the Base of the Tongue Clinical history: A 74-year-old female patient post extirpation of a lymph node metastasis 5 months previously (squamous cell carcinoma, CUP syndrome). The histological findings would match the characteristics of a tonsillar carcinoma, however, status post tonsillectomy in 1956. Considerable familiar disposition. PET/CT indication: Can PET/CT detect evidence of a primary tumour?

Teaching points: Due to the PET findings, the suspicious area was inspected locally and tissue samples were taken. The histological examination of the tissue samples taken in the region where increased uptake was registered at the base of the tongue or in the area of the left tonsillar bed revealed a 6-mm border developing poorly differentiated and not cornifying squamous cell carcinoma in the area of the squamous mucosa. Carcinoma in situ in the glossotonsillar sulcus on the left side. The primary tumour could thus be detected with PET/CT.

Findings: Imaging of increased glucose utilization in the area of the base of the tongue or the tonsillar bed on the left side, in terms of a malignant tumourous infi ltration. Surgical revision of this region is recommended.

Fig. 12.10.1. Transaxial PET/CT slice with increased uptake in the left tonsillar sulcus consistent with malignancy

12.3

Fig. 12.10.2. Late enhancement image of the same region with persistent hypermetabolic activity in the left tonsillar sulcus

Case Studies

539

540

12 CUP Tumours

Patient 11 Bronchial Carcinoma Clinical history: A 65-year-old male with lymph node metastasis of unclear genesis in the right cervical region. PET/CT indication: Search for primary tumour with PET/CT. Findings: The images display increased uptake consistent with malignancy in the branching area of the left upper lobe bronchus which must be classified as a bronchial carcinoma on the left side. Furthermore, the images show large lymph node metastases in the left paratracheal space and smaller metastases on the left side of the arteria pulmonalis. In addition, metastasis in the left suprarenal gland. Teaching points: PET/CT is able to diagnose the primary tumour as a bronchial carcinoma. Lymph node metastases as well as a metastasis in the left suprarenal gland could be detected by the same scan.

Fig. 12.11.1. 3 PET/CT slice planes showing increased uptake in the branching area of the left upper lobe bronchus as well as another area with increased uptake in the left paratracheal space suspicious for metastatic spread into the lymph nodes. MIP image showing the abovementioned increased uptake

12.3

Case Studies

Fig. 12.11.2. 4 transaxial PET/CT slices showing the primary tumour in the area of the left upper lobe bronchus as well as two lymph node metastases in the left paratracheal space

Fig. 12.11.3. Slightly increased uptake displaying the metastasis in the left suprarenal gland as documented by the 4 transaxial PET/CT slices

541

542

12 CUP Tumours

Patient 12 Bronchial Carcinoma Clinical history: A 39-year-old male with osseous metastatic spread of unknown primary in the area of the left wing of the ilium, the left acetabulum as well as the right and left proximal femur shaft. The histological examination revealed an undifferentiated carcinoma. PET/CT indication: Search for the primary tumour as well as other tumour spread with PET/CT. Findings: Confirmation of a small bronchial carcinoma in the area of the apex of the left lung. Furthermore, documentation of further malignant growth in the left iliac wing, both proximal femur shafts and in the area of the right humeral head. In addition, large soft tissue metastasis at the left interior and, less pronounced, also the exterior pelvic wall. Teaching points: Detection of the primary tumour classified as a bronchial carcinoma of the apex of the left lung with PET/CT. In addition, documentation of further metastatic spread into the bone and soft tissue area within the scope of the same scan.

Fig. 12.12.1. Sequence of coronal PET slices documenting the primary tumour in the apex of the left lung

12.3

Fig. 12.12.2. Sequence of coronal slices with osseous metastases in the left iliac wing as well as in the femur and in the soft tissue area

Case Studies

543

544

12 CUP Tumours

12.4 References 1. Adams S, Baum RP, Stuckensen T, Bitter K, Hör G (1998) Prospective comparison of FDG PET with conventional imaging modalities CT, MRI, US in lymph node staging of head and neck cancer. Eur J Nucl Med 25:1255–1260 2. Assar OS, Fischbein NJ, Caputo GR et al. (1999) Metastatic head and neck cancer: role and usefulness of FDG PET in locating occult primary tumours. Radiology 210:177–181 3. Bristow RE, del Carmen MG, Pannu HK et al. (2003) Clinically occult recurrent ovarian cancer: patient selection for secondary cytoreductive surgery using combined PET/CT. Gynecol Oncol 90:519–28 4. Burell StC, Van den Abbeele AD (2005) 2-deoxy-2-(F18) fluoro-D-glucose-positron emission tomography of the head and neck: an atlas of the normal uptake and variants. Mol Imaging Biol 7:244–256 5. Czernin J, Auerbach (2005) Clinical PET/CT imaging: promises and misconceptions. Nuklearmedizin Suppl 1 44:S18–23 6. Delgado-Bolton RC, Fernando-Perez C, Gonzalez-Meta A, Carreras JL (2003) Metaanalysis of the performance of 18F-FDG PET in primary tumour detection in unknown primary tumours. J Nucl Med 44:1301–1314 7. Gambhir SS, Czernin J, Schwimmer J et al. (2001) A tabulated summary of the FDG PET literature. J Nucl Med [Suppl] 42:1–93 8. Greco FA, Hainsworth JD (1993) Cancer of unknown primary site. In: Devita VT Jr, Hellma NS, Rosenberg SA (eds) Cancer: principles and practice of oncology. Lippincott-Raven, Philadelphia, pp 2072–2092 9. Gutzeit A, Antoch G, Kühl H et al. (2005) Unknown primary tumours: detection with dual modality PET/CTInitial experience. Radiology 234:227–234 10. Haskell CM (2001) Cancer treatment. WB Saunders, Philadelphia 11. Hör G (2001) Impact of clinical (satellite-) PET in oncology. Siemens, Erlangen A91100-M2300-A269–1–7600:2–16 12. Hör G, Mantaka P (1998) Application of PET in clinical oncology. In: Limouris GS, Shukla SK, Bender HF, Bier-

sack HJ (eds) Radionuclides for oncology – current status and future aspects. Mediterra, Athens, pp 107–111 13. Israel O, Mor M, Guralnik L et al. (2004) Is 18F-FDG PET/ CT useful for imaging and management of patients with suspected and occult recurrence of cancer? J Nucl Med 45:2045–2051 14. Johansen E, Eiftved A, Buchwald C et al. (2002) Implication of 18F-fluordeoxy-D-2 glukose positron emission tomography on management of carcinoma of unknown primary in the head and neck: a Danish cohort study. Laryngoscope 112:2009–2014 15. Makaiova I, Vesely J, Kovacova S et al. (2002) False positive uptake of 18FDG-fluorodeoxyglucose in the axillary brown fat lipoma (hibernoma)-case report. EANM, Abstr. 16. Manolidis S, Donald PJ, Volk P, Pounds TR (1998) The use of positron emission tomography scanning in occult and recurrent head and neck cancer. Acta Otolaryngol [Suppl] 534:1–11 17. Mantaka P, Hertel A, Adams S et al. (1998) Contribution of PET-FDG in the diagnosis of cancer of unknown primary. In: Limouris GS, Shukla SK, Bender HF, Biersack HJ (eds) Radionuclides for oncology – current status and future aspects. Mediterra, Athens, pp 121–131 18. Regelink G, Brouwer J, de Bree R et al. (2002) Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDG-PET versus conventional modalities. Eur J Nucl Med 29:1024–1030 19. Scott CL, Cudaba I, Stewart JM et al. (2005) The utility of 2-deoxy-2-(F18) fluoro-D-glukose positron emission tomography in the investigation of patients with disseminated carcinoma of unknown primary origin. Mol Imaging Biol 7:236–243 20. Sengupta MS, Lee SJ, Hoh CK et al. (1995) Utility and cost effectiveness of FDG whole body PET in patients with unknown primary malignancies (Abstr. 226). J Nucl Med 36:56 21. Wahl RL (2004) Why nearly all PET of abdominal and pelvic cancers will be performed as PET/CT. J Nucl Med Suppl 1 45:S81–95 22. von Schulthess GK (2003) Clinical molecular anatomic imaging PET, PET/CT and SPECT/CT. Lippincott, London

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Pitfalls

CONTENTS 13.1

Testicular Carcinoma and Other Primary Tumours 546 Universal Organ Spectrum of SPT 546

13.2 Physiological Accumulation of FDG

547

13.3 False Positive FDG Accumulations in the Oncological Sense 547 13.4 Artefacts Due to Technical Factors 13.5 False Negative PET Findings

547

547

13.6 Case Studies Secondary Tumours 548 Patient 1 Inflammatory Carcinoma of the Breast and Papillary Carcinoma of the Inner Genital Tract 548 Patient 2 Carcinoma in Situ with Osteoplastic Metastases 10 years later 551 Patient 3 Recurrence of a Sigmoid Carcinoma, Compression of the Left Ureter 554 Patient 4 Cervical Carcinoma and Rectal Carcinoma 556 Patient 5 Mamma Carcinoma and Colon Carcinoma 558 Patient 6 Mamma Carcinoma and Sigmoid Carcinoma 560 Patient 7 Thymoma 561 Patient 8 Prostate Carcinoma and Colon Carcinoma 564 Patient 9 Renal Cell and Prostate Carcinoma 566 Patient 10 Prostate Carcinoma and Colon Carcinoma 568 Patient 11 Carcinoma in Situ of the Rectum and Bronchial Carcinoma 570 Patient 12 Non-Hodgkin’s Lymphoma and Bronchial Carcinoma 574 Patient 13 Mamma Carcinoma and Bronchial Carcinoma 577 Patient 14 Coecum, Bronchial and Renal Carcinoma 579 Patient 15 Mamma, Cervical and Rectal Carcinoma 583 Patient 16 Parotid and Colon Carcinoma 586

13.7 Case Studies Physiologically Increased Uptake Patient 17 589 Patient 18 590 Patient 19 590 Patient 20 591 Patient 21 592

589

13.8 Case Studies Non-Oncological Increased Uptake of Inflammatory Genesis 593 Patient 22 593 Patient 23 594 Patient 24 596 Patient 25 598 Patient 26 599 Patient 27 600 Patient 28 602 Patient 29 605 Patient 30 608 Patient 31 610 13.9

Case Studies Artefacts 611 Patient 32 611 Patient 33 613 Patient 34 614 Patient 35 615 Patient 36 616 Patient 37 617 Patient 38 618 Patient 39 620

13.10 References

622

As we could show in the previous chapters, imaging of functional or molecular parameters with PET/CT offers great potential for supplementary or early information on the development, propagation and, in some cases, recurrence of a malignant disease. But this advantage is unfortunately correlated with the problems that this imaging method is susceptible to artefacts and that so-called false-positive and false-negative findings cannot be excluded. Good basic knowledge of pathophysiology and a certain understanding of the technical processes involved in the equipment used can help to minimize or even exclude such pitfalls. Regardless of the indication, careful anamnesis as well as inspection and palpation should not be ne-

546

13 Pitfalls

glected, even if highly sophisticated technical equipment is used for the examination. Finally, a critical consideration of the findings that also takes clinical experience into account is indispensable. This will be illustrated by the following cases. Furthermore, we will discuss secondary tumours that were often detected in the patient population described in this chapter and their interpretation. Experimental data gained within the scope of PET and PET/CT studies are obviously not available. This is all the more surprising given that Internet research yielded an unexpectedly high number of clinical contributions and studies. A multitude of tumours display – during their spontaneous development – particularities after radio- and chemotherapy, but also secondary primary tumours after surgical interventions performed to resect a tumour.

13.1

Testicular Carcinoma and Other Primary Tumours

The most comprehensive study we know [64] is focussed on secondary tumours found in 40,576 patients suffering from testicular carcinomas, and this study especially takes into consideration long-time survival patients – epidemiologically and genetically based on a multinational level. SPTs are considered the main cause of death in patients suffering from testicular carcinomas, tak-

ing into account quantified risk profi les. A total of 2,285 SPTs with a relative decline in risk in relation to the patient’s age at diagnosis was recorded: SPT was observed nearly twice as often if the patients were 35 years old. Pleural mesotheliomas and oesophagus carcinomas were the dominating lesions. Precanceroses of testicular tumours (TIN, testicular intraepithelial neoplasia [17]) cannot yet be analyzed with PET. Due to its propagation characteristic, it probably does not represent a patient population in which PET yields reliable results. It could not yet be clarified whether PET plays a role in the genesis of secondary tumours.

Universal Organ Spectrum of SPT Table 13.1 reveals further organ manifestations. Concrete relations can be established in consultation with oncologists and the referring physician to determine whether and when PET scans may be useful; their clinical relevance should be reviewed with respect to studies already available and be taken into account in updated consensus guidelines. Radio- and chemotherapy of primary tumours are potential risk factors regarding SPT. Induction of genome instabilities is being discussed [49, 56]. Epidemiological studies dealing with second tumours include both adults and children. Therapeutic preventive strategies aim at the use of antioxidant vitamins, chemoprevention of late

Table 13.1. Second primary tumours (so-called second tumours) PT SPT

Notes

Literature

Colon/rectum

after radiotherapy, epidemiological risks

[6, 4, 11, 60, 33, 34]

Lung, aerodigestive tract

after chemotherapy, receptor therapy, radiotherapy (alone)

[22, 38, 10, 2, 58, 41, 36, 42]

ENT tumours, breast, cervix, thyroid gland

epidemiological, after cytostasis

[12, 27, 40, 61, 39, 26, 44, 25, 23, 45, 16, 52]

Melanoma, retinoblastoma

after radio-/chemotherapy

[62, 18, 48, 54, 53]

Pancreas, NET, oesophagus

epidemiological, screening, synchronous

[32, 51, 21, 34, 15, 51, 32]

Skin tumours

[43]

Lymphomas

after chemotherapy

[1, 7]

Bladder, kidney, thyroid gland, prostate, cervix, testicles

after radiotherapy

[65, 12, 52, 8, 59, 21, 64]

Paediatric oncology

risk factors, after radiotherapy

[67, 63, 5, 24, 14, 47, 10, 9, 57]

13.2

toxicity related to conventional tumour therapy and the improvement of radiotherapy techniques (3DCRT, IMRI, proton therapy) to optimise tolerance, to minimise the occurrence of SPT and to improve risk prediction [3, 20, 27, 30, 38, 42, 47]. A special register needs to be designed for SPT that takes into account multimodal imaging methods [46].

13.2 Physiological Accumulation of FDG Table 13.2. Physiological Accumulation of 18FDG Survey [29, 55] Increased uptake due to motility/muscle activity

Peristalsis, vocal cords, tongue [31] (talking, swallowing)

Increased uptake in the adipose tissue

BAT, WAT, USA [13]

Elimination enrichment

Kidney, efferent urinary tract, bladder

Thymus

[50]

Mammae

Lactating mammae

Skin

e.g. axillary sweat secretion [35]

13.4

Artefacts Due to Technical Factors

Table 13.4. Artefacts Due to Technical Factors Contrast agent application in general

PET/CT, [19]

Movement

Patient unrest, breath excursions

Contrast agent overcorrection

High-density barium

Bolus, metal implants

In case of undiluted contrast agent, dental protheses, endoprotheses, pacemakers

Physiological Accumulation of FDG

Priority is given to the family history and molecular genetic markers used to detect micrometastases of SPT that cannot be detected by clinical examinations, for example, IGF-1/insulin growth factors and IGF-binding proteins, p53 and K-ras gene mutations [49, 66] for risk prediction.

13.3

False Positive FDG Accumulations in the Oncological Sense

Table 13.3. False positive increased uptake of FDG in the oncological sense [29, 55] Infection, inflammation

e.g. pneumonia, pleuritis

Inflammatory processes in the area of the joints

e.g. arthritis

Granulomatous system diseases

Sarcoidosis

Benign diseases of the thyroid gland

Thyreoiditis, autonomous adenomas

Postoperative processes

e.g. seroma

Posttherapeutical processes in the bone marrow

Medullar expansion after Tx, chemotherapy, CSF therapy

Skin

e.g. before herpes zoster eruption [15, 37]

Vessels

Artherosclerotic plaques [15, 28]

Lung

Iatrogenic foci [29]

13.5

False Negative PET Findings

Table 13.5. Entities with numerous false negative PET findings Lung

Bronchoalveolar carcinoma

Liver

Hepatocellular carcinoma

Lymphomas

MALT lymphomas, low-grade lymphomas

Carcinoids, neuroendocrine tumours Kidney

Renal cell carcinomas

547

548

13 Pitfalls

13.6 Case Studies Secondary Tumours Patient 1 Inflammatory Carcinoma of the Breast and Papillary Carcinoma of the Inner Genital Tract Clinical history: A 55-year-old female was diagnosed with a histologically proven inflammatory carcinoma of the breast with cutaneous lymphangiosis carcinomatosa. A conspicuous symptom was an increase in corpulence in the last few days. PET/CT indication: Propagation diagnosis, mainly also metastatic spread. Findings: Increased glucose metabolic activity consistent with malignancy in the area of the right breast as well as axillary and mediastinal lymphomas. Slightly extended pleural effusions. Extended ascites as well as detection of glucose metabolic activity consistent with malignancy in several small mesenterial foci and of an extended mesenterial conglomerate in the left abdominal region that can-

not be distinguished from the colon descendens. Furthermore, detection of lymphomas in the left paraaortal region. The patient was referred to another institution for diagnosis and therapy where a diagnostic colonoscopy, proctoscopy, biopsy of the lower digestive tract, laparoscopy, endoscopic excision of the left uterine tube as well as endoscopic biopsy of the peritoneum in the Douglas space were performed. In summary, the patient was diagnosed with a serous-papillary carcinoma of the interior genital region and the peritoneum with metastases in the right breast and in lymph nodes in the right axillary region. This new diagnosis thus replaced the histological diagnosis of an inflammatory mamma carcinoma on the right side. The patient is now being treated for papillary carcinoma of the interior genital region. Teaching points: The diagnosis of a mamma carcinoma that originally seemed to be proven by the histological examinations was reviewed due to the extraordinary pattern of metastatic spread revealed by PET, and the rare case of a carcinoma of the interior genital region with metastatic spread to the right breast was newly diagnosed.

Fig. 13.1.1. Sequence of coronal PET slices revealing a particularly suspicious tumour conglomerate in the left abdominal region

13.6

Fig. 13.1.2. Transaxial PET/CT slice with increased glucose metabolic activity consistent with malignancy in the right breast

Case Studies Secondary Tumours

549



Fig. 13.1.3. Transaxial PET/CT slice with 2 affected axillary lymph nodes

550

13 Pitfalls

Fig. 13.1.4. Transaxial PET/CT slice with one mediastinal lymph node package

Fig. 13.1.5. MIP image and sequence of transaxial, coronal and sagittal PET/CT slices showing tumour-specific glucose metabolic activity in the left abdominal region. This image clearly illustrates ascites. The high-resolution images reveal an extended mesenterial conglomerate which can not be distinguished from the colon ascendens and has its origin in the ovary as detected later within the scope of a laparascopic examination

13.6

Case Studies Secondary Tumours

Patient 2 Carcinoma in Situ with Osteoplastic Metastases 10 years later

subpleural region in the area of the left lower lobe of the lung. In addition, osteoblastic osseous metastases in the spine, the sternum and the pelvic skeleton.

Clinical history: A 75-year-old female status post mastectomy due to a mamma carcinoma (carcinoma in situ on the left side) 10 years ago. Now a new lymphoma in the left supraclavicular region was found, histologically diagnosed as metastasis of a mamma carcinoma. PET/CT indication: Propagation diagnosis.

Teaching points: A striking fact regarding the progress of the disease is the long period between the first occurrence of a carcinoma in situ of the left breast 10 years ago and the occurrence of the first metastases some weeks ago. Another striking fact is the spread of osteoblastic bone metastases to the spine, sternum and pelvic skeleton, since osteolytic metastases are normally found in patients suffering from a mamma carcinoma. In summary, the examinations revealed a really extraordinary progress of the disease with late metastatic spread characterized by an untypical pattern.

Findings: Detection of further lymph node metastases in the left supra- and infraclavicular region as well as in the left mediastinal and hilar region. Furthermore, pulmonary metastases in the pleural/

551

Fig. 13.2.1. Transaxial PET/CT slice showing a lymphoma in the left subclavicular region



552

13 Pitfalls

Fig. 13.2.2. Transaxial PET/CT slice showing a small mediastinal lymphoma

Fig. 13.2.3. Transaxial PET/CT slice demonstrating a subpleural metastasis in the left lower lobe of the lung

Fig. 13.2.4. Osteoplastic metastasis in the thoracic spine

13.6

Fig. 13.2.5. Osteoplastic metastasis in the pelvis

Fig. 13.2.6. Transaxial PET/CT slice with bone window setting showing osteoplastic metastasis in the ilium on the right side

Case Studies Secondary Tumours

553

554

13 Pitfalls

Patient 3 Recurrence of a Sigmoid Carcinoma, Compression of the Left Ureter Clinical history: A 61-year-old male status post sigmoidectomy due to an adenocarcinoma. Postoperative radiochemotherapy. Rectoscopy revealed a bleeding ulcus in the anastomosis area, 35 cm from the anus, 1 year later. Exploratory excision revealed a highly differentiated adenocarcinoma. PET/CT indication: Staging for further therapy planning.

dynamic activity consistent with malignancy between the first and the second series of examinations. The recurrent tumour compresses the left ureter so that the left kidney is obstructed. No further evidence for regional lymph node metastases or distant metastases. Teaching points: PET/CT allows non-invasive reliable staging in a previously operated region. In this context, the CT component helps to illustrate the anatomical extent of the compressive effect on the left ureter due to the malignant growth.

Findings: Circumscribed recurrent tumour in the lower left abdominal region sized 2.8 × 2.8 cm with

Fig. 13.3.1. Sequence of coronal and sagittal PET slices displaying readily visible increased uptake in the left lower abdominal region

13.6

Fig. 13.3.2. The 3 PET slice planes show the malignant growth in the lower abdominal region which is also illustrated on the MIP image

Fig. 13.3.3. Transaxial PET/CT slice with a malignoma sized approx. 2.8 × 2.8 cm

Fig. 13.3.4. Sequence of coronal PET/CT slices clearly demonstrating the congested ureter and the malignant growth with their precise location

Case Studies Secondary Tumours

555

556

13 Pitfalls

Patient 4 Cervical Carcinoma and Rectal Carcinoma Clinical history: A 77-year-old female with adenocarcinoma of the cervix uteri, FIGO 2B (barrel carcinoma), rectal carcinoma. Insulin-requiring diabetes mellitus.

PET/CT indication: Tumour staging prior to planned radiotherapy. Findings: As expected for the known rectal carcinoma, the images show increased glucose metabolic activity in the rectal region over a length of 5 cm and with a diameter of approximately 2 cm, with the rectal tumour invading the dorsal uterine wall

Fig. 13.4.1. MIP image with 2 lesions consistent with malignancy in the lower abdominal region as well as transaxial PET/CT image of the rectal carcinoma and one area with focally increased uptake in the projection to the uterus shown on a sequence of sagittal and coronal slices.

Fig. 13.4.2. Tumour-specific involvement of the rectum with increased glucose metabolic activity which is obviously invading the uterine corpus

13.6

Case Studies Secondary Tumours

in some areas. Furthermore, as expected for the known adenocarcinoma of the cervix uteri, the images show glucose metabolic activity consistent with malignancy in both the area of the cervix and the corpus uteri. Suspicion of lymph node metastases between the uterus and the dorsal bladder wall and the uterus and the rectal wall as well as pararectally on both sides. Teaching points: The occurrence of two parallel carcinomas is especially illustrated in this case, and considering the invasion of the rectal carcinoma into the corpus uteri, the pathogenic history will have to be investigated.

Fig. 13.4.3. Increased glucose metabolic activity consistent with malignancy in the rectum and the uterine corpus

Fig. 13.4.4. Sequence of transaxial PET/CT slices showing increased glucose metabolic activity in the rectal area and increased uptake consistent with malignancy in the cervix and the corpus uteri

557

558

13 Pitfalls

Patient 5 Mamma Carcinoma and Colon Carcinoma Clinical history: A 58-year-old female status post mamma carcinoma on the left side. A single lymph node was resected in the axillary region. PET/CT indication: Staging/propagation diagnosis before the start of a planned chemot herapy. Findings: Glucose metabolic activity consistent with malignancy in the areas of the colon ascendens close to the flexura. As a causal relationship with the known mamma carcinoma cannot be established, the patient was suspected of suffering from

a secondary carcinoma. Lymphoma in the area of the splenic hilum. No other evidence for focal lesions suspected of being tumours or metastases was found during the whole-body scan, particularly no evidence for residual tumour in the area of the operated, revised left breast and in the area of the locoregional lymphomas. Teaching points: As an incidental finding in a patient status post mamma carcinoma operation, PET/ CT could detect a secondary carcinoma in the colon ascendens that was classified as an adenocarcinoma after completion of the surgical intervention performed after the examination. The lymphoma in the splenic hilum corresponded to a lymph node affected by this adenocarcinoma.

Fig. 13.5.1. Sequence of coronal PET slices displaying increased uptake consistent with malignancy in the right abdominal region

13.6

Fig. 13.5.2. Markedly increased glucose metabolic activity in a transaxial PET/CT slice

Fig. 13.5.3. Transaxial PET/CT slice with lymphoma in the splenic hilum on the left side

Case Studies Secondary Tumours

559

560

13 Pitfalls

Patient 6 Mamma Carcinoma and Sigmoid Carcinoma Clinical history: A 76-year-old female status post left mastectomy and axillary dissection due to a mamma carcinoma histologically classified as an invasive solid ductal carcinoma. Post-operative chemotherapy. No evidence for metastatic spread found with the PET/CT scan performed after this operation. Secondary finding: kidney agenesia on the right side. Status post hysterectomy and adnectomy on both sides. PET/CT indication: Restaging.

Findings: Metabolically suspicious focus in the proximal sigmoid that is suspected of being consistent with malignancy. Otherwise unsuspicious findings. Teaching points: The focus in the area of the proximal sigmoid could be classified as a circumscribed adenocarcinoma after surgical intervention, and the patient could undergo curative treatment. The PET/ CT whole-body scan thus enabled early diagnosis of malignant growth in the sigmoid area.

Fig. 13.6.1. Circumscribed increased uptake consistent with malignancy in the left lower abdominal region

Fig. 13.6.2. Transaxial PET/CT slice in which this increased uptake consistent with malignancy is projected into the sigmoid wall

13.6

Patient 7 Thymoma Clinical history: A 62-year-old woman with a suspicion of malignant growth in connection with polyneuropathy and paraneoblastic cerebellar ataxia. MRSA-positive. Suspicion of multiple rib fractures. PET/CT indication: Search for an unknown primary tumour whereby the paraclinic drew attention to the suspicion of a neuroendocrine tumour. Findings: Glucose metabolic activity consistent with malignancy in the area of a mass detected in

Case Studies Secondary Tumours

561

the upper anterior mediastinum that is classified as a malignant thymoma. Suspicious metabolic activity in the area of a retroclavicular lymph node on the right side classified as a metastasis. Healing rib fractures or infractions, respectively, on both sides (pathologically under cortisone therapy?). Teaching points: On the other hand, PET is remarkable for permitting the visual diagnostic detection of the thymoma, but finally the CT images made possible the precise localization and therefore the classification as thymoma.

 Fig. 13.7.1. Sequence of coronal PET slices illustrating mainly a round focus with increased uptake in the retrosternal region, smaller areas with increased uptake are located in the left thoracic region.

562

13 Pitfalls

Fig. 13.7.2. MIP image as well as fused transverse, coronal and sagittal PET/CT images. Suspicious fi ndings displayed on the transaxial slice are the hypermetabolic activity in the anterior mediastinum as well as smaller areas with increased uptake in the area of the left thoracic wall

Fig. 13.7.3. Transaxial PET/CT slice with a round focus of increased uptake in the anterior mediastinum which must be classified as a thymoma and slightly increased uptake in the area of the ventral thoracic wall

13.6

Fig. 13.7.4. Increased uptake suspicious for malignancy in the right clavicular region in the area of an approx. 1.0 cm large lymph node

Fig. 13.7.5. Transaxial PET/CT slice with bone window setting showing suspiciously increased uptake in the area of the 10th rib in the right paravertebral region which must not be classified as malignant growth but as a healing rib fracture

Case Studies Secondary Tumours

563

564

13 Pitfalls

Patient 8 Prostate Carcinoma and Colon Carcinoma Clinical history: A 66-year-old male. Newly detected prostate carcinoma with nodal resistances in the right lobe. PSA 82 ng/ml. PET/CT indication: Propagation diagnosis. Metastatic spread?

Findings: Glucose metabolic activity consistent with malignancy in the right part of the prostate. No evidence for growth extending beyond the capsule. No evidence for locoregional lymph nodes displaying tracer uptake consistent with malignancy. Large areas with glucose metabolic activity consistent with malignancy in the area of the colon transversum indicating secondary tumour. No other evidence for further tumorous changes in the whole body.

Fig. 13.8.1. Transaxial PET/CT slice showing two round foci with increased uptake in the area of the right prostate lobe

Fig. 13.8.2. MIP representation as well as PET/CT representation in the 3 slice planes with suspiciously increased uptake in the area of the colon transversum

13.6

Teaching points: The examination that was originally performed to diagnose the propagation of a prostate carcinoma revealed a carcinoma in the area of the colon transversum that was not known and did not give the patient cause for complaint. The resection performed after the scan confirmed the PET findings. The patient could undergo curative treatment.

Fig. 13.8.3. Transaxial PET/CT slice with high glucose metabolic activity in the colon transversum

Fig. 13.8.4. Late enhancement image of the same region with further increase in glucose metabolic activity

Case Studies Secondary Tumours

565

566

13 Pitfalls

Patient 9 Renal Cell and Prostate Carcinoma Clinical history: A 69-year-old male status post nephrectomy due to a renal cell carcinoma. Status post radical prostatectomy due to prostate carcinoma. The bone scintigram does not furnish any evidence for bone metastases. Now a rise in PSA from 0.1 to 2.6 ng/ml. Findings: Tumour-specifically increased tracer uptake in the area of the bladder roof, circumscribed and easy to delineate with respect to the bladder, but with just moderately increased glucose metabolic activity. No further evidence for malignant growth.

Teaching points: The patient underwent lower abdominal laparoscopy. According to the palpatory examination, the lesion in the area of the bladder roof was classified as an induration, which was completely excised without remaining tumour cells. The post-operative phase was unsuspicious. Histology revealed cells of a well to moderately differentiated adenocarcinoma in the excised material that, with regard to its structure and immunohistology, is readily compatible with prostate carcinoma. Evaluation as a late metastasis of a prostate carcinoma operated on 10 years ago.

Fig. 13.9.1. Sequence of coronal and sagittal slices. The lesion in the area of the bladder roof can hardly be delineated although the fi ndings are known

13.6

Fig. 13.9.2. Sagittal PET/CT slice with a minute focus of increased uptake above the bladder roof corresponding to a histology-proven metastasis of the prostate carcinoma

Case Studies Secondary Tumours

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Patient 10 Prostate Carcinoma and Colon Carcinoma Clinical history: A 65-year-old male status post prostate carcinoma with radical prostatectomy as well as lymphadenectomy. Varying PSA values. Hormone therapy. Previous diagnostic examinations including whole-body bone and CT slices ruled out pathological findings. PET/CT indication: Recurrent tumour of the prostate? Metastatic spread? Findings: Proven glucose metabolic activity consistent with malignancy in the area of an infi ltrating inguinal lymphoma on the left side as well as in the pelvis wall on the left side. The focally increased uptake in the area of the colon sigmoideum is evaluated as a circumscribed colon carcinoma. No further suspicious findings. Teaching points: The clarification of varying PSA values with follow-up PET/CT revealed an inguinal lymphoma and, in addition, an adenocarcinoma of the colon signoideum classified as a secondary carcinoma.

Fig. 13.10.1. Sequence of coronal PET/CT slices showing a lymphoma in the left groin

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Fig. 13.10.2. MIP representation as well as PET/ CT images in the 3 slice planes. The transaxial slice shows the groin lymphoma on the left side

Fig. 13.10.3. Transaxial PET/CT slice delineating malignant growth in the colon sigmoideum

Case Studies Secondary Tumours

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Patient 11 Carcinoma in Situ of the Rectum and Bronchial Carcinoma Clinical history: A 67-year-old male with recurrent abdominal complaints. Metabolic activity suspicious for malignancy in the rectum was diagnosed as a result of the PET/CT pre-examination so that a carcinoma in situ was resected within the scope of a surgical intervention in this area. It should still be pointed out that the patient has a long-lasting history of nicotine abuse and suffers from recurrent bronchitis and coughing spells. The present PET/CT scan serves to restage the rectal malignoma and to evaluate the whole-body condition because the patient has recently been in a poor state of health.

Findings: Detection of glucose metabolic activity consistent with malignancy in the area of extended lymphomas in the left mediastinal region and suspicion of left bronchopulmonary NPL. Further histological examinations will have to be performed. No evidence for further organ or lymph node metastases in the rest of the whole-body scan. Teaching point: PET/CT incidentally detects a bronchopulmonary malignant tumour.

Fig. 13.11.1. Restaging of a rectal carcinoma, the lower row shows the result of the pre-examination with rectal carcinoma, the upper row shows the present fi ndings after surgical intervention in the rectal region

13.6

Case Studies Secondary Tumours

571

Fig. 13.11.2. The rectal carcinoma diagnosed during the pre-examination

 Fig. 13.11.3. Upper row: newly appeared bronchial NPL, lower row: unsuspicious fi ndings 2 years ago

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13 Pitfalls

Fig. 13.11.4. Secondary fi nding of the bronchial NPL

Fig. 13.11.5. Secondary fi nding of the bronchial NPL, sagittal slice

13.6

Fig. 13.11.6. Secondary tumour, bronchial NPL, sequence of transaxial slices

Case Studies Secondary Tumours

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13 Pitfalls

Patient 12 Non-Hodgkin Lymphoma and Bronchial Carcinoma Clinical history: A 65-year-old male. A non-Hodgkin lymphoma was first diagnosed 14 months ago with pancreas involvement. Surgical intervention followed by chemotherapy until 8 months ago. A PET/CT scan performed 6 months ago revealed moderate residual activity in the pancreas region. Furthermore, infi ltrate displaying moderate metabolic activity in segment 10 of the right lung. From a differential-diagnostic point of view, the lesion could be evaluated as both lymphoma infi ltrate and inflamed infi ltration in the peribronchial area.

Fig. 13.12.1. Non-Hodgkin’s lymphoma with pancreas involvement. Moderate residual activity in the pancreas after chemotherapy.

This PET/CT scan serves to re-evaluate the peribronchitical findings. Findings: This check-up examination reveals the morphological/metabolic pattern of a bronchial carcinoma in segment 10 of the right lower lobe with extended metastatic spread in the right hilar and mediastinal region. In addition, the scan reveals evidence for metabolically active malignant lymphomas in the right and left retroperitoneal paraaortal region and ventrally at the level of the T11/12 and L1 vertebral bodies. Teaching point: Restaging of the lymphoma reveals the secondary tumour classified as a bronchial carcinoma.

13.6

Case Studies Secondary Tumours

575

Fig. 13.12.2. Newly appearing activity 10 months after the fi rst examination in the bronchial region as well as mediastinal lymph nodes. The left image shows the latest fi ndings, the right image shows the result of the pre-examination.



Fig. 13.12.3. Top: unsuspicious pre-fi ndings. Lower side: activity consistent with malignancy in the right hilar and mediastinal region

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13 Pitfalls

Fig. 13.12.4. Activity consistent with malignancy in the secondary malignoma of segment 10 in the right pulmonary region

Fig. 13.12.5. Metastasis in the suprarenal gland on the left side of the secondary carcinoma

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Patient 13 Mamma Carcinoma and Bronchial Carcinoma Clinical history: A 74-year-old female status post mamma carcinoma on the left side, T2 and suspicion of pulmonary metastases of the mamma carcinoma. From a differential-diagnostic point of view, a left central bronchial carcinoma with metastatic spread to the lymph nodes must be taken into consideration. Findings: Detection of glucose metabolic activity consistent with malignancy in the area of the extended mediastinal and hilar lymphomas described above.

Case Studies Secondary Tumours

577

In connection with a small peripheral round focus in the left anterior upper lobe segment, which also displays metabolic activity consistent with malignancy, the lesion will probably have to be classified as metastatic spread of the mamma carcinoma to the lung and lymph nodes. But a left central bronchial carcinoma cannot finally be completely excluded. Teaching point: Incidentally discovered increased uptake consistent with malignancy in the bronchial region as well as in the area of the mediastinal and hilar lymph nodes.



Fig. 13.13.1. Unsuspicious restaging of the operated mamma carcinoma on the left side

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Fig. 13.13.2. Increased uptake consistent with malignancy in the left hilar region

Fig. 13.13.3. Increased uptake consistent with malignancy in the right hilar region

Fig. 13.13.4. Increased uptake consistent with malignancy in several areas of the hilar mediastinal region on both sides

13.6

Patient 14 Coecum, Bronchial and Renal Carcinoma Clinical history: Original Tumour coecum carcinoma, appearance of small foci of lung and liver metastases 4 years ago, treated with palliative chemotherapy until 2 years ago. Shortly after completion of the chemotherapy new appearance of a left central pulmonary focus that was still growing during ongoing chemotherapy. Upper lobe resection 3 months later. Solitary metastasis of the liver 1 year ago, which was resected with a minimally invasive operation. New lung, liver and lymph node metastases as well as a newly appearing renal tumour discovered 6 months ago during a restaging examination. Chemotherapy until ½ year ago. PET/CT indication: Restaging for further therapy planning.

Case Studies Secondary Tumours

579

Findings: Glucose metabolic activity consistent with malignancy in the centre of the left lung as a consequence of partially necrotized tumour cells whereby, from a differential-diagnostic point of view, this focus may be classified as a metastasis or a secondary tumour in the sense of a bronchial carcinoma. In the area of the right kidney, tumorous mass with suspicion of tumour growth beyond the capsule, indicating first of all a renal cell carcinoma. Furthermore, large retroperitoneal lymph node metastasis in the paracaval area. Teaching point: Considerable metastatic spread of the original tumour. Potential secondary carcinoma in the bronchial region as well as potential carcinoma that might be classified as a renal cell carcinoma. In summary, the PET/CT scan provides much more detailed information.



Fig. 13.14.1. Lung metastasis of a coecum carcinoma, sagittal slice

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Fig. 13.14.2. Lung metastasis of a coecum carcinoma, transaxial slice

Fig. 13.14.3. Sequence of transaxial slices with lung window setting showing the lung metastasis

13.6

Case Studies Secondary Tumours

Fig. 13.14.4. Follow-up scan, with the lower part representing the images of the fi rst scan and the upper part representing the PET/CT images showing the newly appeared renal cell carcinoma which could not be detected during the fi rst scan yet

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Fig. 13.14.5. Lung metastasis of the coecum carcinoma; secondary tumour – renal cell carcinoma

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Fig. 13.14.6. Sequence of transaxial slices showing the renal cell carcinoma on the right side

Fig. 13.14.7. Lymph node metastasis in the right prevertebral region

13.6

Patient 15 Mamma, Cervical and Rectal Carcinoma Clinical history: A 47-year-old female status post mamma carcinoma in the right breast 6 years ago. The patient underwent mastectomy. Furthermore, adenocarcinoma of the cervix uteri 3 years ago with radical hysterectomy and lymphadenectomy. Short time later, relaparotomy due to adhesion ileus. Vaginal and supravaginal recurrence of the cervical carcinoma with small-volume percutaneous radiotherapy to the recurrent tumour in the pelvis with 63 Gy 6 months ago. Now stenosing rectal infi ltration with histologically proven adenocarcinoma. However, it could not yet be clarified whether we have to deal with a primary rectal carcinoma or with the spread of the cervical carcinoma. PET/CT indication: Propagation diagnosis. Metastatic spread.

Case Studies Secondary Tumours

583

Findings: Multilocular glucose metabolic activity consistent with malignancy indicating extended metastatic spread to the lung, the liver as well as the lymph nodes in the lower part of the neck, in the supra-/retroclavicular, mediastinal, retroperitoneal and mesenterial region. Metabolic activity consistent with malignancy also in the area of the histologically proven rectal carcinoma that, due to its extent, seems more likely to be a primary rectal carcinoma. The focal lesion discovered in the area of the posterior wall of the bladder might also indicate a bladder papilloma. Teaching point: After the mamma carcinoma had been discovered and treated as the primary tumour, an adenocarcinoma of the cervix was discovered as a secondary carcinoma, and then the rectal carcinoma was the third carcinoma revealed. Precise staging/restaging with PET/CT.



Fig. 13.15.1. Lung metastasis with status post mamma carcinoma on the right side 6 years ago, cervical carcinoma 3 years ago and newly appearing rectal carcinoma

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a

b

Fig. 13.15a,b. Liver metastases with status post mamma carcinoma, cervical carcinoma and newly appearing rectal carcinoma

Fig. 13.15.4. Affected lymph node and lung metastasis in a patient with multiple carcinoma

13.6

Fig. 13.15.5. Rectal carcinoma as third tumour

Fig. 13.15.6. Glucose metabolic activity consistent with malignancy in the dorsal bladder wall

Case Studies Secondary Tumours

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13 Pitfalls

Patient 16 Parotid and Colon Carcinoma Clinical history: A 76-year-old male with carcinoma of the right parotid gland and metastases in cervical lymph nodes (T3N1). Preoperative radiotherapy with up to 50 Gy had been recommended. An MRI scan of the skull performed approximately 1 year ago revealed a convexity meningioma in the left frontoparietal region sized 23 × 13 × 17 mm displaying partial calcification and a perifocal oedema. PET/CT indication: Propagation diagnosis. Findings: Detection of glucose metabolic activity consistent with malignancy in the area of the right parotid gland.

Fig. 13.16.1. Carcinoma of the right glandula parotis, lymph node metastasis

Furthermore, metabolic activity consistent with malignancy in the area of the right cervical lymph tract as well as in the submandibular, ipsi- and contralateral area of the lymphomas. In addition, detection of bilateral metastatic spread to the lower pulmonary region. Furthermore, there is a strong suspicion of a metastasis in the right parietal cerebral region combined with multilocular meningiomas. A focal lesion in the area of the colon ascendens displays an SUV value suspicious for malignancy and is classified as a secondary tumour. Teaching point: Propagation diagnosis is facilitated by PET/CT and PET/CT also detects cerebral metastases as well as a secondary carcinoma in the colon ascendens.

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Case Studies Secondary Tumours

587

Fig. 13.16.2. Cervical lymph node metastasis of a parotis carcinoma on the right side

Fig. 13.16.3. Brain metastasis of a parotid carcinoma in the right parietal region



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Fig. 13.16.4. Lung metastasis of a parotid carcinoma

Fig. 13.16.5. Second carcinoma of the colon ascendens on the right side associated with metastatic spread of parotid carcinoma

13.7

Case Studies Physiologically Increased Uptake

13.7 Case Studies Physiologically Increased Uptake Patient 17 Fig. 13.17.1. Considerably increased uptake in the laryngeal region shown on a sequence of coronal and sagittal PET slices, due to swallowing

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Patient 18

Fig. 13.18.1. Sequence of coronal PET slices with increased uptake in the area of the entire colon. The slices also show two lymph nodes in the left infraclavicular area and in the area of the distal oesophagus. Excessively increased uptake in the colon occurs frequently and may be further verified by means of follow-up scans (in this case we have to deal with physiologically increased uptake which could no longer be detected after food intake)

Patient 19

Fig. 13.19.1. Transaxial choline PET/CT slice showing an affected lymph node with metabolic activity consistent with malignancy. The urether which displays residual activity and might lead to misinterpretation of another affected lymph node is visible ventrally

13.7

Case StudiesPhysiologically Increased Uptake

Patient 20

Fig. 13.20.1. Transaxial PET/CT slice showing a bladder diverticle originating from the left bladder wall. The diverticle can be delineated and its volume can be evaluated in all 3 slice planes

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Patient 21

Fig. 13.21.1. Sequence of coronal PET slices with asymmetrically increased uptake, mainly in the area of the shoulder girdle and the neck. The symmetry of the findings correspond to a so called “lobster sign”. However, the asymmetrically increased uptake in the lymph nodes in the area of the left mediastinum is due to the basic disease of a non-Hodgkin’s lymphoma

Fig. 13.21.2. Sequence of transaxial, sagittal and coronal PET/CT slices of a follow-up scan after therapy of the same patient. The images illustrate the increased uptake in the area of the neck and the shoulder girdle which, compared with the results of the pre-examination, remains almost unchanged. Changes are discovered with respect to the appearance of the mediastinal lymphoma after chemotherapy

13.8 Case Studies Non-Oncological Increased Uptake of Inflammatory Genesis

13.8

Case Studies Non-Oncological Increased Uptake of Inflammatory Genesis

Patient 22 Clinical history: A 78-year-old male with increased PSA value. Previous prostate biopsies ruled out pathological findings. Status post TUR prostate. PET/CT indication: Does the PET/CT whole-body scan discover evidence for metabolic activity suspicious for or consistent with malignancy?

Fig. 13.22.1. Transaxial PET/CT slice demonstrating increased choline uptake. The image clearly depicts strongly increased uptake in the left prostate lobe. Slightly increased uptake is also discovered on the right side

Fig. 13.22.2. Transaxial choline PET/CT slice with strongly increased uptake in the left undescended testicle

Findings: Choline metabolism consistent with malignancy in the area of an extended focus involving major parts of the left prostate lobe. In addition, smaller circumscribed areas with increased uptake in the right prostate lobe. A striking finding is the considerably increased metabolic activity in the area of the left undescended testicle that is not due to malignant growth. Teaching points: The known undescended testicle displayed considerably increased uptake in the choline PET indicating an activity level that is not due to malignant growth (Figs. 13.22.1, 13.22.2).

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Patient 23 Clinical history: A 66-year-old female patient complained of persistent pain in the whole skeletal system, mainly in the area of the spine and the head. Familiar disposition (mother). In addition, suspicion of undifferentiated collagenosis, e.g. vasculitis associated with autoimmune disease. PET/CT indication: Search for the focus with PET/ CT. Findings: The whole-body scan does not furnish any evidence for glucose metabolic activity suspicious for or consistent with malignancy; however, there is considerably increased uptake in both parotid glands and in both submandibular glands expressing a nonspecific increased glucose metabolic activity within the framework of the autoimmune disease. Teaching points: A nonspecific increased uptake in the area of the salivary glands, but also in the area of the large vessels, indicating an autoimmune disease had to be distinguished from tumour-specific increased uptake. A careful anamnesis is also useful in this case.

Fig. 13.23.1. Coronal and sagittal PET/CT slices with medium-grade symmetrically increased uptake in the area of the salivary glands

13.8

Fig. 13.23.2. MIP representation as well as PET/CT slices in the 3 planes with symmetrically increased uptake of the salivary glands

Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Fig. 13.23.3. Sequence of transaxial slices with strongly increased uptake in the salivary glands

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Patient 24 Clinical history: A 54-year-old female with known ulcerative colitis. Continued sulfasalazin therapy. At present, moderate complaints in the rectal re-

gion. Endoscopic examination now reveals pseudopolypous changes in the sigmoid and descending colon. Status post mamma NPL with radiotherapy on the left side and lymph node dissection. Status post strumectomy.

Fig. 13.24.1. MIP images with strongly increased uptake in the rectal region. The sequences of PET/CT slices also demonstrate considerably increased uptake in the rectal region

Fig. 13.24.2. Late enhancement images of the rectal region demonstrating a constant to slightly regressing glucose metabolic activity in the rectal region in the 3 PET/CT slice planes and the MIP image

13.8

Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

PET/CT indication: Restaging and exclusion of increased uptake consistent with malignancy.

Peculiarities are also not found in the rest of the whole body.

Findings: Circularly increased glucose metabolic activity in the area of the colon rectally from the anus up to the level of the promontorium indicating a florid ulcerative colitis. No further tumoursuspicious increased uptake in the rest of the colon.

Teaching points: A strongly increased uptake can generally be observed in patients suffering from florid ulcerative colitis. A false diagnosis may in such a case be prevented by performing a careful anamnesis and taking a late enhancement image.

Fig. 13.24.3. Sequence of sagittal PET/CT slices with impressingly increased uptake in the rectal region

Fig. 13.24.4. Transaxial PET/CT slice demonstrating a uniformly increased uptake with circular appearance in the rectal region

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Patient 25 Clinical history: A 52-year-old female patient has been complaining for 4 years about chronic-inflammatory reactions in the area of both eyes in spite of normal lacrimation. The eye pressure is normal. PET/CT indication: Does PET/CT reveal evidence for glucose metabolic activity consistent with malignancy? Findings: Significantly increased glucose metabolic activity in the area of the nervus opticus on the right side indicating a neuritis nervi optici. In addition to the increased glucose uptake revealed by PET, the density value is also higher than the density value on the contralateral side. Otherwise unsuspicious findings. Teaching points: PET/CT is useful for evaluating the area of the nervus opticus due to its good resolution and the good anatomical assignment of the increased glucose uptake.

Fig. 13.25.1. Transaxial PET/ CT slice showing a thickened nervus opticus on the right side displaying increased uptake

13.8

Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Patient 26 Clinical history: The patient has an approximately 10-year history of uterus myomatosus. Persistent lower abdominal complaints. Haemorrhagic stool from time to time that might be due to known haemorrhoidal complaints. Considerable familiar history of cancer. PET/CT indication: Malignity evaluation. Findings: PET/CT does not reveal any evidence of metabolic activity suspicious for or consistent with malignancy, but slightly increased metabolic activity in the area of a myoma node on the right cranial side associated with a known and considerable dilated uterus myomatosus. Teaching points: Myoma nodes may in fact display markedly increased glucose uptake. This is particularly true during the menstruation and ovulation periods. In such a case a late enhancement scan or gynaecological exploration might be helpful.

Fig. 13.26.1. The abdominal PET/CT scan with the MIP image and the 3 slice planes demonstrates increase glucose uptake in a myoma node. No further increase in uptake was observed in the late enhancement image which is not shown here

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Patient 27 Clinical history: A 52-year-old female with a long history of sarcoidosis. Thoracic complaints of unclear genesis. Persistent complaints in the left arm with status post subclavian stenosis on the left side (PTA and stent). Suspicion of Takayasu arteritis. Findings: No evidence for glucose metabolic activity suspicious for or consistent with malignancy. The focally pronounced areas with moderately increased glucose metabolic activity in the area of the aorta in both the thoracic and the abdominal region support the tentative diagnosis of a Takayasu arteritis. Strongly increased glucose uptake indicating ulcerative colitis is revealed in the left colon and is less pronounced in the rectal region.

Teaching points: Increased glucose uptake that is not due to malignant growth is frequently found in patients suffering from arteritis. Another cause for increased uptake in a vessel is macrophage accumulation in atheromatomous plaques 1.

1

Ledermann RJ, Raylman RA, Fisher SJ et al. (2001) Detection of atherosclerosis using a novel positron-sensitive probe and 18 fluordeoxyglucose (FDG) Nucl Med Comm 22:747–53

Fig. 13.27.1. Sequence of coronal and sagittal PET slices with strongly increased uptake mainly in the area of the aortic arch and the colon descendens

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Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Fig. 13.27.2. Sequence of transaxial PET/CT slices showing increased uptake in the colon descendens

Fig. 13.27.3. Sequence of coronal PET/CT slices with markedly increased uptake in the aorta 1, mainly in the aortic arch, indicating an unspecifically increased uptake similar to Takayasu arteritis. Furthermore, illustration of strongly increased uptake in the colon descendens similar to colitis ulcerosa

1

Davies JR, Rudd JH, Weissberg PL et al (2004) Molecular and metabolic imaging of atherosclerosis. J Nucl Med 45:1898–1907

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Patient 28 Clinical history: A 66-year-old female with polymyalgia rheumatica. At present, strong complaints in the sacrum. Strongly increased BSG and CRP. PET/CT indication: Exclusion of a paraneoplastic syndrome. Findings: The whole-body scan does not discover any evidence for glucose metabolic activity suspicious for or consistent with malignancy, but obvious signs of a vasculitis in the area of the whole aorta and the supraaortal cervical vessels. Furthermore, signs of increased glucose metabolic activity in the area of the ligamentous apparatus and the muscles of both shoulder joints and both hip joints associated with a known polymyalgia rheumatica.

Teaching points: Rheumatic diseases, particularly if they are associated with arteritis or an involvement of the muscles, may display a strongly increased glucose uptake that is not due to malignant growth. From a differential-diagnostic point of view, it might be useful in such a case to perform a follow-up scan to take late enhancement images as well as a careful anamnesis and to clarify all relevant cardiologic aspects.

Fig. 13.28.1. Sequence of coronal and sagittal PET/ CT slices with impressively increased uptake in the area of the aortic arch and the aorta descendens

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Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

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Fig. 13.28.2. Sequence of coronal slices with strongly increased uptake in the area of the aorta thoracica

Fig. 13.28.3. Late enhancement image of the same patient demonstrating unchanged strong uptake of glucose in the coronal and sagittal PET image



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Fig. 13.28.4. PET/CT late enhancement image. The MIP image and the 3 slice planes show considerably increased uptake in the area of the aortic wall

13.8

Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Patient 29 Clinical history: A 75-year-old female patient was suspected of suffering from a paraneoplastic syndrome with anaemia of unclear genesis and persistent fatigue. Weight reduction. Family history of cancer. PET/CT indication: Search for the focus or tumour, respectively, with PET/CT. Findings: Signs of florid aortitis involving the aorta ascendens as well as the rest of the aorta thoracalis and the aorta abdominalis, partially with beginning thrombus deposition in the area of the aorta thoracalis. The whole-body scan does not reveal any evidence for glucose metabolic activity suspicious for or consistent with malignancy.

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Teaching points: A paraneoplastic syndrome assumed to be the cause of the decrease in vitality and weight could not be confi rmed. However, PET/ CT revealed signs of pronounced aortitis, 1 indicating a reduced functional capacity in the sense of nonspecific increased glucose uptake.

1

From a differential-diagnostic point of view, instable atherosclerotic plaques might also be assumed so that cardiologic examinations might be useful

 Fig. 13.29.1. Sequence of coronal PET slices with considerably increased uptake in the area of the aorta thoracalis

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Fig. 13.29.2. Sagittal PET/CT slice with strongly increased uptake in the aorta thoracalis

Fig. 13.29.3. PET late enhancement image with considerably increased uptake in the aortic wall which, however, is not higher than in the early enhancement image.

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Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Fig. 13.29.4. Late enhancement images with the 3 PET/ CT slice planes and the MIP projection demonstrating unchanged increased uptake in the aortic wall

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Patient 30 Clinical history: A 77-year-old female with persistent high fever and considerable sweating for 7 weeks. Thyroid gland tender to touch, mainly on the left side. Sonographic peculiarities in the right lobe of the thyroid gland. The patient had previously been examined with contrast agent. Status post surgical intervention in the lower abdominal region 10 years ago and several bladder operations due to urinary incontinence. Status post appendectomy, tonsillectomy, cholecystectomy. PET/CT indication: Can the whole-body scan reveal any evidence for glucose metabolic activity suspicious for or consistent with malignancy. Can PET/CT reveal any evidence for an inflammatory focus?

Findings: Detection of considerably increased metabolic activity in the area of the left lobe of the thyroid gland with a maximum SUV of 22.6 in the late enhancement images, involving almost the whole lobe of the thyroid gland. Small, approximately 1.0-cm-large focus in the caudal part of the right lobe of the thyroid gland with a small nodulous struma mainly on the right side. In summary, the findings are suspicious for thyroiditis. The whole-body scan does not detect any evidence for a malignant or tumorous metastatic process. Teaching point: The considerably increased glucose uptake in the area of the left lobe of the thyroid gland and, in addition, also in the rest of the thyroid gland could be attributed to Quervain’s thyroiditis.

Fig. 13.30.1. Quervain’s thyreoiditis of the left lobe of the thyreoid gland

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Case StudiesNon-Oncological IncreasedUptake of Inflammatory Genesis

Fig. 13.30.2. One coronal and 2 transaxial slices demonstrating Quervain’s thyreoiditis of the left lobe of the thyreoid gland

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Patient 31 Clinical history: For ½ year, the 52-year-old female patient had been complaining about problems in the abdominal region without any evidence of a physical disease. PET/CT indication: Exclusion of malignant growth.

Teaching points: The glucose metabolic activity is considerably increased mainly during the ovulation and menstruation period. This effect was particularly pronounced in this case. From a differentialdiagnostic point of view, a late enhancement image and, in case of doubt, a gynaecological exploration might be useful.

Findings: A 2.7 × 3.0-cm-large area with markedly increased glucose metabolic activity in the uterus. This mass turned out to be a histologically proven myoma.

Fig. 13.31.1. Transaxial CT slice with an enlarged and dilated uterus. Structures can not be delineated

Fig. 13.31.2. Transaxial PET/ CT slice showing significantly increased glucose metabolic activity in the area of a myoma uteri

13.9

13.9 Case Studies Artefacts

Case Studies Artefacts

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metal-induced attenuation of the transmission radiation. This is illustrated in both the transmissioncorrected PET images and the PET/CT images. The non-corrected PET images are very helpful in this context.

Patient 32 Clinical history: A 69-year-old male status post thyroidectomy. One year later, reoperation due to metastatic spread of a medullary thyroid carcinoma. Status post pacemaker implantation. PET/CT indication: Metastatic tumour restaging by PET/CT. Findings: The whole-body PET/CT scan does not reveal any evidence for glucose metabolic activity suspicious for or consistent with malignancy. A suspicious finding is an obviously increased uptake in the upper right thoracic region. This false diagnosis is due to a pacemaker artefact causing the region concerned to be over-evaluated due to the

Teaching points: Careful anamnesis is indispensable for adequate PET diagnosis. Furthermore, the uncorrected PET images should generally be reviewed.

 Fig. 13.32.1. Sequence of coronal slices with transmission-corrected PET images. A suspicious fi nding is an apparently increased uptake in the right thoracic region displaying the pacemaker artefact

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Fig. 13.32.2. MIP image as well as images of all 3 slice planes taken with PET/CT. An pacemaker artefact is also displayed in the right thoracic region on this sequence, otherwise unsuspicious fi ndings

13.9

Case Studies Artefacts

Patient 33 Clinical history: A 63-year-old male with unclear thoracic findings on the right side and breathdependent pain in the right thoracic region. Artefact: In addition to the mass displaying increased uptake consistent with malignancy that was detected in the right thoracic region (not shown here), PET/CT could detect strongly increased uptake in the area of the stomach that is not due to malignant growth, but to reduced food intake.

Fig. 13.33.1. Sequence of coronal and sagittal PET slices with strongly increased uptake in the stomach

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Patient 34 Clinical history: A 4-year-old girl who underwent a PET/CT scan to diagnose a rhabdomyosarcoma. Artefact: A suspicious finding was associated with increased uptake in the projection to the efferent urinary tract, which was in this case due to a diaper contaminated with radioactivity eliminated via the kidneys.

Fig. 13.34.1. Sequence of coronal slices demonstrating strongly increased uptake caudal to the bladder region

13.9

Case Studies Artefacts

Patient 35 Clinical history: Status post gastric carcinoma and provision of a gastro-oesophageal anastomosis with rise in tumour marker levels. Artefact: The image presented here shows a strongly increased uptake in the area of the right kidney or the pelvicalyceal system, respectively, due to the obstruction of the urine flow.

Fig. 13.35.1. The transaxial PET/CT slice displays strongly increase uptake in the area of the right kidney which is not due to malignant growth but just obstruction of the urine flow. (In addition, increased uptake due to malignant growth in the area of the abdominal wall in the left abdominal region)

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Patient 36 Clinical history: Status post prostatovesiculectomy. PET/CT indication: Evaluation of the pelvic lymph nodes taking into account rising PSA values. Artefact: The artefact registered during this scan was displayed as increased uptake in the area of the left proximal femur, due to a TEP.

Fig. 13.36.1. Coronal PET/CT slice with excessively increased uptake in the area of the implanted hip TEP on the left side as well as striation artefacts in the area of the bladder, due to improperly corrected PET data falsified by the metal parts of the implant.

Fig. 13.36.2. Transaxial PET/CT slice with typical star-shaped reconstruction artefact in the area of the hip TEP on the left side

13.9

Case Studies Artefacts

Patient 37 Clinical history: Search for metastatic spread with status post resection of a teratoma. Artefact: Conspicuous findings were motion artefacts in the area of the myocardium.

Fig. 13.37.1. Considerable mismatch between the CT image and the increased uptake in the transaxial PET/CT slice

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Patient 38 Clinical history: A 58-year-old male status post bladder carcinoma with involvement of the prostate and the urethra with extensive surgical revision and construction of an ileal conduit as well as abscess formation and fistulation in the small intestine. Restaging. Artefact: The increased uptake displayed on this image is not due to a tumour, but to a dental prosthesis on the one hand and the extracorporal drainage into the ileal conduit on the other.

Fig. 13.38.1. Transaxial PET/CT slice with multiple artefacts in the yaw area

13.9

Case Studies Artefacts

Fig. 13.38.2. MIP image as well as transaxial, sagittal and coronal PET/CT slices demonstrating increased uptake in the operated region and extracorporally in the area of the conduit indicating increased uptake which is not due to a tumour but to radioactive substances drained

Fig. 13.38.3. Sagittal PET/CT slice demonstrating increased uptake which is not due to tracer uptake in the area of the extracorporal drain line

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Patient 39 Clinical history: A 57-year-old female status post mamma carcinoma on the right side. Mastectomy as well as axillary dissection 5 years ago followed by radiochemotherapy. Femara therapy for the past year. Previously tamoxifen for several years. Two months ago, suspicious structural densification in the right humeral head revealed on an X-ray of the thorax. PET/CT indication: Malignancy evaluation.

Findings: The whole-body scan does not reveal any evidence for glucose metabolic activity suspicious for or consistent with malignancy. The changes in the area of the right humeral head/ proximal shaft are probably due to an enchondroma of the shaft or a bone infarct, i.e. we have to deal with benign changes. No evidence for locoregional tumour recurrence or contralateral secondary tumour with status mamma NPL on the right side. Teaching point: Exclusion of malignant growth by PET/CT.

Fig. 13.39.1. Status post mamma carcinoma on the left side, exclusion of metastatic spread, particularly in the right humeral head

13.9

Fig. 13.39.2. Status post mamma carcinoma on the right side, exclusion of malignant changes of the right humeral head, PET/CT revealing an enchondroma of the shaft.

Case Studies Artefacts

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13.10 References 1. Andre M, Mounier N, Leleu X et al (2003) Second cancers and late toxicities after treatment of aggressive nonHodgkin’s lymphoma with the ACVBP regimen: a Gelacohort study on 2,837 patients. Blood 103:1222–1228 2. Aziz TM, Saad RA, Glasser J et al (2002) The management of second primary lung cancers. A single center experience in 15 years. Eur J Cardiothorac Surg 21:527–533 3. Bairati I, Meyer F, Gekinas M et al (2005) A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer. J Natl Cancer Inst 97:481–488 4. Baxter NN, Tepper JE, Durham SB et al (2005) Increased risk of rectal cancer after prostate radiation: a population-based study. Gastroenterology 128:819–824 5. Bhatia S, Sklar C (2002) Second cancers in survivors of childhood cancer. Nat Rev Cancer 2:124–132 6. Birgisson H, Pahlman L, Gunnarsson U, Glimelius B (2005) Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 97:6126–6131 7. Brennan P, Scelo G, Hemminki K et al (2005) Second primary cancers among 109,000 cases of non-Hodgkin’s lymphoma. Br J Cancer 93:159–166 8. Brenner DJ, Hall EJ, Curtis RE, Ron E (2005) Prostate radiotherapy is associated with second cancers in many organs, not just the colorectum. Gastroenterology 129:773–774 9. Broniscer A, Ke W, Fuller CE et al (2004) Second neoplasmas in pediatric patients with primary nervous system tumors: The St. Jude Children’s Research Hospital experience. Cancer 100:2246–2252 10. Cannell E (2002) Second cancers among childhood survivors. Eur J Cancer 38:2 11. Chiang JM, Yeh CY, Changehien CR et al (2004) Clinical features of second other-side primary cancers among sporadic colorectal cancer patients–a hospital-based study of 3,722 cases. Hepatogastroenterology 51:1341–1344 12. Chuang SC, Hashibe M, Yu GP et al (2005) Radiotherapy for primary thyroid cancer as a risk factor for second primary cancers. Cancer Letter (Epub ahead of print) PMID 16044503 13. Cohade Ch, Osman M, Pannu HK, Wahl RL (2003) Uptake in supraclavicular area fat (“USA-FAT”): Description on 18F-FDG PET/CT. J Nucl Med 44:170–176 14. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF Jr (2005) The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer 103:2391– 2396 15. Crocetti E, Carli P (2004) Risk of second primary cancers, other than melanoma, in Italian population-based cohort of cutaneous malignant melanoma patients. Eur J Cancer Prev 13:33–37 16. Crocetti E, Miccinesi G, Paci E, Zapa M (2001) Incidence of second cancers among women with in-situ carcinoma of the breast. Breast 10:438–441 17. Dieckmann KP, Claßen J, Loy V (2005) Präkanzerose der Hodentumoren: Testikuläre intraepitheliale Neoplasie. Dtsch Arztebl 102:A3021–3025

18. Diener-West M, Reynolds SM, Agugliaro DJ et al (2005) Second primary cancers after enrolment in the COMS trial for treatment of choroidal melanoma. COMS Report No 25, 123:601–604 19. Dizendorf EV, Treyer V, von Schulthess GK, Hany TF (2002) Application of oral contrast media in co-registered positron emission tomography CT. Am J Roentgenol 179:477–481 20. Do KA, Johnson MM, Doherty DA et al (2003) Second primary tumors in patients with upper aerodigestive tract cancer: joint effects of smoking and alcohol (United States). Cancer Causes Control 14:131–138 21. Dong C, Lonnstedt I, Kemminki K (2001) Familiar testicular cancer and second primary cancer patients by histological type. Eur J Cancer 37:1878–1885 22. Epstein JP, Feldman R, Dolor RJ, Porter SR (2003) The utility of tolonium chloride linse in the diagnosis of recurrent or second primary cancers in patients with prior upper aerodigestive tract cancer. Head and Neck 25:911–21 23. Evans HS, Newnham A, Hodgson SV, Moller H (2003) Second primary cancers after cervical intraepithelial neoplasia III and invasive cervical cancer in Southeast England. Gynecol Oncol 90:131–136 24. Feig SA (2001) Second malignant neoplasms after successful treatment of childhood cancers. Blood Cells Mol Dis 27:662–666 25. Fowble B, Hanlon A, Freeman G et al (2001) Second cancers after conservative surgery and radiation for stages I-II breast cancer: identifying a subset of women of increased risk. Int J Radiat Oncol Biol Phys 51:679–690 26. Gao X, Fisher SG, Mohideen N, Emami B (2003) Second primary cancers in patients with laryngeal cancers: a population-based study. Int J Rad Oncol Biol Phys 56:427–435 27. Hall EH, Wu CS (2003) Radiation-induced second cancers: The impact of 3D-CRT and IMRI. Int J Rad Oncol Biol Phys 56:83–88 28. Hanif MZ, Ghesani M, Shah AA, Kasai T (2004) F-18 fluordeoxyglucose uptake in atherosclerotic plaque in the mediastinum mimicking malignancy: another potential for error. Clin Nucl Med 29:93–95 29. Hany TF, Heuberger J, von Schulthess GK (2003) Iatrogenic FDG foci in the lungs: a pitfall of PET image interpretation. Eur Radiol 13:2122–27 30. Harrison RM (2004) Second cancers following radiotherapy: a suggested common dosimetry framework for the therapeutic and concomitant exposures. Br J Radiol 77:986–990 31. Heller MT, Meltzer CC, Fukui MB et al (2000) Superphysiological FDG uptake in the non-paralyzed vocal cord. Clin Positron Imaging 3:207–211 32. Hemminki K, Li X (2003) Familial and second primary pancreatic cancers: a nation-wide epidemiologic study from Sweden. Int J Cancer 103:525–530 33. Hemminki K, Li X, Dong C (2001) Second primary cancers after sporadic and familiar colorectal cancer. Cancer Epidemiol Biomarkers Prev 10:793–798 34. Hemminki K, Yang Y (2002) Familial and second esophageal cancers: a nation-wide epidemiologic study from Sweden. Int J Cancer 98:106–109 35. Jacobsson H, Celsing F, Ingva M et al (1998) Accumulation of FDG in axillary sweat glands in hyperhidrosis:

13.10 a pitfall of whole-body PET examination. Eur Radiol 8:482–483 36. Jeremic B (2002) Second primary cancers occurring in patients with early stage non-small-cell lung cancer treated with radiation therapy alone. Eur J Cardiothorac Surg 22:1039–1040 37. Kerrou K, Montravers F, Grahek D et al (2001) 18F-FDG uptake in soft tissue dermatome prior to herpes zoster eruption: an unusual pitfall. Ann Nucl Med 15:455–458 38. Kim JS, Lee H, Kim H et al (2004) Promoter methylation of retinoic acid receptor beta 2 and development of second primary lung cancer in non-small-cell-lung cancer. J Clin Oncol 22:3443–3450 39. Laccourreye O, Veivers FD, Hans S et al (2002) Metachronous second primary cancers after successful partial laryngectomy for invasive squamous cell carcinoma of the true focal cord. Ann Otol Rhinol Laryngol 111:204– 209 40. Levi F, Randimbison L, Te VC, La Vecchia C (2003) Second primary cancers in laryngeal cancer patients. Eur J Cancer 39:265–267 41. Li X, Hemminki K (2003) Familial and second lung cancers: a nationwide epidemiologic study from Sweden. Lung Cancer 39:255–263 42. Lippman SM, Lee JJ, Karp DD et al (2001) Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small cell lung cancer. J Natl Cancer Inst 93:605–618 43. Maitra SK, Gallo H, Rowland-Payne C et al (2005) Second primary cancers in patients with squamous cell carcinoma of the skin. Br J Cancer 92:570–571 44. Matesich SM, Shapiro CL (2003) Second cancer after breast cancer treatment. Semin Oncol 30:740–748 45. Matsuyama Y, Tomonaga T, Nomura Y et al (2000) Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan. Ann Oncol 30:1537–1543 46. McClish D, Penberthy L, Pugh A (2003) Using Medicare claims to identify second primary cancers and recurrences in order to supplement a cancer registry. J Clin Epidemiol 56:760–767 47. Miralbell R, Lomax A, Cella L, Schneider U (2002) Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 54:824–829 48. Moll AC, Imhof SM, Schouten-Van Meeteren AY et al (2001) Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997. Ophthalmology 108:1109–1114 49. Ortiz BH, Ailawadi M, Colitti C et al (2001) Second primary or recurrence? Comparative patterns of p53 and K-ras mutations suggest that serous borderline ovarian tumors and subsequent serous carcinomas are unrelated tumors. Cancer Res 61:7264–7267 50. Patel PM, Alibazoglu H, Ali A, Fordham E, LaMonica G (1996) Normal thymic uptake of FDG on PET imaging. Clin Nucl Med 21:772–775

References

51. Pommegger R, Ensinger C, Steiner P et al (2004) Neuroendocrine tumors and second primary malignancy–a relationship with clinical impact? Anticancer Res 24:1049– 1051 52. Sadetzki S, Calderon-Margalit R, Peretz C et al (2003) Second primary breast and thyroid cancers (Israel). Cancer Causes Contr 14:367–375 53. Schlienger P, Campana F, Vilcoq JR et al (2004) Nonocular second primary tumors after retinoblastoma: retrospective study of 111 patients treated by electron beam radiotherapy with or without TEM. Am J Clin Oncol 27:411–419 54. Schulz CJ, Riddle MP, Valdimirsdottir HB et al (2003) Impact on survivors of retinoblastoma when informed of study results on risk of second cancers. Med Pediatr Oncol 41:36–43 55. Shreve PD, Anzai Y, Wahl RL (1999) Pitfalls in oncological diagnosis with FDG-PET imaging: physiologic and benign variants. Radiographics 19:61–77 56. Sigurdson AJ, Jones IM (2005) Second cancers after radiotherapy: any evidence for radiation-induced genomic instability? (Review). Radiat Res 163:702–703 57. Tateishi U, Hasegawa T, Miyakawa K et al (2003) CT and MRI features of recurrent tumors and second primary neoplasms in pediatric patients with retinoblastoma. Am J Roentgenol 181:879–884 58. Taussky D, Rubifach K, Huguenin P, Allal AS (2005) Risk factors for developing a second aerodigestive cancer after radiotherapy with or without chemotherapy in patients with head and neck cancers: an exploratory outcome analysis. Int J Rad Oncol Biol Phys 62:684–689 59. Tellenberg C, Malmer B, Tavelin B, Gronberg H (2003) Second primary cancers in men with prostate cancer: an increased risk of breast cancer. J Urol 169:1345–1348 60. Tichansky DS, Cagir B, Borrazzo E et al (2002) Risk of second cancers in patients with colorectal carcinoids. Dis Colon Rectum 45:91–97 61. Tomek MS, McGuirt WF (2003) Second head and neck cancers and tobacco usage. Am J Otolaryngol 24:24–27 62. Toth-Molnar E, Hammer H (2005) Secondary malignant tumors in patients with ocular melanoma. Magy Onkol 49:27–30 63. Travis LB, Boice JD Jr, Travis WD (2003) Second primary cancer after thymoma. Int J Cancer 107:868–870 64. Travis LB, Fossa SD, Schonfeld SJ et al (2005) Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97:1354–1365 65. Turkic M, Znaor A, Novosel I et al (2005) Second primary malignant tumors in patients with primary renal cell carcinoma. Acta Med Croatica 59:91–95 66. Wu X, Zhao H, Do KA et al (2004) Serum levels of insulin growth factor(IGF-1)-binding protein predict risk of second primary tumors in patients with head and neck cancer. Clin Cancer Res 10:3988–3995 67. Yasui Y, Liu Y, Neglia JP et al (2003) A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancer. Am J Epidemiol 158:1108–1113

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Radiotherapeutic Aspects

CONTENTS

14.1

Introduction

14.1 Introduction 625 14.2 PET-Assisted Radiotherapy Planning

625

14.3 Advantages of PET/CT Integration 626 14.4 Fundamentals Governing the Use of PET/CT Data for Radiotherapy – Bits and Bytes and DICOM 626 14.5 Case Studies 630 Patient 1 Prostate Cancer 630 Patient 2 Oropharyngeal Cancer 632 Patient 3 Breast Cancer 634 Patient 4 Prostate Cancer 636 Patient 5 Squamous Cell Carcinoma of the Oral Cavity 638 Patient 6 Bronchial Cancer 640 14.6 References

643

Since the first steps taken in the 1980s, radiotherapy, PET technology and radiopharmacy have been considerably modernized. Nevertheless, FDG is still the dominant tracer used under practical conditions, although promising approaches are available in the field of radioimmunotherapy and molecular therapy, e.g. with 68Ga-labeled peptides. Planning, supervision and control have already been made much more reliable with PET alone. PET/ CT-assisted systems initiated the development to more detailed data (see the references on the DVD [Ö 14.2]). In the thoracic region combined PET/CT scanners facilitate the detection of atelectases, and in gynaecology general guidelines have been established for cervical carcinoma, also for IMRI [5]. In more than 50% of the patients, the therapy schedule was changed because the volume of delineation can be determined more precisely (e.g. reduction in size) or a planned curative radiotherapy was modified into palliative radiotherapy if distant metastases were detected with PET.

14.2

PET-Assisted Radiotherapy Planning

Molecular Radiotherapy. First attempts to restrict radiation exposure to the tumour volume with the assistance of scintigraphy were made already in the 1960s, and these first test runs used (tumour-affine) radionuclides and rectilinear scanners, which were already available at that time. The PET era has brought about a revival of these interests with unexpected optimization concepts and first attempts of PET/CT-assisted molecular radiotherapy.

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Radiotherapy Planning. Similar to an experienced radiologist assisting the PET physician with the CT component of PET/CT, the radiotherapist is an expert assisted by a PET physician if external radiotherapy is to be integrated. 3D radiotherapy planning based on FDG-PET planning (3DRTP) and used in intensity-modulated radiotherapy (IMRI) is gaining relevance. Software and navigation problems must be solved to make optimized solutions available in the field of radiotherapy [2, 16, 20]: fully integrated PET/CT simulators, image segmentation and provision of more detailed information on the biological target volume. Optimized diagnostic PET/CT features have a fair chance if suitable navigation tools [18] that are clinically congruent with respect to PET and simulation systems can be made available and ready for application [17]. Experienced proponents of PET/CT maintain that the thesis that lesions examined with PET alone or CT alone cannot be clearly characterized only in 7.4% (!) of all patients [3] is only supported by a minority. PET-guided high-precision radiotherapy with target-oriented definition and therapy planning seems to be a promising outlook for radiotherapists. This newly won PET section was also discussed in the August edition 2004 [13]. Recently published reports confi rm that PET provides supplementary information in up to 47% of all cases (distant metastases, local tumour recurrences, metabolic status of primary tumour, residual tumour tissue after chemotherapy and radiotherapy with improved target volume planning [6]).

14.3

Advantages of PET/CT Integration

 Staging, therapy planning, monitoring,  upstaging/downstaging,  changes with respect to therapy management, presently in approximately 20% of all cases,  therapy concept change from curative to palliative treatment,  modifications concerning therapy planning due to the involvement of metabolically active paraoesophageal or mediastinal lymph nodes verified by PET/CT, for example, in patients suffering from bronchial carcinoma,

 treatment sparing healthy tissue due to differentiation of PET inactive lymph nodes (CT-suspicious “tumour areas”),  more precise localization/delineation of PTV (planning target volume),  exclusion of false-positive PET regions (by PET/ CT), so-called physiological artefacts juxtaposed in the urinary/gastrointestinal tract, e.g. “lymph nodes” vs. urinary tract/ureter diverticulae, ureter artefacts vs. obturator lymph node,  malposition by PET (alone) of metabolically active metastases optimized by CT-based “anatomical landmarking” (precise anatomical level definition of a focus, e.g. in the fossa infratemporalis),  management modification in approximately 20% of all cases [7]. (Micro-, mini-)focal tumour areas resistant to radiotherapy (hypoxic with increased proliferation) can be explored within the scope of experimental studies of the micro-/nanoenvironment (microPET, microCT) in combination with other procedures of nanomedicine (biological conformality).

14.4

Fundamentals Governing the Use of PET/CT Data for Radiotherapy – Bits and Bytes and DICOM

Both PET and CT act mainly as service providers for other medical disciplines. The same applies to PET/CT, which is focussed on the oncological disciplines. Whereas the results of the examinations were transmitted to other physicians involved as printed images and reports in the past, the findings are nowadays increasingly transmitted as digital data (digitalized images). This approach requires a suitable medium on the one hand and a standardized data format on the other to ensure that the referring physician can read the data. Due to the particular format of co-registered PET/CT images, the physician also needs special display software tools that can properly display the slices of both modalities. Figure 14.1 shows a typical network topology of a PET/CT scanner.

14.4

Fundamentals Governing the Use of PET/CT Data for Radiotherapy – Bits and Bytes and DICOM

CT

PET

raw date store

reconstruction server

HIS/RIS Terminal

user terminal

Internet via VPN

LAN

Fig. 14.1. Network topology of a PET/CT scanner

postprocessing workstation

postprocessing workstation

A format standard is not available for PET or for CT raw data. The raw data are stored with manufacturerspecific formats partly based on the Interfile format. However, the utilization of the raw data by the user is restricted to quality control. As the raw data are only intended for intra-system use, the format does not constitute a transmission problem. In order to store the data on an archive server, the native raw data are enclosed in a “DICOM jacket” by using the so-called DICOM-SC (secondary capture). However, the reconstructed image data are generally stored with the DICOM (Digital Imaging and Communications in Medicine) format (http://medical.nema.org/, DICOM). Every manufacturer of a PET/CT system is obliged to publish a DICOM conformance statement describing in detail the implementation and explaining how the system is configured in accordance with the DICOM rules. Every workstation and every printer in the DICOM network is designated as a DICOM node. They are unequivocally distinguished from each other by their IP addresses and AET (application entity title), which must be assigned to every node within the network.

postprocessing workstation

LAN

postprocessing workstation

The DICOM format contains the objects (images, reports, statuses) and the services applied to these objects. These services are further subdivided into service classes. Among others, the following service classes are available:  Work list:  Data exchange with a HIS (hospital information system)  Examinations are registered at the reception system, and all patient data (name, ID, date or birth) are transmitted from the HIS  The HIS can be informed that the examination has been completed. This is called the modalityperformed procedure step (MPPS).  Send:  All DICOM data can be sent to another DICOM node if the storage service (cf. below) is available for this node.  Storage:  Offered by a DICOM node to store the data received.  Storage Commitment:  If the data have been stored successfully, a confirmation can be sent to the sender.

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 Search:  Using the search service, the system can search for objects on another DICOM node and arrange for data transmission to the local node.  Print:  This service transmits the object data to the printer. DICOM standards are available for PET and CT data. These standards are established by ACR-NEMA (American College of Radiology–National Electrical Manufacturers Association) and updated once a year. Unfortunately, a standard for co-registered data, which would considerably facilitate data exchange, has not yet been published. At present, the PET- and the CT-DICOM data sets are sent separately. However, these data sets have already been co-registered by PET/CT and can thus be readily fused by the computer receiving the data. However, changes with respect to the co-registered data, for example, due to compensation of patient movements, with the resulting shifts and rotations, cannot be transmitted by the DICOM. Some manufacturers have developed special formats to store this co-registration matrix. But these formats can only be used for products manufactured by the corresponding company. The DICOM standard will presumably soon be updated so that the co-registration matrix can then also be stored. Within the local network, several services are provided and used by the individual DICOM nodes.

After completion of the scan, the data are printed out by a DICOM printer and/or sent to an archive server. The data volume collected by a single PET/ CT examination amounts to approximately 300 MB for one whole-body scan. In case of dynamic PET examinations or triggered heart examinations, the increase in data volume is proportional to the number of frames or gates generated during the examination. With the above examinations, a storage capacity of 1 GB is often exceeded. The data collected during the examinations are sent to workstations where they are re-worked so that the physician in charge can evaluate the fi ndings. Special software (applications) installed on these workstations enables quick 3D navigation through the digital data collected during the scan. These data can be used to image fused transaxial, sagittal or coronal slices or to display CT images with outlined borders to which PET images are projected with MIP or a single slice (Fig. 14.2). As a PET department acts as a service provider, the data must be made available to the referring institution. The data are transmitted via the local network or the internet with a VPN (virtual private network) connection (Fig. 14.3). Mobile data carriers such as CD, MOD or DVD are also used as readily available carriers, but they have a rather limited storage capacity. Utilization of PET in radiotherapy: The radiotherapist expects PET to be able to outline the meta-

Fig. 14.2. Image of the PET/CT volume in sagittal, coronal and transaxial slices

14.4

Fundamentals Governing the Use of PET/CT Data for Radiotherapy – Bits and Bytes and DICOM

Fig. 14.3. Fused 3D volume CT image of the heart with a short axis PET slice projected onto the slice plane

bolically active tumour area. The tumour contour can only be delineated by the physician evaluating the PET findings. In order to make the limits visible to the radiotherapist, the contour lines are sent along with the data set. A special DICOM format, the RT Structure Set, is available for this purpose (http://medical.nema.org/, DICOM). Special software installed on the substations used to rework the data facilitates the marking work on the fused images. An example is shown in Figure 14.4. The radiotherapist finally has a data set at his/her disposal that can be converted into imaged display of the biological target volume, i.e. the metabolically

Fig. 14.4. The contour line marks the metabolically active area of the tumour. The contour line was marked by a virtual simulator

active tumour tissue, and thus facilitating further therapy planning. The aim of this approach is to optimize radiation planning by making use of the digital information structures. The acceptance of radiological and nuclear medicine imaging procedures has gained exponential importance (cf. the survey at 14528). All those who have learned to comply with the conventional rules of radiotherapy – optimized radiotherapy to the tumour area sparing the healthy tissue – can appreciate the success achieved by modern radiotherapy, as shown by the following attributes: target volume oriented, computer-based, intensity-modulated (IMRI), adapted to the patient and the tumour [21, 10]. Targeted basic planning aids also include correct patient position, fixation masks used to reduce/eliminate breathing artefacts and specific protocol adaptations. With SUV measurements, the four-dimensional therapy planning with breath-triggered PET for the exact PET/CT registration of focal metabolic anatomically correct lesions is made more precise. The diagnostic intervals also have to be correctly adapted to the tumour type, e.g. 4–8 weeks after (neo)adjuvant treatment in case of NSCLC, to register the therapy response more precisely [1, 15, 4, 10]. The interfaces between multidisciplinary and multimodal tumour treatment with successive or simultaneous radiochemotherapy must be determined in the therapy protocols in coordination and agreement with all physicians involved. For more detailed literature, see [8, 9, 11, 12, 14, 19, 22].

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14.5

Case Studies

Patient 1 Prostate Cancer Clinical history: Newly discovered proven prostate carcinoma with unclear propagation diagnosis. The prostate carcinoma in the left prostate lobe was detected during the first PET/CT examination. Furthermore, a bone metastasis was revealed in the area of the os ischii on the left side. The patient underwent surgical intervention to remove the prostate carcinoma.

Then the bone metastasis was irradiated. The PSA values regressed until a value of just slightly above 0 was reached. Later on, a re-increase in PSA value was registered. Another PET/CT scan was performed. Findings: The latest PET/CT scan revealed increased uptake in the area of a lymphoma in the left parailiacal area with a diameter of approximately 6 mm. The data of the PET/CT slices were stored on a DICOM-compatible CD-ROM to enable data transfer for a possibly required radiotherapy for this lymph node.

Fig. 14.1.1. Transaxial PET/ CT slice with increased choline uptake in the dorsal part of the left prostate lobe

Fig. 14.1.2. Transaxial PET/CT slice with bone window setting showing increased uptake in the os ischii on the left side. The scan was performed with 18F choline

14.5 Case Studies

Fig. 14.1.3. PET/CT slices showing increased 18F choline uptake of a lymphoma in the left parailiacal region

Fig. 14.1.4. Typical documentation for potential radiotherapy for the above lymphoma

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Patient 2 Oropharyngeal Cancer Clinical history: Extended oropharyngeal carcinoma (epipharynx, soft palate, tonsil, base of the tongue, hypopharynx) on the left side. Lymph node metastases on both sides. Tumour first diagnosed 6 months ago (moderately differentiated cornifying squamous cell carcinoma). Status post radiochemotherapy with a total dose of 72 Gy ending 4 months ago. Now tumour recurrence or tumour persistence in the oropharynx on the left side.

Findings: Detection of extended tumour recurrence in the area of the left pharynx as well as metabolic activity consistent with malignancy also in the area of a contralateral tumour in the hypopharyngeal region. Furthermore, detection of lymph node metastases in the cervical lymph tract and in the submandibular region on the right side. No signs of further organ or lymph node metastases in the rest of the whole-body scan.

Fig. 14.2.1. Tumour-specific increased uptake in the right pharynx shown in the transaxial PET/CT slice

Fig. 14.2.2. Extended tumourspecific increased uptake in the left pharyngeal area to be irradiated

14.5 Case Studies

Fig. 14.2.3. Lymph node in the area of the lymphatic pathway of the neck, left side

Fig. 14.2.4. Typical documentation of a potential biological target volume of the left pharyngeal region. The upper part of the figure shows the biological target volume as a coloured marked area. On the lower right side we see a 3D documentation of a potential radiotherapeutic target volume

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Patient 3 Breast Cancer Clinical history: A 27-year-old female with multifocal mamma carcinoma on the right side associated with supraclavicular axillary lymphomas as well as liver metastases. The tumour was first diagnosed in the 22nd week of pregnancy. Status post systemic chemotherapy with two cycles FEC as well as four cycles of Epirubicin/Taxol. Continued cytostatic therapy after the baby was born. CT/MRI revealed regression of the liver metastasis. Aim of the PET/CT scan: restaging for further therapy planning. Irradiating the lesion in the right breast was also planned.

Findings: Multifocal tumour mass in the area of the right breast with two foci displaying metabolic activity consistent with malignancy in the area of the upper inner quadrant. The larger focus extends over 1.5 cm and displays glucose metabolic activity consistent with malignancy. The other focus located in the direct vicinity extends over 1.0 cm and displays a less increased SUV value. Three neighbouring foci displaying maximum SUV values of 3.4 are found in the lower outer quadrant of the right breast. No evidence for glucose metabolic activity consistent with malignancy in the left breast. Due to the planned radiotherapy and the lack of indications for surgical treatment, PET/CT was used to localize the lesion, and the data were handed over on a CD-ROM with DICOM-compatible format to support the planned radiotherapeutic treatment.

Fig. 14.3.1. Transaxial PET/CT slice of a patient lying on her back showing a round lesion with considerably increased uptake in the right breast

Fig. 14.3.2. Image of the same lesion as transaxial PET/CT slice of the patient lying face downwards. A second lesion in the right breast displaying slightly reduced hypermetabolic activity is discernible

14.5 Case Studies

Fig. 14.3.3. Typical documentation for transmission of DICOMcompatible data to radiotherapy equipment. On the upper right side we see increased uptake in the right breast, on the right side underneath we see the 3D volume computation for the biologically active volume

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Patient 4 Prostate Cancer Clinical history: A 68-year-old male status post prostate cancer operation 2 years ago followed by radiotherapy ending 15 months ago. An increase in PSA was registered. The PET/CT scan that was then performed revealed an osseous metastasis next to the acetabulum in the right os ischii. The following radiotherapy was successful, i.e. the PSA value returned to normal. The patient was again shown to have an increase in PSA value and pain in the right ischial region. Findings: The latest PET/CT revealed an isolated bone metastasis in the right os ischii. The physicians in charge held the opinion that repeated radiotherapy, now in this region, seemed to be a promising therapy.

Fig.14.4.1. Metabolically active region in the os ischii in a sequence of transaxial PET/CT slices

14.5 Case Studies

Fig. 14.4.2. Typical documentation of the DICOM-compatible data sets required to determine the biological volume. The image on the upper right side shows the biologically active region in the os ischii on the right side. On the lower right side, documentation of the biologically active volume in the bone

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Radiotherapeutic Aspects

Patient 5 Squamous Cell Carcinoma of the Oral Cavity Clinical history: A 53-year-old male with recurrent squamous cell carcinoma of the oral cavity in the area of the lower side of the tongue in the left anterior region. Now multilocular recurrent tumour of the tongue. Suspicious mass in the left pulmonary region. Cervical metastasis on the left side. Status post neck dissection on the left side with suprahyoid lymph node dissection on the right side February 2004. Adjuvant radiochemotherapy. PET/CT indication: Restaging for further therapy planning. Propagation diagnosis.

Findings: The PET/CT scan revealed glucose metabolic activity consistent with malignancy in the area of the tongue in the left lateral region with rising SUV value in the sequence of follow-up images. Another approximately 1.0-cm-large focus consistent with malignancy with a typically increased glucose metabolic activity was detected in the middle of the tongue dorsum. Detection of another focus consistent with malignancy in the ventrobasal region in the area of the anterior right tongue margin. Further tumour-specific lesions detected by the whole-body scan should not be discussed here. Teaching points: Within the scope of radiotherapy planning, the PET/CT scan was intended to localize potential lesions.

Fig. 14.5.1. Markedly increased uptake in the left tongue region as well as further tumour-specific increased uptake in the middle of the tongue dorsum in an MIP image as well as transaxial, sagittal and coronal PET/CT slice

14.5 Case Studies

Fig. 14.5.2. Increased uptake in the left lateral area of the tongue in a PET/CT slice

Fig. 14.5.3. Typical documentation of the DICOM data set with the biologically active region in the left part of the tongue shown in the upper section of the figure and the related 3D data set on the lower right side

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Patient 6 Bronchial Cancer Clinical history: A 73-year-old male status post bronchial carcinoma and upper lobe resection almost 2 years ago. Resection of a recurrent tumour 5 months ago as well as four cycles of chemotherapy. PET/CT indication: Restaging. Propagation diagnosis for therapy planning with target volume determination for radiotherapy post R1 resection. Findings: Detection of metabolic activity consistent with malignancy in the area of a 1.0-cm-large

round focus in the left lung in the dorsobasal region (larger than the focus revealed within the scope of a pre-examination performed at another institution), which must be classified as a pulmonary metastasis. Mediastinal lymphomas with values consistent with malignancy. The operated region examined does not display any metabolically active tumour residues. Teaching points: The biologically active volume was determined with regard to the multiple lymphomas so as to be able to perform targeted irradiation of the mediastinal region.

Fig. 14.6.1a–e. Mediastinal lymphomas shown in transaxial slices from the cranial to the caudal region



a

b

14.5 Case Studies

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c

d

e



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Radiotherapeutic Aspects

Fig. 14.6.2. Typical DICOM data set to be transmitted for potential radiotherapy planning. The upper section shows a transaxial slice delineating the biologically active target volume. On the lower right side we see the exemplary 3D image of an active lymph node

14.6

14.6

References

1. Andrade RS, Heron DE, Degirmenci B et al. (2006) Posttreatment assessment of response using FDG-PET/CT for patients treated with definitive radiation therapy with head and neck cancer. Int J Radiat Oncol Biol Phys 65:1315–1322 2. Bradley JD, Perez CA, Dehdashti F, Siegel BA (2004) Implementing biological target volumes in radiation treatment planning for non-small cell lung cancer. J Nucl Med 45:96–101 3. Buell U, Wieres FJ, Schneider W, Reinartz P (2004) 18FDGPET in 733 consecutive patients with or without side-byside CT evaluation (Analysis of 921 lesions). Nuklearmedizin 43:210–216 4. Cerfolio MD, Bryant AS, Winokur TS et al. (2004) Repeat FDG-PET after neoadjuvant therapy is a predictor of pathological response in patients with NSCL cancer. Ann Thorac Surg 78:1903–1909 5. Coleman RE, Delbeke D, Guiberteau MJ et al. (2005) Concurrent PET/CT with an integrated imaging system: Intersociety dialogue from the joint working group of the American College of Radiology the Society of Nuclear Medicine, and the Society of Computed Body Tomography and Magnetic Resonance. J Nucl Med 46:1225–1239 6. Dietl B, Marienhagen J (2005) Der Einfluss der 18F-FDGGanzkörper-PET auf das therapeutische Management onkologischer Patienten aus strahlentherapeutischer Sicht. Nuklearmedizin 44:8–14 7. Gambhir SS, Czernin J, Schwimmer J et al. (2001) A tabulated summary of the FDG PET literature. J Nucl Med (Suppl) 42:1–93 8. Gärtner A (2005) Medizintechnik und Informationstechnologie 2, Bildmanagement. TÜV Media, Köln 9. Graham RN, Perriss RW, Scarsbrook AF (2005 Nov) DICOM demystified: A review of digital file formats and their use in radiological practice. Clin Radiol 60:1133–1140 10. Gregoire V, Hausermans K, Geets X et al. (2007) PETbased treatment planning in radiotherapy: A new standard? J Nucl Med (Suppl1) 48:68S–77S

References

11. Kabachinski J (2005 Jul–Aug) DICOM: key concepts– part II. Biomed Instrum Technol 39:292–304 12. Kabachinski J (2005 May–Jun) DICOM: key concepts– part I. Biomed Instrum Technol 39:214–216 13. Lucignani G, Jereczek-Fossa BA, Orecchia R (2004) The role of molecular imaging in precision radiotherapy for target definition, treatment planning optimization and quality control. Eur J Nucl Mol Imaging 31:1059–1063 14. Noumeir R (2005) Benefits of the DICOM modality performed procedure step. J Digit Imaging 18:260-269 15. Pottgen C, Levegrun S, Theegarten D et al. (2006) Value of 18 F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction pathologic reponse and times to relaps after neoadjuvant chemoradiotheerapy. Clin Cancer Res 12:97–106 16. Rahn AN, Baum RP, Sengupta S et al. (1998) FDG PET in staging and therapy monitoring of esophageal cancer under radiotherapy. Eur J Nucl Med 25:145 17. Ratib O (2004) PET/CT image navigation and communication. J Nucl Med (Suppl 1) 45:46–45 18. Reubi JC, Körner M, Waser B et al. (2004) High expression of peptide receptors as a novel target in gastrointestinal stromal tumors. Eur J Nucl Med Mol Imaging 31:803–810 19. Riddle WR, Pickens DR (2005) Extracting data from a DICOM file. Med Phys 32:1537–1541 20. Schmücking M, Baum RP, Griesinger F et al. (2003) Molecular whole body cancer staging using positron emission tomography: Consequences for therapeutic management and metabolic radiation treatment planning. Recent Res Cancer Res 162:195–202 21. Thilmann Ch, Oelfke U, Huber P, Debus J (2006) Intensit tsmodulierte Strahlenbehandlung-neue Perspektiven fuer die Tumortherapie. Dtsch Ärztebl 103:A 3268–3273 22. Weisser G, Walz M, Ruggiero S, Kammerer M, Schroter A, Runa A, Mildenberger P, Engelmann U (2005 Oct) Standardization of teleradiology using Dicom e-mail: recommendations of the German Radiology Society. Eur Radiol 15:1–6

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15

Introduction

Nuclear Cardiology – the Situation in Europe

CONTENTS 15.1 Introduction 645 Development of Nuclear Cardiology and the Present State 645 Molecular Cardiac Imaging 647 Fusion Imaging 649 SPECT and SPECT/CT 650 MRI and PET/MRI 652 15.2 Cardiac PET/CT 652 Coronary Sclerosis 652 Diabetes Mellitus and Coronary Sclerosis 654 Plaque Imaging 655 Perfusion 656 Vitality 657 Radiation Exposure and Contrast Medium Safety 657 Artefacts 658 Invasive Diagnostics, Treatment and Treatment Monitoring 658 Prevention 661 Remarks on the Catalogue for Further Training for the Specialization in Nuclear Medicine 661 15.3 Case Studies 663 Patient 1 Mild CHD 663 Patient 2 Status Post Revascularization 666 Patient 3 Status Post Anterior Infarction and Sextuple Bypass 668 Patient 4 Surprise Finding of Stem Stenosis 672 15.4 Reference

676

15.1

Introduction

Development of Nuclear Cardiology and the Present State At the end of the 1960s, the Anger camera, which made dynamic examination of the heart possible, was introduced. Since the beginning of the 1970s, “rest and stress” studies with 43potassium and 81rubidium have been in use. With the introduction of 99mTc radionuclide ventriculography, the estimation of the global and segmental ejection fraction of the left ventricle became possible [140, 142]. 201Tl myocardial perfusion scintigraphy (MPS), introduced in 1972, marks its broad clinical use. Forerunners. Since the end of the 1970s tomograms have been made as SPECTs using the rotating Anger camera. With gated SPECT (gSPECT, from 1990 on with the introduction of the sestamibi and the multidetector camera and of the necessary software) [73, 163], all previously successively determined function parameters can be recorded in a single examination. Gated PET (gPET) also records metabolic FDG rates in preclinical studies. gSPECT is now considered the functional standard worldwide [261, 177], but in practice is used on a routine basis by fewer than 50% of the nuclear medical specialists surveyed [179]. Symptomatic ischemia, preoperative diagnostics and – in rehabilitation – the monitoring of treatment and the estimation of prognoses were modest claims [262], while MPS has an exceptional prognostic information value owing to its high negativepredictive value. This applies to study collectives of both sexes. In comparison with the cardiac catheter – apart from non-invasive MPS – economic reasons also play a role [282, 284].

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The dobutamine stress echo test [62, 120] appeared for a while to be superior to nuclear medicine in the cardiologic routine for the initial presentation of patients with a high pre-test probability, but later on this was not confirmed. Used selectively as an evidence-based risk assessment before surgery, its value and cost efficiency have been presented convincingly in cardiac and vascular surgery [283, 281, 285, 315, 286]. The American Society of Nuclear Cardiology (ASNC) particularly stresses the value of the examination procedure in women [204]. Data displaying normal SPECT results despite risk stratification, even in the presence of relevant diagnosed stenoses, have caused irritation [23, 55]. SPECT/CT has contributed somewhat towards clarifying this paradox. PET perfusion tracers (See also Chap. 15.2.3, Table 15.1) are used mainly in the USA in the quantification of the myocardial or coronary perfusion reserve–in some cases without (e.g. 82mRb), in some cases with the necessarily connected cyclotron (13NH4, H215O, most accurate perfusion markers, very short half-life) – but for various reasons are only of marginal importance in Germany [71]. Problem. The variety of diagnostic procedures has not put an end to the analyses of value that have taken place since the 1980s [211]: Surrogate and endpoint criteria (prognosis until instability) are (still) not sufficient to permit conclusive statements. This dilemma is reflected in the contributions and guidelines of the professional associations that provide doctors with no final security for their patients. All the examinations – from the stress echo to the sophisticated imaging methods of nuclear medicine and radiology – display certain shortcomings. Further longitudinal studies in the form of a direction

comparison still remain to be carried out (see the literature on the CD-ROM). Today, after a long developmental process, PET/CT and PET are the dominant methods for testing myocardial vitality [5, 301, 23]. Since the 1970s, nuclear medicine has encountered difficulties in making a place for itself in invasively orientated cardiology [299]. Pushed aside into unclear situations and treatment monitoring, ambivalently interpretable findings with consequently limited acceptance were the result. Cardiologists who do not work primarily invasively or who work mainly non-invasively warn that – with the exception of the highly regarded stress echo test – the figures for invasive diagnostics and treatment are increasing [120], but by no means cover all items of information. Re-orientation. AGATSTON pointed out again in 2007 that a re-orientation towards preventive cardiology must take place [7, 143]. The statistics compiled by Unger (Salzburg) are also quite clear about this. In the USA, over 1 million angioplasties and 467,000 bypasses per year are performed within the context of invasive treatment. The second opinion program (SOP) [118] and the sometimes effective oculostenotic reflex [292, 305, 331] are likely to unnerve the patient. “Getting the right medicine” is the key and the therapeutic maxim [143]. What impulses cause one to fall back on non-invasive examinations, too? Since 1975, multiply cited consensus conferences [6, 18] have been evaluating – with continuous updates – the indications for imaging diagnostics. Training catalogues have not kept up with these activities. The present consensus is laid down in the relevant guidelines.

Table 15.1. Perfusion diagnostics with SPECT and PET (for comprehensive documentation, see 3229) SPECT

PET

Tracer

201

99m

Phys. half-life

73 h

6h

1.3 min

10.1 min

2.03 min

Peculiarities

Marked redistribution, almost carrier-free, exposure 0.23 mSv/MBq eff. dose equivalent

Hardly any redistribution, trapping in mitochondria, better impulse rate statistics, better image quality, triggering possible

82Sr- generator, no approval

Cyclotron

Cyclotron

TlCl

Tc-MIBI

82

Rb

13

NH4

H215O

15.1

Epidemiology and Costs – Big Changes Ahead. Health economic factors are to be taken into account when considering the expansion of a method [46, 303, 33]. Cost-benefit analyses are becoming more and more relevant in cardiology, too, e.g. in evidence-based secondary prevention [159]. Economic relevance results from the experience that only a fraction of patients with chest pain (in the USA 1.3% of some 500,000) are actually suffering a myocardial infarction [51, 41]. Central nuclear cardiologic issues today are quantitative studies in (non-)obstructive coronary processes as well as the exclusion of ischemia-relevant coronary stenoses at the non-invasive level, which in doubtful cases as well as in high-risk constellations and foreseeable interventions make invasive coronary angiography with ICUS unavoidable [34, 267, 106, 91]. Stenosis Relevance/Collaterals. In the 1980s doubts were raised about the apodictic relevance of what are termed critical stenoses since consecutive infarctions occurred at quite different coronary segments than were expected on the basis of angiography [180] and were also observed in stenoses of less than 50%. The significance of the collateral function has been commented on since 1969, but substantially underestimated [258]. Our index of publications lists more than 20 papers (most recently [105, 161, 259]). Later the quantifiable collateral flow in dipyridamole-82mRb PET as well as the coronary/myocardial perfusion reserve, whose loss is regarded as an initial pathophysiological manifestation of endothelial dysfunction, attracted attention. The modulation of the coronary vasomotor tone and the progression of the endothelial dysfunction (EDF) develop as a function of the stage (see arginine tests). The EDF may be selectively damaged, even in the absence of angiographic or ultrasound manifestations. Long-term observations in case of mild CHD and endothelial function have been published [300, 240, 343, 169, 168]. The papers by the Nobel laureate Furchgott [101] have had seminal repercussions. Meanwhile, pathophysiological consequences of atherosclerotic expansion to the coronary microcirculation have also been researched. Via cardio-SPECT, the degree of severity of coronary single-vessel disease, the duration of angina pectoris as a function of (medicinally) recruitable collaterals, e.g. during balloon angioplasty, and the induction of collateral perfusion with and without improved ischemia have opened up new insights that

Introduction

should receive more attention in the interpretation of load tests of the nuclear medical specialist. Cardio-SPECT/CT, PET/CT, and MRI expand the focal areas at the morphological level. This will continue in the future with inclusion of molecular endothelial markers, which are still undergoing experimental evaluation [230, 308, 10, 56, 272, 25, 275, 274]. Owing to pathophysiological mechanisms, the functional significance of stenoses cannot be forecast with SPECT/CT in every case [127, 128]. What additional information does PET/CT supply? The groundbreaking potentials [213, 214] have been outlined in pilot projects. Empirical and single-center study data point to new, as yet untapped dimensions (see Table 15.2). Cardiologists and heart surgeons will profit in their decision-making in case of preoperatively tested myocardial vitality with a markedly reduced EF for the decision to treat with medications, invasively or surgically. Potential diagnostic guides are:  the mismatch with hypoperfusion in case of hypermetabolism (hibernating myocardium)  the detection of silent ischemia after bypass surgery  the determination of the coronary flow reserve in transplanted hearts as well as the enervation/ re-enervation status of the heart [321, 330, 257, 209, 64, 321].

Molecular Cardiac Imaging “From Molecular Imaging to Molecular Medicine”: In the Highlight Lectures (2006/07), H. N. Wagner outlined the direction [325, 327, 326, 276]: Molecular imaging encompasses among other things the fusion techniques of nuclear medicine and radiology. Visions of molecular cardiac imaging are also being worked on in special research centers in Germany (see the Düsseldorf Declaration [Düsseldorfer Erklärung] [41, 179]). It defi nes prominent areas in which nuclear medicine is promised a competent role in hospitals and research (see Table 15.3). Molecular treatments and/or imaging mean the use and/or the labeling and visualization of chemical-biological signal molecules whose interactions contribute towards life and whose dysfunctions cause disease.

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Table 15.2. Atherosclerosis – nuclear medicine: 18F-FDG-PET Topic

Year

References

Vulnerable plaques: more recent imaging methods

2003, 2004

[36, 342]

Coronary plaque rupture

1995

[92]

Lipid reduction–plaque repression

1993

[47]

Pathogenesis of atherosclerosis

1995

[176]

Vulnerable plaques and degree of stenosis

/

[191]

Metabolic/molecular imaging

2004

[68]

Macrophage PET

2001

[246]

Arterial remodeling, directive vs. obstructive atherosclerosis

2001

[270]

Multiple atheromatous plaque rupture

/

[182]

Multimodal imaging

1994

[95]

Future PET competence

/

[153]

Cardio-PET/CT

2003, 2005

[214]

Long-term prognosis in case of chronic ischemic dysfunction, vitality test with PET after revascularization

Table 15.3. Clinical preferences of nuclear medicine Prognosis/risk stratification Atherosclerosis CHD in women Diabetes mellitus and obesity Dysrhythmia Rheumatic cardiovascular processes Treatment strategies/complications Heart surgery (pre-/postoperatively) PTCA (before/after) Triage ACS

[232, 243]

cro-PET/CT, clinical PET/CT) with molecular cardiology 2. Apoptosis imaging with 99mTc- and 18F-annexin is one of the research topics. Programmed cell death is a multistage cascade of events the details of which exceed the scope of our publication. Only the activators of the cytokine-caspase mechanism are mentioned [157]. Bioenergetic consequences of left-ventricular remodeling (heart failure) are associated with increased uptake as well as a reduction of the ejection fraction (see dilatative cardiomyopathy) [345].

Preventive cardiology Pediatric cardiology (Kawasaki’s disease)

For dysregulations in the genome gene, PET techniques are available for experimental/preclinical application. Not individual components 1 [215], but a plurispectral approach governs the research terrain, even including cardiac gene expression profi les and (also cardiac) NIS transporter systems, NOS and NOS-inhibitors [173, 77, 233, 111] (see Table 15.4). Molecular nuclear medicine is a competency bridge linking radiopharmacy and technology (mi-

1

Platelet instability, MCP-1, metalloproteinases

Biomarkers-Imaging, In-Vitro. The National Institutes of Health (NIH) define imaging biomarkers (IBMs) as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention” [222]. 2

A bicenter study made the following observation as characteristic of the collaboration of metabolic and molecular mechanisms in heart failure: A deregulation of the metabolic gene expression before and after “mechanical unloading” [239], dominant VCP3 expression for the reduction of oxidation-relevant free radicals with energy loss of highly energetic phosphates in case of heart failure, downregulation of the glucose transporters 1 and 4 and other marker enzymes (e.g. mCPT-1, muscle carnitine palmitate transferase) up to 8%

15.1

Introduction

Table 15.4. Atherosclerosis – molecular nuclear medicine Method

PET

SPECT

Signal

Signal description

Tracer

Perfusion reserve (endothelial dysfunction) Inflammation Genetic instability Apoptosis Receptor density

Reduced Macrophages consume Programmed cell death Bmax increased

13

Adhesion Lipids Proliferation Metalloproteinases Apoptosis Neoangiogenesis

Integrin expression Accumulation Smooth muscle activity Matrix expression Programmed cell death Reperfusion

99m

Lucignan [186] sees that the time has come to move from research to patient care. A classification is appropriate:  Type 0 natural course of a disease, long-term correlation with known clinical studies  Type 1 marks intervention effects – interaction with medications  Type 2 as surrogate endpoints Imaging biomarkers can be used repeatedly since they are non-invasive, have a reflecting structure, function, biomolecular variants and, as such, are preferred parameters for translational research. In-vitro biomarkers, on the other hand, are not yet suitable for hospital application in imaging diagnostics. Cardio-tracers for oxidative stress 1 or for free radicals [195] and proinflammatory tracers that enable a visualization of LDL oxidation are also lacking. Earlier studies concerning the water-electrolyte balance and the level of antidiuretic hormone in the plasma were conducted without tracers with hypoxia breathing (in healthy individuals) and oxygen breathing (in case of chronic heart failure) [139].

Fusion Imaging The fusion image of perfusion (SPECT) and FDG uptake (PET) as well as non-invasive computer tomographic coronary angiography constitutes significant progress in cardio-diagnostic imaging [129, 213, 1

Cf. hypoxia markers in case of onco-PET-18F-FMISO

N-ammonia rubidium 15 OH2 18F-FDG 124 I-FIAU 18 F-annexin 11 C-endothelins 11 C-opioids** 82

Tc-annexin I-LDL 111 In-MAB 123 I-MDA 99m Tc-annexin 99m Tc-MIBI 125,123

128, 261, 104, 260, 103]. Ischemia-inducing coronary stenoses are shown simultaneously with the corresponding perfusion territories of the coronary tree. This double functional-anatomical information enables the documentation of normal perfusion with a high degree of diagnostic reliability and therefore the exclusion of hemodynamically relevant stenoses, low and moderate narrowing of the lumen as well as complete lumen obstruction. Differently perfused areas of supply can be assigned to the corresponding coronary arteries, regional, stenosis-dependent perfusion failures or reductions can be detected with the aid of suitable software [22]. The experiences of Zurich and Munich, which– as far as we know – are the first of this kind, are shown in the form of impressive, clinically promising image documents [103]. Subsequently fused image material is helpful, but it has been shown that it does not achieve the level of information of the co-registered image data in hybrid instruments. Bax asked whether the total is greater than the sum of its parts [22]. The additional information obtained surely lies in the simultaneous integration of primarily independent functional-metabolic and angio-morphological methods in one gantry during a single examination procedure that are directly available without having to be reprocessed by the examiner. Whereas in case of oncological issues, no exorbitant demands have to be made of the computer tomographic part, for nuclear cardiology, as in case of CT alone, only CT components with 16 detectors or more come into consideration. At least 64 slices are considered optimal [199, 172, 128, 132].

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Table 15.5. SHAPE task force All types of atherosclerotic plaques with a high likelihood of thrombotic complications and rapid progression

Should be considered as vulnerable plaques

Vulnerable plaques are not the only culprit factors

In the development of – acute coronary syndromes (ACS) – acute (myocardial) infarction – cardiac death – vulnerable blood (prone to thrombosis) – vulnerable myocardium (prone to fatal arrythmia) important role in outcome “vulnerable patient” (prone to cardiac events)

Need to develop a method for cumulative risk assessment

Including variables – Plaque vulnerability – Blood vulnerability – Myocardial vulnerability

Screening of Heart Attack Prevention and Education NAGHAVI M et al. 2003/2006 (quoted: acc. Lucignani G: Hints on new applications of emission tomography and magnetic resonance in neuro-oncology. Eur J Nucl Med Mol Imaging. 2007; 34: 1310–5. Closing remarks Hör G, Berlin 9 May 2007)

Owing to its high NPV, SPECT/CT is of considerable relevance in the exclusion of critical coronary stenoses, but can be usefully combined with PET and radiological methods in the diagnosis of atheromas [160] (see Table 15.5). The parameters of ventricular function may deviate in comparison with SPECT alone [261]: The EF appears discretely higher with CT, the EDV is systematically overrated, and the ESV agrees to a tolerable extent. Pitfalls are, firstly, a non-uniform blurring of myocardial perfusion scintigrams with subsequently distorted image information [164] and, secondly, previous correction methods (attenuation, scatter, depth correction) ignore movement-related artefacts [189]. Further algorithms – phantom-based and clinically evaluated – should be used on a regular basis 1.

SPECT and SPECT/CT In the USA the ratio of coronary angiography to SPECT is 1:3, in Germany it is 3:1 (see Table 15.6). For instance in 2005, 1,370 myocardial SPECTs per 1 million inhabitants were performed in Germany. By comparison, 9,370 coronary angiographies were 1

In the bull’s eye map, up to 6% artefacts were observed, which decimated the shift between respiratory phases to 0.5 min with the algorithm cited (in the bull’s eye SPECT 3.75%)

conducted. 2 Nevertheless, the National Institute of Clinical Excellence (NICE) demands both the expansion of SPECT and an increase in the number of installations [219, 310, 126]. In patients suffering from acute coronary syndrome (ACS) not confirmed in emergency departments, MPS reduced the number of in-patient admissions from 52% (usual care) to 42% – without changing the prognosis (cardiac deaths 1.2%) in comparison with “usual cardiac care.” This reduction (based on cardio-SPECT) is considerable. 3 It is only the result of the MPS that yields the indications for invasive diagnostics and treatment. If the MPS is normal under stress, the medium-term prognosis is excellent [284] and the annual incidence of cardiovascular events less than 1% [140, 320]. Survey in Germany. A questionnaire-based survey collected the DGN data on MPS in 100,000 patients. Of the doctors, 75% performing the treatment used “rest and stress” protocols with 99mTc perfusion markers, and 20% used 201Tl stress redistribution protocols. In 78% the stress was generated ergometrically, pharmacologically therefore only in one-fifth. Only every fifth individual surveyed made attenuation corrections. Only 47% of the demands came from cardiologists (only 21% in-patients) [178].

2 3

Lindner et al. (2007) Nuklearmedizin, 49–55 See also the ERASE study

15.1 Table 15.6. Incidence of invasive coronary diagnostics and treatment

Introduction

Table 15.7. Established risk factors of coronary artery disease (CAD)

2005

D

A

CH

Factors

Cardiac catheterization

668,490

48,791

50,320

Not modifiable

Modifiable

Cardiac catheterization/ million inhabitants

8,253

8,120

7,400

– Age

– Nicotine, alcohol, etc.

– Sex

– Obesity

PTCA/million inhabitants

3,430

220

2,100

– Family medical history

– Hypertension

CABG/million inhabitants

755

430

639

– Physical inactivity – Diabetes mellitus*

Risk Stratification. Individual centers have 8-year follow-ups with SPECT using molecular mechanisms [115] in obesity [264] as well as in:  angina pectoris [89],  CHD-endangered women with chest pain and a normal dobutamine stress SPECT [107], supplemented by myocardial vitality tests in association with chronic ischemic disturbances of left ventricular function [24]  symptomatic patients [86] with stress echo after healed myocardial infarction [87], in some cases also with differential criteria (metabolic activity, contractile reserve) [64]  older patients after revascularization. One-year mortality increased from 0.6% (normal perfusion) to 3.3% with irreversible (23%) and reversible (34%) perfusion defects [88]. The entire 1-year mortality was 1.3% (normal perfusion) and 4.2% (abnormal perfusion); the mortality risk was 4% (in case of multi-vessel disease) and 2.5% (single-vessel disease). The informative value is limited by the fact that the individual ejection fraction,obesity proportion [94], cardiac catheterization data and coronary flow reserve [231] were not taken into account. In summary, it can be said that the primary demand made of SPECT must represent the exclusion of CHD with critical stenoses (NPV between 94% and 98%, depending on the source). The value added by SPECT/CT is obviously significant (also) in case of smaller vascular stenoses and in diagonal branches. SPECT Markers. Derivatives similar to endothelin [78] have until now not been suitable for routine use, and therefore 99mTc perfusion markers still take first place in nuclear medical clinics and practice centers. Pathogenetic keywords for literature on endothelin can be found in Table 15.7.

– Cholesterol status* – LDLN – HDLO *Conditionally modifiable

The role of the mitochondrial potential of MIBI has been investigated in detail in cell cultures of murine fibroblasts, clearance and retention, and metabolic aspects have been characterized also in the focus of type-2 mitochondrial thymidine kinase. The debate also includes an oxidative stress syndrome as the cause of accelerated MIBI clearance with mitochondrial dysfunction [165]: The multiple drug resistance protein (MDR) causes a reduced accumulation of MIBI. As far as we know, side effects are unknown in case of PET tracers, but have been described–until now only in isolated cases – for contaminated 99mTc sestamibi: 16 patients were said to have contracted acute hepatitis after MPS [226]. In cardiology, other inflammation markers (e.g. 111In-leucocytes) have not yet achieved permanent acceptance in identifying infected bypasses, but rather (recently) in accelerated atherosclerosis and restenosis [69, 174]. Gated Pinhole SPECT. This method’s high resolution imparts it status in molecular research: A team in Nancy [307] exposed its value in the monitoring of intramyocardial transplantation of bone marrow stem cells in cases of chronic infarction. With a MIBI uptake of less than 70%, 48 h after transplantation of 111In-BMSCS (bone marrow-derived stem cells), successful results were achieved 3 months later, but not in untreated rats [317, 316, 198]. SPECT has definitely increased in importance over the course of time, but experts rather advocate cardio-PET and postulate the validation of cardioPET/CT on a wider basis.

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The expertise that has been approved at regular intervals over more than 30 years now deserves to be acknowledged and heeded; it is consensual with German and European publications. It remains to be hoped that in the medium-term multicentre studies and randomized, controlled clinical trials will slow the escalation of the diagnostic media.

Coronary Sclerosis – An Infectious Disease? In “classical“ cardiology [187] this question is negated; for infection specialists and immunologists it can still be discussed [297] with Chlamydia pneumoniae as the possible pathogen, even subject to the hypothesis of its being treatable with antibiotics. The precipitating inflammation component that gave the impetus for the intensified PET research with the inflammation marker 18F-FDG remains undisputed.

MRI and PET/MRI “Dream or reality [185]?” Technical incompatibilities of the two systems resulted in slower evolution. Since the beginning of the 1990s [234], intensified efforts have made advances possible. In a pilot study [60], solution pathways were shown. The quantification – complementary to FDG-PET – of the degree of inflammation of atheromas with ionized nanoparticles would be advantageous. Among other things, owing to its high spatial resolution, MRI and MRS, respectively, owing to their large number of metabolic spectra, e.g. also of 19F-glucose are predestined. It cannot, however, be expected that they will become established practice in the near future. Nevertheless, studies with MRI and with PET/MRI with APD-based detectors [119] for the optimization of system compatibility will supplement the imaging horizon in the future: 4.5–7 T is said to reduce the range of the high-energy positron generators.

15.2 Cardiac PET/CT Coronary Sclerosis Over 20 years ago, authors concerned themselves with atherosclerosis of the coronary arteries (again) [121, 318]. Nowadays, molecular in-vitro markers 1 are attracting great interest: More than 1,000 genes have been identified at the RNA level, and a similar number on the protein level by means of mass spectrometry. This guarantees the successful selection of target peptides as the basis of innovative and specific diagnosis [277, 7, 337, 65]. 1

Phage display, gene microarrays [156]

Autopsy Findings. Up to 77% of the coronary findings of soldiers who fell in Korea and Vietnam displayed coronary processes, including groups without previously known ischemic heart disease with a high prevalence of severe coronary obstruction (33–42%) or coronary plaques with and without thromboses [15, 117]. The BOGALUSA Heart Study on aortal and coronary sclerosis in 6 to 30 year olds is also worthy of mention [32, 200]. Coronary plaques were found in 20% of the group of 1 to 20 year olds [13]. In this context, the arteriographic patterns in the early manifestation of coronary syndromes are also of interest [102]. Ischemia-Vulnerability. Etiologically, the focus is generally still on the known laboratory parameters as well as the nutritional risk parameters and lifestyle (see Table 15.7). This appears, however, not to be enough, and a re-orientation of a more recent quality, e.g. within the meaning of the expanded concept to include the “vulnerable patient,” is demanded [212, 191, 67]. Proofs of ischemia and vulnerability with X-ray and CT techniques alone are insufficient. In the formerly practiced EBT technique, subclinical stages were also examined with regard to the “prevalence of silent ischemia” [12, 34, 203]. Calcifications were also considered an important sign. The molecular level became the preferred signal for the earliest stages. Initially – together with MSCT, MRI and PET/ MRI – PET/CT has set new standards for determining the systemic character of the disease more precisely than has hitherto been the case [213, 214, 153, 129, 223]. On the basis of studies, nanotechnological methods, e.g. bioluminescence and thermography, are being developed [36, 254].

15.2

Molecular Markers – In-Vitro. CRP-homocysteine determinations are complementary to imaging methods and molecular markers (see Table 15.8), but simpler, more practicable and cheaper. The CRP level lowers the eNOS expression in aortal endothelial cells and is appreciated as an important marker also for monitoring of statin treatment. That the main emphasis is still on treatment rather than on prevention has been criticized [245]. The anti-inflammatory treatment of atherosclerosis advocated by some authors is also commented on critically in this context, particularly the check used probatorially (in PET and PET/CT studies) [68]. Molecules (VCAM-1 1, hs-CRP, PAI-1, ICAM-1) are tested in vitro with the goal of visualizing lesions activated by inflammation in atherosclerosis. Atheroma foci enrich FDG, as do apoptotic cells of ischemic and reperfused myocardium in a similar way. For MRI, annexin V bound to gallium-DTPA (coated liposomes) is also being researched. Attention is also drawn to (pure) contrast medium depots in aorta walls [3, 339, 270]. PET and PET/CT in women’s CHD. The death rate of female CHD patients is estimated to be at least half a million per year, which is twice as high as that for cancer. Teams have long pleaded for the meaningful use of MPS. The metabolic syndrome modifies CHD risk factors in menopause since the protection of the female functional angioarchitecture provided by estrogen is lost or decimated, and risk factors such as obesity, smoking, diabetes and hypertension are subjected to amplifying effects [196, 184, 204, 250]. Contraceptives and/or hormone replacement treatment are regarded as additional potentially negative influencing factors. Imaging diagnostics contribute towards the selection of silent ischemia and can quantify its degree of risk more precisely. Individual hints for this from nuclear medicine (201Tl-MPS) over 2 decades ago had initially been forgotten. Silent ischemia has been reported on since 1981 [1, 278]. Optimum Aimed for. Since not all coronary stenoses are flow-limited, optimal information results probably are: SPECT/CT and FDG-PET best characterize non-invasively metabolically active coronary plaques, 1

Vascular cellular adhesion molecule 1

Cardiac PET/CT

Table 15.8. Molecular markers (a selection) Marker

Event

References

Annexin

Apoptosis

[162, 210]

MCD-1 VCAM-1

Vulnerable plaques

[134]

Integrin

Angiogenesis

[249]

Antimyosin

Infarction transplant/ rejection

[217,249, 216]

FDG

Unstable plaque

[218]

1 monocyte chemo-attracting protein

which for their part can be shown morphologically (mixed plaques) by means of MSCT angiography. Di Carli [76] stresses the meaning of endothelial factors, coronary flow and coronary reserve. A non-invasive “one-stop-shop” method covering all the interesting factors has not yet been achieved [279, 40]. The diagnostic optimum is therefore a choice of method adapted to the problem in the consultation among experts according to the principles of “personalized medicine.” Calcification vs. 18F-FDG-PET. An Australian group has described CT for calcium identification as the “mammogram of the heart” [75]. Detection of calcification is a sign of completed (or still active) calcification. Historically, the “Munich register” is worthy of mention: In this, EBT examinations of 1,206 patients were carried out and evaluated [289, 290]. This took place without prior knowledge of the AGATSTON score. Schepis et al. (15166/07) presented the following relation for discussion: In case of a calcium score proved by ROC analysis to be ≥709 (as an optional cut-off value), the informative value of the SPECT data is improved as follows: While for gated SPECT alone a sensitivity of 76% and a specificity of 91% applied, when the gated SPECT was used as the basis in combination with the calcium score, a significant increase in sensitivity to 86% was achieved. The specificity decreased slightly (86%). As an inflammation marker, FDG-PET signalizes FDG uptake in macrophages and therefore the existence of a florid metabolic process, which can possibly be localized more precisely by means of the dual point technique. Since the association of calcium

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and – stable or unstable – plaques varies, it may be assumed that both signals document different stages of atherosclerosis [84]. The following situation might be clinically relevant: In case of the “culprit plaque,” FDG-PET/CT is possibly able to identify unstable plaques before they rupture and cause infarction. The GLAGOV phenomenon might also come into view again. 1 In 1987 Glagov described “arterial enlargement” for the first time as a (part) process of arterial remodeling [110]. It was interpreted as an attempt by the organism to keep the coronary lumen protectively open in case of coronary stenoses (“poststenotic dilatation”). The focally compensatory lumen enlargement was also interpreted as the organism’s response to progressive atherosclerosis [181]. Synopsis: The vulnerability with threatening plaque rupture cannot be forecast reliably with PET alone; in the absence of calcification, this cannot be excluded since 20% of the coronary plaques are not calcified anyway. The absence of a proof of calcium does not rule out myocardial infarction in the near future. The plaque burden correlates only poorly with functionally relevant coronary stenosis. The estimation of the individual cardiac event probability on the basis of coronary calcium tomography as well as of an individual risk factor has not been sufficiently proven [34], but constitutes a challenge for nuclear medicine [276]. A calcium score of 400 and over may be regarded as a guideline value for continuing, initially nuclear, cardiologic diagnostic measures [296]. Some teams place the “specificity” for non-obstructive plaques surprisingly highly at 91% [172]. Classification and quantification of the plaque volumes – at least at proximal coronary segments – must be critically observed and possibly balanced with ICUS. In analogy to cardio-CT, an optimum of 64, but at least 16 slices, applies of course for cardio-PET/CT, too. The number of critically examined coronary patients is still small: In 19 patients, Leber et al. [171] report 83% sensitivity for non-calcifying plaques, 94% for “mixed plaques” and 95% for calcified lesions. 2 For entirely non-calcified lesions, some reports speak of only 53% [208]. 1 2

“Arterial enlargement of coronary artery as a sign of arterial remodelling” Compare more unfavorable data in case of non-stenotic plaques with 16-slice [269]

Diabetes Mellitus and Coronary Sclerosis Diabetes Mellitus and Prognosis. The alarming situation of the incidence data [280] has incited active intervention: national guidelines [54] and the “supply paradox” (see Table 15.9) [35] 3. Nuclear medicine can play an adjuvant role here in imaging diagnostics. Following preliminary studies with 13C-glucose the first comments on the optional evaluation of 201Tl-MPS reached us, later with SPECT and PET, in:  diabetics with cardiac symptoms [324, 333]  asymptomatic type II diabetics  angina pectoris coincidence and restricted ventricular function  risk stratification in case of suspected CHD, also in younger diabetics [109]  stenosis coincidence and diabetes with development of a GLAGOV phenomenon ([181] arterial remodeling),  calcium coincidence and diabetes [237]  influence of diabetes on the forecast of the clinical outcome after revascularization in case of ischemic disorders of ventricular function [265]. Two studies are worthy of note: the DIAD study by Wackers et al. and the ERASE study [324, 151, 324]. Every fifth diabetic would be incorrectly classified without SPECT (according to the criteria of the American Diabetes Association). In 7,500 women (out of a total of 20,000 registered patients) the forecast of the cardiac event rate was less than 1% in case of a normal myocardial SPECT. With the increase in perfusion defects (in female diabetics), the incidence of myocardial infarction and cardiac deaths is four to six times greater. In order to optimize the PET protocol with regard to the influence of hyperglycemia on the quality of the PET images, we previously used the concept of the hyperinsulinemic glucose clamp with acipimox, while others recommended late (delayed, dual point) PET images with subsequent insulin injection [271, 309]. Since the first “image separation” study [166], improvements have also been made with regard to the SPECT technique: Compressions of 3D to 2D are said, however, to have been accompanied by loss of contrast. New detectors (CAPD-photon conversion), positron-sensitive semiconductor techniques, DSPECT and U-SPECT are to be used as keywords. 3

For the characterization of cardiovascular complications [122]

15.2 Table 15.9. Diabetes mellitus – stress SPECT Without myocardial infarction/revascularization

Abnormal SPECT

High-risk scans

Asymptomatic diabetes (n=1,738)

58.6%

19.7%

Symptomatic diabetes

59.5%

22.2%

Asymptomatic non-diabetes

46.2%

11.1%

Symptomatic non-diabetes

44.4%

12.5%

Plaque Imaging Not so much the size of the plaque [96] as multiple molecular components are decisive for the site of an incipient myocardial infarction [180]. ICUS is preferred for the analysis of the “pre-rupture profile’” of unstable coronary plaques [205]. Pluricausal mechanisms, however, require multimodal diagnostics. To put it differently: On the one hand, plaque vulnerability is not determined by purely morphological methods; on the other hand, stable angina pectoris is not synonymous with plaque stability. Here already the expectation potential for PET/CT is high. The pathological-anatomical risk factor for plaque rupture is the fibrous capsule of the atheroma (< 70 μm thick, CT resolution approximately 400 μm), which is said to contain a large number of macrophages. The representation of the plaque dynamics on the basis of the cell metabolism and molecular genetics offers future competency lines 1. Experimental studies with 125I-LDL were conducted over 30 years ago. Studies in endothelium research are to be included, and a promising beginning has been made with the molecular markers: NIS–sodium iodide symporters [314, 206]. The primary metabolic target of PET is macrophages; a current problem of PET/CT is the spectrum of different degrees of vulnerability. The characterization of the 18F-FDG uptake in human endothelial cells [197] was the decisive basis in the follow-up to earlier antibody-based evolution patterns 2. Clinically it remains to be seen whether the observation of RUDD – that the proof of plaque lesions in a vascular territory correlates to a large 1

2

On pioneer studies and literature [256] of molecular treatment of heart disease and SECHTEM in Schäfers et al. [254]: If one were successful in switching off genes that encode for atherosclerosis preventive treatment would be conceivable e.g. 111In-antimyosin

Cardiac PET/CT

extent with the occurrence of several inflammatory foci in other regions – can be confirmed [326]. Regulatory molecules of the genome have been added to this. Gene regulator proteins are nowadays decisive detector mechanisms of imaging in onco- as well as in cardio- and neuro-PET. Molecular markers were used with an 11.7-T magnet as imaging indicators before and after intracoronary application. Signal intensity was elevated in early stages of apoptosis. With ICUS, atherosclerotic lesions were discovered in 50% of a collective in linear correlation to the LDL level and to the quantified plaque load. Joint goals with nuclear medical methods concern the imaging of the plaque composition. On the Role of Endothelial Dysfunction in Pathogenesis. Laminar thrust forces and endocrine factors are the focus of early and current studies. The activity of the endothelial nitrite-oxide synthase (eNOS) and of certain transcription and translation factors of the genome is elevated, whereby NO exercises an atheroprotective effect. TNF-alpha and oxLDL are raised with a proapoptotic effect. In case of progressive atherosclerosis with denudation of the coronary endothelium (STARY stage III–IV [295]), staurosporin (apoptosis inducer) is used in counteraction with an increase in the apoptosis/endothelial cell number index. 3 How Large Must a Plaque Be in Order to be Visualized? This is currently a topic of controversy. The focus is on vulnerable plaques, also with respect to the systemic character of atherosclerosis and of the pancoronary infestation, possibly with multiple ruptures. In this context it was criticized that quite a number of the stent implantations are made distally of the actually rupture-threatened atheromas. MSCT and PET/CT provide non-invasive insights and will in the future play a more important role in the diagnosis and choice of suitable treatment [31]. MSCT with 64-slice CTA permits a forecast as to the functional relevance of coronary stenoses in case of stable angina pectoris [128]. Fishbein et al. [96] have asked the question from the point of view of pathology on the basis of the observation that 50% of such lesions occur at precedence sites whose coronary lumen reduction accounts for 3

For substances similar to endothelin, see Table 15.7

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less than 50%. Less than one-fifth of acute complete occlusions even take place in previously angiographically verified lumen narrowings > 75%. There is agreement that most plaque ruptures cause myocardial infarction with small vascular narrowings (< 50%). In case of precipitating occlusion clots, even non-stenotic and hemodynamically insignificant atheromas can rupture to be followed by infarction or sudden cardiac death. Fishbein and Siegel argued that almost all older persons are potentially affected. PET and Atheromas. Initial evidence of the atheromas discovered within the framework of onco-PET with elevated FDG uptake at the aorta and pelvic vessels [229] in the absence of calcification have relativized the original euphoria about the prevalence of calcium phenomena as key factors in infarction pathogenesis. The publications are highly promising although broadly based, multicentre studies still need to be conducted [313]: In Baltimore [50] at least one atheroma lesion was detected in the descending aorta in some 59%, in the aortic arch in 53% [332, 266]. In case of neurological matters, the consideration of FDG foci in the ascending aorta, particularly in case of ischemic cerebral insults as an indication of a risk of ischemic insults, is recommended. Some studies have also looked at inflammatory rheumatic vascular lesions (periaortitis) [251]. Ubiquitin. Protease systems are envisaged among the (non-imaging) detection protocols for plaque instabilities [194]. In case of coincidence with diabetes, plaques are said to contain an elevated macrophage concentration with lymphocytes, HLA-DR and other inflammatory components. Seen in this light the protease system can be discussed as a cofactor in the overall risk analysis of diabetes, which, induced by oxidative stress, can help to promote the systemic character with pancoronary plaque infestation [246, 268].

Perfusion Invasive examinations with the cardiac catheter were performed systematically by Strauer with Büll in the 1970s using dipyridamole and were researched non-invasively with 201Tl. Later studies were carried out with adenosine.

PET Perfusion Imaging with 82Rb. In the USA almost routine imaging, in Germany, apart from an – as far as we know – single study in Ulm, it has not even been evaluated in a study. 82Rb-PET/CT. The

Boston-based study in 510 patients with suspected CHD evaluated what is known as the vasodilatatory “EF reserve” (EFR) with 82Rb-PET/CT [83] together with the non-invasive (CTA) coronary angiography as the standard for an at-risk myocardium. Provisional normal values of the EFR (5–6% EF rise) and of the present or absent vasodilatatory rise in case of severe perfusion defects and coronary multi-vessel disease were defined. It is admitted that the LVEF reserve can only be regarded as an “independent predictor” of a main stem stenosis or multivessel disease. As has long been known, an increase by 5% corresponds to a normal EF rise under maximal ergometry. The NPV is 97%; the PPV, however, is only 41%. The short examination time is an advantage. Rehabilitation centers could perform up to 50 examinations per day using Rb-PET exclusively. O2-water (PFT = perfusable tissue index) Owing to its free diffusion and its absolute quantifiability over a wide perfusion range, the measurement of the perfusion capacity with labeled oxygen is the gold standard of myocardial flow. We know of no studies on this with PET/CT [70, 291, 82]. Gated PET (gPET) with 13N-ammonia remains at the study level for the time being [76, 138]. PET Perfusion versus SPECT Perfusion. Gated SPECT is generally considered the standard method; PET perfusion markers without cyclotron would only be possible with Sr-(Rb) generators, of which there are here in Germany. Advantages of PET or PET/CT (also in case of obesity) are seen in case of rest/stress examinations, in exact perfusion measurement (ml/min/g), in coronary multi-vessel disease, as receptor PET or gene PET. The Boston strategy also sees potential for the future in cardio-PET/CT, as in the evaluation of:  acute ischemia  the degree of severity of CHD  the collateral function  the perfusion reserve after PTCA  the assessment of the clinical prognosis in case of negative 201Tl-SPECT and  of myocardial vitality after infarction.

15.2

Vitality According to the classical defi nition, the hibernating myocardium is characterized by reduced or failed myocardial perfusion (SPECT defect), but maintained metabolic activity (FDG-PET utilization) [238]. The differentiation between the (still vital) hibernating myocardium and irreversible scarring-related perfusion defects harbors a high error probability [112]. 82Rb as a marker of the integrity of the cell membrane has been seen as having advantages [117, 113, 322]. Examinations with 18F-FDG, which were logistically more easily available, ensured the recanalization and (re-) vitality [223]. The concept of viability (vitality) is to be expanded by further pathogenetic constants: coronary recanalization and remodeling (ventricular, arterial) [58]. The relevance of myocardial vitality is an important decision factor for the heart surgeon in the preoperative evaluation of the potential success of bypass surgery, the monitoring of the follow-up and of the long-term postoperative success. Since 1994, in Frankfurt, Germany, cardiologists had regularly resorted to PTCA before and after MPS and to FDG-PET before and after RNV. The protocol variants have changed inasmuch as 99mTc perfusion markers are now used instead of 201Tl. Alternatively, FDG-PET examinations, which can, if appropriate, be replaced by PET/CT or/and SPECT/CT, come into consideration. The threshold value characteristic for the proof of vitality at the perfusion level is in the canon of values for PET: 15OH2 (time perfusable index), 13N-ammonia and 82Rb (for determination of the coronary reserve, less accurately with 11Cacetate) [338]. MRI Viability. Since the first documentation of MRIbased ischemia detection, affirmative publications have been increasing [190]. The expansion of the stenosis plaque concept can be newly/re-integrated: Plaque instability is a new realization factor for ischemia (see also Chap. 1.3, Table 15.5). The stress echo (pharmacological) is non-invasive; the ICUS within the framework of the cardiac catheter is relevant for practice, but no surrogate for the SPECT/CT- and PET/CT-based vitality imaging. Gated SPECT and gated PET supplement quantitative parameters of the metabolically based contractility (wall movement).

Cardiac PET/CT

Radiation Exposure and Contrast Medium Safety In 2005 the Munich group (Ludwig Maximilian University) [130, 129] compiled comprehensive data concerning the investigations conducted in Germany (see also Chap. 15.1.2, Table 15.3): The “load data” achieved per inhabitant fall considerably short of those of radiological diagnostics. Details of radiation exposure are shown in the “foundations” chapter in Beyer. The data situation documented by Beyer is also supported by other authors: There are no objections from the point of view of radiation hygiene in case of a clinical indication [44, 45, 340, 130, 131, 136, 43, 137]. When considering the advantages and disadvantages of PET and MRI, one must particularly take into account that, in comparison with exposure-free MRI, PET/CT displays the greatest molecular sensitivity and therefore appears unrivaled from today’s point of view 1: Arguments that MRI involves no radiation exposure (at all) are to be considered in the light of complement-requiring indications in cardiology [207, 53]. Contrast media are used in the millimolar range in MRI and in the nanomolar range in PET, thus making clear the dimensional difference of the contrast media to be used [29, 31, 30, 260, 275]. It can therefore not be deduced from the present data situation whether molecular methods without radiation exposure will catch on in the future. In 2007 H.N. Wagner gave examination numbers for PET (1.4 million), CT (62 million) and MRI (27 million) [326]. Munich (LMU) has now provided representative data for Germany [293] (see also Chap. 15.1.4, Table 15.6). The Ulm studies (Ulmer Studien) (Fliedner et al. 2007) are fundamental as an essential basis for evidence-based clinical triage after accidental whole-body irradiation. They have no direct connection with nuclear medicine, but are extremely informative for the fundamental effects of irradiation on the bone marrow [97]. PET/CT – Safety of Contrast Media. In the radiology department at Frankfurt, a European-based study was conducted [319] in 52,057 patients with the participation of 210 radiologists: In the general population and high-risk patients (renal insufficiency, NYHA III or IV grade heart failure, hypertension, CHD, diabetes mellitus), the rate of side effects in 1

MRI: millimolar, PET: nanomolar, CT: micromolar [255]

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high-risk patients was 1.39%, while serious events occurred in 0.044% in the overall population and in 0.057% in the high-risk group.

Artefacts The doctor performing imaging diagnostics is constantly faced by the problem of artefacts. The earlier criticized “low specificity” of 201Tl-MPS and -SPECT [72, 323] has not been completely eliminated, but has been minimized by:  improved (storage) techniques and specified methods  software (standard matrix tools or attenuation maps) [100] and  established clinical experience. On the other hand, new artefacts can also be observed in MSCT (MDCT) [61] as well as in PET/CT (e.g. “attenuation-emission misregistration”). Possible sources of error are:  software-related artefacts [167]  coronary artery stents [144]  calcifications at the mitral valves [328]  FDG uptake in the mediastinum (atheroma plaques) [133]  mammary artefacts [114]  respiratory artefacts [225] and  inhomogeneities (treatment-related?) in tumour patients. Kuikka [167] warns of software-related artefacts in SPECT/CT. Multidetector computer tomographs, which can lead to exemplary artefacts when used in connection with multidetector gamma cameras, are said to be delicate. Respiration averaging as a correction model is said to cause an error up to seven times smaller than endrespiratory manipulations [63]. The Baltimore team [170] recorded some respiration-related motion artefacts thta contribute towards misregistration in case of sequential acquisition and therefore may subsequently erroneously influence the registration of myocardial perfusion (rest/stress 82Rb-PET/VCT, General Electric): A “misalignment” of 1 cm caused a “reduction” of 19% in myocardial perfusion in the septum (shift in x-direction). This underscores the necessity of (correction) algorithms.

This may also supply an explanation for why a coexistence of the PET-determined myocardial perfusion and of the CT-based coronary calcification was seen in only some of the coronary patients (82RbPET/CT) [49]. The observation that in cancer patients without known heart disease even “severe defects” in the FDG uptake of the heart occur caused a revisional study to be conducted [146]: With a high-resolution biograph, 16-PET/CT yielded a large spatial and time-related heterogeneity in the myocardial metabolic pattern. This caused the team to issue a warning against concluding myocardial vitality from FDG alone.

Invasive Diagnostics, Treatment and Treatment Monitoring After the introduction of PTCA and coronary stents, 1 treatment monitoring by cardiologic nuclear medicine was simultaneously available on a study basis. Doubts with Regard to the “Diagnostic Cardiac Catheter”? Irrespective of its high acute interventional status, the diagnostic cardiac catheter was questioned as early as 1988 with regard to its informative value concerning the relevance of coronary stenosis and the prognosticability of later infarction [180]. More recent publications criticize that cardiac catheters are used too frequently and often for purely diagnostic purposes. [79]. This is also documented by the examination situation of invasive and noninvasive diagnostic measures already described in Section 1.4. A reverse process, which might initiate some rethinking, is only slowly coming about. Eighty percent of all coronary interventions in Germany are said to involve the implantation of stents. Earlier, purely metal stents (bare metal stents, BMS) were used. In case of the drug-eluted stents (DES) being used increasingly today, thrombogenicity is to be expected prior to integration. Therefore, an adequate additional medicinal anti-proliferative and anti-inflammatory treatment is administered. The restenosis rate is initially lowered, but recent studies show that under long-term observation heart attacks and cardiac death are elevated in comparison 1

1976/77 in Switzerland and in Frankfurt: [99, 287, 288]

15.2

Cardiac PET/CT

with the BMS 1. For this reason a longer dual medicinal treatment with platelet aggregation inhibitors is demanded.

sure with ionizing radiation.” Here the clinical data of FDG-PET are already on more realistic ground [302].

In this Context the Situation in Sweden is Worthy of Mention: The use of DES has been reduced from over 50% to 25%. The discussion is still ongoing and is also being observed by the Food and Drug Administration (FDA), possibly even within the meaning of a possible renaissance of the decreasing bypass surgery. Using 64-slice MSCT, Oncel et al. [224] verified stent restenoses in 30 patients with 89% sensitivity, 95% specificity, 94% PPV and 90% NPV. Attention is also drawn to the guideline for 2007 [183].

Endothelial Dysfunction (EDF) and Prognosis. We have the Nobel laureate FURCHGOTT to thank for the trailblazing discovery of the L-arginine pathway [101]. The prerequisite for the development and interpretation of endothelial SPECT and PET markers is the understanding of the basic molecular phenomenon of the generation of nitrogen oxide from arginine by nitrite oxide synthase (see also Chap. 15.1.2, Table 15.4). The acetylcholine response to the endothelially dependent vasodilatator is recognized and accepted as one of the early signals of atherosclerosis. In a study in 157 CHD sufferers (mild form) that lasted 28 months; however [300], cardiac events (CEs: acute infarctions, PTCA, bypass, sudden cardiac death) manifested in 14% in case of marked and in 0% in case of normal or mild vasoconstrictive response. From this it can be concluded that severe endothelial dysfunction increases the rate of CEs despite the absence of obstructive CHD, and therefore the relevance of the EDF in the progression of atherosclerosis is to be taken into account. Here molecular SPECT and, in particular, PET tracers (Rb-PET and -PET/CT) will play a competent role in future [77, 253, 344, 222].

Instant Ischemia. As after PTCA, stenoses also occur after stent implantation. In a study with 31 patients requiring stents [244, 135], the percentage of stenoses decreased from some 69% to 13% after implantation. In 17% mild to moderate perfusion defects were still present in the area supplied by the dilated coronary artery. Further studies referred to retarded ischemia reversibility despite primary angiographic success and to late results 4 to 6 years after PTCA, restitution and prognosis [192, 66, 74, 108]. Gould et al. [116] und Nienaber et al. [221] also described PET diagnostics in case of PTCA intervention. Preclinical Studies. Initial documentations on repair and regeneration monitoring with SPECT and PET for the monitoring of intracoronary stem cell treatment showed that the combination of the two methods constitutes suitable prognostic instruments in the acute situation and in the long-term follow-up [149, 298, 17, 80, 255]. Gene imaging in diagnostics and treatment came to the fore almost explosively [346, 158, 11, 248, 201] after intramyocardial implantation of stem cells and inductors of neovascularization (EGR, FGF), which are said even to increase the results of the bypass success (see above, [158]). The promotion of myocardial function – a visionary treatment principle? Parallels result from the work of Fliedner (see above 98) “Structure and function of the bone marrow as a response to expo1

See BASKET late study = Basel stent costs effectiveness trial long-term observation

Cardiac Enervation. Simultaneous PET measurements of cardiac and nigrostriatal denervation display new connections. SPECT- and PET-compatible tracers are used. 123I-MIBG can also be used in centers without PET: The adrenergic system is causally involved in rhythm disorders. Cardiac and systemic catecholamine peaks are observed in ischemia and after heart surgery. In cardiomyopathy the autonomic cardiac function is a decisive factor [312], and the same applies to the restitution of the myocardial perfusion in acute cardiac infarction, after angioplasty and stent implantation [220, 152]. Depletion of MIBG can already be observed prior to ischemia correlates, repletion as the success criterion after treatment. Only PET/ cyclotron centers have 11C-HED, primarily within the framework of a program for reducing the risk potential of life-threatening ventricular arrhythmia, which can be estimated by means of the H/M quotient: The arrhythmia rate increases within 2 years if it is elevated [8]. 11C-HED was evaluated in (a few) PET centers in the USA [202, 306, 329, 227].

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Earlier publications from Frankfurt aimed towards the de-/re-enervation of the myocardium before and after PTCA and in patients having undergone heart transplantation (in a direct comparison with the noradrenaline content of the tissue) [124, 123]. Heart surgery. Surgical risks are primarily classified from the point of view of the cardiologist [20]. Cardiac catheterization and invasive coronary angiography are decisive factors for surgical intervention. This will probably remain so in case of highrisk situations, similar to the case of the necessity for stent implantations. Early detection after surgical revascularization requires multimodal practices [341]. During the pioneering age of cardiologic nuclear medicine, 201Tl (in isolated cases 81Rb) was on the syllabus in case of unexplained chest pain after bypass operations with the goal of functional characterization, in case of coronary multi- and singlevessel disease [294, 241, 188, 252, 263]. Then already spectra of advanced CHD with poor ventricular output (EF around/below 30%) dominated. 99mTc perfusion markers, SPECT and PET provided additional impulses. This led to new factors: the pre-, peri- and postoperative evaluation in the consideration of treatment strategy, operability and the risk situation [236, 334]. 201Tl-myocardial scintigraphy has been in use since the 1980s, preoperatively for ischemia identification, postoperatively in case of renewed chest pain of unclear origin [294, 241, 140]. In case of thrombosed bypasses, the EF determination (RNV) was also a welcome parameter. Subsequently, FDG-PET became the recognized method for the perioperative diagnosis of myocardial vitality [141, 232, 242]. The qualitative evaluation of the myocardial vitality by PET alone is a profoundly examined area. Quantitative studies have been relevant for years and are demanded by heart surgeons interested in nuclear medicine [93, 304, 311, 279, 40]. This is challenged by the limited diagnostic capacity, even in the USA (9,364 bypass operations already in 1978), and therefore the possible use of imaging methods has been unable to keep up with these requirements. Therefore, the use is restricted to special indications that – as a rule on the basis of studies – were forgotten again, e.g. selection of angina-free patients after cardiac surgery with markedly restricted EF (before

the age of PET [9]). Infectious processes, formerly examined with 67Ga, should now essentially be located in the domain of PET and PET/CT [4, 242]. Spurts of Innovation. After (before) vascular surgical reconstruction, PET (alone) has already verified active metabolic foci with a good rate of reliability. PET/CT with 18F-FDG makes the diagnosis precise by localizing the inflammation foci: Potentially severe complications (0.5–5%) with septicemia or hemorrhagia can be visualized with approximately 100% sensitivity. CT identifies its anatomical localization and therefore increases the low specificity of 18F-FDG alone. An Israeli study recently confi rmed this finding with a specificity of 88% [154, 150]. Since the end of the 1990s the cardio-SPECT technique has been so far advanced that later even a functional forecast of the follow-up became possible in preoperatively dyssynergic myocardium segments after successful revascularization (Bax et al. [21]). Before heart surgery – in case of markedly restricted global EF – the choice of treatment is crucial: bypass, transplantation or drugs. It remains to be seen to what extent clinically valuable statements on the early diagnosis of transplant rejection can answer questions of neuroadrenergic depletion in combination with the detection of perfusion defects by means of double nuclide studies (201Tl/123I-MIBG) [124]. The Toronto study [28] had presented the first results on this for the stratification on the basis of PET. The testing of myocardial vitality with SPECT/ PET is just as important with respect to intra-, perior postoperative complications [59]. At the Munich Heart Center [125] the SPECT/FDG-PET result was helpful in proving the hibernating myocardium for the evaluation of the myocardial regions with the best chances of revascularization. Experiences until now have confirmed that delayed revascularization in advanced CHD causes an increase in mortality rates [26]. In this context the patients’ perioperative followup, whose treatment planning included PET, proved most favorable. The suggestion from Aachen to add quantitative metabolic rates as a supportive measure to the qualitative or semiquantitative FDG uptake determination [52] has not yet caught on [331]. Differences in the MPS in case of partial and total revascularization were of particular interest postoperatively [135].

15.2

In a cost study conducted in London in 2002 [148], model calculations for saving costs in the choice of bypass candidates with poor ventricular function prior to surgery were published: The PET selection, extrapolated to 1,000 patients having undergone heart surgery, yielded £77,000.00 in “incremental costs per life years saved” [143]. 1 We are expecting prospective studies on the use of PET/CT. It is likely to take years until it is clarified whether long-term survival rates can be improved [147]. Essential compromises between non-invasive and invasive coronary diagnostics must be considered in updated consensus conferences. Bodies of experts (SNM, ACC, AHA and ECNC) have – most recently in 2007 – drew up regulations that include early occlusion and bypass stenosis and the use of new techniques, but do not yet include PET/CT [85, 38, 14].

Prevention Prevention as a “task for society as a whole” from the point of view of public health is being started in initial model projects [247]. Agatston recently (2007, [7]) gave instructions that are worth reading not only for doctors. Prevention programs, for instance, PEP (the Preventive Education Program) [277] are paid little or no attention; the same holds true for risk factor analyses (see also Chap. 15.2.1, Table 15.8) [16, 155, 39, 336]. Established laboratory and hospital strategies have long been in existence; strategies for lowering lipids (titration or solid dose) are being discussed, as, for instance, non-lipid-lowering effects of statins [81, 145]. Studies are currently investigating the question of the genetic determination of the cholesterol level. Analysis data exist from randomized studies concerning the effectiveness and safety of the cholesterol treatment. In case of the statin lipid-lowering agents, the question is not how low the values are, but how long they will stay lowered. The lowering of LDL to 40 mg/dl reduced the rate of cardiac events to 20% within 5 years [335, 19, 48]. 1

See also The economics of dying[90]: “…greatest impact of fi nancial costs in Medicare is spent on dying patients, where no further success is to be awaited…” MASS-II (Medicine Angioplasty Surgery) study

Cardiac PET/CT

Despite interesting clinical studies and research results, the challenge of the implementation of nuclear medical investigations arises in the day-to-day cardiologic routine. The myocardial circulation, its quantification and relation to the glucose metabolism are archived in the annals of nuclear medicine [57]. In 2000, Schelbert [5] characterized options of PET in various variants on the basis of the modification of lifestyle, eating habits, cholesterol control, monitoring lipid-lowering agents, also in connection with the limit problem of coronary stenosis and of coronary endothelial function. The coronary flow reserve monitored for decades by cardiologists–initially invasively – continues to be of interest [235, 273, 27]. The influence of nuclear medicine on preventive cardiologic measures is to be judged similarly. New diagnostic agents have been discussed from the point of view of “risk assessment,” among them Creactive protein and homocysteine [228]. The status of imaging diagnostics still remains to be clarified in this context. This also applies to the minimization of heart attacks that could have been avoided but for misdiagnosis [42].

Remarks on the Catalogue for Further Training for the Specialization in Nuclear Medicine In view of the progress made in clinical nuclear medicine and radiology and its obvious relevance in internal medicine, surgical and conservative disciplines, it is becoming more and more difficult to find a compromise between training that is optimal in terms of the contents and skill and is of an acceptable duration. A European catalogue recently elaborated a suggestion that we consider worthy of discussion [193, 38]. Primarily, non-nuclear medical tangents (ultrasound, CT, MSCT, MRI and densitometry) are also affected to the extent that they fall within the evaluation purview of the nuclear medical specialist. In view of the burden on the aspiring specialists, it remains to be examined whether integrated radiopharmacy, biokinetics, radiation biology, ethics and mathematics are practicable within the required framework and can be achieved in the necessary

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detail. It is a question of the practical procedure both for the training of the nuclear medical specialist and of the radiologist as to how and in what ways additional certificates for SPECT/CT, PET/CT and PET/ MRI can be acquired. The DGN certificate for PET/ CT in Germany can be mentioned as an example. Nuclear medical treatment already today defi nitely affects the differential treatment of adjacent specialties, such as, for example:  oncology  surgery  radiotherapy  analgesia  molecular biology, diagnostics and molecular genetic treatment. The competency framework for the planned specialization is ideal, but possibly difficult to achieve. In the USA the escalation of nuclear cardiology into the field of cardiology, in a way that is not tolerated in Germany and large parts of Europe, appeared on the horizon already earlier [175]. The White Paper published as a European initiative in 2007 [37] is to be mentioned in this context: a consensus document on “multi-modality imaging” that should not be overlooked by any specialist involved.

15.3

15.3

Case Studies

663

diagonal branch. CX and RCA were normal. The MIBI-SPECT displayed a moderate, load-dependent, anteroseptal perfusion disorder. FDG-PET revealed unrestricted myocardial vitality.

Case Studies

Patient 1 Mild CHD Clinical history: A 56-year-old male with moderate angina pectoris. Previous cardiologic diagnostics (exercise ECG, echocardiography) yielded no evidence of heart disease. Findings: The patient achieved up to 125 W in the ergometer test, normal ECG. The calcium score revealed moderate coronary calcification. The CT-angiography revealed moderately marked calcified plaques in the LM area as well as mildly calcified plaques in the LAD and the first

Teaching points: SPECT confirmed moderate myocardial perfusion disorders caused by plaques (see above) proven by CT-angiography. This method proved invasive diagnostics unnecessary.

 Fig. 15.1.1. MIBI-SPECT with reduced anterior and septal storage



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Fig. 15.1.2. Representation of the vascular tree with CT-angiography

Fig. 15.1.3. Calcified plaques of mild severity in the LM and LAD (upper left: section through the plaque region with quantification; upper right: vascular representation of the course of the LAD with plaques; lower left: section through aorta, LM and LAD; lower right: sample evaluation)

15.3

Fig. 15.1.4. Three-dimensional surface representation of the left ventricle with coronary vessels

Fig. 15.1.5. CT-fusion image with MIBI-SPECT data with reduced anterior and septal storage

Case Studies

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Patient 2 Status Post Revascularization Clinical history: A 68-year-old male status post inferobasal myocardial infarction was given an aortocoronary vein bypass (ACVB) 4 years later. Owing to renewed complaints 5 years later, he was given four stents. The patient presented for evaluation of his coronary situation. Findings: The patient achieved up to 50 W in the ergometer test. The calcium score revealed marked coronary calcification. The CT-angiography confirmed a functioning bypass on RCA and LAD, but

a restricted KM influx in the area of the CX as well as a bypass occlusion to the first marginal branch. The MIBI-SPECT confirmed reduced myocardial perfusion, particularly anterolaterally and in the area of the posterior wall. As expected, FDG-PET revealed inferobasal and anterolateral scarring. Teaching points: This examination confirmed myocardial perfusion disorders based on the above-mentioned lesions of the coronary vessels, which were visualized non-invasively. Owing to the myocardial scarring, the patient would not have profited from further revascularization measures. Therefore, the patient was spared this procedure.

Fig. 15.2.1. FDG-PET with representation of lateral and inferior scarring

15.3

Fig. 15.2.2. Representation of the LAD with bypass, clips and plaques

Fig. 15.2.3. Three-dimensional surface representation with coronary and bypass vessels

Case Studies

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Patient 3 Status Post Anterior Infarction and Sextuple Bypass Clinical history: A 65-year-old male suffered an anterior infarction without any previous symptoms and was given an acute sextuple bypass. Thereafter, he changed his lifestyle and eating habits completely to a cardiovascular diet and gave up nicotine. Now, free from symptoms, he wanted his coronary situation to be checked. Findings: The patient achieved up to 125 W in the ergometer test without difficulty; he showed no symptoms. The calcium score revealed considerable calcification in the area of the remaining coronary vessels with a value of 1,613. The CT-angiography

confirmed the calcium score and at the same time was able to rule out the infestation of the bypass vessels (normal KM fi lling). However, multiple plaques were found in the adjacent peripheral coronary portions. The MIBI-SPECT revealed moderate anteroseptal/apical perfusion disorders, but was otherwise normal. The anteroseptal to apical scarring was clearly delimitable by FDG-PET. Teaching points: The complete change in the lifestyle and eating habits reduced the potential risk of renewed plaque development for the bypass regions, which was an unexpected finding and was proven non-invasively by means of CT-angiography. The simultaneous assessment of the myocardial perfusion with MIBI-SPECT confirmed a largely balanced myocardial circulation.

Fig. 15.3.1. Perfusion and left-ventricular function with distinct anteroseptal reduction

15.3

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Fig. 15.3.2. Largely balanced myocardial perfusion post sextuple bypass (hint of reduced anterior and septal storage)



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Fig. 15.3.3. FDG-PET with anteroseptal scarring

Fig. 15.3.4. Three-dimensional surface representation with sextuple bypass, wire cerclagerelated artefacts and clips

15.3

Fig. 15.3.5. CT fusion image with MIBI-SPECT (reduced anteroseptal perfusion)

Fig. 15.3.6. CT fusion image with FDG-PET (anteroseptal scarring)

Case Studies

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Patient 4 Surprise Finding of Stem Stenosis Clinical history: A 46-year-old male patient with a good exercise level (professional sports teacher) presented to his family doctor with unexplained precordial symptoms. The pre-test likelihood of the presence of coronary heart disease (CHD) was rather low, but the patient felt restricted in his professional routine owing to the symptoms and sought clarification. Question: assessment of myocardial perfusion, of myocardial vitality and of the coronary vascular system. Findings: The patient achieved up to 150 W in the ergometer test without difficulty, but presented symptoms of angina pectoris during the last stage. The

calcium score of 195 indicated moderate calcification. The CT-angiography revealed a large calcified plaque with transition to the CX and LAD and a length of 12 mm and the degree of severity “severe” for the main stem. The MIBI-SPECT displayed reduced storage in the entire left-ventricular myocardium with anterior and septal emphasis. The FDGPET revealed a normal pattern of distribution. Teaching points: The CT-angiography revealed as clinically surprising findings a large calcified, hemodynamically relevant plaque in the main stem, which presently only insignificantly impairs the myocardial perfusion and the cardiocirculatory performance of the patient, who has a good level of exercise, but who harbors an elevated risk of infarction. The intervention appears indicated.

Fig. 15.4.1. MIBI-SPECT with reduced anterior and septal storage

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Fig. 15.4.2. Three-dimensional representation of the age-appropriate left-ventricular function

Fig. 15.4.3. Normal FDG-PET



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Fig. 15.4.4. CT-angiography with calcified plaque in the LM with partial inclusion of LAD and CX (upper left: quantification of the plaque; upper right: representation of LM and LAD; lower left: descent of the LM from the aorta with representation of plaque; lower right: sample evaluation)

15.4

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16.1

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Cardiac PET and PET/CT – the Situation in the USA

CONTENTS 16.1 Introduction

16.1

Introduction

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16.2 Coronary Artery Disease 687 Myocardial Perfusion Imaging with PET 688 Accuracy of PET and PET/CT Stress-Rest Myocardial Perfusion Imaging 693 Advantages of Myocardial Perfusion Imaging with PET 696 Hybrid PET/CT Myocardial Perfusion Imaging in Coronary Artery Disease 697 16.3 Myocardial Viability 698 Concepts and Pathophysiology 699 Assessment of Myocardial Viability 699 Imaging of Myocardial Perfusion and Metabolism 701 Clinical Implications of Perfusion Metabolism Imaging 705 PET/CT vs. Stand-Alone PET 707 Clinical Indications of Perfusion Metabolism Imaging 708 16.4 Vascular Inflammation and Atherosclerosis Large Vessel Vasculitis 709 Atherosclerosis and Plaque Imaging 711 16.5 Future Developments 16.6 References

Introduction

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Positron emission tomography has broadened the scope of non-invasive approaches to the study of the human cardiovascular system and for the detection of cardiac disease. Not only is it quantitative and can measure functional processes in absolute units, it also reaches beyond tissue perfusion and fuel substrate delivery. It affords delineation of downstream processes, including substrate metabolism and regulatory mechanisms, as well as biological events at the cellular and molecular level. Combined with computed tomography, PET adds functional information to structurally defined alterations of the cardiovascular system as delineated with CT. Conversely, CT images of the cardiovascular anatomy serve as a map for localization of spatially confined molecular and cellular events uncovered with PET. This chapter examines the current state of cardiac PET and PET/CT and how combined structure-function imaging contributes to and refines the characterization of cardiovascular disease. It focuses on those areas of greatest clinical impact, but also explores emerging approaches of future clinical value. The chapter assesses first the clinical value of PET and PET/CT for the detection of coronary artery disease and its clinical impact, then focuses on the evaluation of myocardial viability and its clinical application and, finally, explores the value of vascular imaging for identifying diseases of the arterial wall.

16.2 Coronary Artery Disease Myocardial perfusion imaging assesses the fluiddynamic consequences of structural, but also functional disturbances of the coronary vessels and thus

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the ischemic burden of coronary artery disease. It aids in establishing the cardiac risk and predicting coronary events and thus guides patient management.

Myocardial Perfusion Imaging with PET Radiotracers of Myocardial Blood Flow: The distribution of myocardial blood flow can readily be imaged with PET and intravenous N-13 ammonia or rubidium-82. High diagnostic quality perfusion images are obtained with either radiotracer, despite distinct differences in physical and tracer kinetic properties between radiotracers. The 9.8-min physical half-life of N-13 ammonia requires on-site production, which confines its use to imaging laboratories equipped with a cyclotron. As is true for most diffusible flow tracers, the myocardial net retention of N-13 ammonia (the product of the first-pass tracer retention fraction and blood flow) increases in proportion to blood flow, however, in a non-linear fashion. Flow increases, especially in the hyperemic range, are associated with progressively smaller increments in radiotracer net uptake. As compared to the about 80% first-pass retention fraction of N-13 ammonia at baseline flows, the first pass extraction fraction for rubidium-82 is lower [1, 2]; it averages about 60% at basal flows, but progressively declines with increasing flows so that again, the myocardial tracer net-retention increases with higher flows in a non-linear fashion. Despite its lower extraction fraction, rubidium-82 offers several practical advantages. It is generator-produced, and its use is thus independent of an on-site cyclotron. The strontium-82/rubidium-82 generator system has a clinical shelf life of about 4 to 5 weeks with as many as 20–40 elutions possible per day. Accordingly, the cost per patient dose is relatively low and offsets the initial purchase cost of the generator. Rubidium-82 is administered through a semi-automated injection system, where the amount of radiotracer activity to be injected can be dialed in and be preselected. Because of its ultra-short physical half-life of only 78 s, rubidium-82 administrations can be repeated at 10–15-min intervals so that a typical stress-rest perfusion imaging study can be completed within less than 30 min. Repeat injections for N-13 ammo-

nia require longer time intervals, approximately 30 to 40 min. Nevertheless, a stress-rest perfusion imaging study with this agent can be completed within less than 90 min. With stand-alone PET systems, transmission images are typically acquired first, followed by administration of the flow tracer and acquisition of emission images. The patient remains in exactly the same position throughout the entire study, including the subsequent intravenous infusion of the pharmacological stress agent (adenosine or dipyridamole) and the repeat radiotracer injection. To account for possible changes in patient position between rest and stress images or between transmission and emission image acquisition, some laboratories obtain a second set of transmission images after the stress perfusion images are acquired. For N-13 ammonia, image acquisition typically begins at 7 min after tracer administration (to allow for tracer clearance from blood) and continues for approximately 15 min, while for rubidium-82, image acquisition begins at 90 s after radiotracer injection and continues for a total of 5 to 7 min (Figs. 16.1 to 16.3).



Measurements of Myocardial Blood Flow: Measurements of myocardial blood flow in units of ml/min/g required dynamic image acquisition in order to capture the initial transit of the radiotracer bolus through the left ventricular blood pool and its retention in myocardium. Typically, sequences of 10-s frames are recorded during the first 2 min of the intravenous radiotracer injection, followed by acquisition of longer duration frames (i.e., each 30 s) and a final frame of longer duration (i.e., 5 min for rubidium-82 and 15 min for N-13 ammonia) [1, 3]. Total dynamic acquisition times usually are 17 min for N-13 ammonia and less than 10 min for rubidium-82. The final image frame serves as a template for assigning regions of interest to the left ventricular blood pool and the left ventricular myocardium. Time activity curves derived from the regions of interest on the serial images represent the arterial radiotracer input function and the myocardial tissue response. Fitted with the operational equations derived from tracer kinetic models, they yield estimates of myocardial blood flow in absolute units [1, 3–6]. With hybrid PET-CT systems, attenuation maps are generated from the transaxial chest CT images. After a scout CT scan for adequate positioning of

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Coronary Artery Disease

Fig. 16.1. Myocardial perfusion imaging with N-13 ammonia: Normal stress (upper row) and rest images (lower row) are shown

the heart in the imaging field, CT images of the chest are recorded followed by radiotracer injection and acquisition of the emission images. After starting infusion of the pharmacologic stress agent, the radiotracer injection and emission image acquisition are repeated. High count rates together with the high temporal sampling capability of PET allow gated acquisition of the perfusion images, both at rest and during (rather than after) stress, so that alterations of regional and global left ventricular function in response to vasodilator stress can be evaluated [7]. Functional responses to stress may add useful diagnostic information on the extent and severity of coronary artery disease. The myocardial perfusion study can be complemented by a non-invasive CT coronary angiogram, also performed before or after the perfusion study, so that structural abnormalities of the coronary artery tree can be related to functional consequences on regional myocardial blood flow during stress or rest.

Attenuation Correction of PET Emission Images: Fundamental to the quantitative imaging capability of PET and its high diagnostic quality and interpretive certainty is the correction of the emission images for photon attenuation. With stand-alone PET systems, transmission images are conventionally acquired with rotating radioactivity sources over several minutes and after merging with the emission image data, and are used for reconstruction of attenuation free emission images. With hybrid PET/ CT, CT images of the chest serve as anatomic maps of photon attenuation and become part of the image reconstruction algorithm. CT-based attenuation correction substantially shortens the study time, yet it is more than the standard transmission image approach susceptible to image misalignment and thus to image artifacts. Different from the standard transmission images, which are averaged over many respiratory and cardiac cycles and closely match the average anatomic outline of the heart, CT-based attenuation maps depend on respiratory and cardiac

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Fig. 16.2. Myocardial perfusion imaging with rubidium-82: Normal stress and rest perfusion images. Stress images are shown on top, rest images below. Courtesy of Marcelo Di Carli, MD, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

motion and frequently match the cardiac outline on the emission images only incompletely. Indeed, misregistration due to incomplete alignment may cause artifacts in a substantial fraction of cardiac PET images [8]. Hence, CT-based attenuation correction requires careful attention to assure adequate image alignment. Besides cardiac and respiratory motion, changes in patient position between attenuation and emission image acquisition are a second major source of misalignment. No uniformly accepted standardized approach for the acquisition of CT attenuation im-

ages has been established. Current CT image acquisition protocols range from cine-CT during normal breathing at rest to helical CT during end-expiration or during shallow breathing as well as to respirationaveraged CT. Some laboratories acquire several fast (snap-shot-like), low-power CT images and select the one for attenuation correction that best matches the emission images. Retrospective and prospective gated acquisition with radiation dose modulation has also been applied [9, 10]. Other laboratories employ slow CT attenuation scanning with shallow breathing for 19 s [11, 12]. Critical for developing

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Coronary Artery Disease

Fig. 16.3. Myocardial perfusion imaging with rubidium-82: Stress-induced perfusion defect in the territory of the left circumflex coronary artery as seen by the severe perfusion defect in the lateral and inferolateral wall on the stress images. The defect resolves almost completely on the rest images. Additionally, there is transient, stress-related dilation of the left ventricle. Courtesy of Marcelo Di Carli, MD, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

a standardized CT-attenuation protocol and its acceptance will be, besides performance, accuracy and robustness, the lowest possible radiation dose to the patient. Adequate alignment of the emission and attenuation images requires careful quality control with visual inspection of the reconstructed PET and CT image data (Fig. 16.4). If misaligned, the PET images are visually repositioned on the CT images, followed by repeat reconstruction of the raw image data [8]. Automated operator-independent realignment approaches are currently under development with the

aim of expediting image reconstruction and quality control as well as reducing the operator-dependent variability [13]. Image Display and Analysis: The transaxially acquired image data are reoriented in standard fashion into short, vertical and long axis images of the left ventricular myocardium. Aside from visual analysis, presence and location of flow defects and their extent and severity can be assessed semi-quantitatively with the now-standard 17-segment model (Figs. 16.5) [14, 15]. Segmental activity

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Fig. 16.4. Alignment of emission images with the CT attenuation map. Orthogonal views are shown with superimposed myocardial PET images on the CT images. The misalignment shown in the upper row causes artificial defects on the myocardial images that resolve after adequate realignment shown in the lower panel. Courtesy of Siemens Molecular Imaging

Fig. 16.5. Seventeen-segment model for grading segmental radiotracer concentrations in the left ventricular myocardium. Segments shown in green are subtended by the left anterior descending coronary artery, in blue by the left circumflex coronary artery and in yellow by the right coronary artery. Courtesy of P. Slomka, Cedars Sinai Medical Center, Los Angeles, CA

concentrations are scored on a 5-point scale where 0 is normal uptake, 1 mildly reduced but not definitely abnormal, 2 moderately reduced but defi nitely abnormal, 3 severely reduced and 4 absent radiotracer activity. The sum of all segmental scores reflects the summed score and is determined for both, the stress and rest perfusion images (SSS, summed stress score; SRS, summed rest scores). The difference in summed scores between stress and rest, the summed difference score (SDS), serves as a measure of the stress-induced defect extent and severity. For a more quantitative analysis of the relative distribution of myocardial blood flow, the short axis cuts are assembled into polar maps and compared to data bases of normal stress and rest perfusion polar maps [12]. The quantitative analysis approach delineates perfusion defects in percentage of the left ventricular myocardium or of the affected coronary territory. In addition to the extent, the polar map approach also provides an estimate of the maximum and average flow defect severity.

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Stress-rest imaging with stand-alone PET systems accurately identifies obstructive coronary artery disease. Compared to standard coronary angiography, obstructive coronary artery disease (defi ned as greater than 50% luminal narrowing) was identified with sensitivities ranging from 78% to 98% and specificities ranging from 78% to 100%, as reported in five investigations in a total of 488 patients [16–20]. Diagnostic accuracies range from 84% to 99% in these investigations with a weighted average of 89% (Fig. 16.6) [21]. One study employed angiographically derived estimates of the coronary flow reserve as a measure of the hemodynamic significance of coronary stenoses [22]. PET perfusion imaging correctly identified 94% of all vessels with angiographic flow reserves of less than three, but also detected perfusion defects in territories subtended by vessels with only mild impairments in flow reserve. The diagnostic accuracy was independent of the flow tracer used; no statistically significant differences in diagnostic accuracy were noted between N-13 ammonia and rubidium-82 [22]. Because patients are required to remain in the same position throughout the emission and transmission image acquisition and, further, because of the short physical half-life of the PET flow tracers, most investigations with PET perfusion imaging employed pharmacologic stress with either adenosine or dipyridamole. Both agents are equally effective in inducing maximum coronary vasodilation [23]. It is possible, however, to evaluate the distribution of myocardial blood flow also during exercise stress. N-13 ammonia or rubidium-82 is injected intravenously during the last 1.5 min of treadmill exercise; patients are immediately repositioned in the PET scanner, and image acquisition begins within 3 min after completion of the exercise [24, 25]. Comparison of the treadmill stress perfusion with the dipyridamole stress perfusion images indicated comparable diagnostic accuracies [24]. Of interest, though, symptom-limited treadmill stress induces larger and more severe perfusion defects than dipyridamole stress [25]. The greater defect size was attributed to pharmacokinetic properties unique to N-13 ammonia; a more likely reason is, however, that endothelial dysfunction combined with increased adrenergic activity during physical

stress accentuated the stenosis severity, as observed during coronary angiography [26], producing larger and more severe perfusion defects. Similar effects of treadmill exercise on stress defect size have also been observed with SPECT perfusion imaging in patients with documented endothelial dysfunction [27]. As an additional explanation, persistence of stress-induced wall motion impairment may have contributed further to the larger flow defects [28]. Exercise stress-induced defects may therefore more accurately reflect the myocardial ischemic burden of coronary artery disease. Information on the diagnostic performance of hybrid PET/CT stress-rest perfusion imaging remains currently limited, but is likely to be forthcoming in the near future. In an initial study in 64 consecutive patients with suspected coronary artery disease, PET/CT rubidium-82 stress perfusion imaging correctly identified in 41 of 44 patients the presence of obstructive coronary artery disease as defined by greater than 70% luminal narrowing on conventional coronary angiography [29]. Corresponding sensitivity and specificity values were 92% and 83%, respectively. Single- and multi-vessel disease was detected with similar sensitivities (92% and 95%); PET/CT rubidium-82 stress-rest perfusion images performed equally well in males and females as well as in obese (BMI ≥30kg/m2) and non-obese

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Fig. 16.6. Detection of coronary artery disease by PET stressrest myocardial perfusion imaging. The data shown represent weighted average values for 5 investigations in a total of 488 patients. Sens, sensitivity; Spec, specificity; PPV and NPV positive and negative predictive value; Accur diagnostic accuracy

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patients. While PET/CT perfusion imaging correctly ruled out coronary artery disease in patients with an only low pre-test likelihood of coronary artery disease (100% normalcy rate), it confi rmed the absence of disease in only 50% of patients with only mild disease on coronary angiography. The reasons for the unexpectedly low specificity remain uncertain, but may be related to technical limitations such as, for example, misregistration of emission and CT-based attenuation maps. It is also possible that “false-positive” flow defects reflected endothelium-dependent functional rather than structural alterations of the coronary arteries and thus did in fact reflect coronary artery disease. As is known from SPECT stress-rest perfusion imaging, standard PET imaging frequently underestimates the number of diseased coronary vessels or stenosis of the left main coronary artery. This is because the myocardial region with the highest radiotracer activity is usually considered as “normal” even when subtended by a coronary vessel with significant disease, though less in severe than in the other coronary arteries. However, the true extent of coronary artery disease can be delineated more accurately with quantitative flow measurements or assessments of vasodilator stress induced changes in left ventricular function [7, 30]. With quantitative flow estimates and threshold values for normal hyperemic flow responses to dipyridamole, apparently “normal” myocardial regions on the perfusion images were correctly identified as subtended by diseased coronary arteries because of attenuated flow responses [30]. Compared to standard qualitative stress-rest perfusion imaging that identified triple or left main disease in only 6 of 13 patients, quantitative flow estimates correctly identified 12 of 13 patients as having triple vessel or left main disease. Second, assessment of left ventricular function during stress can also aid in determining the extent of coronary artery disease. Pharmacological vasodilation in normal individuals induces an about 7% increase in the left ventricular ejection fraction [7]. Measuring the response of the left ventricular ejection fraction (defined as “left ventricular ejection fraction” reserve) from gated rubidium-82 perfusion images in 68 patients during dipyridamole stress, increases in ejection fraction were attenuated, though not significantly, in patients with single- or dual-vessel disease. The ejection fraction, however, failed to increase or even declined in patients with

triple-vessel or left-main disease [7]. In fact, the ejection fraction response was inversely correlated with the number of vessels diseased or, in turn, with the extent of stress-induced perfusion defects. Although the left ventricular ejection fraction reserve was of limited value in predicting the presence of multivessel disease, it ruled out its presence with 97% accuracy. Quantification of Myocardial Blood Flow: Measurements of myocardial blood flow in absolute units, especially of responses to pharmacologic vasodilator stress and sympathetic stimulation, expand the diagnostic potential of PET. In coronary artery disease, measurements of flow responses to pharmacologic vasodilation delineated more accurately than standard perfusion imaging the extent of coronary artery disease. As mentioned above, they more accurately identified patients as having multi-vessel or left main coronary artery disease than standard stress-rest perfusion imaging [30]. Further, because hyperemic flows and flow reserves progressively decline with increasing stenosis severity [31, 32], measurements of hyperemic myocardial blood flows offer information on fluid-dynamic consequences of coronary stenoses, thus on the functional implications of coronary artery disease and thus on the ischemic burden. Further, because the severity of a stenosis as a discreet narrowing of the vascular lumen is usually defined relative to the luminal area in immediately adjacent vessel segments, it may not fully reflect the true functional stenosis effect. For example, diffuse luminal narrowing of a coronary artery without a significant discreet stenosis markedly impairs high-velocity blood flows during pharmacologic stimulation and, accordingly, leads to a downstream perfusion defect without a true angiographic structural correlate [33]. As a consequence, myocardial perfusion, especially during hyperemia, progressively declines longitudinally in the base-to-apex direction and produces a perfusion gradient that can be identified through quantitative flow measurements [34, 35]. Finally, the effects of sympathetically mediated vasoconstriction, likely a consequence of endothelial dysfunction, in coronary artery disease patients during exercise can be measured in absolute units [26]. Even in angiographically normal or only mildly diseased coronary vessels, measurements of flow responses to vasodilator or sympathetic stress with, for example, cold pressor

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Prognostic Value of PET Stress-Rest Perfusion Imaging: Information on the prognostic value of PET stress-rest perfusion imaging is still limited, largely because only few institutions thus far offer PET or PET/CT stress-rest perfusion imaging as a fully implemented clinical service. In a study population of 685 patients with strongly suspected or documented coronary artery disease who were followed for an average time of 41 months, a normal rubidium-82 stress-rest perfusion study was associated with an average 0.9% annual mortality as compared to a significantly higher, 4.3% annual mortality in patients with a rest- and/or stress-induced defect [46]. In patients with a normal stress rest PET perfusion study, electrocardiographic ischemic changes during vasodilator stress did not contain predictive information [24]. Findings in a more recent investigation have emphasized the prognostic value of the summed stress score obtained with rubidium-82 PET dipyridamole stress-rest perfusion imaging [15]. In that study, 378 consecutive patients undergoing rubidium-82 PET stress rest perfusion imaging were followed for an average time of 3.1±0.9 years. Patients were grouped by the summed stress score

(SSS