Atlas of PET-CT : a Quick Guide to Image Interpretation. [2 ed.] 9783662577424, 3662577429


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Table of contents :
Contents
Contributors
Part I: Introduction
Chapter 1: Premises to PET/CT with FDG in Oncology
From the Monocular to the Binocular Vision, from Analogical to Digital Imaging: The Revolution of Hybrid Machines
PET/CT: The Radiologist Point of View
The Choice of Slice Number
CT Contrast Agents
Oral Contrast
Intravenous (IV) Contrast Agents
Contrast Enhancement of CT in PET/CT (PET-CECT)
F-18 Fluorodeoxyglucose (FDG)
Physiology and Pathophysiology of Glucose and FDG’s Biodistribution
FDG “Trapping”
Physiological and Para-Physiological Distribution of FDG
Pathophysiology of FDG Uptake in Cancer (and Benign Diseases)
FDG Uptake in Tumors
FDG’s Uptake in Benign Diseases (and Other Pitfalls)
PET/CT in Oncology
Pre-therapeutic Evaluation: Diagnosis and Staging
FDG Uptake as Guide to Biopsy and/or to Define the Target in Radiotherapy
FDG Uptake as Prognostic Indicator
Post-therapeutic Evaluation: Restaging
Response to Therapy
Usefulness of FDG in Benign Diseases
Differential Diagnosis with PET-FDG in Oncology
Dual-Time Imaging
Role of Quantification
Standardized Uptake Value (SUV)
Chapter 2: Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake in Malignant and Benign Diseases)
FDG Uptake in Tumors
FDG Uptake as Prognostic Indicator
FDG’s Uptake as Recurrence’s Identifier
FDG Uptake as Guide to Biopsy and/or to Define the Target in Radiotherapy
FDG Uptake Variation as an Early Marker of Response to Therapy
False-Positive Results Due to FDG Uptake in Benign Diseases
Usefulness of FDG in Benign Diseases
Differential Diagnosis Using PET-FDG in Oncology
Some Suggestions to Individuate Pitfalls and Artifacts, Avoiding Mistakes
Part II: FDG PET/CT in Oncology
Chapter 3: Malignancies in Hematology
Hodgkin’s and Non-Hodgkin’s Lymphomas
Myeloma
References
Chapter 4: Malignancies in Dermatology
Malignancies in Dermatology
Staging in the AJCC Stages (I and II)
Staging in the AJCC Stages (III and IV)
Recurrence
References
Chapter 5: Thoracic Malignancies
References
Chapter 6: Breast Cancer
References
Chapter 7: Head and Neck Malignancies
References
Chapter 8: Gynecological Malignancies
Ovarian Cancer
Endometrial Cancer
Cancer of the Uterine Cervix
References
Chapter 9: Malignancies of the Upper Gastrointestinal Tract
Esophageal Cancer
Gastric Cancer
Pancreatic Cancer
References
Chapter 10: Malignancies of Lower Gastroenterological Tract
Colorectal Cancer
References
Chapter 11: Urological Malignancies
Bladder Cancer
Testicular Cancer
Renal Clear Cell Carcinoma (RCC)
References
Chapter 12: Malignancy in Orthopedics
References
Chapter 13: Cancers of Unknown Origin
Cancer of Unknown Origin
References
Part III: FDG PET/CT in Non-oncological Diseases
Chapter 14: Infection and Inflammation
Fever of Unknown Origin
Vasculitis
Sarcoidosis
Rheumatoid Arthritis
Inflammatory Bowel Diseases (IBD)
Osteomyelitis
Fungal Infections
References
Chapter 15: Brain 18F-Fluorodeoxyglucose (FDG) PET
References
Recommend Papers

Atlas of PET-CT : a Quick Guide to Image Interpretation. [2 ed.]
 9783662577424, 3662577429

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Atlas of PET-CT A Quick Guide to Image Interpretation Stefano Fanti Mohsen Farsad Luigi Mansi Paolo Castellucci Second Edition

123

Stefano Fanti – Mohsen Farsad – Luigi Mansi – Paolo Castellucci Atlas of PET-CT

Stefano Fanti – Mohsen Farsad – Luigi Mansi – Paolo Castellucci

Atlas of PET-CT A Quick Guide to Image Interpretation Second Edition

Stefano Fanti Metropolitan Nuclear Medicine of Bologna University of Bologna Bologna, Italy Luigi Mansi Section Health and Development Interuniversity Research Center for Sustainability (CIRPS) Naples, Italy

Mohsen Farsad Nuclear Medicine Department Central Hospital Bolzano Bolzano, Italy Paolo Castellucci Metropolitan Nuclear Medicine AOU S.Orsola-Malpighi Hospital Bologna, Italy

ISBN 978-3-662-57740-0    ISBN 978-3-662-57742-4 (eBook) DOI 10.1007/978-3-662-57742-4 Library of Congress Control Number: 2018968534 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, 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. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

Contents

Part 1  Introduction Chapter 1  Premises to PET/CT with FDG in Oncology����������������������������������������������������  3 From the Monocular to the Binocular Vision, from Analogical to Digital Imaging: The Revolution of Hybrid Machines��������������������������������������������������������  4 PET/CT: The Radiologist Point of View ����������������������������������������������������������������������  5 F-18 Fluorodeoxyglucose (FDG)����������������������������������������������������������������������������������  7 Physiology and Pathophysiology of Glucose and FDG’s Biodistribution����������������������������������������������������������������������������������������������������������������������  8 Pathophysiology of FDG Uptake in Cancer (and Benign Diseases) ���������������� 10 PET/CT in Oncology ������������������������������������������������������������������������������������������������������ 12 Usefulness of FDG in Benign Diseases�������������������������������������������������������������������� 15 Differential Diagnosis with PET-FDG in Oncology���������������������������������������������� 16

Chapter 2 Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake in Malignant and Benign Diseases)���������������������������������������������������� 19 FDG Uptake in Tumors�������������������������������������������������������������������������������������������������� 22 FDG Uptake as Prognostic Indicator������������������������������������������������������������������������ 22 FDG’s Uptake as Recurrence’s Identifier������������������������������������������������������������������ 23 FDG Uptake as Guide to Biopsy and/or to define the Target in Radiotherapy �������������������������������������������������������������������������������������������������������������� 23 FDG Uptake Variation as an Early Marker of Response to Therapy���������������� 23 False-Positive Results Due to FDG Uptake in Benign Diseases ���������������������� 23 Usefulness of FDG in Benign Diseases�������������������������������������������������������������������� 24 Differential Diagnosis Using PET-FDG in Oncology�������������������������������������������� 24 Some Suggestions to individuate Pitfalls and Artifacts, Avoiding Mistakes ���������������������������������������������������������������������������������������������������������������������������� 24 Case 1: Normal Distribution of FDG�������������������������������������������������������������������������� 26 Case 2: Myocardial Uptake������������������������������������������������������������������������������������������ 27 Case 3: Cricoarytenoid Muscle ���������������������������������������������������������������������������������� 28 Case 4: Ocular Muscles�������������������������������������������������������������������������������������������������� 29 Case 5: Lingual Tonsils�������������������������������������������������������������������������������������������������� 30 Case 6: Salivary Gland and tonsils ���������������������������������������������������������������������������� 31 Case 7: Salivary Glands�������������������������������������������������������������������������������������������������� 32 Case 8: Great Vessels������������������������������������������������������������������������������������������������������ 33 Case 9: Spinal cord���������������������������������������������������������������������������������������������������������� 34 Case 10: Pulmonary Hilum������������������������������������������������������������������������������������������ 35 Case 11: Nipples�������������������������������������������������������������������������������������������������������������� 36 Case 12: Breasts �������������������������������������������������������������������������������������������������������������� 37 Case 13: Ureters�������������������������������������������������������������������������������������������������������������� 38

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Case 14: Ureters�������������������������������������������������������������������������������������������������������������� 39 Case 15: Testis������������������������������������������������������������������������������������������������������������������ 40 Case 16: Head and Neck—Granuloma�������������������������������������������������������������������� 41 Case 17: Head and Neck—Mucositis������������������������������������������������������������������������ 42 Case 18: Head and Neck—Thyroiditis���������������������������������������������������������������������� 43 Case 19: Thyroiditis—Pattern of FDG Uptake�������������������������������������������������������� 44 Case 20: Thyroid Goiter—Pattern of FDG Uptake������������������������������������������������ 45 Case 21: Head and Neck—Thyroid Nodule������������������������������������������������������������ 46 Case 22: Head and Neck—Flap Reconstructive Surgery ���������������������������������� 47 Case 23: Chest—Thymus���������������������������������������������������������������������������������������������� 48 Case 24: Chest—Ectopic Thymus������������������������������������������������������������������������������ 49 Case 25: Chest—Hiatal Hernia������������������������������������������������������������������������������������ 50 Case 26: Chest—Brown Fat����������������������������������������������������������������������������������������� 51 Case 27: Chest—Esophagitis�������������������������������������������������������������������������������������� 52 Case 28: Chest—Fracture�������������������������������������������������������������������������������������������� 53 Case 29: Chest—Fibroelastoma Dorsi���������������������������������������������������������������������� 54 Case 30: Chest—Talc������������������������������������������������������������������������������������������������������ 55 Case 31: Chest—Lipomatous Hypertrophy of Interatrial Septum ���������������� 56 Case 32: Chest—Silicon Granuloma������������������������������������������������������������������������ 57 Case 33: Abdomen—Gastritis������������������������������������������������������������������������������������ 58 Case 34: Abdomen—Post Surgery���������������������������������������������������������������������������� 59 Case 35: Abdomen—Post Surgery���������������������������������������������������������������������������� 60 Case 36: Abdomen—Focal Nodular Hyperplasia������������������������������������������������ 61 Case 37: Abdomen—Cholecystitis �������������������������������������������������������������������������� 62 Case 38: Abdomen—Diverticulitis���������������������������������������������������������������������������� 63 Case 39: Abdomen—Segmental Bowel FDG Uptake ���������������������������������������� 64 Case 40: Abdomen—Secondary Kidney Lesions ������������������������������������������������ 65 Case 41: Abdomen—Metformin Intake������������������������������������������������������������������ 66 Case 42: Pelvis—Hemorrhoids ���������������������������������������������������������������������������������� 67 Case 43: Pelvis—HIV Infection������������������������������������������������������������������������������������ 68 Case 44: Pelvis—Kidney Lesion���������������������������������������������������������������������������������� 69 Case 45: Pelvis—Bladder Diverticulum ������������������������������������������������������������������ 70 Case 46: Pelvis—Ovarian Cyst������������������������������������������������������������������������������������ 71 Case 47: Bone—Enchondroma���������������������������������������������������������������������������������� 72 Case 48: Bone—Tietze’s Syndrome�������������������������������������������������������������������������� 73

Part 2  FDG PET/CT in Oncology Chapter 3  Malignancies in Hematology������������������������������������������������������������������������������������ 77 Hodgkin’s and Non-Hodgkin’s Lymphomas���������������������������������������������������������� 78 Myeloma���������������������������������������������������������������������������������������������������������������������������� 78 References ������������������������������������������������������������������������������������������������������������������������ 78

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Case 1: HD Staging �������������������������������������������������������������������������������������������������������� 80 Case 2: HD Staging �������������������������������������������������������������������������������������������������������� 81 Case 3: HD Staging �������������������������������������������������������������������������������������������������������� 82 Case 4: NHL Staging������������������������������������������������������������������������������������������������������ 83 Case 5: NHL Staging������������������������������������������������������������������������������������������������������ 84 Case 6: NHL Staging������������������������������������������������������������������������������������������������������ 85 Case 7: Primary Cutaneous NHL—Staging������������������������������������������������������������ 86 Case 8: NHL Follicular—Staging�������������������������������������������������������������������������������� 87 Case 9: Histocytosis—Staging������������������������������������������������������������������������������������ 88 Case 10: NHL Indolent—Staging������������������������������������������������������������������������������ 89 Case 11: HD Staging and Early Therapy Evaluation�������������������������������������������� 90 Case 12: HD Staging and Therapy Evaluation ������������������������������������������������������ 91  ase 13: NHL Low-Grade Intestinal—Staging and Therapy C Evaluation�������������������������������������������������������������������������������������������������������������������������� 92 Case 14: HD Staging and Therapy Evaluation ������������������������������������������������������ 93  ase 15: NHL T cell—Staging and Early Evaluation of C Treatment�������������������������������������������������������������������������������������������������������������������������� 94 Case 16: NHL at 2. Relapse and After Treatment�������������������������������������������������� 95 Case 17: NHL at 1. Relapse and After Treatment ������������������������������������������������ 96 Case 18: NHL Evaluation at the End of Treatment ���������������������������������������������� 97 Case 19: NHL Recurrence Detection������������������������������������������������������������������������ 98 Case 20: Solitary Plasmacytoma�������������������������������������������������������������������������������� 99 Case 21: Multiple Myeloma—Staging �����������������������������������������������������������������  100 Case 22: Multiple Myeloma—Staging �����������������������������������������������������������������  101

Chapter 4  Malignancies in Dermatology�������������������������������������������������������������������������������   103 Malignancies in Dermatology���������������������������������������������������������������������������������  104 Staging in the AJCC Stages (I and II)���������������������������������������������������������������������  104 Staging in the AJCC Stages (III and IV)�����������������������������������������������������������������  104 Recurrence���������������������������������������������������������������������������������������������������������������������  104 References���������������������������������������������������������������������������������������������������������������������  104 Case 1: Melanoma Restaging�����������������������������������������������������������������������������������  105 Case 2: Melanoma Restaging After Local Treatment���������������������������������������  106 Case 3: Melanoma Restaging After Local Treatment���������������������������������������  107 Case 4: Melanoma Restaging�����������������������������������������������������������������������������������  108 Case 5: Melanoma Restaging After Immunotherapy �������������������������������������  109 Case 6: Melanoma Suspicion of Relapse�������������������������������������������������������������  111 Case 7: Melanoma Suspicion of Relapse�������������������������������������������������������������  112 Case 8: Melanoma Restaging�����������������������������������������������������������������������������������  113 Case 9: Melanoma After Surgery: Follow-Up Scan�������������������������������������������  114 Case 10: Melanoma Restaging After Primary Resection���������������������������������  115

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Chapter 5  Thoracic Malignancies ��������������������������������������������������������������������������������������������������������������������������������� 117 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 118 Case 1: Solitary Lung Nodule����������������������������������������������������������������������������������������������������������������������� 119 Case 2: Solitary Lung Nodule����������������������������������������������������������������������������������������������������������������������� 120 Case 3: Solitary Lung Nodule����������������������������������������������������������������������������������������������������������������������� 121 Case 4: Solitary Lung Nodule����������������������������������������������������������������������������������������������������������������������� 122 Case 5: Solitary Lung Nodule����������������������������������������������������������������������������������������������������������������������� 123 Case 6: Bilateral Lung Nodules ������������������������������������������������������������������������������������������������������������������� 124 Case 7: Lung Adenocarcinoma—Staging����������������������������������������������������������������������������������������������� 125 Case 8: Lung Adenocarcinoma—Staging����������������������������������������������������������������������������������������������� 126 Case 9: Lung Adenocarcinoma—Staging����������������������������������������������������������������������������������������������� 127 Case 10: Lung Adenocarcinoma—Staging��������������������������������������������������������������������������������������������� 128 Case 11: Lung Adenocarcinoma—Staging��������������������������������������������������������������������������������������������� 129 Case 12: Lung Adenocarcinoma—Staging��������������������������������������������������������������������������������������������� 130 Case 13: Pancoast Lung Cancer—Staging����������������������������������������������������������������������������������������������� 131 Case 14: Lung Adenocarcinoma—Staging��������������������������������������������������������������������������������������������� 132 Case 15: Mesothelioma—Staging������������������������������������������������������������������������������������������������������������� 133 Case 16: Mesothelioma—Staging������������������������������������������������������������������������������������������������������������� 134 Case 17: Peritoneal Mesothelioma—Staging����������������������������������������������������������������������������������������� 135 Case 18: Lung Adenocarcinoma—Radiation Treatment Planning������������������������������������������������� 136 Case 19: Mesothelioma—Staging and Early Evaluation of Treatment ����������������������������������������� 138 Case 20: Lung Adenocarcinoma—Chemotherapy Evaluation��������������������������������������������������������� 139 Case 21: Mesothelioma—Evaluation of Treatment����������������������������������������������������������������������������� 140 Case 22: Lung Adenocarcinoma—Restaging After Local Relapse Detection����������������������������� 141 Case 23: Lung Adenocarcinoma—Suspicion of Relapse������������������������������������������������������������������� 142 Case 24: Lung Metastasis ����������������������������������������������������������������������������������������������������������������������������� 143

Chapter 6  Breast Cancer��������������������������������������������������������������������������������������������������������������������������������������������������� 145 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 146 Case 1: Breast Cancer—Indeterminate Breast Lesion������������������������������������������������������������������������� 147 Case 2: Breast Cancer—Staging����������������������������������������������������������������������������������������������������������������� 148 Case 3: Breast Cancer—Staging����������������������������������������������������������������������������������������������������������������� 149 Case 4: Breast Cancer—Staging����������������������������������������������������������������������������������������������������������������� 150 Case 5: Breast Cancer—Staging����������������������������������������������������������������������������������������������������������������� 151 Case 6: Breast Cancer—Staging and Evaluation of Treatment��������������������������������������������������������� 153 Case 7: Breast Cancer—Staging and Evaluation of Treatment��������������������������������������������������������� 154 Case 8: Breast Cancer—Restaging After Radiation Treatment��������������������������������������������������������� 155 Case 9: Breast Cancer—Restaging������������������������������������������������������������������������������������������������������������� 156 Case 10: Breast Cancer—Restaging����������������������������������������������������������������������������������������������������������� 157 Case 11: Breast Cancer—Restaging����������������������������������������������������������������������������������������������������������� 158 Case 12: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 159

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Case 13: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 160 Case 14: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 161 Case 15: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 162 Case 16: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 163 Case 17: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 164 Case 18: Breast Cancer—Suspicion of Relapse������������������������������������������������������������������������������������� 165

Chapter 7  Head and Neck Malignancies ������������������������������������������������������������������������������������������������������������������� 167 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 169 Case 1: Rhinopharyngeal Carcinoma—Staging����������������������������������������������������������������������������������� 170 Case 2: Parotid Gland Tumor—Staging��������������������������������������������������������������������������������������������������� 171 Case 3: Medullary Thyroid Carcinoma—Staging ��������������������������������������������������������������������������������� 172 Case 4: Vocal Cord Carcinoma—Staging and Evaluation of Treatment ��������������������������������������� 173 Case 5: Laryngeal Carcinoma—Staging��������������������������������������������������������������������������������������������������� 174 Case 6: Hypopharynx Carcinoma—Staging������������������������������������������������������������������������������������������� 175 Case 7: Oropharyngeal Carcinoma—Staging ��������������������������������������������������������������������������������������� 176 Case 8: Hypopharynx Carcinoma—Staging������������������������������������������������������������������������������������������� 178 Case 9: Pharynx Carcinoma—Staging ����������������������������������������������������������������������������������������������������� 179 Case 10: Hypopharynx Carcinoma—Post Radiation Evaluation����������������������������������������������������� 181 Case 11: Thyroid Lymphoma—Pattern of FDG Uptake����������������������������������������������������������������������� 183 Case 12: Thyroid Carcinoma—Staging and Restaging After Surgery ������������������������������������������� 184 Case 13: Laryngeal Carcinoma—Restaging������������������������������������������������������������������������������������������� 185 Case 14: Thyroid Carcinoma—Detection of Recurrence ������������������������������������������������������������������� 186 Case 15: Thyroid Carcinoma—Detection of Recurrence ������������������������������������������������������������������� 187 Case 16: Thyroid Carcinoma—Detection of Recurrence ������������������������������������������������������������������� 188 Case 17: Thyroid Carcinoma—Detection of Recurrence ������������������������������������������������������������������� 189 Case 18: Thyroid Carcinoma—Detection of Recurrence ������������������������������������������������������������������� 190 Case 19: Adenoid Cystic Carcinoma of Parotid Gland—Suspicion of Recurrence��������������������� 191

Chapter 8  Gynecological Malignancies ��������������������������������������������������������������������������������������������������������������������� 193 Ovarian Cancer������������������������������������������������������������������������������������������������������������������������������������������������� 195 Endometrial Cancer ��������������������������������������������������������������������������������������������������������������������������������������� 195 Cancer of the Uterine Cervix����������������������������������������������������������������������������������������������������������������������� 196 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 196 Case 1: Cervical Carcinoma—Staging������������������������������������������������������������������������������������������������������� 198 Case 2: Cervical Carcinoma—Staging������������������������������������������������������������������������������������������������������� 199 Case 3: Cervical Carcinoma—Staging������������������������������������������������������������������������������������������������������� 200 Case 4: Cervical Carcinoma—Staging������������������������������������������������������������������������������������������������������� 201 Case 5: Cervical Carcinoma—Restaging ������������������������������������������������������������������������������������������������� 202 Case 6: Cervical Cancer at Follow-Up������������������������������������������������������������������������������������������������������� 203 Case 7: Cervical Carcinoma—Restaging ������������������������������������������������������������������������������������������������� 204

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Case 8: Cervical Carcinoma—Restaging ������������������������������������������������������������������������������������������������� 205 Case 9: Cervical Cancer After Bilateral Istero Annessectomy����������������������������������������������������������� 206 Case 10: Endometrial Carcinoma—Staging and Evaluation of Treatment����������������������������������� 207 Case 11: Adnexal Mass—Metabolic Characterization������������������������������������������������������������������������� 208 Case 12: Pelvic Mass—Metabolic Characterization����������������������������������������������������������������������������� 209 Case 13: Adnexal Lesion—Incidental Finding��������������������������������������������������������������������������������������� 210 Case 14: Ovarian Carcinoma—Staging ��������������������������������������������������������������������������������������������������� 211 Case 15: Ovarian Carcinoma—Staging ��������������������������������������������������������������������������������������������������� 212 Case 16: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 213 Case 17: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 214 Case 18: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 215 Case 19: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 216 Case 20: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 217 Case 21: Ovarian Cancer: Detection of Recurrence����������������������������������������������������������������������������� 218 Case 22: Ovarian Carcinoma—Detection of Recurrence������������������������������������������������������������������� 219 Case 23: Peritoneal Carcinomatosis—Patterns of FDG Uptake������������������������������������������������������� 221

Chapter 9  Malignancies of the Upper Gastrointestinal Tract ��������������������������������������������������������������������������������223 Esophageal Cancer����������������������������������������������������������������������������������������������������������������������������������������� 225 Gastric Cancer��������������������������������������������������������������������������������������������������������������������������������������������������� 225 Pancreatic Cancer ������������������������������������������������������������������������������������������������������������������������������������������� 226 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 227 Case 1: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 230 Case 2: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 231 Case 3: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 232 Case 4: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 233 Case 5: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 234 Case 6: Esophageal Carcinoma—Staging����������������������������������������������������������������������������������������������� 235 Case 7: Esophageal Carcinoma—Staging and Evaluation of Neoadjuvant Therapy ��������������� 236 Case 8: Esophageal Carcinoma—Suspicion of Recurrence��������������������������������������������������������������� 237 Case 9: Gastric Carcinoma—Staging��������������������������������������������������������������������������������������������������������� 238 Case 10: Gastric Carcinoma—Staging and Evaluation of Neoadjuvant Therapy����������������������� 239 Case 11: Gastric Carcinoma—Staging and Evaluation of Neoadjuvant Therapy����������������������� 240 Case 12: Gastric Carcinoma—Suspicion of Recurrence��������������������������������������������������������������������� 241 Case 13: Gastric Carcinoma—Detection of Recurrence��������������������������������������������������������������������� 242 Case 14: Gastric Carcinoma—Suspicion of Recurrence��������������������������������������������������������������������� 243 Case 15: Gastric Carcinoma—Suspicion of Recurrence��������������������������������������������������������������������� 244 Case 16: Gastric NHL—Staging������������������������������������������������������������������������������������������������������������������� 245 Case 17: GIST—Staging��������������������������������������������������������������������������������������������������������������������������������� 246 Case 18: GIST—Staging��������������������������������������������������������������������������������������������������������������������������������� 247 Case 19: GIST—Early Evaluation of Treatment��������������������������������������������������������������������������������������� 248

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Case 20: GIST—Staging and Evaluation of Treatment������������������������������������������������������������������������� 249 Case 21: GIST—Staging and Evaluation of Treatment������������������������������������������������������������������������� 250 Case 22: Pancreatic Lesion—Metabolic Characterization����������������������������������������������������������������� 251 Case 23: Pancreatic Lesion—Metabolic Characterization����������������������������������������������������������������� 252 Case 24: Pancreatic Lesion—Metabolic Characterization����������������������������������������������������������������� 253 Case 25: Pancreatic Carcinoma—Suspicion of Recurrence��������������������������������������������������������������� 254 Case 26: Pancreatic Carcinoma—Suspicion of Recurrence��������������������������������������������������������������� 255 Case 27: Neuroendocrine Pancreatic Tumor—Suspicion of Recurrence ������������������������������������� 256 Case 28: Cholangiocarcinoma—Suspicion of Recurrence����������������������������������������������������������������� 257 Case 29: Hepatocarcinoma—Staging������������������������������������������������������������������������������������������������������� 258

Chapter 10  Malignancies of Lower Gastroenterological Tract ��������������������������������������������������������������������������������259 Colorectal Cancer��������������������������������������������������������������������������������������������������������������������������������������������� 261 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 261 Case 1: Colon Carcinoma—Staging����������������������������������������������������������������������������������������������������������� 263 Case 2: Colon Carcinoma—Staging����������������������������������������������������������������������������������������������������������� 264 Case 3: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 265 Case 4: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 266 Case 5: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 267 Case 6: ColoRectal Carcinoma—Staging������������������������������������������������������������������������������������������������� 268 Case 7: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 269 Case 8: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 270 Case 9: Rectal Carcinoma—Staging ��������������������������������������������������������������������������������������������������������� 271 Case 10: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 272 Case 11: ColoRectal Carcinoma—Suspicion of Recurrence ������������������������������������������������������������� 273 Case 12: ColoRectal Carcinoma—Suspicion of Recurrence ������������������������������������������������������������� 274 Case 13: Rectal Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 275 Case 14: Carcinoma of the Left Colon—Suspicion of Recurrence��������������������������������������������������� 276 Case 15: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 277 Case 16: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 278 Case 17: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 279 Case 18: Colon Carcinoma—Restaging��������������������������������������������������������������������������������������������������� 280 Case 19: Rectal Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 281 Case 20: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 282 Case 21: Rectal Carcinoma—Restaging After Detection of Local Relapse����������������������������������� 283 Case 22: Colon Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 284 Case 23: Rectal Carcinoma—Suspicion of Local Relapse������������������������������������������������������������������� 285 Case 24: Colon Carcinoma—Restaging��������������������������������������������������������������������������������������������������� 286 Case 25: Rectal Carcinoma—Staging and Evaluation of Therapy��������������������������������������������������� 287 Case 26: Colon Carcinoma—Restaging and Evaluation of Therapy����������������������������������������������� 288 Case 27: Anus Region—Pattern of FDG Uptake ����������������������������������������������������������������������������������� 289 Case 28: Anus Carcinoma—Staging��������������������������������������������������������������������������������������������������������� 290

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Contents

Chapter 11  Urological Malignancies ����������������������������������������������������������������������������������������������������������������������������� 291 Bladder Cancer������������������������������������������������������������������������������������������������������������������������������������������������� 292 Testicular Cancer ��������������������������������������������������������������������������������������������������������������������������������������������� 292 Renal Clear Cell Carcinoma (RCC)��������������������������������������������������������������������������������������������������������������� 292 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 293 Case 1: Renal Cell Carcinoma—Staging��������������������������������������������������������������������������������������������������� 294 Case 2: Clear Cell Renal Carcinoma—Suspicion of Recurrence������������������������������������������������������� 295 Case 3: Germ Cell Tumor—Restaging������������������������������������������������������������������������������������������������������� 296 Case 4: Renal Cell Carcinoma—Restaging ��������������������������������������������������������������������������������������������� 297 Case 5: Renal Cell Carcinoma—Restaging and Evaluation of Therapy����������������������������������������� 298 Case 6: Bladder Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 299 Case 7: Bladder Carcinoma—Restaging and Evaluation of Treatment����������������������������������������� 300 Case 8: Bladder Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 301 Case 9: Bladder Carcinoma—Suspicion of Recurrence����������������������������������������������������������������������� 302 Case 10: Bladder Carcinoma—Suspicion of Recurrence ������������������������������������������������������������������� 303

Chapter 12  Malignancy in Orthopedics����������������������������������������������������������������������������������������������������������������������� 305 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 306 Case 1: Osteosarcoma Staging ������������������������������������������������������������������������������������������������������������������� 307 Case 2: Synovial Sarcoma����������������������������������������������������������������������������������������������������������������������������� 308 Case 3: Osteosarcoma ����������������������������������������������������������������������������������������������������������������������������������� 309 Case 4: Soft Tissue Sarcoma������������������������������������������������������������������������������������������������������������������������� 310 Case 5: Osteosarcoma—Restaging����������������������������������������������������������������������������������������������������������� 311 Case 6: Ewing Sarcoma—Evaluation of Therapy����������������������������������������������������������������������������������� 312 Case 7: Bone Metastasis from Lung Cancer ������������������������������������������������������������������������������������������� 313 Case 8: Bone Metastasis from Breast Cancer ����������������������������������������������������������������������������������������� 314 Case 9: Bone Metastasis from Clear Cell Renal Cancer����������������������������������������������������������������������� 315 Case 10: Paget Disease����������������������������������������������������������������������������������������������������������������������������������� 316 Case 11: Paget Disease����������������������������������������������������������������������������������������������������������������������������������� 317 Case 12: Post Surgical Artefacts ����������������������������������������������������������������������������������������������������������������� 318

Chapter 13  Cancers of Unknown Origin����������������������������������������������������������������������������������������������������������������������������319 Cancer of Unknown Origin��������������������������������������������������������������������������������������������������������������������������� 320 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 320 Case 1: Head and Neck Cancer������������������������������������������������������������������������������������������������������������������� 322 Case 2: Head and Neck Cancer������������������������������������������������������������������������������������������������������������������� 323 Case 3: Head and Neck Cancer������������������������������������������������������������������������������������������������������������������� 324 Case 4: Head and Neck Cancer������������������������������������������������������������������������������������������������������������������� 325 Case 5: Small-Bowel Malignancy ��������������������������������������������������������������������������������������������������������������� 326 Case 6: Sigmoid Carcinoma������������������������������������������������������������������������������������������������������������������������� 327 Case 7: Peritoneal Carcinomatosis������������������������������������������������������������������������������������������������������������� 328

Contents

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Part 3  FDG PET/CT in Non Oncological Diseases Chapter 14  Infection and Inflammation����������������������������������������������������������������������������������������������������������������������� 331 Fever of Unknown Origin����������������������������������������������������������������������������������������������������������������������������� 332 Vasculitis������������������������������������������������������������������������������������������������������������������������������������������������������������� 332 Sarcoidosis��������������������������������������������������������������������������������������������������������������������������������������������������������� 332 Rheumatoid Arthritis������������������������������������������������������������������������������������������������������������������������������������� 332 Inflammatory Bowel Diseases (IBD)����������������������������������������������������������������������������������������������������������� 332 Osteomyelitis���������������������������������������������������������������������������������������������������������������������������������������������������� 332 Fungal Infections��������������������������������������������������������������������������������������������������������������������������������������������� 333 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 333 Case 1: Fever of Unknown Origin��������������������������������������������������������������������������������������������������������������� 334 Case 2: Fever of Unknown Origin��������������������������������������������������������������������������������������������������������������� 335 Case 3: Fever of Unknown Origin��������������������������������������������������������������������������������������������������������������� 336 Case 4: Large-Vessel Vasculitis—Clinical Suspicion����������������������������������������������������������������������������� 337 Case 5: Large-Vessel Vasculitis—Clinical Suspicion����������������������������������������������������������������������������� 338 Case 6: Bone Infection—Clinical Suspicion ������������������������������������������������������������������������������������������� 339 Case 7: Vascular Prosthesis Infection—Clinical Suspicion����������������������������������������������������������������� 340 Case 8: Polymyalgia Rheumatica (PMR)—Clinical Suspicion ����������������������������������������������������������� 341 Case 9: Large-Vessel Vasculitis—Pre- and Posttreatment����������������������������������������������������������������� 342 Case 10: Sarcoidosis—Clinical Suspicion������������������������������������������������������������������������������������������������� 343 Case 11: Sarcoidosis—Staging ������������������������������������������������������������������������������������������������������������������� 344 Case 12: Sarcoidosis—Staging ������������������������������������������������������������������������������������������������������������������� 345 Case 13: Sarcoidosis—Pre- and Posttreatment������������������������������������������������������������������������������������� 346

Chapter 15  Brain 18F-Fluorodeoxyglucose (FDG) PET��������������������������������������������������������������������������������������������������347 References��������������������������������������������������������������������������������������������������������������������������������������������������������� 349 Case 1: Mild Cognitive Impairment—Alzheimer’s Disease��������������������������������������������������������������� 350 Case 2: Mild Cognitive Impairment—Depression ������������������������������������������������������������������������������� 351 Case 3: Motion Artifact����������������������������������������������������������������������������������������������������������������������������������� 352 Case 4: Mild Cognitive Impairment—Alzheimer’s Disease��������������������������������������������������������������� 353 Case 5: Alzheimer’s Disease—Early Onset���������������������������������������������������������������������������������������������� 354 Case 6: Frontotemporal Dementia—Behavioral Variant ������������������������������������������������������������������� 355 Case 7: Frontotemporal Dementia—Behavioral Variant ������������������������������������������������������������������� 356 Case 8: Alzheimer’s Disease������������������������������������������������������������������������������������������������������������������������� 357 Case 9: Lewy Body Dementia����������������������������������������������������������������������������������������������������������������������� 358 Case 10: Cortico-Basal Degeneration/Syndrome��������������������������������������������������������������������������������� 359 Case 11: Progressive Supranuclear Palsy (PSP) ������������������������������������������������������������������������������������� 360 Case 12: Primary Progressive Aphasia—Logopenic Aphasia����������������������������������������������������������� 361 Case 13: Primary Progressive Aphasia—Semantic Dementia���������������������������������������������������������� 362 Case 14: Primary Progressive Aphasia—Progressive Nonfluent Aphasia������������������������������������� 363 Case 15: Epilepsy—Interictal����������������������������������������������������������������������������������������������������������������������� 364 Case 16: Epilepsy—Ictal��������������������������������������������������������������������������������������������������������������������������������� 365

Contributors

Fabrizio Calliada,  Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy Vincenzo  Cuccurullo, Nuclear Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy Giuseppe Danilo Di Stasio,  Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy Irina  Manea, Research and Development Department, Colentina Clinical Hospital, Bucharest, Romania Silvia  Morbelli, Nuclear Medicine Unit, Department of Health Sciences, IRCCS AOU San Martino – IST, University of Genoa, Genoa, Italy Agnese  Picco, Clinical Neurophysiology, Department of Neurosciences, Ophthalmology and Genetics, IRCCS AOU San Martino – IST, University of Genoa, Genoa, Italy

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Part I Introduction

Chapter 1

Premises to PET/CT with FDG in Oncology  rom the Monocular to the Binocular Vision, F from Analogical to Digital Imaging: The Revolution of Hybrid Machines  ������������������������   4 PET/CT: The Radiologist Point of View  ��������������������   5 F-18 Fluorodeoxyglucose (FDG)  �������������������������������   7 Physiology and Pathophysiology of Glucose and FDG’s Biodistribution  ���������������������   8  athophysiology of FDG Uptake P in Cancer (and Benign Diseases)  �����������������������������   10 PET/CT in Oncology  ��������������������������������������������������   12 Usefulness of FDG in Benign Diseases  ������������������   15  ifferential Diagnosis with PET-FDG D in Oncology  ����������������������������������������������������������������   16

© Springer-Verlag GmbH Germany, part of Springer Nature 2018 S. Fanti et al., Atlas of PET-CT, https://doi/org/10.1007/978-3-662-57742-4_1

1

Premises to PET/CT with FDG in Oncology

hybrid systems which have further increased quality and wideness of results achievable with hybrid machines. Using these new tools an information containing the sum of advantages and the subtraction of disadvantages of the single procedures taken alone has become available, allowing a significantly higher diagnostic accuracy: furthermore, new capabilities, From the Monocular to the Binocular as the definition of “viable” tumor target in radioVision, from Analogical to Digital therapy or a guided biopsy directed to the most Imaging: The Revolution of Hybrid malignant part of the neoplasm, have become feasiMachines ble. Referring the readers to other texts for indicaThe twentieth-century diagnostic imaging scenario tions and information achievable by SPECT/CT and has been based for almost its entire duration on two PET/MRI, we will discuss in this Atlas exclusively separate universes: (1) the morphostructural, PET/CT with FDG. In the last few years, PET stand-alone is almost where information on anatomy and structures is acquired, having pathology as gold standard, and completely disappeared. It has been demonstrated (2) the functional, where normal and altered func- beyond any reasonable doubt the absolute superiortions are analyzed, with pathophysiology as refer- ity of hybrid machines with respect to PET scanners alone, widely justifying their higher cost. Today the ence individuating disease. In the “old medicine” these universes are sepa- achievement of functional PET images nonimplerately observed, as in a monocular vision having mented by CT contribution may be considered the capability to see only half of the whole view; unethical and no more cost effective. Using hybrid tools, a major improvement with therefore, using a single eye, an incomplete information is achievable. To overcome this handicap, respect to individual nuclear medicine’s machines the traditional diagnostic imaging may comple- has been reached in a higher precise anatomical ment individual images, acquired at different times, accuracy of fused image (with an error averaging through a visual comparison; but this approach is 1 mm with respect to 1 cm, typically present when affected by many limitations, mainly due to a sub- using a software-based fusion approach); this upgrading is obtained because the two studies are jective analysis. In the last decades the development of technol- (almost) simultaneously acquired, with the patient ogy and computers determined a revolution that immobile on the same bed. Moreover, a measured killed the analogical imaging, creating a new world attenuation correction, and therefore a more accuonly occupied by digital data. In this scenario, a rate quantitative analysis, may be calculated with major improvement has been obtained with the so-­ the coupled CT.  All these advantages are obtained called fusion imaging, based on the overlap of digital with a faster duration of the diagnostic course, scans acquired, at the beginning separately, by dif- allowing an earlier diagnosis and lower costs of the ferent techniques. As the main consequence, over- whole clinical track. It has to be pointed out that some minor technilapping PET or SPECT scans on digital spatially coincident data, obtained with CT or MRI, it has cal problems continue to exist also using hybrid been possible to produce new implemented images machines, mainly due to differences in acquisition’s containing either the morphostructural or the func- time and spatial resolution between CT and nuclear medicine (NM) techniques; nevertheless, many tional content. An even greater revolution has been determined solutions, as the respiratory gating, are already in when hybrid tools, containing in the same gantry a the clinical practice and many implementations are PET or a SPECT machine coupled with a CT scan- arriving to further improve the whole system in ner, have been produced and commercialized. More optimizing the final result. Significant progresses recently, a further technological improvement has have been obtained either in hardware and software, been obtained with the construction of PET/MRI permitting a more rigorous correction of problems, In this second edition of this Atlas, firstly published in 2009, the introductory chapter has been partially rewritten to better understand the new scenario designed by technological and cultural changes appeared in the last few years.

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such as those determined by scatter and random radiations, field’s inhomogeneities, a too slow time of PET scanning, and so on. Actual PET machines are highly performing, showing a significantly higher sensitivity and spatial resolution with respect to the past. Concerning hardware components, an important evolution has been determined by the introduction of time-of-flight (TOF) systems, which allow improved performances and faster scans, with a better contrast, more evident in obese patients, because of a higher signal-to-noise ratio, furthermore more homogeneous in the whole field of view. A more recent improvement may be connected with the commercial diffusion of completely digitalized PET systems, allowing the achievement of previously unreachable performances. In parallel with technological evolution of PET scanners, innovative solutions have also been introduced in the CT component, actually allowing not only better performances, but also a reduced radiation charge to the patients. Finally, with respect to 2009, when the first edition of this Atlas was published, a further major change occurred at cultural level. In the last few years the professional lecture of the fused image has changed because of the greater relevance associated with the evaluation of its morphostructural content. In other words, while previously CT was mainly utilized to localize pathological uptake seen by PET or to better understand the anatomical context, today it is a fundamental part of the diagnostic information, the morphostructural content being considered essential as the functional data in acquiring the final diagnosis. The CT’s contribution is further increased when contrast media are used to improve diagnostic accuracy. As a consequence, the “professional” interpreter of fused image is no more a nuclear physician educated with only a basic knowledge of anatomy and pathology, but an expert lecturer of CT scans, having the capability to recognize pathological data also in the absence of an increased uptake at PET. The next step, already actively operating in many institutions, is connected with a further evolution in which nuclear physician and radiologist will act together in a single practitioner having the capability to extract the whole content of the fused image by alone. This new “diagnostic imager” must have the competence to see and

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understand either morphostructural or functional data. In this way we will reach a goal where the final result will be no more the sum of two images, but a new image with an implemented content, which may give the opportunity to significantly improve the accuracy in all the fields where diagnostic imaging is a fundamental part of the clinical course. Therefore, with respect to the first edition, this widely renewed publication wants to improve and stimulate the readers not only in individuating all the incredible wealth of knowledge contained in a PET image, but also in significantly enriching their ability to understand and productively interpret CT images.

PET/CT: The Radiologist Point of View The understanding by a nuclear physician of the CT’s role in the combined PET/CT system requires the knowledge of facts about CT technology and CT contrast media.

T he Choice of Slice Number The choice of slice number should really be considered a “nonproblem” matter in an oncologic field. Even an old and simple four-slice CT is able to perform a whole-body examination in an acceptable time allowing the study of every portion of the body with the appropriate timeframe. Increasing the number of slices reduces, of course, the examination time but the diagnostic improvement is especially evident in vascular studies and 64 or more slices are really mandatory only for cardiac exams. For this reason, 8- or 16-slice machines should be considered absolutely adequate for a PET/CT scanner if heart studies are not planned.

C T Contrast Agents To perform a correct diagnostic CT examination, it is necessary to have a good knowledge of main issues concerning contrast agents. Essentially there are two different kinds of contrast: oral contrast and intravenous contrast.

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Oral Contrast

If your CT experience is outperforming probably oral contrast is unnecessary; otherwise oral contrast allows to easily distinguish bowel loops from lymph nodes or other normal and abnormal abdominal structures. It is possible to choose between positive and neutral endo-luminal contrast agents. (a) Positive contrasts are barium sulfate − 1.5 g/100 mL −1000 cc, meglumine diatrizoate −3%–1000 cc. Positive contrast agents allow better delineation of gastrointestinal tract organs from their surrounding structures, but exhibit potential PET attenuation artifacts. (b) Neutral oral contrasts are water or low-­density barium sulfate suspension; they are less evident than positive contrast agents, but exhibit some important advantages: better delineation of the gastrointestinal tract mucosa and intravenous contrast mucosal enhancement (normally obscured by positive oral contrast), without potential PET/CT attenuation artifacts. Which neutral contrast would be more useful? Water is cheap, but quickly absorbed and only good for stomach and proximal small bowel. Lowdensity barium sulfate suspension is more expensive, but allows better distension of small/ large bowel. Intravenous (IV) Contrast Agents

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Intravenous contrast agents allow better anatomic detail, delineate vascular structures, and improve overall CT contrast. Iodine is a temporal and spatial variable introduced in the vascular circulation, allowing better pathophysiological evaluation of the entire body. It permits to study tissue enhancement patterns with improved diagnostic accuracy and confidence, by supporting lesion detection and characterization, especially in tumors with only mild or absent increase in FDG’s uptake. Furthermore, a separate “diagnostic” contrast-­ enhanced CT (CECT) scan is not required, with a consequent reduced radiation dose to the patient. IV iodine contrast agents are different in concentration and iodine content; with multiple options being available, different protocols beforehand have to be chosen. Iodine’s content is variable from 200 to 400 mg/mL. Higher concentrations (350–400) are suitable for abdomi-

nal (especially liver) or vascular studies; lower concentrations (300) are used in lung parenchymal exams. (a) Protocols: Specific organs and whole body protocols are partially dependent on the used scanner and a complete explanation of the matter is out of the aims of this chapter. (b) Iodine pharmacokinetic: Iodine performs as macro- and microvascular enhancer during the first minutes after the IV injection, allowing an easy recognition of normal and abnormal vascularization patterns of organs and tissues. Minimal dimensions of iodine contrast agents determine also some other kinds of different behaviors. The agent is filtered by kidneys and excreted with urine in the excretory system few minutes after the injection; the agent is also extracted by hepatocytes and excreted with the bile up to many hours after the administration. A consistent portion of iodine contrast agent leaves the vessels throw the spaces between the endothelial cells, determining a late interstitial extravascular enhancement.

 ontrast Enhancement of CT in PET/CT C (PET-CECT) The CT part of the combined PET/CT imaging is often applied as a whole-body low-dose scan without application of IV contrast agent (PET-LDCT); this approach is primarily utilized for attenuation correction and for anatomic localization of tracer’s uptake in PET. However, in some clinical conditions the contrast enhancement of CT in PET/CT (PET-­ CECT) may be added to increase diagnostic accuracy and certainty. The optimal PET-CECT scanning protocol is still a point of debate. If you plan to use intravenous contrast agents, the injection can be performed in a single-step procedure, during the acquisition of whole-body CT data used for attenuation correction, or in a two-step approach, after completion of the whole-body low-dose CT and PET data acquisition. The latter approach may be preferred, because a multiphase contrast-enhanced CT can be acquired in the region of interest, avoiding unnecessary radiation exposure if the standard PET/CT procedure,

Premises to PET/CT with FDG in Oncology

performed with a low-dose CT (PET-LDCT), doesn’t show any pathologic or doubtful finding or if it identifies a systemic disease. The benefit of PET-CECT compared to PET-­ LDCT is more pronounced in those diseases in which a surgical intervention or a radiation therapy, as single therapeutic approach, is the most commonly used treatment. It has already been shown that combined PET-CECT is the best available diagnostic modality for staging of patients with localized central bronchial tumors. PET imaging warrants a high sensitivity for detection of distant metastases and CECT allows the exact delineation of mediastinal and chest wall invasion by the primary tumor as well as the exact demarcation of involved juxtaposed lymph nodes and vessels. Comprehensive information regarding tumor delineation is a precondition for planning both a radiotherapeutic treatment and surgical treatments. This procedure manifests a clear benefit, including changes in management as well as in diagnostic confidence. PET imaging’s results can be optimized if doubtful findings are judged on the basis of a CECT assessment. This is particularly true when an area of focal increased uptake cannot be attributed univocally to an anatomical structure only on the basis of low-dose CT (as it may happen in pancreatic malignancies or in benign duodenum inflammatory lesions); similarly, a significant improvement is achieved when a lesion shows only a mild or absent FDG’s uptake. In these cases, a CECT on the region of interest allows lesion’s detection and characterization. A full-dose contrast-enhanced CT should also be performed if small lesions in the liver or spleen are suspected by US and no pathologic findings are identified by PET-LDCT. The lack of sensitivity in detection of such small lesions by PET-LDCT could be due to its lower contrast resolution compared to full-dose CECT. As negative counterpart, a fully diagnostic PET-­ CECT examination results in an increased radiation dose compared to a standard PET-LDCT examination. Therefore, patient referral for PET-CECT studies should be justified in each case to avoid repeated exposures or overexposures. A PET-CECT scanning should be avoided in patients primarily under consideration for systemic therapy, in individuals with recently performed state-of-the-art

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whole-body CT and in subjects referred for therapy monitoring. When the use of an intravenous contrast is planned, a further disadvantage connected with CECT is determined by the need of the onsite presence of a physician, for monitoring and dealing with potential allergic reactions/extravasations. Before the injection it is mandatory to be aware of IV contrast contraindications, as poor renal function, myeloma, diabetes, and so on. In particular, it is obligatory to pre-assess the renal function. Oral contrast is strongly suggested when a correct diagnostic examination in patients with pelvic or abdominal cancers or in patients with suspected peritoneal metastases is requested. Oral contrast allows to better delineate gastrointestinal organs from surrounding structures, improving diagnostic accuracy and confidence. When planning the use of oral contrast, the patient needs to arrive earlier with respect to the scan time’s schedule: contrast drinking starts 90  min before the study, 1 cup every 25  min, and it is important to monitor drinking timetable. To obtain an optimal contrast also in the stomach, a last cup of contrast solution is swallowed just before patient’s positioning on the table. Oral contrast media should be omitted when PET/CT imaging is used for radiotherapy planning, because of interference with densitometry in the field of radiation.

F-18 Fluorodeoxyglucose (FDG) Although partially reduced in percentage with respect to few years ago, because of introduction and diffusion in the clinical practice of a growing number of other radiotracers labeled with positron emitters, F-18 fluorodeoxyglucose (FDG) still remains the most utilized radiopharmaceutical for PET.  Today more than 90% of PET procedures worldwide are performed with FDG, mostly used for oncologic indications, although its clinical use is becoming more diffuse in evaluating other pathological conditions such as neuropsychiatric and cardiovascular diseases, inflammation, and infection. This dominance is dependent at first by practical reasons: Fluorine 18 is one of the four most important positron emitters, easily produced by “standard” cyclotrons, with the capability to radiolabel relevant biological molecules. Because of the

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favorable half-life (110 min) with respect to shorter lived C-11, N-13, and O-15, F-18 is the only one in this series that can be distributed without difficulty also to PET centers nonequipped with cyclotrons. Therefore, it can be used in a wider geographic area covering, in more developed countries, all the national territory. From the chemical point of view, fluorine is a halogen allowing a very stable binding nonaffecting the functional part of the molecule. But the real “absolute” value of F-18 is derived by its capability to radiolabel deoxy-glucose-producing FDG, i.e., the glucose’s tracer.

Physiology and Pathophysiology of Glucose and FDG’s Biodistribution

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Glucose is an essential biomolecule in living organisms, being the most important carbon supplier in energy-producing metabolic processes, depending largely on its availability. At cerebral level it is the only source of energy. For a correct reading of PET-FDG images, based on the interpretation of all the involved molecular events, we have at first to analyze the normal glucose distribution, starting from the knowledge of its pathophysiological behavior. Devoting a deeper analysis of FDG as “molecular tracer” of glucose transporters (many GLUT isoforms have been identified so far) to more extensive and/or specialized publications, it is important to remember that glucose uptake in human cells can take place through two main mechanisms: facilitated diffusion and active transport. The first one is a carrier-mediated intracellular transfer, therefore characterized by saturation (and influenced by insulin, increasing its rate up to 20-fold). It means that a competitive inhibition of transport can occur in the presence of a second ligand that binds to the same carrier. Because FDG utilizes the same transporters of the native molecule, there is a strong interference on FDG’s uptake determined by diabetes and, more in general, by variations in glucose and insulin levels in the blood. For these reasons, to standardize the analysis of FDG’s distribution, it is crucial to define some major issues as a fasting time (at least 4–6 h), a serum glucose range and, in diabetes, the timing after insulin injection. Although chronic hyperglycemia is less

disturbing with respect to the acute one, PET scans have to be preferably performed with serum glucose levels in the range of 70–110  ng/dL.  It is better to avoid examinations in patients with glucose levels higher than 200  ng/dL, with the analysis of PET-­ FDG in patients being critical and more restrictive showing values >150  ng/dL.  In some of the cases with higher glucose values, when possible, the studies have to be rescheduled trying to reach lower glucose levels before the FDG’s injection. Similarly, a warning has to be defined in the presence of hyperinsulinemia, reducing diagnostic accuracy because of a strong interference on Biodistribution. Glucose’s active transport, occurring against an electrochemical gradient, is less diffuse functioning only in certain special epithelial cells specifically adapted for active absorption, as those present in gastrointestinal membranes or at the level of renal tubules. Only in exceptional cases the cellular glucose uptake may also be determined by a passive diffusion.

F DG “Trapping” While glucose and FDG are transported in the large majority of cells through a similar mechanism, their intracellular metabolism is significantly different. The biochemical fate of glucose starts with phosphorylation, occurring immediately after its entrance in cells. The phosphorylation, both for glucose and FDG, is promoted by hexokinase in the large majority of cells, being dependent by glucokinase in the liver. After this first step, glucose-­6-­ phosphate quickly progresses in its metabolic route, after a dephosphorylation mediated by glucose-­6-­ phosphatase, undergoing glycolysis (and/or storage of glycogen and/or conversion to lipids or proteins). Conversely, FDG-6-phosphate is no further metabolized in the glycolytic pathway, remaining “intracellularly trapped,” because of the lack of significant amounts of FDG-6-phosphatase to reverse its phosphorylation. This is the most significant difference between native glucose and FDG, which determine a major advantage for FDG imaging: while radiolabeled “native” glucose has a too fast metabolism to easily permit a PET study, the “trapped” FDG can reliably “in vivo” trace glucose concentration up to two and more hours. Nevertheless, although this is

Premises to PET/CT with FDG in Oncology

not strictly correct from a metabolic point of view, because glucose transport and metabolism are strongly correlated, we can consider FDG as a glucose analogue reliably tracing glucose metabolism in humans. FDG reflects glucose metabolism in all the organisms, except for kidneys. At this level, while normal individuals do not excrete glucose through the urinary system, an intense FDG uptake is observed in kidneys, ureters, and bladder. In fact, whereas normal glucose is freely filtered by glomeruli and rapidly reabsorbed by the nephron, FDG is poorly reabsorbed after filtration, being excreted in a large amount in the urine. Other F-18-labeled radiochemical forms, derived from FDG’s catabolism, can further explain radioactivity in the urinary system at times more distant from the injection. It has to be pointed out that in individuals with ­normal renal function, 50% of the radioactivity reaches the bladder up to 2 h. In this sense the patient has to be invited to urinate before the scan to reduce the pelvic background and dosimetry, because of the consequent lower effective half-life. Conversely, to define a major contraindication, it has to be remembered that FDG crosses the placenta, being distributed mainly in fetal brain and excreted by fetal kidneys. With a high percentage of the total dose of a PET-FDG study derived by CT, in the exceptional cases in which a PET study may be however considered cost effective in a pregnant woman, the choice of a PET/MRI, when available, and a lower FDG’s dosage have to be absolutely preferred. Breastfeeding is contraindicated up to 10 h after IV injection of FDG.

P hysiological and Para-Physiological Distribution of FDG Devoting the knowledge of more precise rules and technical issues to national and/or international protocols, we will briefly describe here the standard procedure as premise to the normal whole-body FDG’s pattern. The patient is IV injected, fasting from at least 4–6 h, in the presence of a good hydration. During the injection and the following uptake’s phase preceding the scan (about 40 min after the administration), the individual has to be at rest, in a quiet

room, comfortable and relaxed. In particular, he/she has to try to avoid actions as chewing, eating, running, and any other exercise and/or sensorial activation affecting FDG distribution, mainly increasing muscular or regional cerebral uptake. Being impossible to avoid swallowing, mainly for patients undergoing a PET scan for head and neck tumors, the effect on the FDG’s uptake in the vocal cords has to be remembered when talking. Then the patient is invited to urinate and the scan starts generally 45–60 min after the IV injection. In a standard condition the highest FDG’s activity is seen at cerebral level (mainly in gray matter), with the brain being the only organ using exclusively glucose as carburant. At fast, cardiac uptake (left ventricle) is variable, but most frequently mild and homogeneous. Occasionally, a difficult analysis can be determined by a high blood pool activity at the level of the great vessels, mainly in mediastinum. While liver and spleen show low-grade diffuse activity, variable uptake is seen in the gastrointestinal system, sometimes creating difficulties in the analysis and problems in differential diagnosis. This activity can be related both to smooth muscle uptake and to the intraluminal content. Low and/or absent concentration is observed at the level of bone marrow. Similarly, no activity is seen at the level of normal lymph nodes, but after FDG’s extravasation at the injection site, determining high focal uptake in the draining regional glands. Moderate activity can be seen in tonsils, salivary glands, myelo-hyoid muscles, and, only in young patients, thymus, adenoidal tissue, and testicles. No uptake is normally seen at the level of lungs, with a slight activity being sometimes present in posterior and inferior segments. The skeletal muscle’s uptake, being low at rest, increases as specific response to stress and/or exercise in the involved muscular cells. An increased uptake can be determined by many conditions as hyperventilation, hiccupping, torticollis, and intense eye movement, as a result of involuntary tensions. The muscular uptake is generally bilateral and symmetric. Conversely, an apparent unilateral pathological concentration can be observed contralaterally to a nerve palsy. The urinary excretion, determining a high background at renal and vesical level, can create difficulties in evaluating FDG’s pathological uptake mainly in kidneys, bladder, and prostate. Small localized areas of ureteric stasis may

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simulate lymph adenopathy. The presence of anomalous locations of kidneys and ureters has to be known, to avoid mistakes in PET image interpretation. Thyroid uptake can be occasionally observed in clinically normal patients, being more frequently caused by thyroiditis or hyperthyroidism, also not clinically evident. In premenopausal women (and/ or in women taking estrogens) breast tissue may often demonstrate moderate symmetrical FDG’s concentration. Intense uptake is showed by breastfeeding mothers. A faint-to-moderate uterine uptake can be observed during menstruation. In adipose tissue a typical symmetric intense uptake can be determined by active brown fat, mainly in winter months in patients with lower body mass index. Increasing this uptake when the patient is injected and/or is stationed in a cold room, it is important to guarantee the injection and the stationing in a warm environment. With the lesion’s detectability in nuclear medicine being dependent on lesion/background ratio, it is evident that major difficulties in PET-FDG’s analysis are present at the cerebral level and/or in the abdominal-pelvic territory, where activities deriving from the gastrointestinal and urinary emunctories can disturb. Nevertheless, many physiological and para-­ physiological uptakes can be easily distinguished when analyzed with the help of morphostructural information obtained by CT. To reduce errors, some authors also suggest the administration of muscle relaxants, cleansing bowel preparations, and placement of a Foley’s catheter. However, because of difficulties in standardizing these procedures and because of the impossibility to reliably avoid possible pitfalls, a strategy of “keep it simple” is more frequently adopted, but in individual particular situations.

 athophysiology of FDG Uptake P in Cancer (and Benign Diseases) Generally, cancer cells present an increased metabolism, requiring a higher amount of glucose (and therefore of FDG) with respect to normal cells. In particular, malignancy is frequently associated with the appearance of phenotypes with a higher expression of glucose transporters, an increasing rate of

cell proliferation, protein and DNA synthesis, and anarchic neo-angiogenesis. All these conditions determine a significant increase of glucose’s uptake, as a fuel necessary to answer to new requests of energy, produced mainly through anaerobic glycolysis. FDG’s uptake and its Biodistribution in tumors are influenced by many parameters such as increased glucose turnover, expression of glucose transporters, and hexokinase activity, being also dependent (through nonspecific mechanisms, independent of neoplastic transformation) on the increased number of cell divisions, a relative hypoxia, and a functional activation. Therefore, although cancer cells may concentrate more FDG with respect to activated normal cells growing at the same rate, an increased FDG’s uptake is nonpathognomonic of cancer, being possible also in some benign conditions. Conversely, a low or null increase of FDG’s uptake may be observed in well-differentiated or slow-growing tumors, in which pathophysiological conditions described above are absent. Devoting a deeper analysis of molecular mechanisms to wider and/or specialized publications, we define here some general behaviors and consequent suggestions helpful in the analysis of PET-FDG images in oncology and other benign diseases to be taken into account for differential diagnosis.

F DG Uptake in Tumors For the reasons described in the previous paragraph, the large majority of malignant tumors show an increased FDG’s uptake. As it has been anticipated, this pathological concentration is influenced by the “biological malignancy,” i.e., by issues as growing rate, hypoxia, histopathology concerning both histotype and grading, and presence and extension of neo-angiogenesis. Intense uptake is more frequently observed in lymphoma, melanoma, colorectal, esophageal and head/neck cancer, non-small cell lung cancer (NSCLC), bone tumors, cervical cancer and seminoma, gastric and pancreatic cancer, sarcoma, and, more generally, high-grade tumors. Many American and European reports describe PET-FDG-appropriate indications for each neoplastic disease, in the different clinical scenario. Nevertheless, a minority of tumors can present low or absent FDG’s uptake. This pattern is mainly

Premises to PET/CT with FDG in Oncology

For the reasons reported above, it is necessary to be very careful when utilizing PET-FDG for a primary diagnosis, mainly in patients with a high prevalence of inflammatory or granulomatous conditions, such as tuberculosis or sarcoidosis. Furthermore, FDG’s uptake can be present at the level of wound healing (in general up to 6 months) and in many benign conditions such as inflammatory reaction after radiotherapy, associated benign lymph adenopathies or infections, lung atelectasis and pleural effusion, and reactive thymus hyperplasia (sometimes appearing in young patients after chemotherapy). Dubious images can also be due to torticollis and other muscle contractions, laryngeal nerve palsy, gastritis, colitis, adenomatous colon’s polyps, gastroesophageal reflux, diverticulitis, inflammatory bowel disease, abscess, hiatal hernia, bladder diverticulum, F DG’s Uptake in Benign Diseases (and benign uterine fibroids, atherosclerotic plaque, Other Pitfalls) and autoimmune diseases such as Graves’ disease. FDG is not a tumor-specific tracer, although the prob- Possible mistakes in diagnosing bone metastases ability of malignancy grows in the presence of a “hot may be determined by an uptake in benign healing spot,” with the percentage of benign lesions being high fractures or arthropathy, with a FDG’s concentrawhich doesn’t concentrate glucose. Nevertheless, a tion being also possible associated with an occult minority of nonneoplastic lesions may be positive at bone infarction or a skeletal fibrous dysplasia. A PET-FDG.  Although the degree of inflammatory diffuse increase at the level of bone marrow (and/ uptake is usually less than the one within neoplastic or of spleen) can be observed after the administratissues, there is clearly an overlap between the two tion of granulocyte colony-stimulating factor. conditions and, in some cases, the uptake could even Pitfalls may also be due to physiological or paraphysiological conditions as brown adipose tissue exceed the neoplastic concentration. FDG accumulates in normal and benign reactive and even ovulation and normal menstrual cycle. cells, as white cells and macrophages, when func- Radioactivity in bowel loops, urinary system, tionally stimulated or activated. As example, the blood vessels, pelvic kidney, and a slight uptake in FDG’s uptake grows in cerebral cells after specific bone marrow can similarly lead to false-positive stimulation, as it happens at the level of calcarine interpretations. However, many of these causes of misinterpretacortex when opening the eyes, or in the muscles under physical stress. With respect to pathological tion described above can be easily recognized. conditions, FDG concentrates at the level of active Proper patient preparation and scanning protocol inflammatory processes either infectious or nonin- are needed for accurate PET/CT imaging. Four to fectious. This uptake may be present either in acute six hours fasten time prior to PET scanning is necescondition or in chronic diseases, where the hyper-­ sary and oral hydration is recommended. Muscle concentration is also dependent on the increased stress, tension, and movement during the FDG’s concentration phase after the IV administration quota of anaerobic glycolysis. False-positive results can create problems more should be minimized to decrease muscle uptake. It in diagnosis (and in staging of patients with cancer), is also important to reduce FDG accumulation than in restaging, for the comparison with the previ- within the urinary bladder, mainly if pelvic maligous scan and an already known diagnosis. The nancies are studied. Patients should void completely implemented support given by CT significantly immediately prior to the start of scanning and the pelvis has to be imaged as early as possible in the increases diagnostic accuracy.

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dependent on a preserved differentiation and/or on slow-growing neoplasm, as evident by the absence of FDG uptake in the large majority of lesions in patients with well-differentiated thyroid carcinoma or neuroendocrine tumors (NET). Low and/or absent FDG uptake is also frequently seen in low-­ grade hepatocarcinoma, also because of the presence of a higher glucose-6-phosphatase activity resulting in a lower FDG uptake, in tumors characterized by a low growing rate, as prostate cancer, in tumors characterized by functional features as the mucinous production, or by a particular tumor morphology, as it can be observed in primary ovarian cancer, frequently consisting of large cystic portions.

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study. Metallic objects (keys and wallets, etc.) should be removed and patient movements during the PET scanning should be avoided. Some potential causes of false-positive results like bowel or tonsil uptake or activity in blood vessels can be easily interpreted only by recognizing the normal FDG uptake distribution: in these cases, the experience of the PET reader is clearly crucial. Many of the pitfalls that have plagued FDG-PET imaging, like correct identification of brown fat and interpretation of focal bone uptake due to nonmalignant processes or of areas of FDG uptake in the bowel, can be avoided carefully analyzing associated CT images, significantly improving diagnostic accuracy and confidence. Finally, a clinical history correctly collected before PET scanning may help to avoid many causes of false-positive results like recent fractures, phase of ovulation or menstrual cycle, recent surgery or radiation therapy, presence of benign thyroid or lung diseases, or many other nonneoplastic pathologic conditions (for example acute or chronic infection), already known or highly suspicious. The interpretation of PET scans is improved when relevant studies, with a major emphasis for other diagnostic radiologic investigations, together with clinical and hematochemical data are considered and carefully reviewed.

PET/CT in Oncology Referring to the following chapters, concerning different organs and apparatus, a wider analysis of indications of PET-FDG in specific territories, we want here to synthesize some of the most important general issues. 12

 re-therapeutic Evaluation: Diagnosis P and Staging As general information, the role of PET-FDG is typically justified in restaging of tumors, less frequently in staging, and only rarely in differential diagnosis. At present the diagnostic use of PET may be suggested for the characterization of solitary pulmonary nodules (SPN), for the identification of cancer of unknown primary (CUP) and of the cause of fever of unknown origin (FUO).

With respect to the first indication, its role is dependent on the capability to increase a diagnostic accuracy in patients who previously underwent CT; this improvement is only present when excluding categories with a high a priori probability of benign diseases determining false-positive results, as sarcoidosis and tuberculosis. It is important to remember that PET-FDG may increase or decrease the probability of neoplasm, but that it is not sufficient to define alone a final diagnosis, however requiring a pathological analysis. Whole-body PET/CT with FDG has been successfully used for identifying CUP of the most common histology, namely adenocarcinomas, squamous cell carcinoma, and poorly differentiated carcinoma, and/or in individuating an oncologic cause, frequently due to lymphomas, in patients affected with a FUO. Despite its limited role in diagnosis, a “pre-­ therapeutic” use of PET-FDG may be suggested, in the presence of a high probability of cancer, for many motivations as follows: (1) a more accurate staging with respect to a traditional approach; (2) when the use of PET-FDG is provided in follow-up, with the aim to detect metastases and/or to diagnose local recurrence, because it is important to demonstrate a basal positive scan to justify the use of PET in follow-up; (3) for a prognostic evaluation, helping in better defining therapeutic strategies; (4) as basal examination to evaluate tumor response; (5) to guide a biopsy; and (6) to design a biological target in radiotherapy. The indication to the use of PET imaging for staging is definitely supported by literature for few tumors, in particular NSCLC and in selected cases of head and neck and esophageal cancer, as well as in some cases of melanoma and lymphoma. Nevertheless, a pre-therapeutic inclusion of PET-­ FDG in the toolbox may be justified in many patients, for the reasons described above. Being however the inclusion of PET-FDG in a pre-­ therapeutic course a clinical responsibility of the oncologist and of the diagnostic imager who have to make a cost-effective evaluation in comparison with alternative procedures, PET-FDG cannot be justified in patients with suspicion of tumors highly differentiated (as thyroid carcinomas or NET), in women with an early primary breast cancer, being more effective the traditional approach and the sen-

Premises to PET/CT with FDG in Oncology

tinel node (SLN) procedure for staging, in subjects with a melanoma, where it is also suggested the SLN technique for staging.

 DG Uptake as Guide to Biopsy and/or F to Define the Target in Radiotherapy In structurally inhomogeneous tumors FDG’s uptake is higher in the most malignant part of the lesion, being lower in differentiated components and absent in necrotic or fibrotic areas. Therefore, PET-FDG can guide a biopsy to the most malignant part of the tumor, when associated to CT, which gives spatial coordinates to correctly reach the tissue that has to be biopsied. For the same reason, PET-FDG allows a better definition of “biological target” in radiotherapy. This is a very important achievement in oncologic therapy, because, thanks to PET-FDG, it has been possible to significantly reduce the target’s extension, excluding areas without neoplastic tissue. Today, mainly in the presence of the so-called tomotherapeutic systems, strictly connecting PET/ CT with radiotherapeutic tools (also including a shared respiratory gating system), PET/CT with FDG image can guide to design a tailored therapeutic plan, giving a higher dosage to the most malignant part of the tumor, saving as much as possible normal tissues. Another major contribution of PET-FDG in defining biological target is given by the increased diagnostic accuracy achievable with respect to CT alone. As example, in a patient with lung cancer, a mediastinal target may be avoided although there is the presence of enlarged lymph nodes, as detected by CT, which suggests a neoplastic involvement requiring the inclusion of this field in treatment’s plan. Using FDG, the radiotherapeutic target may be restricted excluding mediastinum, if the enlarged lymph nodes don’t show glucose’s concentration. In fact, in this case, the probability of absent neoplastic disease is very high, strongly justifying the design of a more favorable treatment plan. Finally, with the therapeutic response to radiotherapy being faster with respect to the morphostructural one, evaluable by CT, PET/CT with FDG could help to sequentially redesign biological target on the basis of the reduced area of FDG’s uptake observed at controls.

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F DG Uptake as Prognostic Indicator As general evidence, when a FDG’s uptake at the level of a lesion is not observed we can reliably make a diagnosis in agreement with a benign disease, being also possible in the presence of a malignant tumor with a favorable prognosis. In other words, as described above, a slight or absent uptake may be observed in a little group of malignancies, when characterized by issues as high differentiation’s grade or slow growing rate, as it happens in the majority of thyroid cancers or in NET. In this group of neoplasm PET-FDG may play a prognostic role when a dedifferentiation is suspected, as it may happen in restaging. It means that we don’t have to propose PET-FDG in the evaluation of a patient undergoing surgery for a differentiated thyroid cancer. Conversely, a justified indication for PET-FDG is present in the same patient when, in follow-up, an increased plasmatic value of thyroglobulin is accompanied by a negative result at a whole-body scan with radioiodine. A relevant prognostic information may also be found in comparing neoplastic patients bearing the same histotype. In this homogeneous category, a higher uptake individuates a worst fate, therefore supporting the choice of more aggressive therapeutic strategies. In fact, as previously described, FDG’s uptake in cancer tissue is determined, among other factors, by tumor proliferation rates, aggressiveness, and rate of neo-angiogenesis. This relationship is however nonlinear, mainly in rapidly growing tumors, being dependent on many parameters, including a various percentage of anaerobic metabolism and presence of necrosis. 13

Post-therapeutic Evaluation: Restaging Routine oncologic follow-up includes clinical evaluation, laboratory tests, morphological imaging, and tumor markers. In most cases, cancer relapse is suggested by an increase in serum tumor markers, while traditional imaging modalities may remain negative for a long time. In the presence of increased markers and negative or inconclusive conventional imaging, FDG-PET is frequently able to find a locoregional relapse and/or distant metastases, thus

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Premises to PET/CT with FDG in Oncology

changing the clinical management in a large number of patients. The usefulness of FDG-PET in restaging has been reported in a wide number of tumors, including breast, ovarian, testicle, non-small cell lung cancer, melanoma, head and neck, pancreas, esophagus, stomach, and others. In all these tumors, in case of inconclusive findings or of discordance between conventional imaging techniques and hematochemical data, FDG-PET has to be proposed for identifying early recurrent cancer. For a fewer number of malignancies, as lymphoma and colorectal cancer, FDG-PET has been suggested as a systematic tool in follow-up. PET-FDG is effective in restaging of patients with all the cancers showing a high FDG’s uptake at pre-therapeutic scan. Although a higher sensitivity is generally observed in detecting distant metastases with respect to alternative procedures, the diagnosis of recurrence may be more difficult. Mainly at an early evaluation, a differentiation from post-­ therapeutic outcomes is not ever easy determining pathological and functional changes similar to those connected with the persistence of a little amount of residual tumor or with an early appearance of relapse. PET-FDG should be used in the search of a local recurrence only in patients showing a FDG’s uptake before therapy. In this sense, although it is not mandatory, a pre-therapeutic PET-FDG scan should be suggested, at least in patients having a high probability of using PET-FDG in follow-up, as in lymphoma. Recurrent disease, because of the tendency to lose differentiated features, is in general characterized by a higher FDG’s uptake with respect to the primary tumor. Therefore, because of its greater malignancy, a recurrent tumor should be individuated also when of little size; nevertheless, its evidence may be conditioned by unfavorable conditions, such as an increased background also determined by physiologic and para-physiologic conditions associated with increased permeability, wound-healing process, and benign inflammatory reaction. Even more than in pre-therapeutic phase, the reliability of a diagnosis of recurrence has to be reinforced by the complementary contribution given by CT.  The diagnostic accuracy grows with the time, becoming more reliable starting 6 months after surgery or other therapeutic major interventions.

When needed, i.e., in the presence of a high probability of relapse, PET-FDG could be performed also before 6  months, mainly because of a high negative predictive value. In fact, there is no FDG’s uptake in the absence of viable cancer cells, i.e., in necrosis and/or fibrosis. In cancer patients, showing a FDG’s uptake at pre-therapeutic control, a negative PET scan in follow-up can reliably exclude relapse. On the contrary, as it has been several times repeated, the opposite is not ever true: in restaging FDG’s uptake is not necessarily determined by recurrence, because of possible false-­ positive results, decreasing when carefully evaluating complementary CT data.

R esponse to Therapy Chemotherapy is currently the treatment of choice in many patients affected with oncologic diseases such as lymphomas or various metastatic solid tumors, including breast, colorectal, ovarian, lung cancer, and others; chemotherapy is frequently in combination with surgery and/or radiotherapy, being also used alone in several cases, mainly when they are with a more advanced stage. Traditionally, structural changes in tumor volume are used to assess therapeutic action as a surrogate endpoint for other measures of clinical benefit, such as disease-free period and overall survival. Moreover, in routine practice, clinicians are keen to use volume changes, as evidenced by CT, MRI, and US, to modify therapeutic approach. Since tissue metabolism changes occur before morphological modifications, variations in FDG’s uptake are evermore frequently used to evaluate tumor response to therapy. A typical example is in malignant lymphomas, where anatomical imaging after completion of therapy often reveals residual masses that could represent either persistent disease or fibrotic tissue. Identification of residual disease after radio- or chemotherapy is clearly influencing further treatment options. Positive FDG-PET findings after therapy completion in patients affected by lymphoma are a strong predictor of relapse, while a negative PET study has been demonstrated to be an excellent predictor of a favorable prognosis. Several studies have already demonstrated the utility of FDG-PET for

Premises to PET/CT with FDG in Oncology

response’s evaluation during the treatment. Early possessing tyrosine kinase (TK) activity. Though identification of chemotherapy-resistant lymphoma many actions of these receptors involve physiologipatients provides a basis for alternative treatment cal processes, perturbation of TK signaling can strategies. Multi-trial experiences and strict interac- result in malignant transformation. During the last tion between some of the most authoritative inter- few decades, these signaling networks have been national experts in onco-hematology allowed the studied in detail and finally agents targeted at key proposal and the clinical utilization of shared proto- molecules have been produced. These pharmacocols, defined by consensus, using interim PET as an logical tools have rapidly become part of standard effective marker to be performed after a defined care for common tumors like breast, colorectal, ovarian, lung, and head and neck cancers. Actually number of courses. Unfortunately, either because of a wider histo- many multi-target agents have been introduced and type variation and number of therapeutic strategies, yielded promising results; newer and probably even or probably for difficulties in reaching an interna- more effective agents for a tailored therapy are being tional consensus, a shared strategy has not yet been developed. Until now, no predictor of response to found in defining standardized protocols for interim target therapy has been fully validated; yet the selecPET in evaluating early tumor response in solid tion of patients who are likely to benefit from TK tumors. Nevertheless, being evident that response inhibitors is mandatory not only for clinical but also assessment by changes in tumor size (using conven- for economic reasons: being very expensive, this tional imaging) requires a longer period and is fre- therapy has to be reserved only to patients in which quently less accurate than changes in metabolism, as an early evaluation of effective tumor response may demonstrated by PET, FDG has been proposed and be demonstrated. In this sense molecular imaging is evermore widely used for an early individuation with PET could be proposed as a tool to recruit these individuals. of nonresponders. Although many positive results have already PET can predict the tumor response after few cycles of chemotherapy in several solid tumors. been achieved, some issues, as those concerning an Helpful results have been achieved in metastatic early prediction of a “complete response,” have to be breast cancer, making PET-FDG also a valid tool for further studied. This problem seems more difficult prognostic stratification, in patients with stage III to be solved in patients affected with solid tumors; and IV NSCLC, usually treated with chemotherapy the difficulty increases in case of polyclonal and/or or chemoradiotherapy, in the management of locally dedifferentiated neoplasm, showing different taradvanced rectal cancer, undergoing chemo-­ gets and therefore a heterogeneous tumor response. In this sense, the definition of multicenter trials radiotherapy before surgery. The importance of FDG-PET in assessing neo- shared by leading groups is important in individuatadjuvant chemoradiotherapy response, due to its ing specific strategies in which PET/CT could give intrinsic capacity to precociously identify changes reliable answers in evaluating tumor response. In in tumor behavior, has been underlined in many parallel with studies analyzing patients undergoing papers. FDG-PET has been reported to be superior chemotherapy, a further evaluation is also needed to to CT and MRI in early predicting pathologic define protocols useful in evaluating tumor response response to preoperative treatment. Useful results, to radiotherapy and/or to newer target therapies. although sometimes more difficult to be interpreted, because of a possible early reactive benign increase in FDG’s uptake, may also be obtained in Usefulness of FDG in Benign Diseases evaluating tumor response in patients undergoing radiotherapy. We will not discuss in this publication the clinical The usefulness of PET in this setting is likely to usefulness of PET/CT with FDG in cardiology, with be further increased by the diffusion of targeted this issue being out of the aims of this Atlas. therapy. As example, one of the principal mecha- Similarly, we will not analyze in this chapter metanisms of communication between cells is the bind- bolic and pathophysiological issues concerning ing of polypeptide ligands to cell surface receptors the brain, with the clinical role of PET-FDG in

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Premises to PET/CT with FDG in Oncology

neuropsychiatry being described in the following pages of this book. Conversely we will briefly analyze the possible usefulness of PET-FDG in evaluating benign diseases, where many indications may be individuated. At first, PET-FDG is a first-line procedure in diagnosis of fever of unknown origin (FUO), because of the need in these patients of the highest sensitivity to detect occult lesions, not negatively counterbalanced by a reduced specificity. It has to be remembered that occult lesions determining fever may be individuated either as neoplasm, including frequently lymphoma or head and neck cancers, or as inflammatory diseases, often in an active chronic phase. Other useful information may be provided by PET-FDG in defining the activity in many inflammatory diseases, as Crohn’s disease or sarcoidosis, to detect activated atherosclerotic plaques in great vessels, to determine the presence of an inflammatory reaction in the area surrounding prosthetic devices, in autoimmune diseases, and so on.

D ual-Time Imaging For PET-FDG, two main approaches have been developed, based on the rationale that malignant lesions have a higher uptake with respect to the benign ones and on different kinetics. With respect to the latter approach, dual-time procedures have been suggested on the basis of the observation that in the first few hours after iv injection, while FDG’s uptake tends to grow or remain stationary in cancer, at the opposite it decreases in benign lesions. This differential diagnostic strategy didn’t find at the moment a wide diffusion, either because of the lack of a full and wide evidence in all the kind of pathological lesions and because of the high cost (not yet justified on the basis of clinical data acquired up to now) of a second scan, which clearly may significantly reduce the number of patients that can be daily studied with a PET scanner.

R ole of Quantification  ifferential Diagnosis with PET-FDG D in Oncology

16

Although a FDG’s uptake is “probably” connected with the presence of neoplastic cells, this event is nonpathognomonic of malignancy, because of the possible presence of false-positive results. Similarly, the absence of uptake cannot exclude the presence of neoplasm, because of the possibility of false negatives due to many parameters as histologic type (low or absent uptake in differentiated neoplasm), size (under 0.5 mm or even more in some territories), and location (difficult detection for cerebral metastases). Therefore, a differential diagnosis cannot be based exclusively on PET-FDG, requiring an implementation at first based on clinical and hematochemical data and on the relevant complementary contribution given by CT, mainly when implemented with the use of contrast media. Nevertheless, in many cases a certain diagnosis is difficult to be obtained and therefore many procedures trying to increase the diagnostic accuracy have been developed and proposed in clinical routine.

More applicable is the use of a quantitative approach. Although it has been demonstrated that neoplastic cells may concentrate more glucose with respect to normal cells growing at the same rate, this information cannot be reliably acquired only using FDG in routine studies, requiring the simultaneous correction of measured uptake for the number of cells and for their growing rate (as it could be evaluated, for example, with F-18 thymidine). Furthermore, a rigorous comparison should be based on absolute quantitative methods, but at the present there are not yet noninvasive, easy, and repeatable procedures applicable in the clinical practice. Therefore, waiting for more rigorous techniques, to increase information acquired through visual analysis semiquantitative methods have been developed and proposed in the clinical practice. The presentation and critical evaluation of the most important procedures are out of the goal of our publication. Although more precise and rigorous quantitative procedures have been proposed, the only one today consolidated in the clinical routine is still the so-called SUV, for which we will spend few words.

Premises to PET/CT with FDG in Oncology

Standardized Uptake Value (SUV)

SUV is a semiquantitative method, defining the FDG uptake’s entity, based on a ratio approximately referring the lesion value to the whole-body activity. It is affected by many issues, as serum glucose level, body weight, and compartmental glucose distribution. Furthermore, it is strongly affected by many factors as the machine, detector, used procedure, and including possible improvement achievable, as example, by respiratory gating. Furthermore, it is not possible to compare a SUV measured with a TOF scanner with respect to the one calculated with a standard machine or a PET/ MRI, being in general nonidentical values calculated in the same patient when studied in different Institutions. For these reasons SUV cannot be considered an absolutely reliable information and a warning has to be declared in using this value in the clinical report, for the possible confusion determined in the practitioner when reading values obtained in various centers. Nevertheless, when critically analyzed by nuclear physicians in a homogeneous context (as example, using the same machine) SUV can show a useful clinical role, complementary with visual analysis, increasing (or decreasing) a diagnostic probability of malignancy, better defining a prognostic

1

value in a single histotype population, and more precisely determining temporal variations in follow­up of the same patient or in the evaluation of a tumor response. Therefore, SUV is widely used for acquiring information described above. Furthermore, SUV has also been proposed to increase a diagnostic accuracy in differential diagnosis of primary tumors, such as pulmonary solitary nodules through the definition of an uptake’s threshold: for lesions greater than 1  cm, cancer is more probable in the presence of a SUV higher than 2.5. At present the usefulness of SUV may also be suggested in all the cases in which a semiquantitative evaluation may be important for a prognostic evaluation and/or when PET-FDG is provided to be used in the evaluation of a therapeutic response. In all the cases, SUV (and/or other semiquantitative methods) has to be evaluated very carefully, and its role has to be considered more useful in evaluating a tumor response and/or a prognostic evolution than in differential diagnosis of a primary cancer. It has to clearly be pointed out that a higher diagnostic accuracy in differential diagnosis may be more reliably reached when PET interpretation is complemented by the important contribution of CT, mainly when performed as CECT.

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Chapter 2

Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake in Malignant and Benign Diseases) FDG Uptake in Tumors  ���������������������������������������������   22 FDG Uptake as Prognostic Indicator  ���������������������   22 FDG’s Uptake as Recurrence’s Identifier  ���������������   23  DG Uptake as Guide to Biopsy and/or F to Define the Target in Radiotherapy  ��������������������   23  DG Uptake Variation as an Early Marker F of Response to Therapy  �������������������������������������������   23  alse-Positive Results Due to FDG Uptake F in Benign Diseases  ����������������������������������������������������   23 Usefulness of FDG in Benign Diseases  ������������������   24  ifferential Diagnosis Using PET-FDG D in Oncology  ����������������������������������������������������������������   24  ome Suggestions to Individuate Pitfalls S and Artifacts, Avoiding Mistakes  ���������������������������   24 Case 1

Normal Distribution of FDG  ���������������������   26

Case 2

Myocardial Uptake  ������������������������������������   27

Case 3

Cricoarytenoid Muscle  �����������������������������   28

Case 4

Ocular Muscles  ������������������������������������������   29

Case 5

Lingual Tonsils  �������������������������������������������   30

Case 6

Salivary Gland and tonsils  �����������������������   31

© Springer-Verlag GmbH Germany, part of Springer Nature 2018 S. Fanti et al., Atlas of PET-CT, https://doi/org/10.1007/978-3-662-57742-4_2

2 Case 7

Salivary Glands  ������������������������������������������   32

Case 8

Great Vessels  ����������������������������������������������   33

Case 9

Spinal cord  �������������������������������������������������   34

Case 10 Pulmonary Hilum  ��������������������������������������   35 Case 11 Nipples  �������������������������������������������������������   36 Case 12 Breasts  ��������������������������������������������������������   37 Case 13 Ureters  ��������������������������������������������������������   38 Case 14 Ureters  ��������������������������������������������������������   39 Case 15 Testis  �����������������������������������������������������������   40 Case 16 Head and Neck—Granuloma  �������������������   41 Case 17 Head and Neck—Mucositis  ����������������������   42 Case 18 Head and Neck—Thyroiditis  ��������������������   43 Case 19 Thyroiditis—Pattern of FDG Uptake  ������   44 Case 20 Thyroid Goiter—Pattern of FDG Uptake  �������������������������������������������   45 Case 21 Head and Neck—Thyroid Nodule  �����������   46 Case 22 Head and Neck—Flap Reconstructive Surgery  �������������������������������������������������������   47 Case 23 Chest—Thymus 

�����������������������������������������   48

Case 24 Chest—Ectopic Thymus 

���������������������������   49

Case 25 Chest—Hiatal Hernia  ��������������������������������   50 Case 26 Chest—Brown Fat  �������������������������������������   51 Case 27 Chest—Esophagitis  Case 28 Chest—Fracture 

����������������������������������   52

����������������������������������������   53

Case 29 Chest—Fibroelastoma Dorsi  �������������������   54 Case 30 Chest—Talc 

������������������������������������������������   55

2 Case 31 Chest—Lipomatous Hypertrophy of Interatrial Septum  ��������������������������������   56 Case 32 Chest—Silicon Granuloma  �����������������������   57 Case 33 Abdomen—Gastritis 

���������������������������������   58

Case 34 Abdomen—Post Surgery  �������������������������   59 Case 35 Abdomen—Post Surgery  �������������������������   60 Case 36 Abdomen—Focal Nodular Hyperplasia  ������������������������������������������������   61 Case 37 Abdomen—Cholecystitis 

�������������������������   62

Case 38 Abdomen—Diverticulitis 

�������������������������   63

Case 39 Abdomen—Segmental Bowel FDG Uptake  ������������������������������������������������   64 Case 40 Abdomen—Secondary Kidney Lesions  ��������������������������������������������������������   65 Case 41 Abdomen—Metformin Intake  �����������������   66 Case 42 Pelvis—Hemorrhoids 

�������������������������������   67

Case 43 Pelvis—HIV Infection  ��������������������������������   68 Case 44 Pelvis—Kidney Lesion  ������������������������������   69 Case 45 Pelvis—Bladder Diverticulum  �����������������   70 Case 46 Pelvis—Ovarian Cyst  ��������������������������������   71 Case 47 Bone—Enchondroma  �������������������������������   72 Case 48 Bone—Tietze’s Syndrome  ������������������������   73

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Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake…

One of the main goals of this Atlas is to help the readers in distinguishing pathological images from the normal ones, also identifying pitfalls and artifacts. Before analyzing how to interpret FDG’s uptake in patients suspected and/or affected with all the most frequent neoplasms, in this chapter we present pictures acquired in subjects showing a normal and/ or paraphysiological FDG’s distribution. Cases related to some of the most important possibilities of error are displayed. Being out of the aims of this publication to discuss pitfalls and artifacts due to technical issues dependent on the scanner, we here present subjects showing apparent anomalies in FDG’s distribution, independent of the presence of cancer. In the next part of this book the possible role of PET-FDG in non-oncologic indications will also be discussed. Reconnecting the analysis to what was already discussed in the previous chapter, we want at first to briefly confirm how and when the probability of cancer in FDG’s hot spots may augment. Cancer cells are generally characterized by an increased glucose metabolism with respect to the normal ones. In particular, malignancy is frequently associated with the appearance of new phenotypes with a higher expression of glucose transporters, an increasing rate of cell proliferation, protein and DNA synthesis, and anarchic neo-angiogenesis. All these conditions determine a significant enhancement of glucose’s uptake, as a fuel necessary to answer new requests of energy, produced mainly through the anaerobic glycolysis. FDG’s uptake and Biodistribution in tumors are therefore influenced by many parameters such as increased glucose turnover, expression of glucose transporters, and hexokinase activity, being also dependent (through nonspecific mechanisms, independent of the neoplastic transformation) on the increased number of cell divisions and/or a hyperactive metabolism. Devoting a deeper analysis of molecular mechanisms to wider and/or specialized publications, and avoiding the discussion of pathophysiological premises to clinical indications in cardiology and neurology, we define here some general behaviors and consequent suggestions helpful in the analysis of PET-FDG images in oncology and other benign diseases to be taken into account for differential diagnosis.

FDG Uptake in Tumors

• The large majority of malignant tumors show an

increased FDG uptake. uptake is influenced by the “biological malignancy,” i.e., by issues as the growing rate, hypoxia, and histopathology concerning both the histotype and the grading. Intense uptake is more frequently observed in lymphoma, melanoma, colorectal, esophageal and head/neck cancer, NSCLC, and, more generally, high-grade tumors. A minority of tumors can present low or absent FDG’s uptake. This pattern is mainly dependent on differentiation, as evident by the absence of FDG’s uptake in the large majority of lesions in patients with well-differentiated thyroid carcinoma or neuroendocrine tumors (NETs). Low and/or absent FDG uptake is also frequently seen in low-grade hepatocarcinoma, also because of the presence of a higher glucose-6-phosphatase activity resulting in a low FDG uptake, in tumors characterized by a low growing rate as prostate cancer, in tumors characterized by functional features as the mucinous production, or in a particular tumor morphology, as it can be observed in primary ovarian cancer, frequently consisting of large cystic portions.

• FDG’s



FDG Uptake as Prognostic Indicator

• In tumors with a greater prevalence of normally



non-concentrating lesions, as NETs, and thyroid or liver carcinomas, a high FDG’s concentration defines a worst prognosis with respect to patients not showing uptake. Similarly, in a very large majority of tumors, comparing in a single category all the patients bearing the same histotype, a higher uptake individuates a worst fate. In fact, it has been demonstrated that FDG’s uptake in cancer tissue is determined, among other factors, by tumor proliferation rates, aggressiveness, and rate of neo-­ angiogenesis. This relationship is however nonlinear, mainly in rapidly growing tumors, being dependent on many parameters, including the various percentage of anaerobic metabolism and the presence of necrosis.

Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake…

FDG’s advantage has been already demonstrated in many patients submitted to chemotherapy (and to radiotherapy, although in these cases the analysis may be more complex). A wider and deeper experience on the possible clinical usefulness in oncology, including all histotypes, better defining timing of evaluation and capability to predict also the response to radiotherapy, is under evaluation. Important results on the role of an “interim PET study” have already been reached in lymphoma. Intriguing perspectives are connected with the evaluation of tumor response in cytostatic (and non-cytoreductive) new treatments, in which radiological standard procedures, such as RECIST, may present major problems.

FDG’s Uptake as Recurrence’s Identifier

• Recurrent disease, because of the loss of differen• •

tiated features, is in general characterized by a higher FDG’s uptake with respect to the primary tumor. There is no FDG’s uptake in the absence of viable cancer cells and therefore in the presence of necrosis and/or fibrosis. In the majority of cancer patients, in which a FDG’s uptake is observed at diagnosis and/or at the pre-therapeutic control, a negative PET scan at follow-up can reliably exclude recurrence with respect to post-therapeutic fibrosis and/or necrosis. The opposite is not ever true, i.e., in follow-up FDG’s uptake is not necessarily determined by a local recurrence, because of possible false-positive results (see below).

 DG Uptake as Guide to Biopsy and/or F to Define the Target in Radiotherapy

• In



inhomogeneous tumors FDG’s uptake is higher in the most malignant part of the lesion, being lower in the most differentiated components, and absent in necrotic or fibrotic areas. Therefore, PET-FDG can guide a biopsy to the most malignant part of the tumor. For the same reason, PET-FDG allows a better definition of the “biological target” in radiotherapy. PET/CT image can guide to design a tailored therapeutic plan, giving a higher dosage to the most malignant part of the tumor, reducing radiations to normal tissues.

 alse-Positive Results Due to FDG F Uptake in Benign Diseases FDG may accumulate in activated white cells and macrophages. Therefore, it can be concentrated at the level of active inflammatory processes either infectious or noninfectious.

• The highest percentage of benign lesions doesn’t •

 DG Uptake Variation as an Early F Marker of Response to Therapy

• Glucose

uptake rapidly decreases after an effective therapeutic action, remaining unchanged and/or increasing in nonresponders. Therefore, FDG’s uptake can be an earlier marker of the therapeutic response in tumors with respect to the information allowed by CT, US, and MRI detecting late variations on size and structure, sometimes less reliably connected with a therapeutic efficacy. This

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present FDG’s uptake, being therefore distinguishable by malignant ones, in terms of probability, in the large majority of cases. A minority of benign lesions can show FDG’s uptake, generally with a lower entity with respect to malignant tumors. The presence of false-­ positive results can create problems more in diagnosis (and staging), being less critical in restaging and at follow-up. A particular attention must be paid in the cases of suspicious local relapse, mainly in cases analyzed too early after a major therapeutic intervention. In these cases, false-positive results may be due to an inflammatory reaction, an infection, and/or an actively healing tissue. It is necessary to be very careful in utilizing PET-­ FDG for a primary diagnosis, mainly in patients with a high prevalence of inflammatory or ­granulomatous conditions (such as tuberculosis, sarcoidosis, asbestosis). FDG’s uptake can be present at the level of the wound healing (in general up to 6 months), in

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Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake…

the inflammatory reaction after radiotherapy, in associated benign lymphadenopathy or infections, in lung atelectasis and pleural effusion, and in reactive thymus hyperplasia (sometimes appearing in young patients after chemotherapy). Dubious images can also be due to pathological conditions as gastritis, gastroesophageal reflux, diverticulitis, inflammatory bowel disease, abscess, hiatal hernia, and benign uterine fibroids. Critical can be, for possible mistakes in diagnosing bone metastases, the uptake determined by benign healing fractures or arthropathies. A diffuse increase at the level of bone marrow (and/or of spleen) can be observed after the administration of granulocyte colony-­ stimulating factor.

very useful in patients affected with chronic disease, which may require toxic therapies only in the presence of an active pathological condition.

 ifferential Diagnosis Using PET-FDG D in Oncology

• Role



Usefulness of FDG in Benign Diseases We will not discuss here the clinical usefulness of PET-FDG in cardiology and in neuropsychiatry. Putting in evidence that false positives and false negatives in oncology are only a very low percentage of the PET-FDG results, in case of appropriate indication, it has to be pointed out that FDG uptake can also determine useful clinical indications in benign diseases.

• As example, PET-FDG is a first-line procedure

24



in the diagnosis of fever of unknown origin (FUO), because of the need of the highest sensitivity to detect occult lesions, not negatively counterbalanced by a low specificity. It means that, with most of the FUO being dependent on slow-­growing tumors or inflammation/infection, many of the pathological sites may be individuated as FDG’s hot spot, although a further differential diagnosis of malignancy is requested. Other useful information can be obtained in defining the activity in many inflammatory diseases, to detect activated atherosclerotic plaques in great vessels, to determine the presence of a reaction in the area surrounding prosthetic devices, sometimes in better defining autoimmune diseases, etc. This information may be

of quantitation: To increase information acquired through the visual analysis, quantitative and/or semiquantitative methods can be utilized. This evaluation is out of the goal of our publication. Although precise and rigorous quantitative procedures have been proposed, the only one today in the clinical routine is the so-called SUV, as reported in the first chapter. It has to be taken into account that all the most advanced technologies, such as respiratory gating and/or fully digitalized PET cameras, may increase SUV values, but without improving differential diagnosis. In fact, as example, the increase of a SUV either in benign or malignant solitary pulmonary nodules (SPN) determines the need to raise the discrimination threshold of 2.5 suggested under standard conditions.

 ome Suggestions to Individuate S Pitfalls and Artifacts, Avoiding Mistakes

• Pathological hot spots are more typically asym•



metrical. A symmetrical uptake is more frequently normal and/or due to a pitfall. It is very important to recognize emunctories and para-physiological and pathological circumstances determining an altered FDG’s distribution. The presence of catheters and other surgical and medical tools must always be recorded. Great care must be taken in recognizing the radioactive contamination. The FDG’s distribution may be dependent on age and/or physiological and para-physiological conditions. As example, a thymic and/or testicular uptake, mainly when bilateral, may be normal in pediatrics, being pathological in adults.

Normal Distribution, Variants, and Artifacts (Versus Pathological Uptake…



Similarly, a slight uptake in breast and in the genital system may be present in young women, dependent on the menstrual cycle. Conversely, a ­similar uptake is highly suspicious in the postmenopausal phase. It is very important to know the effects on FDG’s uptake of many situations such as fast, glycemia, insulin, hydration, cold (on brown fat), and motor-sensory activation. It is very important to

2

check the patient for the presence of metallic and other attenuating tools, such as pacemakers, coins, and keys. The effect of radiological contrast media on attenuation has to be well known. We can conclude remembering that to avoid mistakes, it is mandatory to have a careful anamnesis and a rigorous evaluation not only of PET, but also of CT images.

25

2

C ase 1 

Normal Distribution of FDG

Grey matter Uptake

Liver uptake Spleen uptake Kidney Excretion Bone marrow Uptake

Bladder Excretion

26



Case 2  Myocardial Uptake

2

Myocardial uptake

Teaching point Myocardial uptake is quite unpredictable, as related to several factors, probably the most important being fasting.

27

2

C ase 3 

Cricoarytenoid Muscle

Teaching point Every muscle usually does not avidly concentrate FDG, given that fasting has been respected and that intense contraction has not occurred during the uptake period (especially first 20 min after FDG injection). However it may be difficult to prevent patients from talking and swallowing; therefore some uptake in the head and neck muscle has to be expected.

28



Case 4  Ocular Muscles

2

Teaching point To avoid muscle uptake it is mandatory to have patient at rest for at least 20 min after injection; also administration of miorelaxant has been suggested. With the use of PET/CT fused images it is usually possible to distinguish muscle uptake from pathologic findings.

29

2

C ase 5 

Lingual Tonsils

Mild uptake at insertion of genioglossus muscle

Lingual tonsils

30



Case 6  Salivary Gland and Tonsils

SALIVARY GLAND

2

TONSIL UPTAKE

Teaching point Also salivary glands and lymphatic tissue can show a variable degree of FDG uptake; this has to be taken into particular account in diseases affecting these organs.

31

2

Case 7  Salivary Glands

SUBMANDIBULAR

PAROTID

Teaching point Usually physiologic uptake in the salivary glands is symmetric, but not necessarily in all cases and glands. Again PET/CT fusion images are extremely helpful to establish the site of uptake. 32

Case 8  Great Vessels



2

BLOOD POOL ACTIVITY OF GREAT VESSELS

33

2

C ase 9 

Spinal Cord

Teaching point Faint FDG uptake by several regions of the spinal cord is not uncommon and is usually seen in the cervical, last two dorsal, and first lumbar levels. This must be recognized as physiological, to avoid misdiagnosis.

34



Case 10  Pulmonary Hilum

2

ASPECIFIC HILAR UPTAKE

Teaching point Nonspecific uptake at both lung hilum can be observed quite frequently, maybe related with nonspecific inflammation. It has to be taken into particular care in order to avoid wrong report: it is usually nonintense and symmetrical.

35

2

C ase 11 

Nipples

ASPECIFIC NIPPLE UPTAKE

36

Case 12  Breasts

2

ASPECIFIC BREAST UPTAKE

Teaching point Breast and nipples frequently show a faint uptake. It should be considered physiological, given that no focal area of intense uptake is observed.

37

2

Case 13  Ureters

BILATERAL URETERAL FDG EXCRETION

Teaching point As FDG is excreted through the urinary pathway, intense tracer concentration can be observed in the kidney pelvis, ureters, and bladder. 38

Case 14  Ureters



2

ASYMMETRIC URETERS VISUALIZATION

39

2

Case 15  Testis

TESTICULAR FDG UPTAKE

Teaching point The testis almost always shows a faint FDG uptake; in young patients the degree of uptake can be more relevant.

40



Case 16  Head and Neck—Granuloma

2

⊡⊡ FDG uptake due to the odontogenic ­granuloma

41

2

C ase 17 

Head and Neck—Mucositis

⊡⊡ FDG uptake due to mucositis

Teaching point The scan was carried out few weeks after external radiation therapy, which is a well-known cause of inflammatory changes.

42



Case 18  Head and Neck—Thyroiditis

2

⊡⊡ Increased FDG uptake in thyroiditis

Teaching point Inflammatory lesions are well-known causes of increased FDG uptake; a frequent site of unknown chronic inflammation is thyroid gland. 43

2

C ase 19 

Thyroiditis—Pattern of FDG Uptake Female 57 yo

Transaxial CT

Transaxial PET MIP

Fused Transaxial

⊡⊡ Known thyroiditis

PET findings PET shows moderate and diffuse FDG uptake at thyroid gland site, consistent with thyroiditis 44

Teaching point Though usually PET-FDG is used to identify malignancy, homogenous, diffuse with variable degree of FDG uptake in the thyroid may be eloquent in suggesting benign thyroid disease.

Case 20  Thyroid Goiter—Pattern of FDG Uptake

2

Male 49 yo

Transaxial CT

Transaxial PET

MIP

Fused Transaxial

⊡⊡ Thyroid enlargement (goiter)

⊡ ⊡ PET findings Faint and diffuse FDG uptake involving enlarged thyroid tissue in mediastinum

Teaching point Benign conditions, such as goiter, may present faint FDG uptake. The intensity and distribution of FDG along with blood tests and anamnesis should guide a correct diagnosis.

45

2

Case 21  Head and Neck—Thyroid Nodule

⊡⊡ Focal FDG uptake in the thyroid nodule

Teaching point

46

Occult thyroid cancer is an occasional incidental finding during imaging exams for other indications. Although most nodules are benign, in the presence of focal suspect findings further investigations are mandatory (this case resulted to be a malignant cancer at FNA).

Case 22  Head and Neck—Flap Reconstructive Surgery



Transaxial CT

2

Transaxial PET

47

Fused Transaxial

MIP

⊡⊡ Intense FDG uptake due to flap reconstructive surgery in a patient with head and neck cancer

2

C ase 23 

Chest—Thymus

⊡⊡ FDG uptake due to the thymus

Teaching point FDG uptake at thymus is frequent in young patients. The appearance of the organ is usually well recongnized, at anteromediastinal level, with the typical aspect of thymus.

48

Case 24  Chest—Ectopic Thymus



2

FDG UPTAKE DUE TO THE ECTOPIC LEFT LOBE OF THYMUS

Teaching point FDG uptake at thymus may be challenging to be recognized in anatomic variants.

49

2

C ase 25 

Chest—Hiatal Hernia

⊡⊡ Intense FDG uptake due to hiatal hernia

⊡⊡ Faint FDG uptake due to hiatal hernia

Teaching point

50

Inflammatory lesions are well-known causes of increased FDG uptake; in many cases a careful evaluation of patient history, and attention to CT images, can help avoiding false-positive report.



Case 26  Chest—Brown Fat

2

⊡⊡ FDG uptake in brown fat

51

Teaching point Degree of FDG uptake in brown fat can be variable, and sometimes is asymmetrical and not easy to be identified in unusual location. PET/CT is extremely useful to locate the uptake in the area of fat density.

2

C ase 27 

Chest—Esophagitis

⊡⊡ FDG uptake due to esophagitis

Teaching point Increased uptake of FDG can be observed in the presence of inflammatory disease of the esophagus; it is usually diffuse and of moderate degree.

52



Case 28  Chest—Fracture

2

⊡⊡ Mild FDG uptake at a rib due to recent fracture

Teaching point During the anamnesis it is fundamental to ask the patient if he/she had in the last months any fractures, crash, or falls.

53

2

C ase 29 

Chest—Fibroelastoma Dorsi

⊡⊡ Faint FDG muscle uptake due fibroelastoma dorsi

Teaching point Some benign soft tissue processes may show increased FDG uptake; PET/ CT is very useful to identify anatomic abnormalities and characterize some benign lesions.

54

Case 30  Chest—Talc



2

Transaxial CT

Fused Transaxial

Sagittal CT

Fused Sagittal

⊡⊡ High FDG uptake in the in pleural talc deposits in the left lung

Teaching point Talc deposits produce areas of highly increased F-FDG uptake, because of talc-­ induced inflammation.

55

2

C ase 31 

Chest—Lipomatous Hypertrophy of Interatrial Septum

⊡⊡ Moderate FDG uptake in the interatrial septum due to a benign lesion

Teaching point

56

Lipomatous hypertrophy of interatrial septum shows high FDG-PET uptake. It should not be misinterpreted as malignant lesion.



Case 32  Chest—Silicon Granuloma

2

⊡⊡ Solid nodule with high FDG uptake behind breast implant

Teaching point Although FDG-PET has high accuracy for detection of tumor recurrence, it has to be remembered that benign entities may also demonstrate high accumulation of FDG. In this case the intense uptake was due to silicone granuloma behind breast implant.

57

2

C ase 33 

Abdomen—Gastritis

⊡⊡ Intense FDG uptake in the stomach. Diagnosis: gastritis

Teaching point

58

FDG uptake is likely to be intense in the presence of clinically evident gastritis. In inflammatory diseases the uptake is usually diffuse to the entire stomach: in case of focal uptake further investigations can be recommended.



Case 34  Abdomen—Post Surgery

2

POSTSURGERY FDG UPTAKE

59

2

C ase 35 

Abdomen—Post Surgery

⊡⊡ FDG uptake due to inflammatory changes due to recent terminoterminal anastomosis of bowel

Teaching point Surgery will affect FDG uptake due to inflammatory processes. Increased uptake is almost constant for several months at scar level, but also near surgical bed. It may therefore be difficult to identify the local recurrence of disease within few months from intervention.

60

Case 36  Abdomen—Focal Nodular Hyperplasia



2

FOCAL NODULAR HYPERPLASIA

Teaching point Other liver lesions (such as focal nodular hyperplasia) are not showing any increased uptake of FDG, and therefore will not be detectable on FDG-PET.

61

2

C ase 37 

Abdomen—Cholecystitis

Transaxial CT

Transaxial PET

CHOLECYSTITIS

Fused Transaxial

Teaching point 62

Although FDG-PET has high accuracy for detection of tumor lesions, it has to be remembered that benign entities may also demonstrate high accumulation of FDG. In this case the intense uptake was due to cholecystitis.

Case 38  Abdomen—Diverticulitis



Transaxial CT

2

Transaxial PET

Fused transaxial

63

Coronal CT

Coronal PET

Fused Coronal

Teaching point Diverticulitis may show high FDG uptake.

2

C ase 39 

Abdomen—Segmental Bowel FDG Uptake

Transaxial CT

Transaxial PET

Fused Transaxial

64

⊡⊡ Segmental intense FDG uptake in rectum and sigma

Teaching point The patterns and degree of colonic FDG uptake may help to guide diagnosis; nodular-focal high FDG uptake in the colon may be related to tumor tissue and should be further investigated with

colonoscopy. A diffuse colonic FDG uptake pattern, regardless of degree, is usually related to normal findings, whereas a segmental high uptake may imply an inflammatory condition that warrants follow-up diagnostic studies.

Case 40  Abdomen—Secondary Kidney Lesions



MIP

Transaxial Fused

Transaxial CECT

Transaxial Fused

Transaxial CECT

2

⊡⊡ Intense FDG uptake due to bilateral secondary renal lesions

Teaching point Accumulation of FDG activity in the kidney interferes with the visualization of tumor lesions. Areas with high FDG accumulation should be evaluated very carefully.

65

2

C ase 41 

Abdomen—Metformin Intake

⊡⊡ Intense FDG bowel uptake due to the use of metformin

Teaching point

66

Metformin-induced FDG bowel uptake can hinder evaluation of the bowel. Metformin should be discontinued prior to PET imaging.

Case 42  Pelvis—Hemorrhoids



2

Teaching point

Transaxial CT

Many different causes may determine FDG uptake in the anal region, as muscle activity, sphincter activity, and constipation. Also hemorrhoids, as in this case, may be considered as a possible cause of focal high FDG uptake.

Transaxial PET

Fused Transaxial

⊡⊡ FDG focal uptake in anal region

67

2

C ase 43 

Coronal CT

Pelvis—HIV Infection

Coronal PET

Transaxial CT

Fused Coronal

Sagittal CT

Sagittal PET

Transaxial PET

Fused Sagittal

Fused Transaxial

⊡⊡ Intense FDG uptake in inguinal lymph nodes bilaterally

Teaching point

68

Inflammatory lymph nodes may show very intense FDG uptake, as in this case (HIV-positive patient). The degree of FDG uptake alone does not allow often to differentiate between benign and malignant tissue.

Case 44  Pelvis—Kidney Lesion



Fused Transaxial

MIP

Transaxial PET

Fused Coronal

2

Fused Sagittal

Transaxial CECT

⊡⊡ Right kidney lesion without FDG uptake

Teaching point Urinary excretion of FDG does not allow to investigate accurately kidney lesions. Low-dose CT images of PET/CT imaging should be carefully evaluated for identification of renal anatomical alterations.

69

2

C ase 45 

Pelvis—Bladder Diverticulum

⊡⊡ Intense FDG uptake due to the bladder diverticulum

70

Case 46  Pelvis—Ovarian Cyst



Fused Transaxial

Fused Coronal

Transaxial CT

2

Fused Sagittal

Transaxial CECT

⊡⊡ Hypodense lesion in the pelvis without FDG uptake 71

Teaching point Ovarian cysts are frequently incidentally found in asymptomatic women by imaging and are usually a physiologic finding (having to do with ovulation). It should be remembered that ovarian cysts may also be borderline (low malignant potential), or malignant.

2

C ase 47 

Bone—Enchondroma

72

Teaching point Although FDG-PET has high accuracy for detection of tumor lesions, it has to be remembered that benign entities may also demonstrate accumulation of FDG. In this case the FDG uptake was due to a benign bone lesion (enchondroma).



Case 48  Bone—Tietze’s Syndrome

2

Teaching point Tietze’s syndrome of the sternoclavicular joint characterized by tender swelling in the region of the sternoclavicular joint shows high FDG uptake.

73

Part II FDG PET/CT in Oncology

Chapter 3

Malignancies in Hematology

Hodgkin’s and Non-Hodgkin’s Lymphomas  ���������   78 Myeloma  ���������������������������������������������������������������������   78 References  ������������������������������������������������������������������   78 Case 1

HD Staging  �������������������������������������������������   80

Case 2

HD Staging  �������������������������������������������������   81

Case 3

HD Staging  �������������������������������������������������   82

Case 4

NHL Staging  �����������������������������������������������   83

Case 5

NHL Staging  �����������������������������������������������   84

Case 6

NHL Staging  �����������������������������������������������   85

Case 7

Primary Cutaneous NHL—Staging  ���������   86

Case 8

NHL Follicular—Staging  ���������������������������   87

Case 9

Histocytosis—Staging 

������������������������������   88

Case 10 NHL Indolent—Staging  ����������������������������   89 Case 11 HD Staging and Early Therapy Evaluation  ��������������������������������������������������   90 Case 12 HD Staging and Therapy Evaluation  ������   91 Case 13 NHL Low-Grade Intestinal—Staging and Therapy Evaluation  ���������������������������   92 Case 14 HD Staging and Therapy Evaluation  ������   93 Case 15 NHL T cell—Staging and Early Evaluation of Treatment  ���������������������������   94 Case 16 NHL at 2. Relapse and After Treatment  ���������������������������������������������������   95 Case 17 NHL at 1. Relapse and After Treatment  ��   96 Case 18 NHL Evaluation at the End of Treatment    97 Case 19 NHL Recurrence Detection  ����������������������   98 Case 20 Solitary Plasmacytoma  �����������������������������   99 Case 21 Multiple Myeloma—Staging  �����������������  100 Case 22 Multiple Myeloma—Staging  �����������������  101

© Springer-Verlag GmbH Germany, part of Springer Nature 2018 S. Fanti et al., Atlas of PET-CT, https://doi/org/10.1007/978-3-662-57742-4_3

3

Malignancies in Hematology

Hodgkin’s and Non-Hodgkin’s Lymphomas Positron-emission tomography with computed tomography (PET/CT) using 18F-FDG is the imaging of choice in lymphomas [1]. Almost all subtypes of lymphoma (with the exception of some low-grade NHL) show high metabolic activity and that condition makes the staging of the disease very accurate either in the detection of nodal, extranodal, or bone marrow involvement [2]. In the assessment of response to therapy, PET plays a crucial role. The metabolic changes assessed by PET during the treatment (in most cases after few cycles of therapy) have proved to be highly predictive of the response to treatments and the outcome of the patient [3]. Moreover, the information provided by PET may help in modulate therapies based on the grade of PET response. This has been found to be particularly useful in some selected patient populations especially in advanced Hodgkin’s lymphoma [4]. 18 F-FDG PET/CT plays also a significant role in the selection of patient candidates to transplantation and provides useful prognostic information to clinicians [5]. During follow-up the use of 18F-FDG PET/CT is still controversial; however, some reports showed its ­usefulness especially in the first 2 years after the end of treatments [6].

Myeloma

78

Imaging plays a crucial role in the diagnosis and in the initial staging of multiple myeloma (MM) and it is useful in the differential diagnosis with other plasma cell disorders. For many years planar X-ray has been the imaging of choice in the diagnosis of MM.  However, its known low sensitivity, limited specificity, and its inability to detect extraosseous lesions make this method in most cases insufficient for an accurate diagnosis of this condition. For these reasons, whole-body low-dose CT is currently replacing planar X-rays for this purpose [7]. MRI at the present should be considered the method of choice for the staging of the disease since it has been found to be the most sensitive imaging in the detection of bone involvement [8].

18 F-FDG PET/CT has gained much interest in the last few years for the diagnosis of myeloma. Main advantages of such metabolic imaging methods are high sensitivity for the detection of bone lytic lesions; the ability to diagnose the presence of extraosseous lesions in a reasonable time for the scan; and its high accuracy in the assessment of treatment monitoring and detection of relapse in patients at follow-up [8, 9]. Main limitation of 18F-FDG PET/CT is the difficult interpretation of the scans. Authors have tried to overcome this problem trying to standardize the interpretation criteria in a recent publication [10].

References 1. Cheson BD.  PET/CT in lymphoma: current overview and future directions. Semin Nucl Med. 2018; 48(1):76–81. https://doi.org/10.1053/j.semnuclmed. 2017.09.007. 2. Adams HJ, Kwee TC, de Keizer B, Fijnheer R, de Klerk JM, Littooij AS, Nievelstein RA.  Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol. 2014;25(5):921–7. https://doi.org/10.1093/annonc/ mdt533. Epub 2013 Dec 18 3. Barrington SF, Kluge R. FDG PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging. 2017;44(Suppl 1):97–110. https://doi.org/10.1007/s00259-017-3690-8. 4. Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mulé A, Picardi M, Romano A, Cantonetti M, La Nasa G, Trentin L, Bolis S, Rapezzi D, Battistini R, Gottardi D, Gavarotti P, Corradini P, Cimminiello M, Schiavotto C, Parvis G, Zanotti R, Gini G, Ferreri AJM, Viero P, Miglino M, Billio A, Avigdor A, Biggi A, Fallanca F, Ficola U, Gregianin M, Chiaravalloti A, Prosperini G, Bergesio F, Chauvie S, Pavoni C, Gianni AM, Rambaldi A. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018;23:JCO2017752543. https://doi.org/10.1200/ JCO.2017.75.2543. 5. Adams HJ, Kwee TC.  Pretransplant FDG-PET in aggressive non-Hodgkin lymphoma: systematic review and meta-analysis. Eur J Haematol. 2017;98(4):337– 47. https://doi.org/10.1111/ejh.12837.

Malignancies in Hematology

6. Zinzani PL, Stefoni V, Tani M, Fanti S, Musuraca G, Castellucci P, Marchi E, Fina M, Ambrosini V, Pellegrini C, Alinari L, Derenzini E, Montini G, Broccoli A, Bacci F, Pileri S, Baccarani M.  Role of [18F]fluorodeoxyglucose positron emission tomography scan in the follow-up of lymphoma. J Clin Oncol. 2009;27(11):1781–7. https://doi.org/10.1200/ JCO.2008.16.1513. 7. Suntharalingam S, Mikat C, Wetter A, Guberina N, Salem A, Heil P, Forsting M, Nassenstein K. Whole-­ body ultra-low dose CT using spectral shaping for detection of osteolytic lesion in multiple myeloma. Eur Radiol. 2018;28(6):2273–80. https://doi. org/10.1007/s00330-017-5243-8. 8. Shah SN, Oldan JD.  PET/MR imaging of multiple myeloma. Magn Reson Imaging Clin N Am.

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2017;25(2):351–65. https://doi.org/10.1016/j.mric. 2017.01.00. 9. Bailly C, Leforestier R, Jamet B, Carlier T, Bourgeois M, Guérard F, Touzeau C, Moreau P, Chérel M, Kraeber-Bodéré F, Bodet-Milin C.  PET imaging for initial staging and therapy assessment in multiple myeloma patients. Int J Mol Sci. 2017;18(2):pii: E445. https://doi.org/10.3390/ijms18020445. 10. Nanni C, Versari A, Chauvie S, Bertone E, Bianchi A, Rensi M, Bellò M, Gallamini A, Patriarca F, Gay F, Gamberi B, Ghedini P, Cavo M, Fanti S, Zamagni E. Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging. 2017;45(5):712–9. https://doi.org/10.1007/ s00259-017-3909-8.

79

3

Case 1  HD Staging Female 32 yo

⊡⊡ Staging of HD

⊡ ⊡ PET findings Several areas of FDG increased uptake in the mediastinum and in left axillary nodes

80

Teaching point PET is highly sensitive in detecting nodal and extranodal involvement in HD. However, care has to be paid to some district areas where physiological uptake may occur, like stomach and bone marrow (as in this case).

Case 2  HD Staging

3

Male 48 yo

Transaxial CT

MIP

Transaxial PET

81

Fused Transaxial

⊡⊡ Staging HD

⊡ ⊡ PET findings Multiple areas of increased uptake in supradiaphragmatic lymph nodes. Single focal uptake in an infradiaphragmatic paracaval lymph node

Teaching point Whole-body FDG-PET may correctly upstage patients showing unknown positive lymph nodes. In this case patient has been correctly uptstaged to stage III.

3

Case 3  HD Staging Male 34 yo

MIP

Sagittal CT

Coronal CT

82

Sagittal PET

Coronal PET

Fused Sagittal

Fused Coronal

⊡⊡ Staging

⊡ ⊡ PET findings Multiple areas of increased uptake in lymph nodes and bone marrow

Teaching point Whole-body FDG-PET shows a high accuracy of identification of bone marrow involvement in lymphoma patients. If FDG PET/CT is performed for staging of HL, bone marrow biopsy is no longer needed.

Case 4  NHL Staging

3

Male 46 yo

⊡ ⊡ PET findings Many areas of increased uptake in the laterocervical, axillary, mediastinal, paraaortic, interaortocaval, iliac, and inguinal lymph nodes. The spleen is also enlarged and with diffusely increased uptake consistent with disease infiltration

Teaching point

⊡⊡ Staging of NHL

PET is highly sensitive in detecting nodal and extranodal involvement by most histologic subtypes of lymphoma prior to treatment. Most common types of lymphoma (e.g., diffuse large B-cell NHL, follicular NHL, mantle cell NHL, HD) are routinely FDG avid with a sensitivity and a specificity that exceed 90%.

83

3

Case 5  NHL Staging Female 36 yo

a

b

⊡⊡ Staging of NHL

⊡ ⊡ PET findings Many areas of FDG increased uptake in the abdomen (a) and at a left supraclavicular lymph node (b), not known before PET scanning 84

Teaching point PET is highly sensitive in lymphoma staging; nonetheless the identification of more involved nodes, as compared to CT, does not necessarily have an impact on patient management. The identification of nodal involvement above the diaphragm in this case modifies the stage and the treatment of the patient.

Case 6  NHL Staging

3

Male 36 yo

Transaxial CT

MIP

Fused Transaxial

⊡⊡ NHL at presentation

⊡ ⊡ PET findings Small area of increased uptake in the soft tissue surrounding the right iliac bone. Patient underwent a bone marrow biopsy 2 days before the scan

Teaching point Bone marrow biopsy may be carried out at the level of posterior iliac bone. The area of increaed uptake should not be misinterpreted and confused with a positivity of PET in the bone marrow. A correct clinical history of patients should always be collected before the scan.

85

3

Case 7  Primary Cutaneous NHL—Staging Female 56 yo

⊡⊡ Staging primary cutaneous lymphoma

MIP

86

⊡ ⊡ PET findings Areas of intense FDG uptake in skin nodules in the right leg

Teaching point PET may help in staging aggressive subtypes of primary cutaneous lymphomas.

Case 8  NHL Follicular—Staging

3

Male 75 yo

Transaxial CT MIP

⊡ ⊡ PET findings

Transaxial PET

Multiple areas of FDG faint uptake in retroperitoneal lymph nodes

Teaching point

Fused Transaxial

⊡⊡ Follicular NHL at presentation

The degree of uptake in follicular lymphoma is variable as the uptake of FDG could be faint or moderate. CT co-­ registered images should be evaluated with attention in order to detect enlarged lymph nodes characterized by faint uptake of FDG.

87

3

Case 9  Histocytosis—Staging Male 45 yo

Coronal CT

Coronal PET

Transaxial CT

Transaxial PET

Fused Coronal

MIP

Fused Transaxial

⊡⊡ Staging histiocytosis

⊡ ⊡ PET findings 88

Multiple areas of increased uptake in lymph nodes (axillas, retroperitoneal, and right iliac chain) and bone (skull, ribs, left pelvis)

Teaching point Whole-body FDG-PET may be useful to correctly stage Langerhans cell histiocytosis and to note the lytic lesions in the skull. The physiological uptake of FDG in the brain tissue may hide the focal FDG uptake that however corresponds exactly to a small lytic lesion in the left parietal bone.

Case 10  NHL Indolent—Staging

3

Male 34 yo

Transaxial CT

Fused Transaxial

Transaxial CT

Fused Transaxial

⊡ ⊡ PET findings No areas of FDG uptake in the enlarged laterocervical and mediastinal lymph nodes

Teaching point

MIP

⊡⊡ Staging indolent lymphoma

Whole-body FDG-PET is a very accurate diagnostic technique for evaluation of aggressive lymphoma like DLBCL, but not indolent lymphoma.

89

3

Case 11  HD Staging and Early Therapy Evaluation Female 43 yo

a

b

⊡⊡ HD at presentation and after two courses of treatment (ABVD)

⊡ ⊡ PET findings 90

Staging PET (a) shows some hypermetabolic areas in right laterocervical, bilateral supraclavicular, and antero-mediastinal nodes. Post-therapy PET (b): complete response to therapy

Teaching point PET has been used for early evaluation of HD and NHL during treatment. Early PET scan can be performed after three, two, or even one single course of chemotherapy, allowing to discriminate patients with a good prognosis (early responder) from those with a worst prognosis [tbd].

Case 12  HD Staging and Therapy Evaluation

3

Male 51 yo

a

b

⊡⊡ HD at presentation (a) and after therapy (b)

⊡ ⊡ PET findings Staging PET (a) shows elevated hypermetabolism of a bulky mediastinal mass. Complete remission after chemo + radiotherapy (b)

Teaching point Despite the complete response, CT imaging shows the bulky mass almost unchanged. Conventional imaging indeed is generally unable to detect the differences between tumor tissue and fibrosis, while PET evaluates metabolism and therefore active residual tumor.

91

3

Case 13  NHL Low-Grade Intestinal—Staging and Therapy Evaluation Male 61 yo

a

b

⊡⊡ Low-grade intestinal NHL at presentation (a) and after therapy (b)

⊡ ⊡ PET findings Staging PET (a) shows active disease at bowel level. Complete remission after chemotherapy (b)

92

Teaching point PET can demonstrate the presence and extension of disease also in low-­ grade lymphomas and in challenging localizations (bowel, bone, spleen), even if the accuracy can be lower. In such cases PET can surely be used to evaluate the response to treatment.

Case 14  HD Staging and Therapy Evaluation

3

Female 21 yo

a

b

⊡⊡ HD at presentation (a) and after therapy (b)

⊡ ⊡ PET findings Staging PET (a) shows a large mediastinal mass with involvement of other supradiaphragmatic nodes. Complete response after chemotherapy (b) with evident thymic rebound

Teaching point PET can demonstrate the response to therapy. In young patients PET images after treatment should be carefully evaluated. Note the FDG uptake in mediastinum with the typical aspect and shape of thymus: this finding is frequent and should be recognized. 93

3

Case 15  NHL T cell—Staging and Early Evaluation of Treatment Male 56 yo

Coronal CT

Coronal PET

Fused Coronal MIP

Coronal CT

Coronal PET

Fused Coronal MIP

94

⊡⊡ NHL T-cell staging

⊡ ⊡ PET findings Multiple areas of pathological FDG uptake in the enlarged laterocervical and mediastinal lymph nodes

Teaching point T-cell lymphomas are generally FDG avid as B-cell lymphoma but not in all cases. Therefore it is mandatory to perform a baseline whole-body FDG-PET if a response assessment is needed.

Case 16  NHL at 2. Relapse and After Treatment

3

Female 21 yo

a

b

⊡⊡ NHL at second relapse (a) and after therapy (b)

⊡ ⊡ PET findings PET (a) shows a relapse in left supraclavicular nodes and in mediastinum PET (b) performed after second line therapy shows complete remission

Teaching point PET can demonstrate the response to treatment after completion of therapy. It is usually suggested to wait at least 4 weeks after chemotherapy completion and 3 months after radiotherapy or radioimmunotherapy completion.

95

3

Case 17  NHL at 1. Relapse and After Treatment Female 31 yo

a

b

⊡⊡ NHL at first relapse (a) and after therapy (b)

⊡ ⊡ PET findings Relapse PET (a) shows active disease at mediastinal and lung level. Partial remission after chemotherapy (b)

96

Teaching point PET can demonstrate the persistence of disease after completion of therapy. In the first scan (a) a focal area of increased uptake is evident in the left pelvis, consistent with folliculum (physiological finding after ovulation).

Case 18  NHL Evaluation at the End of Treatment

3

Male 38 yo

97

⊡⊡ NHL after chemotherapy

⊡ ⊡ PET findings

Teaching point

Several small areas of increased uptake at lymph nodes (not enlarged at CT), consistent with residual disease

PET can demonstrate the presence of residual disease more accurately than CT.

3

Case 19  NHL Recurrence Detection Female 39 yo

CT Transaxial Fused Transaxial

⊡⊡ Recurrence of NHL

⊡ ⊡ PET findings Several areas of FDG increased uptake in the mediastinum, bilateral supraclavicular (brown fat), paracardiac, right homerus, and left iliac wing (recurrence) 98

Teaching point In presence of sites of relapse and active brown fat, the degree of uptake has limited value to discriminate between relapse and physiological uptake. CT imaging may help in the differential diagnosis.

Case 20  Solitary Plasmacytoma

3

Male 55 yo

a

b

⊡⊡ Solitary plasmacytoma of the left pelvis

⊡ ⊡ PET findings FDG PET/CT showing increased uptake in the left pelvis lesion (a) supposed to be solitary plasmacytoma of bone after WB-Rx and MRI. PET showed a second right-rib lesion (b) shifting the diagnosis to MM

Teaching point FDG PET/CT is more sensitive for the detection of lytic bone lesions than WB Rx. False-negative results are likely caused by previous chemotherapy administration, which must be avoided to correctly stage patients. In comparison with MRI, PET detects the same number of lytic lesions in spine and pelvis, but its advantage is the large field of view. However, PET/CT is not able to detect infiltrative patterns of the spine.

99

3

Case 21  Multiple Myeloma—Staging Female 71 yo

⊡⊡ Multiple myeloma. Staging

⊡ ⊡ PET findings Multiple hypermetabolic lesions of the humerus, scapula, rib, pelvis, sternum, and femur

100

Teaching point Currently, conventional radiographic skeletal surveys, magnetic resonance imaging, and F-18 FDG PET/CT examinations are the most useful instruments for staging myeloma (PET sensivity is 85% and specificity is 92%). FDG-PET is also useful for evaluating therapy response.

Case 22  Multiple Myeloma—Staging

3

Male 52 yo

⊡⊡ Myeloma with a solitary lesion at conventional imaging. Staging

⊡ ⊡ PET findings Increased uptake at pelvic known lesion; evidence of another lesion at right scapula

Teaching point At disease presentation it is particularly important to identify all active lesions, as treatment of multiple myeloma may be different in case of solitary lesion. In these unfrequent cases PET should be performed in order to rule out the presence of other localizations.

101

Chapter 4

Malignancies in Dermatology

Malignancies in Dermatology  ������������������������������  104 Staging in the AJCC Stages (I and II)  ��������������������  104 Staging in the AJCC Stages (III and IV)  ����������������  104 Recurrence  ���������������������������������������������������������������  104 References  ����������������������������������������������������������������  104 Case 1

Melanoma Restaging  ������������������������������  105

Case 2

Melanoma Restaging After Local Treatment  �������������������������������������������������  106

Case 3

Melanoma Restaging After Local Treatment  �������������������������������������������������  107

Case 4

Melanoma Restaging  ������������������������������  108

Case 5

Melanoma Restaging After Immunotherapy  ��������������������������������������  109

Case 6

Melanoma Suspicion of Relapse  �����������  111

Case 7

Melanoma Suspicion of Relapse  �����������  112

Case 8

Melanoma Restaging  ������������������������������  113

Case 9

Melanoma After Surgery: Follow-Up Scan  ����������������������������������������  114

Case 10 Melanoma Restaging After Primary Resection  �����������������������������������  115

© Springer-Verlag GmbH Germany, part of Springer Nature 2018 S. Fanti et al., Atlas of PET-CT, https://doi/org/10.1007/978-3-662-57742-4_4

4

Malignancies in Dermatology

Malignancies in Dermatology Cutaneous melanoma represents 5% of all malignant tumors and its incidence has increased in recent years [1]. Melanoma is aggressive due to its ability to metastasize in early stages of the disease. Early diagnosis is essential for a better prognosis. A four-stage scale (I, II, III, IV) has been proposed by the American Joint Committee on Cancer (AJCC) [2]. PET/CT using FDG may have a role in some steps of the natural history of melanoma.

Staging in the AJCC Stages (I and II) The method of choice to stage lymph node status in patients with melanoma is sentinel lymph node biopsy [3]. The value of FDG PET/CT in the detection of nodal involvement in melanoma is limited by the low sensitivity [4]. FDG PET/CT has shown good accuracy in the detection of distant lesions; however the likelihood of distant metastases in early stages is very low, so that the use of FDG PET/CT should be reserved to selected cases [4].

Staging in the AJCC Stages (III and IV)

104

FDG PET/CT has a role in the detection of distant lesions in stage III or IV and it performs better than conventional imaging [5]. FDG PET/CT has shown a sensitivity that ranges between 80 and 100%. Moreover, it may change the initial stage in a significant proportion of patients and in a small percent of the cases it may also lead to a change in clinical management. According to these good results a pre-­ therapy FDG PET/CT may be suggested in many patients at high risk for the presence of distant lesions.

Recurrence FDG PET/CT has a major role in the detection of recurrent melanoma. In this application PET has shown an accuracy that ranges from 70 to 100% [6].

Main limitation of PET is the low sensitivity in the detection of brain lesions so that a brain CT or MR should always be added to the diagnostic flowchart of these patients [6]. Finally, as for other solid tumors FDG PET/CT may be used to assess treatment response and to correlate metabolic response to disease-free survival and overall survival [7]. In conclusion, FDG PET/CT may be a useful tool in staging melanoma with high-risk factors for distant metastases [8]. It may be useful to detect recurrence or to restage disease, and finally it may be used to assess response to chemotherapy or immunotherapy. References 1. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et  al. Final version of the American joint committee on cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635–48. 2. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206. 3. Morton DL, Cohcran AJ, Thompson JF, Elashoff R, Essner R, Glass EC, et  al. Sentinel node biopsy for early-stage of melanoma: accuracy and m ­ orbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302–13. 4. Wagner T, Meyer N, Zerdoud S, Julian A, Chevreau C, Payoux P, et al. Fluorodeoxyglucose positron emission tomography fails to detect distant metastases at initial staging of melanoma patients with metastatic involvement of sentinel lymph node. Br J Dermatol. 2011;164:1235–40. 5. Strobel K, Dummer R, Husarik DB, Pérez Lago M, Hany TF, Steinert HC.  High-risk melanoma: accuracy of FDG PET/CT with added CT morphologic information for detection of metastases. Radiology. 2007;244:566–74. 6. Danielsen M, Højgaard L, Kjær A, Fischer BM.  Positron emission tomography in the followup of cutaneous malignant melanoma patients: a systematic review. Am J Nucl Med Mol Imaging. 2013;4(1):17–28. 7. Rohren EM.  PET/computed tomography and patient outcomes in melanoma. PET Clin. 2015;10(2):243–54. 8. Cha J, Kim S, Wang J, Yun M, Cho A. Evaluation of 18F-FDG PET/CT parameters for detection of lymph node metastasis in cutaneous melanoma. Nucl Med Mol Imaging. 2018;52(1):39–45.

Case 1  Melanoma Restaging

4

Female 74 yo

⊡⊡ Advanced vulvar melanoma; restaging

⊡ ⊡ PET findings Several areas of increased uptake at local level, bones, lung, and liver

Teaching point Whole body PET/CT scanning is strongly suggested in advanced stages.

105

4

Case 2  Melanoma Restaging After Local Treatment Male 54 yo

⊡⊡ Advanced melanoma, after local treatment; restaging

106

⊡ ⊡ PET findings Several areas of increased uptake in the head and neck region, liver, and subcutaneous nodules

Teaching point Melanoma may spread to all parts of the body. FDG-PET scanning should be preferably performed as a full total body scan.

Case 3  Melanoma Restaging After Local Treatment

4

Male 54 yo

⊡⊡ Advanced melanoma, after local treatment; restaging

⊡ ⊡ PET findings Several areas of increased uptake in the supradiaphragmal and infradiaphragmal lymph nodes and at the brain

Teaching point 107

Usually FDG-PET scanning shows limited value for detection of brain secondary lesions; however high uptake of melanoma lesions permits to detect also brain metastases. It should be pointed out that MR remains the elective method for evaluation of brain lesions.

4

Case 4  Melanoma Restaging Male 52 yo

Teaching point

⊡⊡ Melanoma of the back after surgery followup scan a

b

108

⊡ ⊡ PET findings Soft tissue hypermetabolic lesions in paravertebral region, loin and gluteus (red arrows on MIP), axillary and abdominal lymph nodes (b), and liver (a)

Melanoma of the skin may spread either locally or regionally and to distant sites through predictable or unpredictable metastatic pathways. Routine protocols based on clinical examinations and traditional radiologic evaluations are not cost effective for the detection of systemic disease. In the last decade, nuclear medicine techniques, such as lymphoscintigraphy-directed lymphatic mapping with sentinel lymphadenectomy and PET, have played key roles in nodal and distant staging of melanoma.

Case 5  Melanoma Restaging After Immunotherapy

4

Male 54 yo

a ⊡⊡ Restaging melanoma after immunotherapy

b

109

4

Case 5  Melanoma Restaging After Immunotherapy Male 54 yo

a

b

⊡ ⊡ PET findings Several areas of increased uptake due to disseminated advanced melanoma before (a) and after immunotherapy (b)

110

Teaching point The role of FDG-PET for response assessment of patient treated with immunomodulation therapies is under investigation. FDG-PET seems to be a promising tool for early response assessment, evaluation of treatment response duration, and monitoring resistences. This might help to shorten therapy regimes and avoid unnecessary side effects in the future.

Case 6  Melanoma Suspicion of Relapse

4

Female 49 yo

⊡⊡ Melanoma operated 9 years before (left arm), at CT-suspected adrenal mass

⊡ ⊡ PET findings Increased uptake in a left adrenal mass and in a right nuchal lymph node

Teaching point PET is useful for restaging melanoma patients with suspected recurrence.

111

4

Case 7  Melanoma Suspicion of Relapse Male 35 yo

⊡⊡ Melanoma already operated, suspected abdominal recurrence at CT scan

⊡ ⊡ PET findings 112

Several hypermetabolic areas in abdominal and pelvic lymph nodes and in the lets chest (subcutaneous small nosdule)

Teaching point The localization of recurrence sites of melanoma may be difficult, and CT images are almost necessary to properly identify the lesions.

Case 8  Melanoma Restaging

4

Male 72 yo

⊡⊡ Advanced melanoma, restaging

⊡ ⊡ PET findings Several areas of increased uptake in the lower limb; area of high uptake in the bowel

Teaching point Melanoma may spread to all parts of the body. FDGPET-detected metastasis in the bowel, which is not easy to identify with other diagnostic methods

113

4

Case 9  Melanoma After Surgery: Follow-Up Scan Male 52 yo

Teaching point 114

⊡⊡ Melanoma already operated, follow-­up scan

⊡ ⊡ PET findings Two hyper metabolic areas in a thoracic vertebra and in the spleen

Melanoma of the skin may spread either locally or regionally and to distant sites through predictable or unpredictable metastatic pathways. In this case the increased uptake in the bowel is also evident, especially in the distal colon, not attributable to oncological origin but simply to inflammatory and irritative causes.

Case 10  Melanoma Restaging After Primary Resection

4

Male 48 yo

⊡⊡ Follow-up in patient with melanoma of the right leg

Teaching point

⊡ ⊡ PET findings Intense FDG uptake in a retroperitoneal lymph node

In early-stages melanoma. Whole body PET/CT scan does not impact on management. However Whole body PET/ CT should be suggested in: • Individuals with a high risk for distant metastases based on the extent of loco-­regional disease • Patients with findings that are suspicious for distant metastases at Conventional Imaging • Individuals with known metastasis who may benefit from customized therapies

115

Chapter 5

Thoracic Malignancies

References  ����������������������������������������������������������������  118 Case 1

Solitary Lung Nodule  ������������������������������  119

Case 2

Solitary Lung Nodule  ������������������������������  120

Case 3

Solitary Lung Nodule  ������������������������������  121

Case 4

Solitary Lung Nodule  ������������������������������  122

Case 5

Solitary Lung Nodule  ������������������������������  123

Case 6

Bilateral Lung Nodules  ���������������������������  124

Case 7

Lung Adenocarcinoma—Staging  ����������  125

Case 8

Lung Adenocarcinoma—Staging  ����������  126

Case 9

Lung Adenocarcinoma—Staging  ����������  127

Case 10 Lung Adenocarcinoma—Staging  ����������  128 Case 11 Lung Adenocarcinoma—Staging  ����������  129 Case 12 Lung Adenocarcinoma—Staging  ����������  130 Case 13 Pancoast Lung Cancer—Staging  �����������  131 Case 14 Lung Adenocarcinoma—Staging  ����������  132 Case 15 Mesothelioma—Staging 

������������������������  133

Case 16 Mesothelioma—Staging 

������������������������  134

Case 17 Peritoneal Mesothelioma—Staging  �����  135 Case 18 Lung Adenocarcinoma—Radiation Treatment Planning  ��������������������������������  136 Case 19 Mesothelioma—Staging and Early Evaluation of Treatment  �������  138 Case 20 Lung Adenocarcinoma—Chemotherapy Evaluation  ������������������������������������������������  139 Case 21 Mesothelioma—Evaluation of Treatment  ��������������������������������������������  140 Case 22 Lung Adenocarcinoma—Restaging After Local Relapse Detection  ���������������  141 Case 23 Lung Adenocarcinoma—Suspicion of Relapse  �������������������������������������������������  142 Case 24 Lung Metastasis  ��������������������������������������  143 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 S. Fanti et al., Atlas of PET-CT, https://doi/org/10.1007/978-3-662-57742-4_5

5

118

Thoracic Malignancies

Lung cancer is the leading cause of cancer death worldwide. The management of non-small cell lung cancer (NSCLC) requires a multidisciplinary approach to diagnose, stage, and address patients to a correct therapy. In the last few years, the advent of FDG PET/CT has dramatically influenced the staging, the treatment, and the follow-up of NSCLC patients. Main applications of PET/CT are evaluation of pulmonary lesions, staging, response to treatment assessment, and follow-up of patients with NSCLC. In the primary evaluation of pulmonary lesions, FDG-PET scans are useful to distinguish between benign and malignant etiologies. Although numerous non-­malignancy-­related conditions within the lungs take up FDG, including infection and inflammation, extensive work has been done in correlating FDG-PET positivity with pathological malignancy. PET is particularly useful in differentiating benign from malignant obstructions in the setting of atelectasis. However only lesions bigger than 1 cm in size can be characterized with a high accuracy by FDG-PET.  In a recent study PET showed a positive predictive value (PPV) to be significantly lower in lesions