Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies

Abstract

Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy in the assessment of focal liver lesions. Clinical context (presence of liver cirrhosis, history of other malignancy versus incidental finding) is crucial for the correct interpretation of CEUS findings. CEUS has to be preceded by structured anamnesis and clinical examination as well as accurate B-mode sonography. Metastases are the most common malignant liver lesions in a non-cirrhotic liver. According to their contrast enhancement in the arterial phase, metastases are categorized as hyper- and hypo-vascular metastases. A common feature of all metastatic lesions is washout of the contrast agent in the portal venous or late phase. In the context of liver cirrhosis, > 95 % of focal liver lesions are hepatocellular carcinomas (HCCs). HCCs typically show arterial phase hyperenhancement, followed by mild and gradual contrast washout occurring very late in the late phase. For intrahepatic cholangiocellular carcinoma (ICC), the pattern of contrast enhancement in the arterial phase can vary. However, all ICCs typically show early and pronounced washout. Other liver malignancies like lymphoma, angiosarcoma, epithelioid hemangioendothelioma and others are very rare. Except for the contrast washout seen in all liver malignancies, they do not display pathognomonic enhancement patterns upon CEUS. Thus, biopsy is indispensable for definite diagnosis of the tumor entity. Furthermore, CEUS is used for the detection of metastases and therapeutic monitoring after local ablative procedures. The examination procedure differs slightly depending on the specific indication (characterization, detection).

Zusammenfassung

Die Kontrastmittelsonografie (CEUS, contrast enhanced ultrasound) hat eine hohe diagnostische Genauigkeit in der Dignitätsbeurteilung fokaler Leberläsionen. Der klinische Kontext (zirrhotische versus nicht zirrhotische Leber, maligne Grunderkrankung versus Zufallsbefund) ist entscheidend für die differenzialdiagnostische Einordnung von Leberraumforderungen. In jedem Fall muss der Kontrastmittelsonografie eine eingehende Anamnese und sorgfältige B-Bild-Sonografie der gesamten Leber vorangehen. Die häufigsten malignen Leberläsionen in nicht zirrhotischer Leber sind Metastasen, die nach ihrer Kontrastmittelaufnahme in der arteriellen Phase unterschieden werden in hyper- und hypovaskularisierte Metastasen. Allen Metastasen gemeinsam ist ein Kontrastmittelauswaschen in der portalvenösen Phase oder Spätphase. In zirrhotischer Leber sind > 95 % der soliden Läsionen hepatozelluläre Karzinome (HCCs). HCCs zeigen typischerweise ein arterielles Hyperenhancement und ein mildes, sehr spätes Kontrastmittelauswaschen in der Spätphase. Intrahepatische cholangiozelluläre Karzinome (ICCs) zeigen in der arteriellen Phase ein variables Kontrastmittel-Enhancement und in der Regel ein sehr frühes und stark ausgeprägtes Kontrastmittelauswaschen. Andere Lebermalignome (wie z. B. Lymphome, Angiosarkome, epitheloide Hämangioendotheliome etc.) sind Raritäten. Mit Ausnahme des für alle Lebermalignome charakteristischen Kontrastmittelauswaschens zeigen diese Raritäten kein pathognomonisches Kontrastierungsmuster; zur Bestimmung der Tumorentität ist eine Biopsie erforderlich. Weitere Einsatzgebiete der Kontrastmittelsonografie sind die Metastasen-Detektion sowie die Erfolgskontrolle nach lokalablativen Verfahren. Der Untersuchungsablauf in der Kontrastmittelsonografie unterscheidet sich je nach Indikation (Charakterisierung, Detektion).

• References

• 1 Claudon M, Dietrich CF, Choi BI. et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall in Med 2013; 34: 11-29
• 2 Dietrich CF, Lorentzen T, Appelbaum L. et al. The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version). Ultraschall in Med 2016; 37: 27-45
• 3 Sidhu PS, Cantisani V, Dietrich CF. et al. EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part III – Abdominal Treatment Procedures (Short Version). Ultraschall in Med 2018; 39: 154-180
• 4 Friedrich-Rust M, Klopffleisch T, Nierhoff J. et al. Contrast-Enhanced Ultrasound for the differentiation of benign and malignant focal liver lesions: a meta-analysis. Liver Int 2013; 33: 739-755
• 5 Sporea I, Badea R, Martie A. et al. Contrast enhanced ultrasound for the characterization of focal liver lesions. Med Ultrason 2011; 13: 38-44
• 6 Strobel D, Seitz K, Blank W. et al. Contrast-enhanced ultrasound for the characterization of focal liver lesions--diagnostic accuracy in clinical practice (DEGUM multicenter trial). Ultraschall in Med 2008; 29: 499-505
• 7 Giorgio A, Montesarchio L, Gatti P. et al. Contrast-Enhanced Ultrasound: a Simple and Effective Tool in Defining a Rapid Diagnostic Work-up for Small Nodules Detected in Cirrhotic Patients during Surveillance. J Gastrointestin Liver Dis 2016; 25: 205-211
• 8 Westwood M, Joore M, Grutters J. et al. Contrast-enhanced ultrasound using SonoVue® (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis. Health Technol Assess 2013; 17: 1-243
• 9 Dietrich CF. Contrast-Enhanced Ultrasound of Benign Focal Liver Lesions. Ultraschall Med 2019; 40: 12-29
• 10 D'Onofrio M, Crosara S, De Robertis R. et al. Malignant focal liver lesions at contrast-enhanced ultrasonography and magnetic resonance with hepatospecific contrast agent. Ultrasound 2014; 22: 91-98
• 11 D'Onofrio M, Vecchiato F, Cantisani V. et al. Intrahepatic peripheral cholangiocarcinoma (IPCC): comparison between perfusion ultrasound and CT imaging. Radiol Med 2008; 113: 76-86
• 12 Seitz K, Greis C, Schuler A. et al. Frequency of tumor entities among liver tumors of unclear etiology initially detected by sonography in the noncirrhotic or cirrhotic livers of 1349 patients. Results of the DEGUM multicenter study. Ultraschall in Med 2011; 32: 598-603
• 13 Dietrich CF, Sharma M, Gibson RN. et al. Fortuitously discovered liver lesions. World J Gastroenterol 2013; 19: 3173-3188 . doi:10.3748/wjg.v19.i21.3173
• 14 D'Onofrio M, Crosara S, De Robertis R. et al. Contrast-Enhanced Ultrasound of Focal Liver Lesions. Am J Roentgenol 2015; 205: W56-W66
• 15 Durot I, Wilson SR, Willmann JK. Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY) 2018; 43: 819-847
• 16 Negrão de Figueiredo G, Müller-Peltzer K, Rübenthaler J. et al. CEUS-Diagnostic of malignant liver lesions. Radiologe 2018; 58: 528-537
• 17 Leoni S, Piscaglia F, Granito A. et al. Characterization of primary and recurrent nodules in liver cirrhosis using contrast-enhanced ultrasound: which vascular criteria should be adopted?. Ultraschall in Med 2013; 34: 280-287
• 18 Wildner D, Bernatik T, Greis C. et al. CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients – early or late washout matters: a subanalysis of the DEGUM multicenter trial. Ultraschall in Med 2015; 36: 132-139
• 19 Wildner D, Pfeifer L, Goertz RS. et al. Dynamic contrast-enhanced ultrasound (DCE-US) for the characterization of hepatocellular carcinoma and cholangiocellular carcinoma. Ultraschall in Med 2014; 35: 522-527
• 20 Li R, Yuan MX, Ma KS. et al. Detailed analysis of temporal features on contrast enhanced ultrasound may help differentiate intrahepatic cholangiocarcinoma from hepatocellular carcinoma in cirrhosis. PLoS One 2014; 9: e98612
• 21 Liu GJ, Wang W, Lu MD. et al. Contrast-Enhanced Ultrasound for the Characterization of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Liver Cancer 2015; 4: 241-252
• 22 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69: 182-236
• 23 Schellhaas B, Wildner D, Pfeifer L. et al. LI-RADS-CEUS – Proposal for a Contrast-Enhanced Ultrasound Algorithm for the Diagnosis of Hepatocellular Carcinoma in High-Risk Populations. Ultraschall in Med 2016; 37: 627-634
• 24 Piscaglia F, Wilson SR, Lyshchik A. et al. American College of Radiology Contrast Enhanced Ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) for the diagnosis of Hepatocellular Carcinoma: a pictorial essay. Ultraschall in Med 2017; 38: 320-324
• 25 Kono Y, Lyshchik A, Cosgrove D. et al. Contrast Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS®): the official version by the American College of Radiology (ACR). Ultraschall in Med 2017; 38: 85-86
• 26 Schellhaas B, Goertz RS, Pfeifer L. et al. Diagnostic accuracy of contrast-enhanced ultrasound for the differential diagnosis of hepatocellular carcinoma: ESCULAP versus CEUS-LI-RADS. Eur J Gastroenterol Hepatol 2017; 29: 1036-1044
• 27 Schellhaas B, Pfeifer L, Kielisch C. et al. Interobserver Agreement for Contrast-Enhanced Ultrasound (CEUS)-Based Standardized Algorithms for the Diagnosis of Hepatocellular Carcinoma in High-Risk Patients. Ultraschall Med 2018; 39: 667-674
• 28 Schellhaas B, Hammon M, Strobel D. et al. Interobserver and intermodality agreement of standardized algorithms for non-invasive diagnosis of hepatocellular carcinoma in high-risk patients: CEUS-LI-RADS versus MRI-LI-RADS. Eur Radiol 2018; 28: 4254-4264
• 29 Dong Y, Wang WP, Cantisani V. et al. Contrast-enhanced ultrasound of histologically proven hepatic epithelioid hemangioendothelioma. World J Gastroenterol 2016; 22: 4741-4749
• 30 Foschi FG, Dall'Aglio AC, Marano G. et al. Role of contrast-enhanced ultrasonography in primary hepatic lymphoma. J Ultrasound Med 2010; 29: 1353-1356
• 31 Rafaelsen SR, Jakobsen A. Contrast-enhanced ultrasound vs multidetector-computed tomography for detecting liver metastases in colorectal cancer: a prospective, blinded, patient-by-patient analysis. Colorectal Dis 2011; 13: 420-425
• 32 Berger-Kulemann V, Schima W, Baroud S. et al. Gadoxetic acid-enhanced 3.0 T MR imaging versus multidetector-row CT in the detection of colorectal metastases in fatty liver using intraoperative ultrasound and histopathology as a standard of reference. Eur J Surg Oncol 2012; 38: 670-676
• 33 Dietrich CF, Kratzer W, Strobel D. et al. Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI. World J Gastroenterol 2006; 12: 1699-1705
• 34 Cantisani V, Grazhdani H, Fioravanti C. et al. Liver metastases: Contrast-enhanced ultrasound compared with computed tomography and magnetic resonance. World J Gastroenterol 2014; 20: 9998-10007
• 35 Larsen LP, Rosenkilde M, Christensen H. et al. Can contrast-enhanced ultrasonography replace multidetector-computed tomography in the detection of liver metastases from colorectal cancer?. Eur J Radiol 2009; 69: 308-313
• 36 Piscaglia F, Corradi F, Mancini M. et al. Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer. BMC Cancer 2007; 7: 171
• 37 Bernatik T, Schuler A, Kunze G. Benefit of Contrast-Enhanced Ultrasound (CEUS) in the Follow-Up Care of Patients with Colon Cancer: A Prospective Multicenter Study. Ultraschall in Med 2015; 36: 590-593
• 38 Leonardi F, Maria N, Villa E. Anticoagulation in cirrhosis: a new paradigm?. Clin Mol Hepatol 2017; 23: 13-21
• 39 Frieser M, Kiesel J, Lindner A. et al. Efficacy of contrast-enhanced US versus CT or MRI for the therapeutic control of percutaneous radiofrequency ablation in the case of hepatic malignancies. Ultraschall in Med 2011; 32: 148-153
• 40 Roccarina D, Garcovich M, Ainora ME. et al. Usefulness of contrast enhanced ultrasound in monitoring therapeutic response after hepatocellular carcinoma treatment. World J Hepatol 2015; 7: 1866-1874
• 41 Chen MH, Yang W, Yan K. et al. Large liver tumors: protocol for radiofrequency ablation and its clinical application in 110 patients--mathematic model, overlapping mode, and electrode placement process. Radiology 2004; 232: 260-271