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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5762_Библиотеки_им_академика_М_И_Перельмана.pdf
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- •Preface
- •Contents
- •1.1 Historical Remarks
- •1.1.1 Contrast Enhanced Ultrasound
- •2.2 Machine Settings
- •1.4 CEUS Phases
- •1.8 Three-Dimensional (3D) CEUS
- •1.9 CEUS Guidelines
- •References
- •2.1 Introduction
- •2.2.2 Image Depth Penetration
- •2.2.3 Focus
- •2.2.5 Background Signal (Noise)
- •2.2.6 Dynamic Range
- •2.2.7 Frame Rate
- •2.6 Artifacts
- •2.6.1 Long Liver Enhancement
- •2.7 Safety
- •References
- •3.1 Introduction
- •3.7 Detection by Intraoperative Contrast Enhanced Ultrasound (IO-CEUS)
- •References
- •4: Malignant Liver Tumors
- •4.1 Hepatocellular Carcinoma
- •4.1.1 Introduction
- •4.1.6 Surveillance
- •4.1.7 CEUS LI-RADS
- •4.1.8 Small HCC
- •4.1.9 Treatment Response Follow Up
- •4.1.9.1 Ablation Therapy
- •4.1.9.2 Transarterial Chemoembolization
- •4.1.9.3 Targeted Therapy
- •4.2 Intrahepatic Cholangiocarcinoma
- •4.2.2 Imaging
- •4.2.2.1 Conventional Ultrasound Findings
- •4.2.2.2 Contrast Enhanced Ultrasound Findings
- •4.2.2.3 CT Findings
- •4.2.2.4 MRI Findings
- •4.2.2.5 Other Imaging Findings
- •4.2.2.6 Best Imaging Protocol Advices
- •4.2.3.1 Hepatocellular Carcinoma
- •4.2.4 Pathology
- •4.2.4.1 General Features
- •4.2.5 Clinical Issues
- •4.2.5.1 Presentation
- •4.2.5.2 Prognosis
- •4.2.5.3 Treatment
- •4.3 Liver Metastases
- •4.3.1 Terminology
- •4.3.2 Imaging Features
- •4.3.2.1 Conventional Ultrasound Findings
- •4.3.2.2 Contrast Enhanced Ultrasound Findings
- •4.3.2.3 CT Findings
- •4.3.2.4 MRI Findings
- •4.3.3.1 Hepatocellular Carcinoma
- •4.3.3.2 Intrahepatic Cholangiocarcinoma
- •4.3.3.3 Focal Fatty Liver Change
- •4.4 Dysplasia Nodules
- •4.4.1 Terminology
- •4.4.2 Imaging
- •4.4.2.1 Conventional Ultrasound Findings
- •4.4.2.2 Contrast Enhanced Ultrasound Findings
- •4.4.2.3 CT Findings
- •4.4.2.4 MRI Findings
- •4.4.2.5 Best Imaging Protocol Advices
- •4.4.4 Pathology
- •4.4.4.1 General Features
- •4.4.5 Clinical Issues
- •4.4.5.1 Presentation
- •4.4.5.2 Prognosis
- •4.4.5.3 Treatment
- •References
- •5: Benign Liver Tumors
- •5.1 Hepatic Hemangioma
- •5.1.1 Terminology
- •5.1.2 Imaging
- •5.1.2.1 Conventional Ultrasound Findings
- •5.1.2.2 Contrast Enhanced Ultrasound Findings
- •5.1.2.3 CT Findings
- •5.1.2.4 MRI Findings
- •5.1.2.5 Other Imaging Findings
- •5.1.2.6 Best Imaging Protocol Advices
- •5.1.3.1 Hepatocellular Carcinoma
- •5.1.3.2 Metastatic Hepatic Carcinoma
- •5.1.3.3 Focal Angiosarcoma
- •5.1.3.4 Abscess
- •5.1.3.5 Hepatic Adenoma
- •5.1.4 Pathology
- •5.1.4.1 General Features
- •5.1.5 Clinical Issues
- •5.1.5.1 Presentation
- •5.1.5.2 Prognosis
- •5.1.5.3 Treatment
- •5.2 Focal Nodular Hyperplasia
- •5.2.1 Terminology
- •5.2.2 Imaging
- •5.2.2.1 Conventional Ultrasound Findings
- •5.2.2.2 Contrast Enhanced Ultrasound Findings
- •5.2.2.3 CT Findings
- •5.2.2.4 MRI Findings
- •5.2.2.5 Other Imaging Findings
- •5.2.2.6 Best Imaging Protocol Advices
- •5.2.3.1 Hepatic Adenoma
- •5.2.3.2 Hepatocellular Carcinoma
- •5.2.3.3 Fibrolamellar Hepatocellular Carcinoma
- •5.2.4 Pathology
- •5.2.4.1 General Features
- •5.2.5 Clinical Issues
- •5.2.5.1 Prognosis
- •5.2.5.2 Treatment
- •5.3 Hepatocellular Adenoma
- •5.3.1 Terminology
- •5.3.2 Imaging
- •5.3.2.1 Ultrasonographic Findings
- •5.3.2.2 Contrast Enhanced Ultrasound Findings
- •5.3.2.3 CT Findings
- •5.3.2.4 MRI Findings
- •5.3.2.5 Imaging Recommendations
- •5.3.3.1 Focal Nodular Hyperplasia
- •5.3.3.2 Hepatocellular Carcinoma
- •5.3.3.3 Fibrolamellar Hepatocellular Carcinoma
- •5.3.3.4 Hepatic Hemangioma
- •5.3.4 Pathology
- •5.3.4.1 General Features
- •5.3.5 Clinical Issues
- •5.3.5.1 Presentation
- •5.3.5.2 Complications
- •5.4.1 Terminology
- •5.4.2 Imaging
- •5.4.2.1 Conventional Ultrasound Findings
- •5.4.2.2 Contrast Enhanced Ultrasound Findings
- •5.4.2.3 CT Findings
- •5.4.2.4 MRI Findings
- •5.4.2.5 Other Imaging Findings
- •5.4.2.6 Best Imaging Protocol Advices
- •5.4.3.1 Hepatocellular Carcinomas
- •5.4.3.2 Metastases
- •5.4.3.3 Hemangioma
- •5.4.4 Pathology
- •5.4.4.1 General Features
- •5.4.5 Clinical Issues
- •5.4.5.1 Presentation
- •5.4.5.2 Prognosis
- •5.4.5.3 Treatment
- •References
- •6: Rare Malignant Liver Tumors
- •6.1 Hepatic Lymphoma
- •6.1.1 Terminology
- •6.1.2 Imaging
- •6.1.2.1 Conventional Ultrasound Findings
- •6.1.2.2 Contrast Enhanced Ultrasound Findings
- •6.1.2.3 CT Findings
- •6.1.2.4 MRI Findings
- •6.1.2.5 Other Imaging Findings
- •6.1.2.6 Best Imaging Protocol Advices
- •6.1.4 Pathology
- •6.1.4.1 General Features
- •6.1.5 Clinical Issue
- •6.1.5.1 Presentation
- •6.1.5.2 Prognosis
- •6.1.5.3 Treatment
- •6.2.1 Terminology
- •6.2.2 Imaging
- •6.2.2.1 General Features
- •6.2.2.2 Conventional Ultrasound Findings
- •6.2.2.3 Contrast Enhanced Ultrasound Findings
- •6.2.2.4 CT Findings
- •6.2.2.5 MRI Findings
- •6.2.2.6 Other Imaging Findings
- •6.2.2.7 Imaging Recommendations
- •6.2.4 Pathology
- •6.2.4.1 General Features
- •6.2.5 Clinical Issues
- •6.2.5.1 Presentation
- •6.2.5.2 Prognosis
- •6.2.5.3 Treatment
- •6.3.1 Terminology
- •6.3.2 Imaging
- •6.3.2.1 Conventional Ultrasound Findings
- •6.3.2.3 Computed Tomography Findings
- •6.3.2.4 Magnetic Resonance Imaging Findings
- •6.3.2.5 Nuclear Medicine Findings
- •6.3.2.6 Imaging Recommendations
- •6.3.3.1 Focal Nodular Hyperplasia
- •6.3.3.2 Hepatocarcinoma
- •6.3.3.4 Hepatoadenoma
- •6.3.3.5 Intrahepatic Cholangiocarcinoma
- •6.3.4 Pathology
- •6.3.4.1 General Features
- •6.3.5 Clinical Issues
- •6.3.5.1 Presentation
- •6.3.5.2 Prognosis
- •6.3.5.3 Treatment
- •6.4 Hepatic Biliary Cystadenocarcinoma
- •6.4.1 Terminology
- •6.4.2 Imaging
- •6.4.2.1 Conventional Ultrasound Findings
- •6.4.2.2 Contrast Enhanced Ultrasound Findings
- •6.4.2.3 CT Findings
- •6.4.2.4 MRI Findings
- •6.4.2.5 Other Imaging Findings
- •6.4.2.6 Best Imaging Protocol Advices
- •6.4.3.1 Hepatic Biliary Cystadenoma
- •6.4.3.2 Simple Hepatic Cysts
- •6.4.3.3 Hemorrhagic Hepatic Cysts
- •6.4.3.4 Metastatic Tumor
- •6.4.3.5 Hepatic Abscesses
- •6.4.3.6 Hydatid Disease
- •6.4.3.9 Mesenchymal Hamartoma
- •6.4.4 Pathology
- •6.4.4.1 General Features
- •6.4.5 Clinical Issues
- •6.4.5.1 Presentation
- •6.4.5.2 Prognosis
- •6.4.5.3 Treatment
- •6.5 Neuroendocrine Neoplasm
- •6.5.1 Terminology
- •6.5.2 Image
- •6.5.2.1 Ultrasonographic Findings
- •6.5.2.2 Contrast Enhanced Ultrasound Findings
- •6.5.2.3 CT Findings
- •6.5.2.4 MR Findings
- •6.5.2.5 Other Imaging Finding
- •6.5.2.6 Best Imaging Protocol Advices
- •6.5.3.1 Hepatocellular Carcinoma
- •6.5.3.2 Metastatic Hepatic Carcinoma
- •6.5.4 Pathology
- •6.5.4.1 General Features
- •6.5.5 Clinical Issues
- •6.5.5.1 Presentation
- •6.5.5.2 Prognosis
- •6.5.5.3 Treatment
- •6.6.1 Terminology
- •6.6.2 Imaging
- •6.6.2.1 Conventional Ultrasound Findings
- •6.6.2.2 Contrast Enhanced Ultrasound Findings
- •6.6.2.3 CT Findings
- •6.6.2.4 MRI Findings
- •6.6.2.5 PET/CT Findings
- •6.6.2.6 Best Imaging Protocol Advices
- •6.6.3.1 Hepatocellular Carcinoma
- •6.6.3.2 Cholangiocarcinoma
- •6.6.3.3 Metastatic Liver Cancer
- •6.6.4 Pathology
- •6.6.5 Clinical Issues
- •References
- •7: Rare Benign Liver Tumors
- •7.1 Hepatic Angiomyolipoma
- •7.1.1 Terminology
- •7.1.2 Imaging
- •7.1.2.1 Conventional Ultrasound Findings
- •7.1.2.2 Contrast Enhanced Ultrasound Findings
- •7.1.2.3 CT Findings
- •7.1.2.4 MRI Findings
- •7.1.2.5 Other Imaging Findings
- •7.1.2.6 Best Imaging Protocol Advices
- •7.1.4 Pathology
- •7.1.4.1 General Features
- •7.1.5 Clinical Issues
- •7.1.5.1 Presentation
- •7.1.5.2 Prognosis
- •7.1.5.3 Treatment
- •7.2 Hepatic Biliary Cystadenoma
- •7.2.1 Terminology
- •7.2.2 Imaging
- •7.2.2.1 Conventional Ultrasound Findings
- •7.2.2.2 Contrast Enhanced Ultrasound Features
- •7.2.2.3 CT Findings
- •7.2.2.4 MRI Findings
- •7.2.2.5 Other Imaging Findings
- •7.2.2.6 Best Imaging Protocol Advices
- •7.2.3.1 Hepatic Biliary Cystadenocarcinoma
- •7.2.3.2 Simple Hepatic Cyst
- •7.2.3.3 Hemorrhagic Hepatic Cysts
- •7.2.3.4 Metastatic Tumor
- •7.2.3.5 Hepatic Abscesses
- •7.2.3.6 Hydatid Disease
- •7.2.3.9 Mesenchymal Hamartoma
- •7.2.4 Pathology
- •7.2.4.1 General Features
- •7.2.5 Clinical Issues
- •7.2.5.1 Presentation
- •7.2.5.2 Prognosis
- •7.2.5.3 Treatment
- •References
- •8: Hepatic Parasitosis
- •8.1 Terminology
- •8.1.1 Echinococcosis
- •8.1.2 Amebiasis
- •8.1.3 Schistosomiasis
- •8.2 Imaging
- •8.2.1 Conventional Ultrasound Findings
- •8.2.1.1 Echinococcosis
- •8.2.1.2 Amebiasis
- •8.2.1.3 Schistosomiasis
- •8.2.2 Contrast Enhanced Ultrasound Findings
- •8.2.2.1 Echinococcosis
- •8.2.3 CT Findings
- •8.2.3.1 Echinococcosis
- •8.2.3.2 Amebiasis
- •8.2.3.3 Schistosomiasis
- •8.2.4 MRI Findings
- •8.2.4.1 Echinococcosis
- •8.2.4.2 Amebiasis
- •8.2.4.3 Schistosomiasis
- •8.2.5 Other Imaging Findings
- •8.2.5.1 Echinococcosis
- •8.2.6 Best Imaging Protocol Advices
- •8.2.6.1 Echinococcosis
- •8.2.6.2 Amebiasis
- •8.2.6.3 Schistosomiasis
- •8.3 Pathology
- •8.3.1 General features
- •8.3.1.1 Echinococcosis
- •8.3.1.2 Amebiasis
- •8.3.2.1 Echinococcosis
- •8.4 Clinical Issues
- •8.4.1 Presentation
- •8.4.1.1 Echinococcosis
- •8.4.1.2 Amebic Liver Abscess
- •8.4.1.3 Schistosomiasis
- •8.4.2 Prognosis
- •8.4.2.1 Echinococcosis
- •8.4.2.2 Amebiasis
- •8.4.2.3 Schistosomiasis
- •8.4.3 Treatment
- •8.4.3.1 Echinococcosis
- •8.4.3.2 Amebiasis
- •8.4.3.3 Schistosomiasis
- •References
- •9: Hepatic Inflammatory Pseudotumor
- •9.1 Terminology
- •9.2 Imaging
- •9.2.1 Conventional Ultrasound Findings
- •9.2.2 Contrast Enhanced Ultrasound Findings
- •9.2.3 CT Findings
- •9.2.4 MRI Findings
- •9.2.5 Other Imaging Findings
- •9.2.6 Best Imaging Protocol Advices
- •9.3.1 Hepatocellular Carcinoma
- •9.3.2 Liver Metastasis Tumor
- •9.3.3 Intrahepatic Cholangiocarcinoma
- •9.3.4 Liver Abscess
- •9.4 Pathology
- •9.4.1 General Features
- •9.5 Clinical Issues
- •9.5.1 Presentation
- •9.5.2 Prognosis
- •9.5.3 Treatment
- •References
- •10: Hepatic Artery Aneurysm
- •10.1 Terminology
- •10.2 Hepatic Artery Aneurysm
- •10.3 Imaging
- •10.3.1 General Features
- •10.3.2 Radiographic Findings
- •10.3.3 DSA Findings
- •10.3.4 CT Findings
- •10.3.5 Conventional Ultrasound Findings
- •10.3.7 MRI Findings
- •10.3.8 Best Imaging Protocol Advices
- •10.3.9 Protocol Advice
- •10.5 Pathology
- •10.5.1 General Features
- •10.6 Clinical Issues
- •10.6.1 Presentation
- •10.6.2 Prognosis
- •10.6.3 Treatment
- •References
- •11: Peliosis Hepatis
- •11.1 Terminology
- •11.2 Imaging
- •11.2.1 Conventional Ultrasound Findings
- •11.2.2 Contrast Enhanced Ultrasound Findings
- •11.2.3 CT Findings
- •11.2.4 MRI Findings
- •11.2.5 Other Imaging Findings
- •11.2.6 Best Imaging Protocol Advices
- •11.3.1 Hepatic Adenoma
- •11.3.2 Hemangioma
- •11.3.3 Focal Nodular Hyperplasia
- •11.3.4 Hepatic Abscess
- •11.3.5 Hypervascular Metastases
- •11.3.6 Hepatocellular Carcinoma
- •11.3.7 Arteriovenous Malformations
- •11.4 Pathology
- •11.4.1 General Features
- •11.5 Clinical Issues
- •11.5.1 Presentation
- •11.5.2 Prognosis
- •11.5.3 Treatment
- •References
- •12.1 Introduction
- •12.8 Summary
- •References
- •References
- •14.1 Introduction
- •14.2 Indications
- •14.3 Equipment
- •14.4 3D-CEUS Procedures
- •14.5 Clinical Application
- •References
- •15: Future Prospects
- •15.2 Improved Liver Metastasis Detection (Sonazoid)
- •References

Wen-PingWang· YiDong
ChristophF.Dietrich
Ernst MichaelJungEditors
Contrast-Enhanced
Ultrasound Imaging
ofHepatic Neoplasms
123

Contrast-Enhanced Ultrasound Imaging
of Hepatic Neoplasms

Wen-Ping Wang • Yi Dong
Christoph F. Dietrich • Ernst Michael Jung
Editors
Contrast-Enhanced
Ultrasound Imaging
of Hepatic Neoplasms

Editors
Wen-Ping Wang
Department of Ultrasound
Zhongshan Hospital
Fudan University
Shanghai
China
Yi Dong
Department of Ultrasound
Zhongshan Hospital
Fudan University
Shanghai
China
Christoph F. Dietrich
Allgemeine Innere Medizin
Kliniken Hirslanden Beau Site & Salem
und Permanence Bern
Bern
Switzerland
Ernst Michael Jung
Institute of Diagnostic Radiology
Interdisciplinary Ultrasound Department
University Hospital Regensburg
Regensburg
Germany
ISBN 978-981-16-1760-7 ISBN 978-981-16-1761-4 (eBook)
https://doi.org/10.1007/978-981-16-1761-4
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or
part of the material is concerned, specically the rights of reprinting, reuse of illustrations, recitation, broadcasting,
reproduction on microlms 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 specic 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,
expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been
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This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface
Contrast-enhanced ultrasound (CEUS) has revolutionized the clinical practice of liver tumor in
recent decades. Nowadays, ultrasound contrast agents (UCA) are usually well tolerated without hepatotoxic or nephrotoxic side effects. The advantages of CEUS include no radiation,
wide availability, absence of contraindications, no adverse events, and good cost efciency. In
comparison to CT or MRI, CEUS is the only “real-time” imaging technique that allows accurate and precise observation of contrast enhancement in the arterial phase. Liver tumors are
most commonly used area of CEUS clinically. CEUS has a high diagnostic accuracy in the
preoperative diagnosis of various malignant and benign focal liver lesions. Up till now, a standard textbook of clinical experience focusing on CEUS liver tumor has not been published.
For the last few decades, Zhongshan Hospital, Fudan University, is one of the most famous
and earliest application centers of liver CEUS throughout China. The editors have accessed a
wealth of experience from their expert contributors, who present the subject matter as concretely as possible and offer vivid descriptions of their own clinical practical techniques and
experiences. In this book, the editors and authors explore general aspects of CEUS features of
various kinds of benign and malignant liver tumors. It has a high diagnostic accuracy in the
differential diagnosis of focal liver lesions. Furthermore, CEUS is used for the detection of
metastases and therapeutic monitoring after local ablative procedures. The authors also introduce specic dynamic CEUS analysis and future developments. The editors and authors regard
patient’s clinical background information, such as presence of liver cirrhosis, history of other
malignancy, or incidental nding crucial for the correct interpretation of CEUS ndings. Also,
the examination procedure differs slightly depending on the specic clinical indications, such
as detection, characterization, or treatment response follow-up.
This book is an expression of interdisciplinary and multi-professional viewpoints. The principle of “clinical practice” is expressed in everyday practice. Particular attention should be
given to clinical signicance. We hope that this book will be useful for medical researchers and
clinicians—both students at the beginning of their careers and experienced investigators who
are well established. We are particularly hopeful that those at the beginning of their liver CEUS
careers will take this book as a way forward in understanding complex diseases, and this book
will help them in this journey. We also hope that clinicians will nd useful information here as
well and explore new application areas of liver CEUS, which will lead to new treatment
approaches and provide useful insights into future clinical practice.
Shanghai, China Wen-PingWang
Shanghai, China YiDong
Bern, Switzerland ChristophF.Dietrich
Regensburg, Germany ErnstMichaelJung
v

Contents
1 Contrast Enhanced Ultrasound: History and Basic Principles . . . . . . . . . . . . . . . 1
Christoph F. Dietrich, Yi Dong, and Wen-Ping Wang
2 Contrast Enhanced Ultrasound: How to Perform It in Liver Tumors? . . . . . . . . . 15
Christoph F. Dietrich, Yi Dong, and Wen-Ping Wang
3 Improved Detection of Focal Liver Lesions with
Contrast Enhanced Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Bei-Jian Huang, Yi Dong, and Wen-Ping Wang
4 Malignant Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Yi Dong, Wen-Ping Wang, Pei-Li Fan, Feng Mao, Han- Sheng Xia,
Jia-Ying Cao, and Bei-Jian Huang
5 Benign Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Jia-Ying Cao, Yi Dong, Wen-Ping Wang, Han-Sheng Xia, and Pei-Li Fan
6 Rare Malignant Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Qing Lu, Pei-Li Fan, Yi Dong, Jia-Ying Cao, and Wen-Ping Wang
7 Rare Benign Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Pei-Li Fan, Yi Dong, Wen-Ping Wang, and Jia-Ying Cao
8 Hepatic Parasitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Feng Mao, Yu-Li Zhu, and Yi Dong
9 Hepatic Inflammatory Pseudotumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Yi Dong, Pei-Li Fan, and Wen-Ping Wang
10 Hepatic Artery Aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Hong Han, Jia-Ying Cao, and Wen-Ping Wang
11 Peliosis Hepatis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Yi Dong, Feng Mao, and Wen-Ping Wang
12 Dynamic Vascular Pattern and Quantitative Analysis in Liver Tumors . . . . . . . . 241
Ernst Michael Jung and Yi Dong
13 Contrast Enhanced Ultrasound (CEUS) and Image Fusion for
Liver Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .251
Ernst Michael Jung and Yi Dong
14 Dynamic Three-Dimensional Contrast Enhanced Ultrasound with
Quantification of Focal Liver Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Jia-Ying Cao, Yi Dong, and Wen-Ping Wang
15 Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Wen-Ping Wang, Bei-Jian Huang, and Yi Dong
vii

Contrast Enhanced Ultrasound: History
andBasic Principles
ChristophF.Dietrich, YiDong, andWen-PingWang
1
Abbreviations
AASLD American Association for the Study of Liver
Disease
AUC Area under the (time intensity) curve
AUWI Area under the wash-in curve
AUWO Area under the wash-out curve
CCA Cholangiocellular Adenocarcinoma
CECT Contrast Enhanced Computed Tomography
CEMRI Contrast Enhanced Magnetic Resonance
Imaging
CEUS Contrast Enhanced Ultrasound
CT Computed Tomography
EASL European Association for the Study of the
Liver
FLL Focal Liver Lesion
FNH Focal Nodular Hyperplasia
HA Hepatic Artery
HCA Hepatocellular Adenoma
HCC Hepatocellular Carcinoma
ICC Intrahepatic Cholangiocellular Carcinoma
IO-CEUS Intraoperative contrast enhanced ultrasound
IOUS Intraoperative Ultrasound
IV Intravenous
IVC Inferior Vena Cava
C. F. Dietrich (*)
Department Allgemeine Innere Medizin (DAIM), Kliniken
Hirslanden Beau Site, Salem und Permanence, Hirslanden,
Bern, Switzerland
Y. Dong · W.-P. Wang
Department of Ultrasound, Zhongshan Hospital, Fudan University,
Shanghai, China
e-mail: dong.yi@zs-hospital.sh.cn
MI Mechanical Index
MRI Magnetic Resonance Imaging
MTT Mean transit time
PI Peak Intensity
PV Portal Vein
RECIST Response Evaluation Criteria in Solid
Tumours
SWI Slope of the wash-in
TIC Time Intensity Curve
TICA Time Intensity Curve Analysis
TPI Time to peak intensity
UCA Ultrasound Contrast Agent
US Ultrasound or ultrasonography
US-FDA United States (of America) Food and Drug
Administration
1.1 Historical Remarks
The rst mention of “echo” might be in Greek mythology.
Echo was a nymph who was punished for talking too much,
by being prevented from initiating speech: she could only
repeat what others had said. In the rst century, the Roman
architect Vitruvius rst used the word echo in a scientic
sense during his study of reected sounds and building
acoustics.
The French scientist/priest Marin Mersenne (1588–
1648) had an interest in music, which led him to study the
physics of a vibrating string. He measured the time of
return of an echo and provided the rst estimate of the
speed of sound (published in Harmonie Universelle in
1636). The Swiss mathematician and physicist Daniel
Bernoulli (1700–1782) studied the pressure, velocity and
equilibrium of uids (published in Hydrodynamica in
1738), and thus laid out the principles for uid dynamics; a
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021
W.-P. Wang et al. (eds.), Contrast-Enhanced Ultrasound Imaging of Hepatic Neoplasms,
https://doi.org/10.1007/978-981-16-1761-4_1
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C. F. Dietrich et al.
modied version of Bernoulli's hydraulic formula is used
today in Doppler ultrasonography. Ultrasound itself was
discovered in 1794 by Italian biologist Lazzaro Spallanzani
(1729–1799), who observed that bats oriented themselves
through echoes by emitting high frequency, inaudible
sound. In 1842, Austrian mathematician Christian Doppler
(1803–1853) made the important discovery that the perceived change in frequency of sound waves was due to the
relative motion of observer and source; this is now called
the Doppler effect. The ability to produce ultrasound
depended on the 1880 discovery of piezoelectricity by
Pierre and Jacques Curie, who noted that an electric charge
was produced when certain crystalline materials were compressed. The reverse was also true, i.e. when a crystal was
subjected to an electric potential, it oscillated and emitted
high-frequency sound.
The concept of using an external contrast agent to provide "contrast", i.e. to increase the visibility of anatomical
structures during a sonographic examination, was an accidental nding by Clause Joiner who made the discovery
written up by Gramiak and Shah. The rst echo contrast
signals were detected in M-mode images of cardiac cavities
and large vessels [1]. They injected indocyanine dye to
study a patient's cardiac output at the level of the aorta, and
at ultrasound they unexpectedly observed an area of intense
echogenicity over the right ventricle. The initial experience
included mainly self-made hand-agitated or sonicated bubble suspensions.
Much later the development of commercial ultrasound
contrast agents (UCAs) was started. In 1982 W.F.Armstrong
and colleagues used a microbubble contrast agent to assess
myocardial perfusion. In the early 1980s, S.B. Feinstein
and colleagues experimented with sonication to create
small, stable microbubbles. This led the United States
Federal Drug Administration in 1990 to approve Albunex
(Molecular Biosystems), consisting of sonicated albumin,
as the rst commercial ultrasound contrast agent for visualisation of cardiac cavities by intravenous
administration.
The rst contrast agent with broader use was Echovist®
(Schering AG Berlin, Germany). The Echovist® suspension of galactose microparticles releases air microbubbles
after mixing with an aqueous solution for imaging of the
right heart chambers and did not cross the pulmonary circulation. Therefore, Echovist® could not be used for liver
imaging.
1.1.1 Contrast Enhanced Ultrasound
Contrast enhanced ultrasound/Computed Tomography/
Magnetic Resonance Imaging (CEUS) was the term introduced by members of the European Federation of Societies
for Ultrasound in Medicine and Biology (EFSUMB) [2].
CEUS was developed to enhance Doppler signals, both with
Levovist® (Figs. 1.1 and 1.2) and SonoVue® (Fig. 1.3).
After the rst clinical use contrast specic low mechanical
index techniques were developed thereafter.
1.1.2 Ultrasound Contrast Agents
fortheLiver
The rst important CA for the liver was Levovist®, where
the air microbubbles are stabilized by a coating with palmitic
acid allowing left ventricular opacication and liver imaging
in patients with normal pulmonary artery pressure. Although
Levovist® was developed to enhance the intensity of Doppler
signals in the peripheral circulation, even in small vessels in
parenchymal organs, Levovist® also showed some enhancement in the liver in the post-vascular phase (after clearance
from the bloodstream), due to uptake by phagocytosing cells
(e.g. the Kupffer cells in the liver sinusoids) (Fig.1.4). This
phenomenon allowed discrimination of hepatic from nonhepatic tissue in the late phase. Levovist® was approved in
Europe in 1995. Although this rst-generation CA with airbased microbubbles was exciting at that time, it showed
major limitations in contrast duration due to the rapid escape
of the bubbles from the blood circulation. This is explained
by pressure instability since the air is highly diffusible with
high solubility in the bloodstream. Therefore, there was a
need for next-generation microbubbles, containing more
stable and therefore, high molecular weight lipophilic gases
with low solubility in blood.
The next generation and nally the most important contrast agent entering the European and Asian market was
SonoVue® (in the USA marketed as Lumason®), developed by Bracco (Italy). SonoVue® consists of microbubbles
with a very exible and therefore, highly echogenic shell of
phospholipids, with a response over a broad range of frequencies from 1 to 10MHz. SonoVue® has obtained regulatory approval for the use in children for liver imaging (USA)
and detection of vesico–ureteric reux in children (China,
Europe, USA). SonoVue® obtained European approval in

1 Contrast Enhanced Ultrasound: History andBasic Principles
3
a
b
c
Fig. 1.1 Levovist® enhanced Doppler signals in liver contrast
enhanced ultrasound. Hepatocellular carcinoma (HCC) smaller than
10mm and located deeply in liver. Conventional colour ow ultrasound
2001 for the use in echocardiography (left ventricular opacication), macrovascular imaging (cerebral, carotid, and
peripheral arteries) and microvascular imaging (characterisation of liver and breast lesions). SonoVue® is by far the
most frequently used CA for CEUS liver imaging. Echogen®
was approved for the liver but withdrawn from the market
due to possible side effects.
In some Asian and European countries (Japan, South
Korea, China, and Norway) Sonazoid®, developed by
Nycomed in Oslo, Norway, has been licensed. Sonazoid®
obtained national regulatory approval in 2006in Japan and
2018 in China for assessment of focal liver lesions and is
marketed by GE Healthcare and by Daiichi-Sankyo. The
detected tiny blood ow signals inside the lesion (a). After injection of
Levovist®, rich colour ow signals could be detected inside the lesion
(b). Arterial spectrum with high RI (0.84) was measured afterwards (c)
shell of Sonazoid® is more rigid and contains hydrogenated
egg phosphatidylserine embedded in an amorphous sucrose
structure, requiring a higher insonation power to produce
non-linear signals. Similar to Levovist, Sonazoid® shows an
uptake by cells of the reticulo-endothelial system (RES)
resulting in a post-vascular phase enhancement in the liver
(sometimes also called “Kupffer phase”) [3, 4].
In an early comparative study focused on the detection of
primary liver cancer with injection of CO
hepatic arterio-
2
sonography (CO2–HAS) as ultrasound contrast agent, CO2–
HAS enhanced ultrasound and conventional ultrasound were
compared in detection of primary liver cancer in 46 focal liver
lesions (FLLs). Among which 22 FLLs were ≤3cm, the other

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C. F. Dietrich et al.
a
Fig. 1.2 Levovist® enhanced Doppler signals in a surgery and histopathologically proved hepatocellular carcinoma lesion. Conventional
colour ow ultrasound detected tiny blood ow signals inside the lesion
a
b
(a). After injection of Levovist®, rich colour ow signals could be
detected inside the lesion (b)
b
c
Fig. 1.3 SonoVue® enhanced Doppler signals in hepatocellular carcinoma (HCC) lesion. Conventional colour ow ultrasound detected no
blood ow signals inside the lesion (a). After injection of Levovist®,
rich colour ow signals could be detected inside the lesion (b). Arterial
spectrum with high RI (0.71) was measured afterwards (c)
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