Advertisement

Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver–Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS

      Abstract

      The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.

      Key Words

      Introduction

      The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound (CEUS), which was initiated by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) (
      • Albrecht T.
      • Blomley M.
      • Bolondi L.
      • Claudon M.
      • Correas J.M.
      • Cosgrove D.
      • Greiner L.
      • Jager K.
      • Jong N.D.
      • Leen E.
      • Lencioni R.
      • Lindsell D.
      • Martegani A.
      • Solbiati L.
      • Thorelius L.
      • Tranquart F.
      • Weskott H.P.
      • Whittingham T.
      • Group E.S.
      Guidelines for the use of contrast agents in ultrasound. January 2004.
      ). The previous updated editions of the guidelines reflected changes in the available ultrasound contrast agents (UCAs) and updated the guidelines for not only hepatic but also non-hepatic applications (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ;
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (short version).
      ,
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
      ).
      The 2012 guideline requires updating, as previously the differences in contrast agents were not precisely described, evidence-based recommendations were not given and differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. This update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration (FDA) approval and extensive Asian experience, to produce a truly international perspective.
      The requirement for worldwide guidelines on the use of CEUS in the liver instigated the World Federation for Ultrasound in Medicine and Biology (WFUMB) to facilitate discussions, in conjunction with its component federations, namely, the Asian Federation of Societies for Ultrasound in Medicine and Biology (AFSUMB), American Institute of Ultrasound in Medicine (AIUM), Australasian Society for Ultrasound in Medicine (ASUM), Federation of Latin America Ultrasound (FLAUS), and EFSUMB and in collaboration with the International Contrast Ultrasound Society (ICUS), to bring the 2012 liver guidelines up-to-date, recognizing the fact that UCAs are now licensed in increasing parts of the world. Of the 38 authors, 19 were from nine European countries representing EFSUMB; 13 from China, Japan, Korea and India representing AFSUMB; 5 from the United States representing AIUM; and 1 from MASU and FLAUS.
      As for the previous guidelines, this document is based on comprehensive literature surveys, including results from prospective clinical trials. We followed an EFSUMB Policy Document on development strategy for clinical practice guidelines, position statements and technological reviews adopted by WFUMB (
      • Jenssen C.
      • Gilja O.H.
      • Serra A.L.
      • Piscaglia F.
      • Dietrich C.F.
      • Rudd L.
      • Sidhu P.S.
      European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) policy document development strategy: Clinical practice guidelines, position statements and technological reviews.
      ). For each key topic, the authors performed a systematic literature search based on an explicit search strategy using Medline, Cochrane library and, if appropriate, further defined databases/sources. The search strategy was pre-defined with respect to sources (e.g., Medline), inclusion criteria (e.g., language of the publication, time period, study type, full publication), exclusion criteria and search terms. The evidence used to substantiate recommendations was summarized in evidence tables including information on study type (e.g., systematic review and meta-analysis, randomized control trial, prospective/retrospective cohort study with defined outcome parameters, case series), case numbers, important outcomes and limitations. On topics for which no significant study data were available, evidence was obtained from expert committee reports or was based on the consensus of experts in the fields of ultrasound (US) and CEUS during the consensus conferences. Recommendations were prepared in task force groups and finally discussed and voted on in a meeting of CEUS experts held in Granada in June 2019. Level of evidence (LoE) was assigned to recommendations based on evidence tables.
      This joint effort has again resulted in simultaneous publication in the official journals of WFUMB and EFSUMB (i.e., Ultrasound in Medicine and Biology and Ultraschall in der Medizin/European Journal of Ultrasound).
      These guidelines and recommendations provide general advice on the use of UCAs. They are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis and to improve the management of patients. Individual cases must be managed on the basis of all clinical data available.

      Worldwide commercial availability of UCAs

      Availability of UCAs for clinical use is based on the approval by regulatory agencies specific to the territory of intended use. Currently, four agents are available internationally for use in the liver, listed here with their manufacturers.
      • Definity/Luminity (Lantheus Medical Imaging, Inc., North Billerica, MA, USA)
      • SonoVue/Lumason (Bracco Suisse SA, Geneva, Switzerland)
      • Optison (GE Healthcare AS, Oslo, Norway)
      • Sonazoid (GE Healthcare AS, Oslo, Norway)
      The approval of these agents varies throughout the world along with the approved indications. ICUS in collaboration with WFUMB has developed an interactive map (Fig. 1).
      Fig 1
      Fig. 1Approval status of ultrasound contrast agents. The International Contrast Ultrasound Society (ICUS) in collaboration with the World Federation for Ultrasound in Medicine and Biology (WFUMB) has developed an interactive map on the approval status of contrast agents. An updated version of this map can be found online. (http://icus-society.org)

      Indications, contraindications, safety considerations

      The indications and contraindications differ among different UCAs; detailed information can be found in the official package inserts of the drugs.

       Safety considerations

      UCAs can be administered safely in various applications with minimal risk to patients (
      • Piscaglia F.
      • Bolondi L.
      The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations.
      ;
      • Main M.L.
      • Goldman J.H.
      • Grayburn P.A.
      Thinking outside the “box”-The ultrasound contrast controversy.
      ,
      • Main M.L.
      • Goldman J.H.
      • Grayburn P.A.
      Ultrasound contrast agents: balancing safety versus efficacy.
      ;
      • Dietrich C.F.
      • Bamber J.
      • Berzigotti A.
      • Bota S.
      • Cantisani V.
      • Castera L.
      • Cosgrove D.
      • Ferraioli G.
      • Friedrich-Rust M.
      • Gilja O.H.
      • Goertz R.S.
      • Karlas T.
      • de Knegt R.
      • de Ledinghen V.
      • Piscaglia F.
      • Procopet B.
      • Saftoiu A.
      • Sidhu P.S.
      • Sporea I.
      • Thiele M.
      EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography—Update 2017 (short version).
      ;
      • Tang C.
      • Fang K.
      • Guo Y.
      • Li R.
      • Fan X.
      • Chen P.
      • Chen Z.
      • Liu Q.
      • Zou Y.
      Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: Retrospective analysis of 30,222 cases.
      ;
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (short version).
      ). They are not excreted through the kidneys and can be administered to patients with renal insufficiency with no risk of contrast-related nephropathy or nephrogenic systemic fibrosis. There is no additional need for biochemical assessment or fasting before injection, and there is no evidence of any effect on thyroid function, as UCAs do not contain iodine (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ). UCAs have a very low rate of anaphylactoid-type reactions (1/7000 patients, corresponding to 14/100,000 or 0.014%) (
      • Kitzman D.W.
      • Goldman M.E.
      • Gillam L.D.
      • Cohen J.L.
      • Aurigemma G.P.
      • Gottdiener J.S.
      Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images.
      ;
      • Piscaglia F.
      • Bolondi L.
      The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations.
      ;
      • Wilson S.R.
      • Burns P.N.
      Microbubble-enhanced US in body imaging: what role?.
      ;
      • Tang C.
      • Fang K.
      • Guo Y.
      • Li R.
      • Fan X.
      • Chen P.
      • Chen Z.
      • Liu Q.
      • Zou Y.
      Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: Retrospective analysis of 30,222 cases.
      ), significantly lower than the rate for current iodinated computed tomography (CT) agents (35–95/100,000 patients, 0.035%–0.095%) (
      • Cochran S.T.
      • Bomyea K.
      • Sayre J.W.
      Trends in adverse events after IV administration of contrast media.
      ) and anaphylactoid reactions associated with gadolinium-based contrast agents (4/64 (6.3%) (
      • Hunt C.H.
      • Hartman R.P.
      • Hesley G.K.
      Frequency and severity of adverse effects of iodinated and gadolinium contrast materials: retrospective review of 456,930 doses.
      ). Serious anaphylactoid-type reactions to UCAs are observed in approximately 1 in 10,000 exposures (0.01%) (
      • Tang C.
      • Fang K.
      • Guo Y.
      • Li R.
      • Fan X.
      • Chen P.
      • Chen Z.
      • Liu Q.
      • Zou Y.
      Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: Retrospective analysis of 30,222 cases.
      ;
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
      ).
      SonoVue data pooled from 75 completed studies (of 6307 patients) in Europe, North America and Asia revealed that the most frequent adverse events were headache (2.1%), nausea (0.9%), chest pain (0.8%) and chest discomfort (0.5%). All other adverse events occurred at a frequency of less than 0.5% (

      Committee for Medicinal Products for Human Use (CHMP). Assessment report EMA/84084/2014. SonoVue. international non-properietary name: sulfur hexafluoride, Procedure No. EMEA/H/C/000303/II/0025. 2014.

      ). Most adverse events were mild and resolved spontaneously within a short time without sequelae. Most cases of allergy-like events and hypotension occurred within a few minutes after injection of the agent. The overall reported rate of fatalities attributed to SonoVue is low (14/2,447,083 exposed patients, 0.0006%) and compares favorably with the risk for fatal events reported for iodinated contrast agents (approximately 0.001%). In all reported fatalities after use of an UCA, in both cardiac and non-cardiac cases, an underlying patient medical circumstance played a major role in the fatal outcome.
      The intravesical administration of UCAs has been evaluated in a total of 7082 children described in 15 studies and in a European survey of 4131 children, 0.8% of whom reported adverse events, mostly related to bladder catheterization (
      • Darge K.
      • Papadopoulou F.
      • Ntoulia A.
      • Bulas D.I.
      • Coley B.D.
      • Fordham L.A.
      • Paltiel H.J.
      • McCarville B.
      • Volberg F.M.
      • Cosgrove D.O.
      • Goldberg B.B.
      • Wilson S.R.
      • Feinstein S.B.
      Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS).
      ;
      • Papadopoulou F.
      • Ntoulia A.
      • Siomou E.
      • Darge K.
      Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux: prospective evaluation of contrast safety in 1,010 children.
      ). Intravenous CEUS is also used in the pediatric population (
      • Sidhu P.S.
      • Cantisani V.
      • Deganello A.
      • Dietrich C.F.
      • Duran C.
      • Franke D.
      • Harkanyi Z.
      • Kosiak W.
      • Miele V.
      • Ntoulia A.
      • Piskunowicz M.
      • Sellars M.E.
      • Gilja O.H.
      Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: An EFSUMB position statement.
      ) and in numerous other documented areas (
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
      ). The FDA recently approved the use of Lumason for pediatric liver imaging (
      • Sidhu P.S.
      • Cantisani V.
      • Deganello A.
      • Dietrich C.F.
      • Duran C.
      • Franke D.
      • Harkanyi Z.
      • et al.
      Authors' Reply to Letter: Role of Contrast-Enhanced Ultrasound (CEUS) in Paediatric Practice: An EFSUMB Position Statement.
      ), which is an important development. This application is, however, still off label in pediatric imaging in many countries. A significant reduction in exposure to ionizing radiation is likely to be achieved in many areas by using CEUS in pediatric patients (
      • Sellars M.E.
      • Deganello A.
      • Sidhu P.S.
      Paediatric contrast-enhanced ultrasound (CEUS): a technique that requires co-operation for rapid implementation into clinical practice.
      ;
      • Sidhu P.S.
      • Cantisani V.
      • Deganello A.
      • Dietrich C.F.
      • Duran C.
      • Franke D.
      • Harkanyi Z.
      • Kosiak W.
      • Miele V.
      • Ntoulia A.
      • Piskunowicz M.
      • Sellars M.E.
      • Gilja O.H.
      Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: An EFSUMB position statement.
      ).
      Most recently it was reported that the use of SonoVue appears to be safe in pregnant women (
      • Schwarze V.
      • Marschner C.
      • Negrao de Figueiredo G.
      • Rubenthaler J.
      • Clevert D.A.
      Single-center study: Evaluating the diagnostic performance and safety of contrast-enhanced ultrasound (CEUS) in pregnant women to assess hepatic lesions.
      ).
      • Recommendation 1. Intravenous use of UCAs in adult populations is safe. (LoE 2) (Pro 28, Against 0, Abstain 0)
      • Recommendation 2. Intravenous use of UCAs in pediatric populations is safe. (LoE 3) (Pro 28, Against 0, Abstain 0)
      • Recommendation 3. Intracavitary use of UCAs is safe. (LoE 2) (Pro 27, Against 0, Abstain 1).

      Liver CEUS: Scanning technique and basic image interpretation

      The study procedure is well documented in previous CEUS guidelines (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ) and has been described in detail in a recent WFUMB position paper (
      • Dietrich C.F.
      • Atkinson N.S.S.
      • Lee W.J.
      • Kling K.
      • Neumayr A.
      • Braden B.
      • Richter J.
      • Akpata R.
      • Southisavath P.
      • Schreiber-Dietrich D.
      • Dong Y.
      Never seen before? Opisthorchiasis and clonorchiasis.
      ). Before performing a liver CEUS study, it is necessary to review the patient's clinical history, laboratory data and any prior imaging findings (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ).

       Study procedure

      Before CEUS, cysts and calcifications must be identified by conventional US because these structures do not exhibit contrast enhancement and could therefore be erroneously interpreted as a malignant infiltration if only scanned in the late phase (LP). When cysts are missed by the baseline examination, it is necessary to carefully review both the contrast and reference images and to analyze the B-mode pattern of the liver tissue after the disappearance of the microbubbles.

       Interpretation

      CEUS of the liver has three overlapping vascular phases after the injection of UCA because of the dual blood supply of the liver, that is, hepatic artery and portal vein (respectively 25%–30% and 70%–75% of liver blood flow in non-cirrhotic conditions) (Table 1).
      • The arterial phase (AP) provides information on the degree and pattern of the arterial vascular supply of a focal liver lesion (FLL). Early arterial enhancement pattern and vascular architecture are best seen in slow replay of a stored cine loop.
      • The portal venous phase (PVP) represents the arrival of UCA through the portal system, resulting in diffuse and maximal enhancement of normal liver parenchyma.
      • The late phase (LP) lasts until clearance of the UCA from the circulation and depends on the type and dose of UCA, total scanning time, acoustic power output and sensitivity of the US system.
      • The post-vascular phase is observed only with Sonazoid and represents uptake of the UCA by phagocytotic cells (e.g., Kupffer cells).
      Table 1Vascular phases in contrast-enhanced ultrasound of the liver (visualization post-injection time).
      PhaseStart (s)End (s)
      Arterial10–2030–45
      Portal venous30–45120
      Late>120Bubble disappearance (approximately 4–8 min)
      Post-vascular>8 minApproximately 30 min
      Slight/moderate variations of timing may occur, particularly in the case of cardiac dysfunction and in patients with vascular liver disease.
      Vascular architecture and phase-specific contrast enhancement of the lesion compared with the adjacent liver parenchyma are the most important diagnostic features for the characterization of FLLs (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ).

      Differences between CEUS and other contrast-enhanced imaging modalities (contrast-enhanced computed tomography [CECT], contrast-enhanced magnetic resonance imaging [CEMRI])

      UCAs comprise gas-filled particles (microbubbles), differ in fundamental respects from the agents used in CECT and CEMRI and, for this reason, play a complementary problem-solving role for indeterminate FLLs. Unlike CT and MR agents, microbubbles are not excreted by the kidneys. With the exception of Sonazoid, UCAs are purely intravascular agents. Therefore, CEUS should be considered as the first contrast imaging modality in patients with renal insufficiency. UCAs can be safely administered more than once during the same examination. While the dynamic phases of liver enhancement with UCA resemble those of CECT with iodinated agents and CEMRI with gadolinium chelates, imaging is real time with US. Other important differences exist and are well described in the literature (
      • Faccioli N.
      • D'Onofrio M.
      • Comai A.
      • Cugini C.
      Contrast-enhanced ultrasonography in the characterization of benign focal liver lesions: activity-based cost analysis.
      ;
      • Wilson S.R.
      • Kim T.K.
      • Jang H.J.
      • Burns P.N.
      Enhancement patterns of focal liver masses: discordance between contrast-enhanced sonography and contrast-enhanced CT and MRI.
      ;
      • Rossi S.
      • Ghittoni G.
      • Ravetta V.
      • Torello Viera F.
      • Rosa L.
      • Serassi M.
      • Scabini M.
      • Vercelli A.
      • Tinelli C.
      • Dal Bello B.
      • Burns P.N.
      • Calliada F.
      Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma.
      ;
      • D'Onofrio M.
      • Crosara S.
      • De Robertis R.
      • Canestrini S.
      • Mucelli R.P.
      Contrast-enhanced ultrasound of focal liver lesions.
      ). For FLL characterization, an overall improvement in sensitivity and specificity is found for CEUS compared with CECT (
      • Quaia E.
      • Calliada F.
      • Bertolotto M.
      • Rossi S.
      • Garioni L.
      • Rosa L.
      • Pozzi-Mucelli R.
      Comparison of diagnostic performance of unenhanced vs SonoVue-enhanced ultrasonography in focal liver lesions characterization: The experience of three Italian centers.
      ;
      • Seitz K.
      • Strobel D.
      • Bernatik T.
      • Blank W.
      • Friedrich-Rust M.
      • Herbay A.
      • Dietrich C.F.
      • Strunk H.
      • Kratzer W.
      • Schuler A.
      Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions-Prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the Ultrasound Dreilandertreffen 2008.
      ;
      • Trillaud H.
      • Bruel J.M.
      • Valette P.J.
      • Vilgrain V.
      • Schmutz G.
      • Oyen R.
      • Jakubowski W.
      • Danes J.
      • Valek V.
      • Greis C.
      Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.
      ;
      • Friedrich-Rust M.
      • Klopffleisch T.
      • Nierhoff J.
      • Herrmann E.
      • Vermehren J.
      • Schneider M.D.
      • Zeuzem S.
      • Bojunga J.
      Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: A meta-analysis.
      ;
      • D'Onofrio M.
      • Crosara S.
      • De Robertis R.
      • Canestrini S.
      • Cantisani V.
      • Morana G.
      • Mucelli R.P.
      Malignant focal liver lesions at contrast-enhanced ultrasonography and magnetic resonance with hepatospecific contrast agent.
      ;
      • Barr R.G.
      Contrast enhanced ultrasound for focal liver lesions: how accurate is it?.
      ). CEUS, in addition, is reported to be invaluable in providing characterization of indeterminate FLLs on CT, magnetic resonance imaging (MRI) and positron emission tomography (
      • Burns P.N.
      • Wilson S.R.
      Focal liver masses: enhancement patterns on contrast-enhanced images—Concordance of US scans with CT scans and MR images.
      ;
      • Laghi F.
      • Catalano O.
      • Maresca M.
      • Sandomenico F.
      • Siani A.
      Indeterminate, subcentimetric focal liver lesions in cancer patients: additional role of contrast-enhanced ultrasound.
      ;
      • Parsai A.
      • Miquel M.E.
      • Jan H.
      • Kastler A.
      • Szyszko T.
      • Zerizer I.
      Improving liver lesion characterisation using retrospective fusion of FDG PET/CT and MRI.
      ). It is also reported that CEUS should be the subsequent imaging modality for all CT- and MR-indeterminate nodules before biopsy is undertaken (
      • Jo P.C.
      • Jang H.J.
      • Burns P.N.
      • Burak K.W.
      • Kim T.K.
      • Wilson S.R.
      Integration of contrast-enhanced US into a multimodality approach to imaging of nodules in a cirrhotic liver: How I do it.
      ).
      • Recommendation 4. CEUS is recommended in patients with inconclusive findings at CT or MR imaging. (LoE 2, strong recommendation) (Pro 30, Against 1, Abstain 0)
      • Recommendation 5. CEUS should be considered as the first contrast imaging modality in patients with renal insufficiency. (LoE 5, strong recommendation) (Pro 31, Against 0, Abstain 0)

      Detection of malignant FLLs: Transabdominal approach

      Conventional US is the most frequently used modality for the primary imaging of abdominal organs, including the liver, but is less sensitive in the detection of FLLs than CECT, CEMRI or intra-operative US.  A number of studies (
      • Konopke R.
      • Kersting S.
      • Saeger H.D.
      • Bunk A.
      [Detection of liver lesions by contrast-enhanced ultrasound–Comparison to intraoperative findings].
      ,
      • Konopke R.
      • Kersting S.
      • Bergert H.
      • Bloomenthal A.
      • Gastmeier J.
      • Saeger H.D.
      • Bunk A.
      Contrast-enhanced ultrasonography to detect liver metastases: A prospective trial to compare transcutaneous unenhanced and contrast-enhanced ultrasonography in patients undergoing laparotomy.
      ;
      • Dietrich C.F.
      • Kratzer W.
      • Strobe D.
      • Danse E.
      • Fessl R.
      • Bunk A.
      • Vossas U.
      • Hauenstein K.
      • Koch W.
      • Blank W.
      • Oudkerk M.
      • Hahn D.
      • Greis C.
      Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
      ;
      • Quaia E.
      • D'Onofrio M.
      • Palumbo A.
      • Rossi S.
      • Bruni S.
      • Cova M.
      Comparison of contrast-enhanced ultrasonography versus baseline ultrasound and contrast-enhanced computed tomography in metastatic disease of the liver: diagnostic performance and confidence.
      ;
      • Larsen L.P.
      • Rosenkilde M.
      • Christensen H.
      • Bang N.
      • Bolvig L.
      • Christiansen T.
      • Laurberg S.
      The value of contrast enhanced ultrasonography in detection of liver metastases from colorectal cancer: a prospective double-blinded study.
      ,
      • Larsen L.P.
      • Rosenkilde M.
      • Christensen H.
      • Bang N.
      • Bolvig L.
      • Christiansen T.
      • Laurberg S.
      Can contrast-enhanced ultrasonography replace multidetector-computed tomography in the detection of liver metastases from colorectal cancer?.
      ;
      • Piscaglia F.
      • Corradi F.
      • Mancini M.
      • Giangregorio F.
      • Tamberi S.
      • Ugolini G.
      • Cola B.
      • Bazzocchi A.
      • Righini R.
      • Pini P.
      • Fornari F.
      • Bolondi L.
      Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer.
      ;
      • Cantisani V.
      • Ricci P.
      • Erturk M.
      • Pagliara E.
      • Drudi F.
      • Calliada F.
      • Mortele K.
      • D'Ambrosio U.
      • Marigliano C.
      • Catalano C.
      • Marin D.
      • Di Seri M.
      • Longo F.
      • Passariello R.
      Detection of hepatic metastases from colorectal cancer: Prospective evaluation of gray scale US versus SonoVue low mechanical index real time-enhanced US as compared with multidetector-CT or Gd-BOPTA-MRI.
      ;
      • Muhi A.
      • Ichikawa T.
      • Motosugi U.
      • Sou H.
      • Nakajima H.
      • Sano K.
      • Sano M.
      • Kato S.
      • Kitamura T.
      • Fatima Z.
      • Fukushima K.
      • Iino H.
      • Mori Y.
      • Fujii H.
      • Araki T.
      Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI.
      ;
      • Itabashi T.
      • Sasaki A.
      • Otsuka K.
      • Kimura T.
      • Nitta H.
      • Wakabayashi G.
      Potential value of sonazoid-enhanced intraoperative laparoscopic ultrasonography for liver assessment during laparoscopy-assisted colectomy.
      ) have reported that CEUS has a considerably higher sensitivity of up to 80%–90% in detecting liver metastases, comparable with those of CECT (
      • Larsen L.P.
      Role of contrast enhanced ultrasonography in the assessment of hepatic metastases: A review.
      ) and CEMRI (
      • Cantisani V.
      • Ricci P.
      • Erturk M.
      • Pagliara E.
      • Drudi F.
      • Calliada F.
      • Mortele K.
      • D'Ambrosio U.
      • Marigliano C.
      • Catalano C.
      • Marin D.
      • Di Seri M.
      • Longo F.
      • Passariello R.
      Detection of hepatic metastases from colorectal cancer: Prospective evaluation of gray scale US versus SonoVue low mechanical index real time-enhanced US as compared with multidetector-CT or Gd-BOPTA-MRI.
      ). Furthermore, some reports have indicated that CEUS is of particular usefulness with metastases ≤10 mm (
      • Forner A.
      • Vilana R.
      • Ayuso C.
      • Bianchi L.
      • Sole M.
      • Ayuso J.R.
      • Boix L.
      • Sala M.
      • Varela M.
      • Llovet J.M.
      • Bru C.
      • Bruix J.
      Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
      ;
      • Dong Y.
      • Zhang X.L.
      • Mao F.
      • Huang B.J.
      • Si Q.
      • Wang W.P.
      Contrast-enhanced ultrasound features of histologically proven small (≤20 mm) liver metastases.
      ). CEUS has dramatically increased the capability of US to detect FLLs and has the potential to be incorporated into the diagnostic algorithm for malignant FLLs.

       Study procedures

      The study procedure is described above. A second contrast administration (re-injection technique) can be used to confirm the metastatic nature of focal areas of contrast washout by demonstrating (secondary) AP enhancement within the areas of contrast washout.

       Detection of metastatic lesions

      The typical and almost invariable appearance of metastases is focal contrast washout. The enhancement patterns observed during the AP have limited clinical utility in lesion detection (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ;
      • Dietrich C.F.
      • Potthoff A.
      • Helmberger T.
      • Ignee A.
      • Willmann J.K.
      • Group C.L.-R.W.
      [Contrast-enhanced ultrasound: Liver Imaging Reporting and Data System (CEUS LI-RADS)].
      ).
      With vascular phase agents (SonoVue/Lumason, Definity/Luminity, Optison), several studies have reported that the accuracy of detection of liver metastases is comparable with those of CECT and CEMRI, when scanning conditions allow complete imaging of all liver segments (
      • Larsen L.P.
      • Rosenkilde M.
      • Christensen H.
      • Bang N.
      • Bolvig L.
      • Christiansen T.
      • Laurberg S.
      The value of contrast enhanced ultrasonography in detection of liver metastases from colorectal cancer: a prospective double-blinded study.
      ). However, it should be noted that most of the studies have used initial and/or follow-up imaging (mostly CT examinations and sometimes MRI, and intra-operative US) as a reference standard, and very few reports include histologic or pathologic confirmation. Nonetheless, as CT and MRI are currently the modalities of choice for metastatic FLL detection, comparison of CEUS with these techniques seems reasonable in evaluating the diagnostic efficacy of CEUS. In addition, histologic confirmation of every malignant FLL in patients with clear imaging diagnosis might not be ethically appropriate. According to a meta-analysis including 828 metastases from 18 studies, the overall sensitivity of CEUS for diagnosis of metastases was 91% (95% confidence interval [CI]: 87%–95%) (
      • Friedrich-Rust M.
      • Klopffleisch T.
      • Nierhoff J.
      • Herrmann E.
      • Vermehren J.
      • Schneider M.D.
      • Zeuzem S.
      • Bojunga J.
      Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: A meta-analysis.
      ).
      • Recommendation 6. CEUS can be used for liver metastasis detection as part of a multimodality imaging approach. (LoE 2, weak recommendation) (Pro 31, Against 0, Abstain 0)

       Detection of HCCs and intrahepatic cholangiocellular carcinoma (ICC)

      With all UCAs, most hepatocellular carcinomas (HCCs) exhibit AP hyper-enhancement (APHE), but the short duration of APHE makes adequate assessment of the whole liver impracticable. The LP lasts long enough for a detailed examination, but the appearance of HCC varies. Importantly, not all HCCs exhibit contrast washout in the LP, limiting the sensitivity of CEUS for HCC detection. CEUS is not recommended for staging of HCCs except for patients with a portal vein tumor thrombus (
      • Tang A.
      • Bashir M.R.
      • Corwin M.T.
      • Cruite I.
      • Dietrich C.F.
      • Do R.K.G.
      • Ehman E.C.
      • Fowler K.J.
      • Hussain H.K.
      • Jha R.C.
      • Karam A.R.
      • Mamidipalli A.
      • Marks R.M.
      • Mitchell D.G.
      • Morgan T.A.
      • Ohliger M.A.
      • Shah A.
      • Vu K.N.
      • Sirlin C.B.
      LI-RADS Evidence Working Group
      Evidence supporting LI-RADS major features for CT- and MR imaging-based diagnosis of hepatocellular carcinoma: A systematic review.
      ;
      • Wilson S.R.
      • Lyshchik A.
      • Piscaglia F.
      • Cosgrove D.
      • Jang H.J.
      • Sirlin C.
      • Dietrich C.F.
      • Kim T.K.
      • Willmann J.K.
      • Kono Y.
      CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI.
      ).
      With the post-vascular phase UCA (Sonazoid), scanning the entire liver ≥10 min after injection helps to detect malignant nodules, as the typical HCC appears as an enhancement defect (
      • Karhunen P.J.
      Benign hepatic tumours and tumour like conditions in men.
      ;
      • Hatanaka K.
      • Kudo M.
      • Minami Y.
      • Ueda T.
      • Tatsumi C.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Hagiwara S.
      • Chung H.
      • Ueshima K.
      • Maekawa K.
      Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid.
      ;
      • Maruyama H.
      • Takahashi M.
      • Ishibashi H.
      • Okugawa H.
      • Okabe S.
      • Yoshikawa M.
      • Yokosuka O.
      Ultrasound-guided treatments under low acoustic power contrast harmonic imaging for hepatocellular carcinomas undetected by B-mode ultrasonography.
      ;
      • Moriyasu F.
      • Itoh K.
      Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial.
      ;
      • Guang Y.
      • Xie L.
      • Ding H.
      • Cai A.
      • Huang Y.
      Diagnosis value of focal liver lesions with SonoVue-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis.
      ;
      • Martie A.
      • Bota S.
      • Sporea I.
      • Sirli R.
      • Popescu A.
      • Danila M.
      The contribution of contrast enhanced ultrasound for the characterization of benign liver lesions in clinical practice: A monocentric experience.
      ). However, approximately half of well-differentiated HCCs do not exhibit enhancement defects in the post-vascular phase (
      • Arita J.
      • Hasegawa K.
      • Takahashi M.
      • Hata S.
      • Shindoh J.
      • Sugawara Y.
      • Kokudo N.
      Correlation between contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of resected hepatocellular carcinoma.
      ).
      ICCs behave in virtually the same manner as metastases, washing out rapidly and appearing as defects in the LP, regardless of their appearance in the AP (
      • Xu H.X.
      • Lu M.D.
      • Liu G.J.
      • Xie X.Y.
      • Xu Z.F.
      • Zheng Y.L.
      • Liang J.Y.
      Imaging of peripheral cholangiocarcinoma with low-mechanical index contrast-enhanced sonography and SonoVue: initial experience.
      ). This pattern may facilitate detection of satellite nodules adjacent to a larger lesion that were not visualized on conventional US.
      • Recommendation 7. Routine use of CEUS for the surveillance of patients at risk for HCC is not recommended. (LoE 4, strong recommendation) (Pro 29, Against 2, Abstain 0)
      • Recommendation 8. Routine use of CEUS for staging of HCC is not recommended. (LoE 2, strong recommendation) (Pro 31, Against 0, Abstain 0)

      CEUS for characterization of focal liver lesions

      Before starting liver CEUS, it is necessary to review the patient's clinical history, laboratory data and any prior imaging. The entire liver and the FLL should be interrogated using conventional B-mode and color Doppler US to obtain reproducible information regarding segmental localization, size and relation to vessels and other anatomic landmarks, as well as to guarantee optimal examination quality and ascertain whether underlying cirrhosis is present. The range of tumor types differs between cirrhotic and non-cirrhotic livers, with description of the characterization of FLL discussed separately for each.
      • Recommendation 9. Before performing CEUS to characterize FLLs, it is recommended that a systematic liver examination be performed using B-mode and Doppler US. (LoE 5, strong recommendation) (Pro 32, Against 0, Abstain 0)

       Characterization of FLLs in the non-cirrhotic liver

      The probability of an FLL being benign (including inflammatory) or malignant depends on the symptoms and past medical history. An incidentally detected FLL in otherwise healthy and asymptomatic persons is likely benign (
      • Linhart P.
      • Bonhof J.A.
      • Baque P.E.
      • Pering C.
      [Ultrasound in diagnosis of benign and malignant liver tumors].
      ;
      • Hirche T.O.
      • Russler J.
      • Schroder O.
      • Schuessler G.
      • Kappeser P.
      • Caspary W.F.
      • Dietrich C.F.
      The value of routinely performed ultrasonography in patients with Crohn disease.
      ), whereas with pre-existing malignant disease, the probability of malignancy is significantly higher (
      • Albrecht T.
      • Blomley M.
      • Bolondi L.
      • Claudon M.
      • Correas J.M.
      • Cosgrove D.
      • Greiner L.
      • Jager K.
      • Jong N.D.
      • Leen E.
      • Lencioni R.
      • Lindsell D.
      • Martegani A.
      • Solbiati L.
      • Thorelius L.
      • Tranquart F.
      • Weskott H.P.
      • Whittingham T.
      • Group E.S.
      Guidelines for the use of contrast agents in ultrasound. January 2004.
      ). In patients with supportive symptomatology, FLLs may raise suspicion for phlegmonous inflammation or abscess formation.
      The primary aim of CEUS in patients with a non-cirrhotic liver is to differentiate benign from malignant FLLs (
      • Karhunen P.J.
      Benign hepatic tumours and tumour like conditions in men.
      ;
      • Volk M.
      • Strotzer M.
      • Lenhart M.
      • Techert J.
      • Seitz J.
      • Feuerbach S.
      Frequency of benign hepatic lesions incidentally detected with contrast-enhanced thin-section portal venous phase spiral CT.
      ;
      • Dietrich C.F.
      • Ignee A.
      • Trojan J.
      • Fellbaum C.
      • Schuessler G.
      Improved characterization of histologically proven liver tumours by contrast enhanced ultrasonography during the portal venous and specific late phase of SHU 508 A.
      ,
      • Dietrich C.F.
      • Schuessler G.
      • Trojan J.
      • Fellbaum C.
      • Ignee A.
      Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.
      ,
      • Dietrich C.F.
      • Kratzer W.
      • Strobe D.
      • Danse E.
      • Fessl R.
      • Bunk A.
      • Vossas U.
      • Hauenstein K.
      • Koch W.
      • Blank W.
      • Oudkerk M.
      • Hahn D.
      • Greis C.
      Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
      ,
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • Schuessler G.
      • Ott M.
      • Ignee A.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ;
      • Strobel D.
      • Seitz K.
      • Blank W.
      • Schuler A.
      • Dietrich C.
      • von Herbay A.
      • Friedrich-Rust M.
      • Kunze G.
      • Becker D.
      • Will U.
      • Kratzer W.
      • Albert F.W.
      • Pachmann C.
      • Dirks K.
      • Strunk H.
      • Greis C.
      • Bernatik T.
      Contrast-enhanced ultrasound for the characterization of focal liver lesions-Diagnostic accuracy in clinical practice (DEGUM multicenter trial).
      ,
      • Strobel D.
      • Seitz K.
      • Blank W.
      • Schuler A.
      • Dietrich C.F.
      • von Herbay A.
      • Friedrich-Rust M.
      • Bernatik T.
      Tumor-specific vascularization pattern of liver metastasis, hepatocellular carcinoma, hemangioma and focal nodular hyperplasia in the differential diagnosis of 1349 liver lesions in contrast-enhanced ultrasound (CEUS).
      ,
      • Strobel D.
      • Bernatik T.
      • Blank W.
      • Schuler A.
      • Greis C.
      • Dietrich C.F.
      • Seitz K.
      Diagnostic accuracy of CEUS in the differential diagnosis of small (≤20 mm) and subcentimetric (≤10 mm) focal liver lesions in comparison with histology: Results of the DEGUM multicenter trial.
      ;
      • Seitz K.
      • Strobel D.
      • Bernatik T.
      • Blank W.
      • Friedrich-Rust M.
      • Herbay A.
      • Dietrich C.F.
      • Strunk H.
      • Kratzer W.
      • Schuler A.
      Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions-Prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the Ultrasound Dreilandertreffen 2008.
      ,
      • Seitz K.
      [EFSUMB-guidelines for CEUS are directive and effective].
      ,
      • Seitz K.
      • Greis C.
      • Schuler A.
      • Bernatik T.
      • Blank W.
      • Dietrich C.F.
      • Strobel D.
      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.
      ;
      • Trillaud H.
      • Bruel J.M.
      • Valette P.J.
      • Vilgrain V.
      • Schmutz G.
      • Oyen R.
      • Jakubowski W.
      • Danes J.
      • Valek V.
      • Greis C.
      Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.
      ;
      • Bernatik T.
      • Seitz K.
      • Blank W.
      • Schuler A.
      • Dietrich C.F.
      • Strobel D.
      Unclear focal liver lesions in contrast-enhanced ultrasonography—Lessons to be learned from the DEGUM multicenter study for the characterization of liver tumors.
      ;
      • Devine A.S.
      • Jackson C.S.
      • Lyons L.
      • Mason J.D.
      Frequency of incidental findings on computed tomography of trauma patients.
      ;
      • Trojan J.
      • Hammerstingl R.
      • Engels K.
      • Schneider A.R.
      • Zeuzem S.
      • Dietrich C.F.
      Contrast-enhanced ultrasound in the diagnosis of malignant mesenchymal liver tumors.
      ;
      • von Herbay A.
      • Westendorff J.
      • Gregor M.
      Contrast-enhanced ultrasound with SonoVue: differentiation between benign and malignant focal liver lesions in 317 patients.
      ;
      • Guang Y.
      • Xie L.
      • Ding H.
      • Cai A.
      • Huang Y.
      Diagnosis value of focal liver lesions with SonoVue-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis.
      ;
      • Xie L.
      • Guang Y.
      • Ding H.
      • Cai A.
      • Huang Y.
      Diagnostic value of contrast-enhanced ultrasound, computed tomography and magnetic resonance imaging for focal liver lesions: a meta-analysis.
      ;
      • Martie A.
      • Bota S.
      • Sporea I.
      • Sirli R.
      • Popescu A.
      • Danila M.
      The contribution of contrast enhanced ultrasound for the characterization of benign liver lesions in clinical practice: A monocentric experience.
      ;
      • Sporea I.
      • Badea R.
      • Martie A.
      • Dumitru E.
      • Ioanitescu S.
      • Sirli R.
      • Socaciu M.
      • Popescu A.
      • Danila M.
      • Voiculescu M.
      Contrast enhanced ultrasound for the evaluation of focal liver lesions in daily practice: A multicentre study.
      ,
      • Sporea I.
      • Badea R.
      • Popescu A.
      • Sparchez Z.
      • Sirli R.L.
      • Danila M.
      • Sandulescu L.
      • Bota S.
      • Calescu D.P.
      • Nedelcu D.
      • Brisc C.
      • Ciobaca L.
      • Gheorghe L.
      • Socaciu M.
      • Martie A.
      • Ioanitescu S.
      • Tamas A.
      • Streba C.T.
      • Iordache M.
      • Simionov I.
      • Jinga M.
      • Anghel A.
      • Cijevschi Prelipcean C.
      • Mihai C.
      • Stanciu S.M.
      • Stoicescu D.
      • Dumitru E.
      • Pietrareanu C.
      • Bartos D.
      • Manzat Saplacan R.
      • Parvulescu I.
      • Vadan R.
      • Smira G.
      • Tuta L.
      • Saftoiu A.
      Contrast-enhanced ultrasound (CEUS) for the evaluation of focal liver lesions-A prospective multicenter study of its usefulness in clinical practice.
      ;
      • Sandrose S.W.
      • Karstrup S.
      • Gerke O.
      • Rafaelsen S.
      Contrast enhanced ultrasound in CT-undetermined focal liver lesions.
      ). Thus, CEUS is useful in facilitating the clinical decision as to whether a sonographically detected liver lesion requires further investigation or surgery (
      • Bartolotta T.V.
      • Sandonato L.
      • Taibbi A.
      • Latteri S.
      • Soresi M.
      • Lombardo G.
      • Genova C.
      • Latteri M.A.
      [Focal liver lesions: clinical usefulness of contrast-enhanced ultrasound in the selection of surgical patients].
      ).
      • Recommendation 10. CEUS is recommended as the first-line imaging technique for the characterization of incidentally detected, indeterminate FLLs at US in patients with a non-cirrhotic liver and without a history or clinical suspicion of malignancy. (LoE 1, strong recommendation) (Pro 30, Against 0, Abstain 2)
      • Recommendation 11. CEUS is suggested as the first-line imaging technique for the characterization of FLLs detected with US in patients with non-cirrhotic livers with a history or clinical suspicion of malignant disease. (LoE 2, weak recommendation) (Pro 31, Against 0, Abstain 0)
      • Recommendation 12. CEUS is recommended for the characterization of FLLs in the non-cirrhotic liver in patients with inconclusive findings at CT or MRI (LoE 2, strong recommendation) and is suggested if biopsy of the FLL was inconclusive. (LoE 5, weak recommendation). (Pro 30, Against 1, Abstain 0)
      • Recommendation 13. CEUS is recommended for characterization of FLLs in the non-cirrhotic liver if both CT and MRI are contraindicated. (LoE 5, strong recommendation) (Pro 32, Against 0, Abstain 0)
      For differential diagnosis of FLL, CEUS is superior to CT and equivalent to MR imaging (
      • Dietrich C.F.
      • Kratzer W.
      • Strobe D.
      • Danse E.
      • Fessl R.
      • Bunk A.
      • Vossas U.
      • Hauenstein K.
      • Koch W.
      • Blank W.
      • Oudkerk M.
      • Hahn D.
      • Greis C.
      Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
      ;
      • Seitz K.
      • Strobel D.
      • Bernatik T.
      • Blank W.
      • Friedrich-Rust M.
      • Herbay A.
      • Dietrich C.F.
      • Strunk H.
      • Kratzer W.
      • Schuler A.
      Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions-Prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the Ultrasound Dreilandertreffen 2008.
      ,
      • Seitz K.
      • Bernatik T.
      • Strobel D.
      • Blank W.
      • Friedrich-Rust M.
      • Strunk H.
      • Greis C.
      • Kratzer W.
      • Schuler A.
      Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions in clinical practice (DEGUM Multicenter Trial): CEUS vs. MRI–A prospective comparison in 269 patients.
      ,
      • Seitz K.
      • Greis C.
      • Schuler A.
      • Bernatik T.
      • Blank W.
      • Dietrich C.F.
      • Strobel D.
      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.
      ;
      • Friedrich-Rust M.
      • Klopffleisch T.
      • Nierhoff J.
      • Herrmann E.
      • Vermehren J.
      • Schneider M.D.
      • Zeuzem S.
      • Bojunga J.
      Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: A meta-analysis.
      ). CEUS has been shown to be the most cost-effective imaging modality in some countries in Europe (
      • Westwood M.
      • Joore M.
      • Grutters J.
      • Redekop K.
      • Armstrong N.
      • Lee K.
      • Gloy V.
      • Raatz H.
      • Misso K.
      • Severens J.
      • Kleijnen J.
      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.
      ).

       Benign solid FLLs

      In addition to contrast enhancement of the FLL compared with the adjacent tissue, vascular architecture during AP can further characterize FLLs. The enhancement patterns are summarized in Table 2.
      Table 2Enhancement patterns of benign focal liver lesions in the non-cirrhotic liver
      LesionArterial phasePortal venous phaseLate phasePost-vascular phase
      Hemangioma
       Typical featuresPeripheral nodular enhancementPartial/complete centripetal fill-inIncomplete or complete enhancementIso-/slightly hypo-enhancing
       Additional featuresSmall lesion: complete, rapid centripetal enhancementNon-enhancing regionsNon-enhancing regions
      Focal nodular hyperplasia
       Typical featuresHyper-enhancing from the center, complete, earlyHyper-enhancingIso-/hyper-enhancingIso-/slightly hyper- or hypo-enhancing
       Additional featuresSpoke-wheel arteriesUn-enhanced central scarUn-enhanced central scar
      Feeding artery
      Hepatocellular adenoma
       Typical featuresHyper-enhancing, completeIso-enhancingIso-enhancing
       Additional featuresNon-enhancing regionsHyper-enhancingSlightly hypo-enhancing
      Non-enhancing regionsNon-enhancing regions
      Focal fatty infiltration
       Typical featuresIso-enhancingIso-enhancingIso-enhancingIso-enhancing
      Focal fatty sparing
       Typical featuresIso-enhancingIso-enhancingIso-enhancingIso-enhancing
      Abscess
       Typical featuresPeripheral enhancement, no central enhancementHyper-/iso-enhancing rim, no central enhancementHypo-enhancing rim, no central enhancementHypo-enhancing rim
       Additional featuresHypo-enhancing rim
      Enhanced septaEnhanced septa
      Hyper-enhanced liver segmentHyper-enhanced liver segment
      Simple cyst
       Typical featuresNon-enhancingNon-enhancingNon-enhancingNon-enhancing

       Hemangioma

      After focal fatty sparing, hemangioma is the second most common benign solid lesion of the liver (
      • Hirche T.O.
      • Russler J.
      • Schroder O.
      • Schuessler G.
      • Kappeser P.
      • Caspary W.F.
      • Dietrich C.F.
      The value of routinely performed ultrasonography in patients with Crohn disease.
      ;
      • Kaltenbach T.E.
      • Engler P.
      • Kratzer W.
      • Oeztuerk S.
      • Seufferlein T.
      • Haenle M.M.
      • Graeter T.
      Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients.
      ). In asymptomatic patients with a normal-appearing liver on US and without findings or history of malignant or chronic liver disease, a well-circumscribed, round-shaped hyper-echoic and homogeneous FLL <30 mm without intra-lesional vessels at color Doppler and without halo sign is diagnostic of hemangioma. CEUS or other contrast-enhanced imaging modalities are not recommended for further characterization (
      • Dietrich C.F.
      • Sharma M.
      • Gibson R.N.
      • Schreiber-Dietrich D.
      • Jenssen C.
      Fortuitously discovered liver lesions.
      ;
      • Vidili G.
      • De Sio I.
      • D'Onofrio M.
      • Mirk P.
      • Bertolotto M.
      • Schiavone C.
      • Experts Committee S.I.U.M.B.
      SIUMB guidelines and recommendations for the correct use of ultrasound in the management of patients with focal liver disease.
      ). CEUS is indicated when a definitive diagnosis of a hemangioma cannot be achieved using conventional US, as the addition of CEUS markedly improves the diagnostic accuracy in 90%–95% of cases (
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • Schuessler G.
      • Ott M.
      • Ignee A.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ;
      • Strobel D.
      • Seitz K.
      • Blank W.
      • Schuler A.
      • Dietrich C.
      • von Herbay A.
      • Friedrich-Rust M.
      • Kunze G.
      • Becker D.
      • Will U.
      • Kratzer W.
      • Albert F.W.
      • Pachmann C.
      • Dirks K.
      • Strunk H.
      • Greis C.
      • Bernatik T.
      Contrast-enhanced ultrasound for the characterization of focal liver lesions-Diagnostic accuracy in clinical practice (DEGUM multicenter trial).
      ;
      • Trillaud H.
      • Bruel J.M.
      • Valette P.J.
      • Vilgrain V.
      • Schmutz G.
      • Oyen R.
      • Jakubowski W.
      • Danes J.
      • Valek V.
      • Greis C.
      Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.
      ).
      The typical CEUS feature of a hemangioma is peripheral, discontinuous nodular (globular) enhancement in the AP with progressive centripetal partial or complete fill-in (
      • Foschi F.G.
      • Dall'Aglio A.C.
      • Marano G.
      • Lanzi A.
      • Savini P.
      • Piscaglia F.
      • Serra C.
      • Cursaro C.
      • Bernardi M.
      • Andreone P.
      • Stefanini G.F.
      Role of contrast-enhanced ultrasonography in primary hepatic lymphoma.
      ;
      • Sienz M.
      • Ignee A.
      • Dietrich C.F.
      [Reference values in abdominal ultrasound-Biliopancreatic system and spleen].
      ;
      • Cui X.W.
      • Ignee A.
      • Jedrzejczyk M.
      • Dietrich C.F.
      Dynamic Vascular Pattern (DVP), a quantification tool for contrast enhanced ultrasound.
      ;
      • Chiorean L.
      • Caraiani C.
      • Radzina M.
      • Jedrzejczyk M.
      • Schreiber-Dietrich D.
      • Dietrich C.F.
      Vascular phases in imaging and their role in focal liver lesions assessment.
      ). Complete fill-in occurs only in 40%–50% of cases during the LP. This fill-in is often more rapid in smaller lesions, and the entire lesion may be hyper-enhancing in the AP. Persistent iso- or hyper-enhancement is sustained through the LP (
      • Lamuraglia M.
      • Escudier B.
      • Chami L.
      • Schwartz B.
      • Leclere J.
      • Roche A.
      • Lassau N.
      To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound.
      ;
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • Schuessler G.
      • Ott M.
      • Ignee A.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ,
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Dong Y.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ;
      • Hirche T.O.
      • Ignee A.
      • Hirche H.
      • Schneider A.
      • Dietrich C.F.
      Evaluation of hepatic steatosis by ultrasound in patients with chronic hepatitis C virus infection.
      ;
      • Sienz M.
      • Ignee A.
      • Dietrich C.F.
      [Sonography today: reference values in abdominal ultrasound: aorta, inferior vena cava, kidneys].
      ;
      • Inoue T.
      • Hyodo T.
      • Korenaga K.
      • Murakami T.
      • Imai Y.
      • Higaki A.
      • Suda T.
      • Takano T.
      • Miyoshi K.
      • Koda M.
      • Tanaka H.
      • Iijima H.
      • Ochi H.
      • Hirooka M.
      • Numata K.
      • Kudo M.
      Kupffer phase image of Sonazoid-enhanced US is useful in predicting a hypervascularization of non-hypervascular hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced MRI: a multicenter retrospective study.
      ). On post-vascular imaging using Sonazoid, hemangiomas appear iso- to hypo-enhancing relative to the surrounding liver parenchyma, and may resemble metastatic tumors and HCCs (
      • Little J.M.
      • Richardson A.
      • Tait N.
      Hepatic dystychoma: a five year experience.
      ;
      • Sugimoto K.
      • Moriyasu F.
      • Saito K.
      • Yoshiara H.
      • Imai Y.
      Kupffer-phase findings of hepatic hemangiomas in contrast-enhanced ultrasound with sonazoid.
      ). The overall sensitivity of CEUS for diagnosis of hemangioma is 86% (95% CI: 81%–92%) according to a meta-analysis including 612 cases from 20 studies (
      • Friedrich-Rust M.
      • Klopffleisch T.
      • Nierhoff J.
      • Herrmann E.
      • Vermehren J.
      • Schneider M.D.
      • Zeuzem S.
      • Bojunga J.
      Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: A meta-analysis.
      ).
      Atypical appearances, particularly LP hypo-enhancement (UCA washout) or lack of centripetal fill-in, have been described and may be explained by the destruction of microbubbles that are not adequately replenished because of very long bubble transit times within the lesion (
      • Chiorean L.
      • Caraiani C.
      • Radzina M.
      • Jedrzejczyk M.
      • Schreiber-Dietrich D.
      • Dietrich C.F.
      Vascular phases in imaging and their role in focal liver lesions assessment.
      ). Hemangiomas with arteriovenous shunts (also called high-flow or shunt hemangiomas) exhibit rapid homogeneous hyper-enhancement in the AP and, therefore, can be confused with focal nodular hyperplasia (FNH) or even hepatocellular adenoma (HCA) or HCC (
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • Schuessler G.
      • Ott M.
      • Ignee A.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ). They are almost always hyper-enhancing in the PVP and LP. Thrombosed hemangiomas exhibit a lack of enhancement and can be confused with malignancy if only identified during the later CEUS phases (
      • Dietrich C.F.
      • Mertens J.C.
      • Braden B.
      • Schuessler G.
      • Ott M.
      • Ignee A.
      Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
      ;
      • Klinger C.
      • Stuckmann G.
      • Dietrich C.F.
      • Berzigotti A.
      • Horger M.S.
      • Debove I.
      • Gilot B.J.
      • Pauluschke-Frohlich J.
      • Hoffmann T.
      • Sipos B.
      • Frohlich E.
      Contrast-enhanced imaging in hepatic epithelioid hemangioendothelioma: retrospective study of 10 patients.
      ).

       Focal nodular hyperplasia

      On CEUS, an FNH typically appears as a hyper-enhancing homogeneous lesion in all phases. The hyper-enhancement might be only mild during the PVP and LP (
      • Dietrich C.F.
      • Schuessler G.
      • Trojan J.
      • Fellbaum C.
      • Ignee A.
      Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.
      ,
      • Dietrich C.F.
      • Tana C.
      • Caraiani C.
      • Dong Y.
      Contrast enhanced ultrasound (CEUS) imaging of solid benign focal liver lesions.
      ;
      • Strobel D.
      • Seitz K.
      • Blank W.
      • Schuler A.
      • Dietrich C.F.
      • von Herbay A.
      • Friedrich-Rust M.
      • Bernatik T.
      Tumor-specific vascularization pattern of liver metastasis, hepatocellular carcinoma, hemangioma and focal nodular hyperplasia in the differential diagnosis of 1349 liver lesions in contrast-enhanced ultrasound (CEUS).
      ;
      • Piscaglia F.
      • Gianstefani A.
      • Ravaioli M.
      • Golfieri R.
      • Cappelli A.
      • Giampalma E.
      • Sagrini E.
      • Imbriaco G.
      • Pinna A.D.
      • Bolondi L.
      Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation.
      ,
      • Piscaglia F.
      • Venturi A.
      • Mancini M.
      • Giangregorio F.
      • Vidili G.
      • Magnolfi F.
      • Mirarchi M.
      • Fornari F.
      • Bolondi L.
      Diagnostic features of real-time contrast-enhanced ultrasound in focal nodular hyperplasia of the liver.
      ;
      • Pei X.Q.
      • Liu L.Z.
      • Xiong Y.H.
      • Zou R.H.
      • Chen M.S.
      • Li A.H.
      • Cai M.Y.
      Quantitative analysis of contrast-enhanced ultrasonography: Differentiating focal nodular hyperplasia from hepatocellular carcinoma.
      ). Hyper-enhancement is usually marked in the AP (
      • Pei X.Q.
      • Liu L.Z.
      • Xiong Y.H.
      • Zou R.H.
      • Chen M.S.
      • Li A.H.
      • Cai M.Y.
      Quantitative analysis of contrast-enhanced ultrasonography: Differentiating focal nodular hyperplasia from hepatocellular carcinoma.
      ), with a rapid fill-in from the center outward (a spoke-wheel pattern) (70%) or sometimes with an eccentric vascular or multilocular arterial supply (30%) (
      • Dietrich C.F.
      • Schuessler G.
      • Trojan J.
      • Fellbaum C.
      • Ignee A.
      Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.
      ;
      • Cui X.W.
      • Ignee A.
      • Jedrzejczyk M.
      • Dietrich C.F.
      Dynamic Vascular Pattern (DVP), a quantification tool for contrast enhanced ultrasound.
      ). A centrally hypo- or non-enhancing located scar may be seen in the LP. This, together with the direction of filling of the lesion in the AP, if recognizable (centrifugal vs. centripetal), is an important feature in distinguishing FNH from shunt (high-flow) hemangiomas. In distinction to FNH, hepatocellular adenomas and hyper-vascular malignant FLLs exhibit washout as the most important CEUS feature (
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Dong Y.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ).
      In the vast majority of cases (93.5%), iso-enhancement or only slight hyper-enhancement of FNH is observed in the PVP compared with the surrounding liver parenchyma, whereas in the remainder (6.5%), hypo-enhancement is observed (
      • Jones E.C.
      • Chezmar J.L.
      • Nelson R.C.
      • Bernardino M.E.
      The frequency and significance of small (less than or equal to 15 mm) hepatic lesions detected by CT.
      ;
      • Lee J.
      • Jeong W.K.
      • Lim H.K.
      • Kim A.Y.
      Focal Nodular hyperplasia of the liver: Contrast-enhanced ultrasonographic features with Sonazoid.
      ).
      The overall sensitivity of CEUS in the diagnosis of FNH is 88% (95% CI: 81%–94%) according to a large meta-analysis of 365 cases FNH from 18 studies (
      • Friedrich-Rust M.
      • Klopffleisch T.
      • Nierhoff J.
      • Herrmann E.
      • Vermehren J.
      • Schneider M.D.
      • Zeuzem S.
      • Bojunga J.
      Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: A meta-analysis.
      ). Several studies have suggested that the diagnostic accuracy of CEUS for diagnosis of FNH is a “matter of size”, with accuracy decreasing in patients with lesion size >30 mm (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ).

       Hepatocellular adenoma

      HCA is a rare, benign and sometimes estrogen-dependent hepatic neoplasm. Typical imaging characteristics of HCAs are displayed in smaller lesions <50 mm (
      • Dietrich C.F.
      • Schuessler G.
      • Trojan J.
      • Fellbaum C.
      • Ignee A.
      Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.
      ,
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Dong Y.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ). At CEUS, HCA exhibits homogeneous arterial hyper-enhancement, typically with rapid, complete, peripherally dominated filling without a spoke-wheel pattern and without a peripheral globular enhancement pattern, which often enables the correct differential diagnosis, except in telangiectatic and inflammatory HCAs (
      • Foschi F.G.
      • Dall'Aglio A.C.
      • Marano G.
      • Lanzi A.
      • Savini P.
      • Piscaglia F.
      • Serra C.
      • Cursaro C.
      • Bernardi M.
      • Andreone P.
      • Stefanini G.F.
      Role of contrast-enhanced ultrasonography in primary hepatic lymphoma.
      ). However, HCCs and hyper-enhancing metastases may exhibit a similar arterial enhancement pattern, making the differentiation impossible during the AP. In the early PVP, HCAs usually become iso-enhancing or, more rarely, remain slightly hyper-enhancing (
      • Dietrich C.F.
      • Schuessler G.
      • Trojan J.
      • Fellbaum C.
      • Ignee A.
      Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.
      ;
      • Piscaglia F.
      • Lencioni R.
      • Sagrini E.
      • Pina C.D.
      • Cioni D.
      • Vidili G.
      • Bolondi L.
      Characterization of focal liver lesions with contrast-enhanced ultrasound.
      ). Previous bleeding episodes or necrotic portions exhibit intra-tumoral non-enhancing areas in larger HCA. In most cases, washout occurs in the LP, requiring biopsy to exclude malignancy (
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Dong Y.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ). Because of the different subtypes of HCA, characterization and differentiation (e.g., from FNH and HCCs, such as the inflammatory subtype) may be difficult using CEUS as well as MRI, and biopsy (HCA <50 mm) or surgery (≥50) is indicated for final diagnosis (
      • Lamuraglia M.
      • Escudier B.
      • Chami L.
      • Schwartz B.
      • Leclere J.
      • Roche A.
      • Lassau N.
      To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound.
      ). Liver-specific contrast-enhanced MRI may be helpful when HCA is suspected at CEUS to exclude multilocularity. No studies are available for the diagnosis of HCA using Sonazoid.

       Focal fatty change

      Focal fatty changes, either by fat infiltration or fatty sparing, usually appear on conventional B-mode US as oval or polygonal areas located along the portal bifurcation or close to the hepatic hilum and gallbladder. On visualization of possible focal fat infiltration, atypical location or history of malignancy should prompt further characterization to exclude malignant lesions. Focal fatty change exhibits the same degree of enhancement (iso-enhancing) as the surrounding liver parenchyma during all phases (
      • Hirche T.O.
      • Ignee A.
      • Hirche H.
      • Schneider A.
      • Dietrich C.F.
      Evaluation of hepatic steatosis by ultrasound in patients with chronic hepatitis C virus infection.
      ;
      • Janica J.
      • Ustymowicz A.
      • Lukasiewicz A.
      • Panasiuk A.
      • Niemcunowicz-Janica A.
      • Turecka-Kulesza E.
      • Lebkowska U.
      Comparison of contrast-enhanced ultrasonography with grey-scale ultrasonography and contrast-enhanced computed tomography in diagnosing focal fatty liver infiltrations and focal fatty sparing.
      ). Typically, a centrally located artery can be identified (
      • Hirche T.O.
      • Ignee A.
      • Hirche H.
      • Schneider A.
      • Dietrich C.F.
      Evaluation of hepatic steatosis by ultrasound in patients with chronic hepatitis C virus infection.
      ;
      • Dietrich C.F.
      • Jenssen C.
      [Focal liver lesion, incidental finding].
      ;
      • Dietrich C.F.
      • Sharma M.
      • Gibson R.N.
      • Schreiber-Dietrich D.
      • Jenssen C.
      Fortuitously discovered liver lesions.
      ).

       Infection

      The CEUS findings in phlegmonous inflammation are variable. During the early stage of infection, lesions often appear hyper-enhancing, while mature lesions develop non-enhancing foci as liquefaction progresses. Mature liver abscesses on CEUS exhibit enhancement of the margins and frequently of the septae in the AP, which sometimes can be followed by PVP hypo-enhancement. The most prominent feature on CEUS is the non-enhancement of the liquefied portions combined with arterial rim enhancement (
      • Biecker E.
      • Fischer H.P.
      • Strunk H.
      • Sauerbruch T.
      Benign hepatic tumours.
      ;
      • Catalano O.
      • Sandomenico F.
      • Raso M.M.
      • Siani A.
      Low mechanical index contrast-enhanced sonographic findings of pyogenic hepatic abscesses.
      ,
      • Catalano O.
      • Sandomenico F.
      • Nunziata A.
      • Raso M.M.
      • Vallone P.
      • Siani A.
      Transient hepatic echogenicity difference on contrast-enhanced ultrasonography: sonographic sign and pitfall.
      ;
      • Liu G.J.
      • Lu M.D.
      • Xie X.Y.
      • Xu H.X.
      • Xu Z.F.
      • Zheng Y.L.
      • Liang J.Y.
      • Wang W.
      Real-time contrast-enhanced ultrasound imaging of infected focal liver lesions.
      ;
      • Anderson S.W.
      • Kruskal J.B.
      • Kane R.A.
      Benign hepatic tumors and iatrogenic pseudotumors.
      ). Diffuse hyper-enhancement of the affected liver subsegment(s) in the AP and LP washout of liver parenchyma surrounding the non-enhancing necrotic area have been described in the majority of cases (
      • Anderson S.W.
      • Kruskal J.B.
      • Kane R.A.
      Benign hepatic tumors and iatrogenic pseudotumors.
      ).
      The appearance of granulomas and focal tuberculosis on CEUS varies, which makes it hard and sometimes impossible to differentiate these from malignancy (
      • Liu G.J.
      • Lu M.D.
      • Xie X.Y.
      • Xu H.X.
      • Xu Z.F.
      • Zheng Y.L.
      • Liang J.Y.
      • Wang W.
      Real-time contrast-enhanced ultrasound imaging of infected focal liver lesions.
      ;
      • Cao B.S.
      • Li X.L.
      • Li N.
      • Wang Z.Y.
      The nodular form of hepatic tuberculosis: contrast-enhanced ultrasonographic findings with pathologic correlation.
      ;
      • Dietrich C.F.
      • Kabaalioglu A.
      • Brunetti E.
      • Richter J.
      Fasciolosis.
      ,
      • Dietrich C.F.
      • Atkinson N.S.S.
      • Lee W.J.
      • Kling K.
      • Neumayr A.
      • Braden B.
      • Richter J.
      • Akpata R.
      • Southisavath P.
      • Schreiber-Dietrich D.
      • Dong Y.
      Never seen before? Opisthorchiasis and clonorchiasis.
      ,
      • Dietrich C.F.
      • Averkiou M.
      • Nielsen M.B.
      • Barr R.G.
      • Burns P.N.
      • Calliada F.
      • Cantisani V.
      • Choi B.
      • Chammas M.C.
      • Clevert D.A.
      • Claudon M.
      • Correas J.M.
      • Cui X.W.
      • Cosgrove D.
      • D'Onofrio M.
      • Dong Y.
      • Eisenbrey J.
      • Fontanilla T.
      • Gilja O.H.
      • Ignee A.
      • Jenssen C.
      • Kono Y.
      • Kudo M.
      • Lassau N.
      • Lyshchik A.
      • Franca Meloni M.
      • Moriyasu F.
      • Nolsoe C.
      • Piscaglia F.
      • Radzina M.
      • Saftoiu A.
      • Sidhu P.S.
      • Sporea I.
      • Schreiber-Dietrich D.
      • Sirlin C.B.
      • Stanczak M.
      • Weskott H.P.
      • Wilson S.R.
      • Willmann J.K.
      • Kim T.K.
      • Jang H.J.
      • Vezeridis A.
      • Westerway S.
      How to perform contrast-enhanced ultrasound (CEUS).
      ,
      • Dietrich C.F.
      • Potthoff A.
      • Helmberger T.
      • Ignee A.
      • Willmann J.K.
      • Group C.L.-R.W.
      [Contrast-enhanced ultrasound: Liver Imaging Reporting and Data System (CEUS LI-RADS)].
      ,
      • Dietrich C.F.
      • Tana C.
      • Caraiani C.
      • Dong Y.
      Contrast enhanced ultrasound (CEUS) imaging of solid benign focal liver lesions.
      ).

       Other solid benign liver lesions

      A range of other, very rare, solid benign liver lesions can be seen including the following entities:
      • Active hemorrhage (including spontaneous, traumatic and iatrogenic liver bleedings) appear as contrast extravasation, whereas hematomas appear as non-enhancing areas.
      • Inflammatory pseudotumor is a rare disease whose definite diagnosis is usually made only at surgery. It may exhibit arterial enhancement and LP hypo-enhancement, falsely suggesting malignancy.
      • Hepatic angiomyolipoma is a rare benign mesenchymal tumor. It appears homogeneous in most cases and strongly hyper-echogenic at baseline US. CEUS reveals arterial hyper-enhancement (
        • Dietrich C.F.
        • Mertens J.C.
        • Braden B.
        • Schuessler G.
        • Ott M.
        • Ignee A.
        Contrast-enhanced ultrasound of histologically proven liver hemangiomas.
        ;
        • Wang Z.
        • Xu H.X.
        • Xie X.Y.
        • Xie X.H.
        • Kuang M.
        • Xu Z.F.
        • Liu G.J.
        • Chen L.D.
        • Lin M.X.
        • Lu M.D.
        Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound.
        ).
      • Cholangiocellular adenomas (CCAs or bile duct adenomas) are rare lesions that are usually small (90% <1 cm). CEUS may reveal strong arterial hyper-enhancement and early washout in the PVP and LP (they lack portal veins), falsely suggesting malignancy (
        • Ignee A.
        • Piscaglia F.
        • Ott M.
        • Salvatore V.
        • Dietrich C.F.
        A benign tumour of the liver mimicking malignant liver disease—Cholangiocellular adenoma.
        ;
        • Corvino A.
        • Catalano O.
        • Setola S.V.
        • Sandomenico F.
        • Corvino F.
        • Petrillo A.
        Contrast-enhanced ultrasound in the characterization of complex cystic focal liver lesions.
        ).
      • Hepatic epithelioid hemangioendotheliomas (HEHEs) often manifest as multinodular FLLs. On CEUS, HEHEs exhibit rim-like or heterogeneous hyperenhancement in the AP and hypo-enhancement in the PVP and LP, a sign of malignancy (
        • Cui X.W.
        • Ignee A.
        • Woenckhaus M.
        • Dietrich C.F.
        Hemangioendothelioma, an imaging challenge.
        ;
        • Dong Y.
        • Wang W.P.
        • Cantisani V.
        • D'Onofrio M.
        • Ignee A.
        • Mulazzani L.
        • Saftoiu A.
        • Sparchez Z.
        • Sporea I.
        • Dietrich C.F.
        Contrast-enhanced ultrasound of histologically proven hepatic epithelioid hemangioendothelioma.
        ;
        • Klinger C.
        • Stuckmann G.
        • Dietrich C.F.
        • Berzigotti A.
        • Horger M.S.
        • Debove I.
        • Gilot B.J.
        • Pauluschke-Frohlich J.
        • Hoffmann T.
        • Sipos B.
        • Frohlich E.
        Contrast-enhanced imaging in hepatic epithelioid hemangioendothelioma: retrospective study of 10 patients.
        ). Some patients exhibit centrally located un-enhanced areas. In contrast, all hemangiomas and FNH exhibit hyper- or iso-enhancement in the PVP and LP, which is their most distinguishing feature.
      For liver trauma we refer to the recently published EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (short version).
      ,
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • Gilja O.H.
      • Saftoiu A.
      • Bartels E.
      • Bertolotto M.
      • Calliada F.
      • Clevert D.A.
      • Cosgrove D.
      • Deganello A.
      • D'Onofrio M.
      • Drudi F.M.
      • Freeman S.
      • Harvey C.
      • Jenssen C.
      • Jung E.M.
      • Klauser A.S.
      • Lassau N.
      • Meloni M.F.
      • Leen E.
      • Nicolau C.
      • Nolsoe C.
      • Piscaglia F.
      • Prada F.
      • Prosch H.
      • Radzina M.
      • Savelli L.
      • Weskott H.P.
      • Wijkstra H.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
      ).

       Malignant solid FLLs

      In patients with a non-cirrhotic liver, metastases are more common than primary liver malignant tumors, though conventional US is occasionally helpful in detecting the malignant nature of an FLL, by demonstrating a hypo-echoic halo and infiltration of intrahepatic vessels. Contrast-enhanced imaging is necessary to determine the malignant nature in many circumstances, which is true for US, CT and MRI (
      • Lu S.N.
      • Wang L.Y.
      • Chang W.Y.
      • Chen C.J.
      • Su W.P.
      • Chen S.C.
      • Chuang W.L.
      • Hsieh M.Y.
      Abdominal sonographic screening in a single community.
      ;
      • Dietrich C.F.
      • Kratzer W.
      • Strobe D.
      • Danse E.
      • Fessl R.
      • Bunk A.
      • Vossas U.
      • Hauenstein K.
      • Koch W.
      • Blank W.
      • Oudkerk M.
      • Hahn D.
      • Greis C.
      Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
      ). Contrast washout in the PVP and LP is the most important feature to determine malignancy (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ). Almost all metastases exhibit this feature, regardless of the enhancement pattern in the AP. Very few exceptions to this rule have been reported, mainly in liver metastases of neuroendocrine tumors and atypical HCC (Table 3).
      Table 3Enhancement patterns of malignant focal liver lesions in the non-cirrhotic liver
      TumorArterial phase (10–30 s)Portal venous phase (20–120 s)Late phase (120–300 s)Post vascular phase (>10 min)
      Metastasis
      Typical featuresRim enhancementHypo-enhancingHypo-/non-enhancingHypo-/non-enhancing
      Additional featuresComplete enhancementNon-enhancing regionsNon-enhancing regionsNon-enhancing regions
      Hyper-enhancement
      Non-enhancing regions
      Hepatocellular carcinoma
      Typical featuresHyper-enhancingIso-enhancingHypo-/non-enhancingHypo-/non-enhancing
      Additional featuresNon-enhancing regionsNon-enhancing regionsNon-enhancing regionsNon-enhancing regions
      Cholangiocarcinoma
      Typical featuresRim-like hyper-enhancement, central hypo-enhancementHypo-enhancingHypo-/non-enhancingHypo-/non-enhancing
      Additional featuresNon-enhancing regionsNon-enhancing regionsNon-enhancing regionsNon-enhancing regions
      Inhomogeneous hyper-enhancement

       Hepatocellular carcinoma in the non-cirrhotic liver

      Hepatocellular carcinoma is the most common primary liver malignancy, and most of the patients at risk have known or unknown liver cirrhosis (
      • Forner A.
      • Llovet J.M.
      • Bruix J.
      Hepatocellular carcinoma.
      ). There are few articles on the value of CEUS in the diagnosis of HCC in the non-cirrhotic liver. Generally, the enhancement patterns of HCC in the non-cirrhotic liver on CEUS are similar to those of HCC in the cirrhotic liver, but the size at the time of diagnosis tends to be larger (
      • Linhart P.
      • Bonhof J.A.
      • Baque P.E.
      • Pering C.
      [Ultrasound in diagnosis of benign and malignant liver tumors].
      ). HCA and FNH are the main differential diagnoses (
      • Zheng S.G.
      • Xu H.X.
      • Liu L.N.
      Management of hepatocellular carcinoma: The role of contrast-enhanced ultrasound.
      ;
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Dong Y.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ). HCCs in the non-cirrhotic liver are usually hyper-enhancing in the AP, typically with a chaotic vascular pattern (
      • Hayashi H.
      • Nishigaki Y.
      • Tomita E.
      • Watanabe C.
      • Watanabe S.
      • Watanabe N.
      • Suzuki Y.
      • Kato T.
      • Naiki T.
      Usefulness of early vascular phase images from contrast-enhanced ultrasonography using Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma.
      ), and variably iso- or hypo-enhancing in the PVP and LP (
      • Inoue T.
      • Hyodo T.
      • Korenaga K.
      • Murakami T.
      • Imai Y.
      • Higaki A.
      • Suda T.
      • Takano T.
      • Miyoshi K.
      • Koda M.
      • Tanaka H.
      • Iijima H.
      • Ochi H.
      • Hirooka M.
      • Numata K.
      • Kudo M.
      Kupffer phase image of Sonazoid-enhanced US is useful in predicting a hypervascularization of non-hypervascular hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced MRI: a multicenter retrospective study.
      ). Hyper-enhancement in the AP is often homogenous but starts predominantly along the periphery (
      • Goto E.
      • Masuzaki R.
      • Tateishi R.
      • Kondo Y.
      • Imamura J.
      • Goto T.
      • Ikeda H.
      • Akahane M.
      • Shiina S.
      • Omata M.
      • Yoshida H.
      • Koike K.
      Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma.
      ). The fibrolamellar variant of HCC has a non-specific appearance at CEUS. According to expert opinions and case reports, these exhibit rapid wash-in with a heterogeneous pattern in the AP and early PVP and early and marked washout thereafter (
      • Mandry D.
      • Bressenot A.
      • Galloy M.A.
      • Chastagner P.
      • Branchereau S.
      • Claudon M.
      Contrast-enhanced ultrasound in fibro-lamellar hepatocellular carcinoma: a case report.
      ;
      • Arita J.
      • Hasegawa K.
      • Takahashi M.
      • Hata S.
      • Shindoh J.
      • Sugawara Y.
      • Kokudo N.
      Correlation between contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of resected hepatocellular carcinoma.
      ).

       Cholangiocarcinoma (ICC)

      ICC is the second most common primary malignant liver tumor and usually arises in healthy liver parenchyma. The different treatment approaches and prognoses necessitate that ICC be distinguished from HCC (
      • Galassi M.
      • Iavarone M.
      • Rossi S.
      • Bota S.
      • Vavassori S.
      • Rosa L.
      • Leoni S.
      • Venerandi L.
      • Marinelli S.
      • Sangiovanni A.
      • Veronese L.
      • Fraquelli M.
      • Granito A.
      • Golfieri R.
      • Colombo M.
      • Bolondi L.
      • Piscaglia F.
      Patterns of appearance and risk of misdiagnosis of intrahepatic cholangiocarcinoma in cirrhosis at contrast enhanced ultrasound.
      ). Although rarely observed in Europe and America, ICC is more frequently seen in Asia, where combined HCC–ICC also exists (
      • Dong Y.
      • Teufel A.
      • Trojan J.
      • Berzigotti A.
      • Cui X.W.
      • Dietrich C.F.
      Contrast enhanced ultrasound in mixed hepatocellular cholangiocarcinoma: Case series and review of the literature.
      ).
      In distinction to the late enhancement on CECT or CEMRI, ICC exhibits a variety of patterns in the AP at CEUS, but all show washout in the LP (
      • Xu H.X.
      • Lu M.D.
      • Liu G.J.
      • Xie X.Y.
      • Xu Z.F.
      • Zheng Y.L.
      • Liang J.Y.
      Imaging of peripheral cholangiocarcinoma with low-mechanical index contrast-enhanced sonography and SonoVue: initial experience.
      ;
      • Chen L.D.
      • Xu H.X.
      • Xie X.Y.
      • Lu M.D.
      • Xu Z.F.
      • Liu G.J.
      • Liang J.Y.
      • Lin M.X.
      Enhancement patterns of intrahepatic cholangiocarcinoma: comparison between contrast-enhanced ultrasound and contrast-enhanced CT.
      ;
      • Wang Z.
      • Xu H.X.
      • Xie X.Y.
      • Xie X.H.
      • Kuang M.
      • Xu Z.F.
      • Liu G.J.
      • Chen L.D.
      • Lin M.X.
      • Lu M.D.
      Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound.
      ). The typical pattern of malignancy is better revealed by CEUS than by CECT or CEMRI (
      • Schellhaas B.
      • Hammon M.
      • Strobel D.
      • Pfeifer L.
      • Kielisch C.
      • Goertz R.S.
      • Cavallaro A.
      • Janka R.
      • Neurath M.F.
      • Uder M.
      • Seuss H.
      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.
      ,
      • Schellhaas B.
      • Pfeifer L.
      • Kielisch C.
      • Goertz R.S.
      • Neurath M.F.
      • Strobel D.
      Interobserver agreement for contrast-enhanced ultrasound (CEUS)-based standardized algorithms for the diagnosis of hepatocellular carcinoma in high-risk patients.
      ).
      There is controversy over the differential diagnosis of HCC and ICC with CEUS (
      • Little J.M.
      • Richardson A.
      • Tait N.
      Hepatic dystychoma: a five year experience.
      ;
      • Laghi F.
      • Catalano O.
      • Maresca M.
      • Sandomenico F.
      • Siani A.
      Indeterminate, subcentimetric focal liver lesions in cancer patients: additional role of contrast-enhanced ultrasound.
      ;
      • Leoni S.
      • Piscaglia F.
      • Golfieri R.
      • Camaggi V.
      • Vidili G.
      • Pini P.
      • Bolondi L.
      The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria.
      ;
      • Zech C.J.
      [Incidental livers lesions–A modern approach].
      ;
      • Barreiros A.P.
      • Piscaglia F.
      • Dietrich C.F.
      Contrast enhanced ultrasound for the diagnosis of hepatocellular carcinoma (HCC): Comments on AASLD guidelines.
      ;
      • Dietrich C.F.
      • Averkiou M.A.
      • Correas J.M.
      • Lassau N.
      • Leen E.
      • Piscaglia F.
      An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion.
      ,
      • Dietrich C.F.
      • Cui X.W.
      • Boozari B.
      • Hocke M.
      • Ignee A.
      Contrast-enhanced ultrasound (CEUS) in the diagnostic algorithm of hepatocellular and cholangiocellular carcinoma, comments on the AASLD guidelines.
      ,
      • Dietrich C.F.
      • Serra C.
      • Jedrejczyk M.
      Ultrasound of liver.
      ;
      • Frydrychowicz A.
      • Lubner M.G.
      • Brown J.J.
      • Merkle E.M.
      • Nagle S.K.
      • Rofsky N.M.
      • Reeder S.B.
      Hepatobiliary MR imaging with gadolinium-based contrast agents.
      ;
      • Kim T.K.
      • Noh S.Y.
      • Wilson S.R.
      • Kono Y.
      • Piscaglia F.
      • Jang H.J.
      • Lyshchik A.
      • Dietrich C.F.
      • Willmann J.K.
      • Vezeridis A.
      • Sirlin C.B.
      Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) 2017-A review of important differences compared to the CT/MRI system.
      ;
      • Kono Y.
      • Lyshchik A.
      • Cosgrove D.
      • Dietrich C.F.
      • Jang H.J.
      • Kim T.K.
      • Piscaglia F.
      • Willmann J.K.
      • Wilson S.R.
      • Santillan C.
      • Kambadakone A.
      • Mitchell D.
      • Vezeridis A.
      • Sirlin C.B.
      Contrast enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS): the official version by the American College of Radiology (ACR).
      ;
      • Piscaglia F.
      • Wilson S.R.
      • Lyshchik A.
      • Cosgrove D.
      • Dietrich C.F.
      • Jang H.J.
      • Kim T.K.
      • Salvatore V.
      • Willmann J.K.
      • Sirlin C.B.
      • Kono Y.
      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.
      ;
      • Wilson S.R.
      • Lyshchik A.
      • Piscaglia F.
      • Cosgrove D.
      • Jang H.J.
      • Sirlin C.
      • Dietrich C.F.
      • Kim T.K.
      • Willmann J.K.
      • Kono Y.
      CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI.
      ). Compared with HCCs, ICCs exhibit less intense enhancement in the AP and early (<60 s) and marked washout compared with the typically late and mild washout in HCCs (
      • Little J.M.
      • Richardson A.
      • Tait N.
      Hepatic dystychoma: a five year experience.
      ). ICCs can be subcategorized into three types: mass-forming periductal infiltrating and intraductal growing. Mass-forming ICCs can exhibit four enhancement patterns in the AP: peripheral irregular rim-like enhancement, heterogeneous hyper-enhancement, homogeneous hyper-enhancement and heterogeneous hypo-enhancement (
      • Chen L.D.
      • Xu H.X.
      • Xie X.Y.
      • Lu M.D.
      • Xu Z.F.
      • Liu G.J.
      • Liang J.Y.
      • Lin M.X.
      Enhancement patterns of intrahepatic cholangiocarcinoma: comparison between contrast-enhanced ultrasound and contrast-enhanced CT.
      ;
      • Wang Z.
      • Xu H.X.
      • Xie X.Y.
      • Xie X.H.
      • Kuang M.
      • Xu Z.F.
      • Liu G.J.
      • Chen L.D.
      • Lin M.X.
      • Lu M.D.
      Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound.
      ). Mass-forming ICCs usually exhibit washout in the PVP and invariably marked hypo-enhancement in the LP, followed by complete hypo-enhancement in the post-vascular phase (
      • Hatanaka K.
      • Kudo M.
      • Minami Y.
      • Maekawa K.
      Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignanciesc: Comparison with contrast-enhanced CT.
      ,
      • Hatanaka K.
      • Kudo M.
      • Minami Y.
      • Ueda T.
      • Tatsumi C.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Hagiwara S.
      • Chung H.
      • Ueshima K.
      • Maekawa K.
      Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid.
      ;
      • Xu H.X.
      • Chen L.D.
      • Liu L.N.
      • Zhang Y.F.
      • Guo L.H.
      • Liu C.
      Contrast-enhanced ultrasound of intrahepatic cholangiocarcinoma: correlation with pathological examination.
      ).
      During the AP, periductal infiltrating ICCs appear heterogeneously enhancing, and intraductal growing ICCs exhibit homogeneous hyper-enhancement in most cases. Both lesions exhibit marked washout during the PVP and LP (
      • Xu H.X.
      • Chen L.D.
      • Liu L.N.
      • Zhang Y.F.
      • Guo L.H.
      • Liu C.
      Contrast-enhanced ultrasound of intrahepatic cholangiocarcinoma: correlation with pathological examination.
      ).

       Metastases

      Liver metastases are the most common malignant lesions of the liver, arising mainly from cancers of the gastrointestinal tract, breast, pancreas or lung. Compared with conventional US, CEUS markedly improves the detection of liver metastases. Liver metastases can be detected and characterized reliably as hypo-enhancing lesions during the PVP and LP, with few exceptions. Washout is of marked degree and with early onset, usually before 60 s after UCA injection. In the LP, very small metastases may be conspicuous, and lesions that were occult on B-mode US can be detected (
      • Dietrich C.F.
      • Kratzer W.
      • Strobe D.
      • Danse E.
      • Fessl R.
      • Bunk A.
      • Vossas U.
      • Hauenstein K.
      • Koch W.
      • Blank W.
      • Oudkerk M.
      • Hahn D.
      • Greis C.
      Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
      ). Because of the lack of Kupffer cells, metastatic lesions on post-vascular phase imaging with Sonazoid are clearly demarcated and completely hypo-enhancing (
      • Hatanaka K.
      • Kudo M.
      • Minami Y.
      • Maekawa K.
      Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignanciesc: Comparison with contrast-enhanced CT.
      ,
      • Hatanaka K.
      • Kudo M.
      • Minami Y.
      • Ueda T.
      • Tatsumi C.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Hagiwara S.
      • Chung H.
      • Ueshima K.
      • Maekawa K.
      Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid.
      ;
      • Zech C.J.
      [Incidental livers lesions–A modern approach].
      ;
      • Frydrychowicz A.
      • Lubner M.G.
      • Brown J.J.
      • Merkle E.M.
      • Nagle S.K.
      • Rofsky N.M.
      • Reeder S.B.
      Hepatobiliary MR imaging with gadolinium-based contrast agents.
      ;
      • Dietrich C.F.
      • Averkiou M.A.
      • Correas J.M.
      • Lassau N.
      • Leen E.
      • Piscaglia F.
      An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion.
      ,
      • Dietrich C.F.
      • Cui X.W.
      • Boozari B.
      • Hocke M.
      • Ignee A.
      Contrast-enhanced ultrasound (CEUS) in the diagnostic algorithm of hepatocellular and cholangiocellular carcinoma, comments on the AASLD guidelines.
      ,
      • Dietrich C.F.
      • Serra C.
      • Jedrejczyk M.
      Ultrasound of liver.
      ;
      • Ying L.
      • Lin X.
      • Xie Z.L.
      • Tang F.Y.
      • Hu Y.P.
      • Shi K.Q.
      Clinical utility of acoustic radiation force impulse imaging for identification of malignant liver lesions: a meta-analysis.
      ).
      Metastases usually exhibit at least some contrast enhancement in the AP and, sometimes, marked and chaotic enhancement. Rim or halo enhancement is often seen (
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012.
      ,
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • Piscaglia F.
      • Wilson S.R.
      • Barr R.G.
      • Chammas M.C.
      • Chaubal N.G.
      • Chen M.H.
      • Clevert D.A.
      • Correas J.M.
      • Ding H.
      • Forsberg F.
      • Fowlkes J.B.
      • Gibson R.N.
      • Goldberg B.B.
      • Lassau N.
      • Leen E.L.
      • Mattrey R.F.
      • Moriyasu F.
      • Solbiati L.
      • Weskott H.P.
      • Xu H.X.
      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.
      ).

       Lymphoma

      Lymphoma exhibits variable arterial enhancement but characteristic fast and marked washout in the PVP and LP, predictive of malignancy (
      • Foschi F.G.
      • Dall'Aglio A.C.
      • Marano G.
      • Lanzi A.
      • Savini P.
      • Piscaglia F.
      • Serra C.
      • Cursaro C.
      • Bernardi M.
      • Andreone P.
      • Stefanini G.F.
      Role of contrast-enhanced ultrasonography in primary hepatic lymphoma.
      ;
      • Heller E.
      • Gorg C.
      [Focal liver lesions in patients with malignant haematological disease: value of B-mode ultrasound in comparison to contrast-enhanced ultrasound—A retrospective study with N = 61 patients].
      ;
      • Trenker C.
      • Kunsch S.
      • Michl P.
      • Wissniowski T.T.
      • Goerg K.
      • Goerg C.
      Contrast-enhanced ultrasound (CEUS) in hepatic lymphoma: retrospective evaluation in 38 cases.
      ).

       Focal cystic liver lesions (benign and malignant)

      Focal cystic liver lesions (FCLLs) represent a wide spectrum of benign and malignant disease (
      • Corvino A.
      • Catalano O.
      • Setola S.V.
      • Sandomenico F.
      • Corvino F.
      • Petrillo A.
      Contrast-enhanced ultrasound in the characterization of complex cystic focal liver lesions.
      ). Benign FCLLs include simple cysts, hematomas and hemorrhagic hepatic cysts (
      • Zhang Y.L.
      • Yuan L.
      • Shen H.
      • Wang Y.
      Haemorrhagic hepatic cysts mimicking biliary cystadenoma.
      ;
      • Corvino A.
      • Catalano O.
      • Corvino F.
      • Sandomenico F.
      • Petrillo A.
      Diagnostic performance and confidence of contrast-enhanced ultrasound in the differential diagnosis of cystic and cysticlike liver lesions.
      ); abscesses, bilomas and hydatid cysts (
      • Vachha B.
      • Sun M.R.
      • Siewert B.
      • Eisenberg R.L.
      Cystic lesions of the liver.
      ); cystic cavernous hemangiomas (
      • Cha E.Y.
      • Kim K.W.
      • Choi Y.J.
      • Song J.S.
      • Cho K.J.
      • Lee M.G.
      Multicystic cavernous haemangioma of the liver: Ultrasonography, CT, MR appearances and pathologic correlation.
      ); and cystic HCAs and other rare entities (
      • Barreiros A.P.
      • Chiorean L.
      • Braden B.
      • Dietrich C.F.
      Ultrasound in rare diffuse liver disease.
      ;
      • Chiorean L.
      • Cui X.W.
      • Tannapfel A.
      • Franke D.
      • Stenzel M.
      • Kosiak W.
      • Schreiber-Dietrich D.
      • Jungert J.
      • Chang J.M.
      • Dietrich C.F.
      Benign liver tumors in pediatric patients—Review with emphasis on imaging features.
      ). Malignant FCLLs include cystic HCCs (
      • Lin M.X.
      • Xu H.X.
      • Lu M.D.
      • Xie X.Y.
      • Chen L.D.
      • Xu Z.F.
      • Liu G.J.
      • Xie X.H.
      • Liang J.Y.
      • Wang Z.
      Diagnostic performance of contrast-enhanced ultrasound for complex cystic focal liver lesions: Blinded liver study.
      ), cystic lymphoma, cystic metastases as typically seen in neuroendocrine tumors (
      • Mork H.
      • Ignee A.
      • Schuessler G.
      • Ott M.
      • Dietrich C.F.
      Analysis of neuroendocrine tumour metastases in the liver using contrast enhanced ultrasonography.
      ) and other rare entities.
      Simple cysts are completely non-enhancing on CEUS. CEUS is not indicated for assessment of simple cysts but is useful in evaluating complicated or atypical cysts (
      • Corvino A.
      • Catalano O.
      • Corvino F.
      • Sandomenico F.
      • Petrillo A.
      Diagnostic performance and confidence of contrast-enhanced ultrasound in the differential diagnosis of cystic and cysticlike liver lesions.
      ).
      With complex cystic masses, CEUS characterizes the vascular flow within septa in cystadenoma and cystadenocarcinoma (
      • Albrecht T.
      • Blomley M.
      • Bolondi L.
      • Claudon M.
      • Correas J.M.
      • Cosgrove D.
      • Greiner L.
      • Jager K.
      • Jong N.D.
      • Leen E.
      • Lencioni R.
      • Lindsell D.
      • Martegani A.
      • Solbiati L.
      • Thorelius L.
      • Tranquart F.
      • Weskott H.P.
      • Whittingham T.
      • Group E.S.
      Guidelines for the use of contrast agents in ultrasound. January 2004.
      ;
      • Piscaglia F.
      • Lencioni R.
      • Sagrini E.
      • Pina C.D.
      • Cioni D.
      • Vidili G.
      • Bolondi L.
      Characterization of focal liver lesions with contrast-enhanced ultrasound.
      ). Such septa are often visualized by US but not by CT and MRI. Some atypical cystic lesions may have a solid appearance at conventional US, thus mimicking a malignant lesion, particularly a cystic metastasis or biliary cystadenocarcinoma (
      • Albrecht T.
      • Blomley M.
      • Bolondi L.
      • Claudon M.
      • Correas J.M.
      • Cosgrove D.
      • Greiner L.
      • Jager K.
      • Jong N.D.
      • Leen E.
      • Lencioni R.
      • Lindsell D.
      • Martegani A.
      • Solbiati L.
      • Thorelius L.
      • Tranquart F.
      • Weskott H.P.
      • Whittingham T.
      • Group E.S.
      Guidelines for the use of contrast agents in ultrasound. January 2004.
      ;
      • Barr R.G.
      Contrast enhanced ultrasound for focal liver lesions: how accurate is it?.
      ).
      On CEUS, the distinguishing feature in the differential diagnosis of hepatic cystadenoma (HBCA) from hepatic cystadenocarcinoma (HBCAC) is the honeycomb septal hyper-enhancement during the AP for HBCA and the hypo-enhancement during the PVP and LP for HBCAC (
      • Albrecht T.
      • Blomley M.
      • Bolondi L.
      • Claudon M.
      • Correas J.M.
      • Cosgrove D.
      • Greiner L.
      • Jager K.
      • Jong N.D.
      • Leen E.
      • Lencioni R.
      • Lindsell D.
      • Martegani A.
      • Solbiati L.
      • Thorelius L.
      • Tranquart F.
      • Weskott H.P.
      • Whittingham T.
      • Group E.S.
      Guidelines for the use of contrast agents in ultrasound. January 2004.
      ).
      • Recommendation 14. If CEUS has definitively characterized a benign FLL, further investigations are not recommended to confirm the diagnosis. (LoE 1, strong recommendation) (Pro 26, Against 0, Abstain 5)
      • Recommendation 15. CEUS can be used to characterize hepatic abscess in the appropriate clinical setting. (LoE 2, weak recommendation) (Pro 24, Against 1, Abstain 2)

      CEUS for characterization of FLLs in liver cirrhosis

       Study procedure

      In addition to the general recommendations for the study of FLLs, important aspects should be followed if the liver is cirrhotic. As the AP is crucial in characterization of FLLs in cirrhosis, good visualization of the nodule is important. Despite the use of a low mechanical index (MI), microbubbles can be disrupted and acoustic output power should then be reduced, while maintaining sufficient signal intensity to allow contrast persistence until the very LP (beyond 3–4 min), crucial for detecting washout and establishing a diagnosis of HCC. Furthermore, when the arterial/early PVP is complete (after 60 s), it is recommended that the lesion is imaged intermittently (usually brief scan every 30–60 s), rather than continuously, to minimize microbubble destruction, which may cause problems in the identification of subtle or late washout.

       Image interpretation and evaluation

      The key feature for the diagnosis of HCC in liver cirrhosis is APHE, followed by late-onset mild washout (>60 s after injection) (
      • Dietrich C.F.
      • Potthoff A.
      • Helmberger T.
      • Ignee A.
      • Willmann J.K.
      • Group C.L.-R.W.
      [Contrast-enhanced ultrasound: Liver Imaging Reporting and Data System (CEUS LI-RADS)].
      ;
      • Lyshchik A.
      • Kono Y.
      • Dietrich C.F.
      • Jang H.J.
      • Kim T.K.
      • Piscaglia F.
      • Vezeridis A.
      • Willmann J.K.
      • Wilson S.R.
      Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group.
      ;
      • Rodgers S.K.
      • Fetzer D.T.
      • Gabriel H.
      • Seow J.H.
      • Choi H.H.
      • Maturen K.E.
      • Wasnik A.P.
      • Morgan T.A.
      • Dahiya N.
      • O'Boyle M.K.
      • Kono Y.
      • Sirlin C.B.
      • Kamaya A.
      Role of US LI-RADS in the LI-RADS algorithm.
      ;
      • Kono Y.
      • Sirlin C.B.
      • Fetzer D.T.
      • Kim T.K.
      • Rodgers S.K.
      • Piscaglia F.
      • Lyshchik A.
      • Dietrich C.F.
      • Wilson S.R.
      Time to clarify common misconceptions about the liver imaging reporting and data system for contrast-enhanced US.
      ;
      • Wang J.Y.
      • Feng S.Y.
      • Xu J.W.
      • Li J.
      • Chu L.
      • Cui X.W.
      • Dietrich C.F.
      Usefulness of the contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System in diagnosing focal liver lesions by inexperienced radiologists [e-pub ahead of print].
      ). This pattern of washout in an HCC is seen in more than 97% of cases according to a large retrospective series (
      • Terzi E.
      • Iavarone M.
      • Pompili M.
      • Veronese L.
      • Cabibbo G.
      • Fraquelli M.
      • Riccardi L.
      • De Bonis L.
      • Sangiovanni A.
      • Leoni S.
      • Zocco M.A.
      • Rossi S.
      • Alessi N.
      • Wilson S.R.
      • Piscaglia F.
      CEUS LI-RADS. Italy Study Group Collaborators
      Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules.
      ). Arterial hyper-enhancement is usually homogeneous and intense in HCCs but may be inhomogeneous in larger nodules (>5 cm) that are necrotic. Rim enhancement is atypical for HCC. Washout is observed overall in about half the cases of HCC, but rarely in small nodules (20%–30% in those 1–2 cm, 40%–60% in those 2–3 cm) (
      • Forner A.
      • Vilana R.
      • Ayuso C.
      • Bianchi L.
      • Sole M.
      • Ayuso J.R.
      • Boix L.
      • Sala M.
      • Varela M.
      • Llovet J.M.
      • Bru C.
      • Bruix J.
      Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
      ;
      • Leoni S.
      • Piscaglia F.
      • Golfieri R.
      • Camaggi V.
      • Vidili G.
      • Pini P.
      • Bolondi L.
      The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria.
      ;
      • Sangiovanni A.
      • Manini M.A.
      • Iavarone M.
      • Romeo R.
      • Forzenigo L.V.
      • Fraquelli M.
      • Massironi S.
      • Della Corte C.
      • Ronchi G.
      • Rumi M.G.
      • Biondetti P.
      • Colombo M.
      The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.
      ). Washout is observed more frequently in HCCs with poorer grades of differentiation than in well-differentiated HCCs, which tend to be iso-enhancing in the LP (
      • Fan Z.H.
      • Chen M.H.
      • Dai Y.
      • Wang Y.B.
      • Yan K.
      • Wu W.
      • Yang W.
      • Yin S.S.
      Evaluation of primary malignancies of the liver using contrast-enhanced sonography: correlation with pathology.
      ;
      • Jang H.J.
      • Kim T.K.
      • Burns P.N.
      • Wilson S.R.
      Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation.
      ;
      • Iavarone M.
      • Sangiovanni A.
      • Forzenigo L.V.
      • Massironi S.
      • Fraquelli M.
      • Aghemo A.
      • Ronchi G.
      • Biondetti P.
      • Roncalli M.
      • Colombo M.
      Diagnosis of hepatocellular carcinoma in cirrhosis by dynamic contrast imaging: the importance of tumor cell differentiation.