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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
2 Christoph F. Dietrich and Christian Pállson Nolsøe are co-first authors.
Christoph F. Dietrich
Correspondence
Address correspondence to: Christoph F. Dietrich, Department Allgemeine Innere Medizin (DAIM), Kliniken Hirslanden Beau Site, Salem und Permanence, Bern, Switzerland.
2 Christoph F. Dietrich and Christian Pállson Nolsøe are co-first authors.
Affiliations
Department Allgemeine Innere Medizin (DAIM), Kliniken Hirslanden Beau Site, Salem und Permanence, Bern, SwitzerlandJohann Wolfgang Goethe Universitätsklinik, Frankfurt, Germany
2 Christoph F. Dietrich and Christian Pállson Nolsøe are co-first authors.
Christian Pállson Nolsøe
Footnotes
2 Christoph F. Dietrich and Christian Pállson Nolsøe are co-first authors.
Affiliations
Center for Surgical Ultrasound, Dep of Surgery, Zealand University Hospital, Køge. Copenhagen Academy for Medical Education and Simulation (CAMES). University of Copenhagen, Denmark
National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, and Department of Clinical Medicine, University of Bergen, Norway
Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaDepartments of Health and Science and Technology and Medical Device Management and Research, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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.
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) (
). 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 (
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.
The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (short version).
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 (
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. 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)
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 (
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.
Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images.
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 (
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).
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.
The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
), 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 (
Single-center study: Evaluating the diagnostic performance and safety of contrast-enhanced ultrasound (CEUS) in pregnant women to assess hepatic lesions.
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.
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.
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).
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 (
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 (
Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma.
Comparison of diagnostic performance of unenhanced vs SonoVue-enhanced ultrasonography in focal liver lesions characterization: The experience of three Italian centers.
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.
). CEUS, in addition, is reported to be invaluable in providing characterization of indeterminate FLLs on CT, magnetic resonance imaging (MRI) and positron emission tomography (
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 (
Contrast-enhanced ultrasonography to detect liver metastases: A prospective trial to compare transcutaneous unenhanced and contrast-enhanced ultrasonography in patients undergoing laparotomy.
Comparison of contrast-enhanced ultrasonography versus baseline ultrasound and contrast-enhanced computed tomography in metastatic disease of the liver: diagnostic performance and confidence.
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.
Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI.
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.
Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
). 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 (
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.
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 (
). 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%) (
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 (
LI-RADS Evidence Working Group Evidence supporting LI-RADS major features for CT- and MR imaging-based diagnosis of hepatocellular carcinoma: A systematic review.
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 (
Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial.
Diagnosis value of focal liver lesions with SonoVue-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis.
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 (
). 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 (
Improved characterization of histologically proven liver tumours by contrast enhanced ultrasonography during the portal venous and specific late phase of SHU 508 A.
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).
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.
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.
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.
Unclear focal liver lesions in contrast-enhanced ultrasonography—Lessons to be learned from the DEGUM multicenter study for the characterization of liver tumors.
Diagnosis value of focal liver lesions with SonoVue-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis.
). Thus, CEUS is useful in facilitating the clinical decision as to whether a sonographically detected liver lesion requires further investigation or surgery (
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 (
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.
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.
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.
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.
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
Lesion
Arterial phase
Portal venous phase
Late phase
Post-vascular phase
Hemangioma
Typical features
Peripheral nodular enhancement
Partial/complete centripetal fill-in
Incomplete or complete enhancement
Iso-/slightly hypo-enhancing
Additional features
Small lesion: complete, rapid centripetal enhancement
). 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 (
). 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 (
The typical CEUS feature of a hemangioma is peripheral, discontinuous nodular (globular) enhancement in the AP with progressive centripetal partial or complete fill-in (
). 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 (
To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound.
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 (
). 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 (
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 (
). 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 (
). 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 (
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 (
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).
Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation.
), 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%) (
). 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 (
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 (
). 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 (
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.
HCA is a rare, benign and sometimes estrogen-dependent hepatic neoplasm. Typical imaging characteristics of HCAs are displayed in smaller lesions <50 mm (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
Comparison of contrast-enhanced ultrasonography with grey-scale ultrasonography and contrast-enhanced computed tomography in diagnosing focal fatty liver infiltrations and focal fatty sparing.
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 (
). 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 (
The appearance of granulomas and focal tuberculosis on CEUS varies, which makes it hard and sometimes impossible to differentiate these from malignancy (
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 (
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 (
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 (
). 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 (
The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (short version).
The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
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 (
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
Tumor
Arterial phase (10–30 s)
Portal venous phase (20–120 s)
Late phase (120–300 s)
Post vascular phase (>10 min)
Metastasis
Typical features
Rim enhancement
Hypo-enhancing
Hypo-/non-enhancing
Hypo-/non-enhancing
Additional features
Complete enhancement
Non-enhancing regions
Non-enhancing regions
Non-enhancing regions
Hyper-enhancement
Non-enhancing regions
Hepatocellular carcinoma
Typical features
Hyper-enhancing
Iso-enhancing
Hypo-/non-enhancing
Hypo-/non-enhancing
Additional features
Non-enhancing regions
Non-enhancing regions
Non-enhancing regions
Non-enhancing regions
Cholangiocarcinoma
Typical features
Rim-like hyper-enhancement, central hypo-enhancement
). 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 (
Usefulness of early vascular phase images from contrast-enhanced ultrasonography using Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma.
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.
). 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 (
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 (
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.
Interobserver agreement for contrast-enhanced ultrasound (CEUS)-based standardized algorithms for the diagnosis of hepatocellular carcinoma in high-risk patients.
Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) 2017-A review of important differences compared to the CT/MRI system.
Contrast enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS): the official version by the American College of Radiology (ACR).
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.
). 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 (
). 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 (
). 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 (
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 (
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 (
). Because of the lack of Kupffer cells, metastatic lesions on post-vascular phase imaging with Sonazoid are clearly demarcated and completely hypo-enhancing (
Metastases usually exhibit at least some contrast enhancement in the AP and, sometimes, marked and chaotic enhancement. Rim or halo enhancement is often seen (
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.
[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].
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