J Liver Cancer.  2023 Sep;23(2):272-283. 10.17998/jlc.2023.08.25.

Diagnosis of hepatocellular carcinoma using Sonazoid: a comprehensive review

Affiliations
  • 1Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 2Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Abstract

Sonazoid contrast-enhanced ultrasonography (CEUS) is a promising technique for the detection and diagnosis of focal liver lesions, particularly hepatocellular carcinoma (HCC). Recently, a collaborative effort between the Korean Society of Radiology and Korean Society of Abdominal Radiology resulted in the publication of guidelines for diagnosing HCC using Sonazoid CEUS. These guidelines propose specific criteria for identifying HCC based on the imaging characteristics observed during Sonazoid CEUS. The suggested diagnostic criteria include nonrim arterial phase hyperenhancement, and the presence of late and mild washout, or Kupffer phase washout under the premise that the early or marked washout should not occur during the portal venous phase. These criteria aim to improve the accuracy of HCC diagnosis using Sonazoid CEUS. This review offers a comprehensive overview of Sonazoid CEUS in the context of HCC diagnosis. It covers the fundamental principles of Sonazoid CEUS and its clinical applications, and introduces the recently published guidelines. By providing a summary of this emerging technique, this review contributes to a better understanding of the potential role of Sonazoid CEUS for diagnosing HCC.

Keyword

Ultrasonography; Contrast-enhanced ultrasound; Carcinoma, hepatocellular; Sonazoid; Perfluorobutane

Figure

  • Figure 1. Examination protocol and typical findings of HCC, intrahepatic cholangiocarcinoma, hemangioma, and focal nodular hyperplasia on Sonazoid contrast-enhanced ultrasound. HCC, hepatocellular carcinoma; APHE, arterial phase hyperenhancement; WO, washout; KPWO, Kupffer phase washout; ICC, intrahepatic cholangiocarcinoma; FNH, focal nodular hyperplasia.

  • Figure 2. Examples of arterial phase hyperenhancement. Nonrim APHE refers to arterial phase enhancement without a rim pattern (A), while rim APHE exhibits a peripheral enhancement pattern (B). Spoke-wheel APHE resembles spokes and is associated with focal nodular hyperplasia (C). Peripheral discontinuous nodular APHE exhibits nodular enhancement with interruptions, and is observed in hepatic hemangiomas (D). APHE, arterial phase hyperenhancement.

  • Figure 3. Examples of washout. Washout on contrast-enhanced ultrasound can be classified by the degree (mild or marked) and onset time (early or late). Mild washout shows partial reduction (A), while marked washout indicates near-complete loss of enhancement (B). Early onset occurs within 60 seconds (C), while late onset takes longer than 60 seconds (D).

  • Figure 4. Examples of tumor in vein (A), mosaic (B), and nodule in nodule (C) architecture. (A) Tumor in vein and microbubbles in the tumor thrombus were seen in the early arterial phase (arrows). (B) The other two findings are ancillary findings favoring HCC. Mosaic architecture is the composition of fibrous septa (arrowheads) between the cellular components (arrow), and (C) nodule in nodule architecture is a distinct growth pattern of HCC, which involves the presence of a larger outer nodule (arrowheads) containing a smaller inner nodule (arrows). HCC, hepatocellular carcinoma.

  • Figure 5. A 56-year-old male with hepatocellular carcinoma. The B-mode ultrasound image revealed a peripheral hypoechoic nodule located in the subcapsular area of the liver. (A) During the arterial phase of the contrast-enhanced ultrasound, the nodule exhibited gradual enhancement. (B) The microbubbles began to wash out from 1 minute and 30 seconds after contrast injection (arrow), (C) becoming even more pronounced at 2 minutes and 20 seconds (arrow). (D) During the Kupffer phase, the nodule became more evident, indicating Kupffer phase washout (arrow). The patient underwent treatment with radiofrequency ablation for the hepatocellular carcinoma.

  • Figure 6. A 63 -year- old male with intrahepatic cholangiocarcinoma. A rim-like hyperenhancement was observed in the arterial phase of contrast-enhanced ultrasound (A). Subsequently, at a delay of 1 minute and 30 seconds, marked washout of the contrast agent was evident (B). Additionally, prominent washout was observed during the Kupffer phase (C). Following surgical resection, the lesion was confirmed to be a moderately differentiated adenocarcinoma.

  • Figure 7. A 37-year-old female with a liver lesion found incidentally. (A) A B-mode ultrasound image revealed two nodules; one with a hypoechoic center, hyperechoic rim, and posterior enhancement (solid arrow), and an ill-defined, hyperechoic nodule (open arrow). (B-G) During the arterial phase of the contrast-enhanced ultrasound exam, (B) the first nodule displayed rapid peripheral enhancement that gradually expanded in a discontinuous pattern (solid arrow). (F) The second nodule exhibited slow, gradual growth with centrifugal enhancement (open arrow). During the Kupffer phase (H), the first nodule showed mild washout (solid arrow), which is indicative of a typical hepatic hemangioma. The second nodule appeared isoechoic on the Kupffer phase image (open arrow), suggesting a benign lesion, such as atypical focal nodular hyperplasia or peliosis hepatis.


Reference

References

1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018; 69:182–236.
2. Korean Liver Cancer Association (KLCA); National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Korean J Radiol. 2022; 23:1126–1240.
3. Korean Liver Cancer Association (KLCA); National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J Liver Cancer. 2023; 23:1–120.
4. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023; May. 22. doi: 10.1097/HEP.0000000000000466. [Epub ahead of print].
5. Jeong WK, Kang HJ, Choi SH, Park MS, Yu MH, Kim B, et al. Diagnosing hepatocellular carcinoma using sonazoid contrast-enhanced ultrasonography: 2023 guidelines from the Korean Society of Radiology and the Korean Society of Abdominal Radiology. Korean J Radiol. 2023; 24:482–497.
6. Watanabe R, Matsumura M, Munemasa T, Fujimaki M, Suematsu M. Mechanism of hepatic parenchyma-specific contrast of microbubble-based contrast agent for ultrasonography: microscopic studies in rat liver. Invest Radiol. 2007; 42:643–651.
7. Yanagisawa K, Moriyasu F, Miyahara T, Yuki M, Iijima H. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol. 2007; 33:318–325.
8. Moriyasu F, Itoh K. Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial. AJR Am J Roentgenol. 2009; 193:86–95.
9. Kudo M, Hatanaka K, Kumada T, Toyoda H, Tada T. Doublecontrast ultrasound: a novel surveillance tool for hepatocellular carcinoma. Am J Gastroenterol. 2011; 106:368–370.
10. Mandai M, Koda M, Matono T, Nagahara T, Sugihara T, Ueki M, et al. Assessment of hepatocellular carcinoma by contrast-enhanced ultrasound with perfluorobutane microbubbles: comparison with dynamic CT. Br J Radiol. 2011; 84:499–507.
11. Lee JY, Minami Y, Choi BI, Lee WJ, Chou YH, Jeong WK, et al. The AFSUMB consensus statements and recommendations for the clinical practice of contrast-enhanced ultrasound using Sonazoid. Ultrasonography. 2020; 39:191–220.
12. Gramiak R, Shah PM, Kramer DH. Ultrasound cardiography: contrast studies in anatomy and function. Radiology. 1969; 92:939–948.
13. Calliada F, Campani R, Bottinelli O, Bozzini A, Sommaruga MG. Ultrasound contrast agents: basic principles. Eur J Radiol. 1998; 27 Suppl 2:S157–S160.
14. Lee H, Kim H, Han H, Lee M, Lee S, Yoo H, et al. Microbubbles used for contrast enhanced ultrasound and theragnosis: a review of principles to applications. Biomed Eng Lett. 2017; 7:59–69.
15. Chung YE, Kim KW. Contrast-enhanced ultrasonography: advance and current status in abdominal imaging. Ultrasonography. 2015; 34:3–18.
16. Sontum PC, Ostensen J, Dyrstad K, Hoff L. Acoustic properties of NC100100 and their relation with the microbubble size distribution. Invest Radiol. 1999; 34:268–275.
17. Landmark KE, Johansen PW, Johnson JA, Johansen B, Uran S, Skotland T. Pharmacokinetics of perfluorobutane following intravenous bolus injection and continuous infusion of sonazoid in healthy volunteers and in patients with reduced pulmonary diffusing capacity. Ultrasound Med Biol. 2008; 34:494–501.
18. Li P, Hoppmann S, Du P, Li H, Evans PM, Moestue SA, et al. Pharmacokinetics of perfluorobutane after intra-venous bolus injection of Sonazoid in healthy Chinese volunteers. Ultrasound Med Biol. 2017; 43:1031–1039.
19. Uran S, Landmark K, Normann PT, Hals PA, Toft KG, Skotland T. A respiration-metabolism chamber system and a GC-MS method developed for studying exhalation of perfluorobutane in rats after intravenous injection of the ultrasound contrast agent Sonazoid. J Pharm Biomed Anal. 2005; 39:746–751.
20. Toft KG, Hustvedt SO, Hals PA, Oulie I, Uran S, Landmark K, et al. Disposition of perfluorobutane in rats after intravenous injection of Sonazoid. Ultrasound Med Biol. 2006; 32:107–114.
21. Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. 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. Ultrasound Med Biol. 2020; 46:2579–2604.
22. Sontum PC. Physicochemical characteristics of Sonazoid, a new contrast agent for ultrasound imaging. Ultrasound Med Biol. 2008; 34:824–833.
23. Kang HJ, Lee JM, Yoon JH, Lee K, Kim H, Han JK. Contrastenhanced US with sulfur hexafluoride and perfluorobutane for the diagnosis of hepatocellular carcinoma in individuals with high risk. Radiology. 2020; 297:108–116.
24. Sugimoto K, Kakegawa T, Takahashi H, Tomita Y, Abe M, Yoshimasu Y, et al. Usefulness of modified CEUS LI-RADS for the diagnosis of hepatocellular carcinoma using Sonazoid. Diagnostics (Basel). 2020; 10:828.
25. Hwang JA, Jeong WK, Min JH, Kim YY, Heo NH, Lim HK. Sonazoidenhanced ultrasonography: comparison with CT/MRI liver imaging reporting and data system in patients with suspected hepatocellular carcinoma. Ultrasonography. 2021; 40:486–498.
26. Kang HJ, Kim JH, Yoo J, Han JK. Diagnostic criteria of perfluorobutane-enhanced ultrasonography for diagnosing hepatocellular carcinoma in high-risk individuals: how is late washout determined? Ultrasonography. 2022; 41:530–542.
27. Tang A, Bashir MR, Corwin MT, Cruite I, Dietrich CF, Do RKG, et al. Evidence supporting LI-RADS major features for CT- and MR imaging-based diagnosis of hepatocellular carcinoma: a systematic review. Radiology. 2018; 286:29–48.
28. Elsayes KM, Kielar AZ, Chernyak V, Morshid A, Furlan A, Masch WR, et al. LI-RADS: a conceptual and historical review from its beginning to its recent integration into AASLD clinical practice guidance. J Hepatocell Carcinoma. 2019; 6:49–69.
29. Cunha GM, Fowler KJ, Roudenko A, Taouli B, Fung AW, Elsayes KM, et al. How to use LI-RADS to report liver CT and MRI observations. Radiographics. 2021; 41:1352–1367.
30. Kim TK, Noh SY, Wilson SR, Kono Y, Piscaglia F, Jang HJ, et al. Contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) 2017 - a review of important differences compared to the CT/MRI system. Clin Mol Hepatol. 2017; 23:280–289.
31. Jo PC, Jang HJ, Burns PN, Burak KW, Kim TK, Wilson SR. Integration of contrast-enhanced US into a multimodality approach to imaging of nodules in a cirrhotic liver: how i do it. Radiology. 2017; 282:317–331.
32. Bartolotta TV, Terranova MC, Gagliardo C, Taibbi A. CEUS LIRADS: a pictorial review. Insights Imaging. 2020; 11:9.
33. Ohama H, Imai Y, Nakashima O, Kogita S, Takamura M, Hori M, et al. Images of Sonazoid-enhanced ultrasonography in multistep hepatocarcinogenesis: comparison with Gd-EOB-DTPA-enhanced MRI. J Gastroenterol. 2014; 49:1081–1093.
34. Kim TK, Lee E, Jang HJ. Imaging findings of mimickers of hepatocellular carcinoma. Clin Mol Hepatol. 2015; 21:326–343.
35. Kim TK, Choi BI, Han JK, Hong HS, Park SH, Moon SG. Hepatic tumors: contrast agent-enhancement patterns with pulse-inversion harmonic US. Radiology. 2000; 216:411–417.
36. Lee J, Jeong WK, Lim HK, Kim AY. Focal nodular hyperplasia of the liver: contrast-enhanced ultrasonographic features with Sonazoid. J Ultrasound Med. 2018; 37:1473–1480.
37. Kang TW, Jeong WK, Kim YY, Min JH, Kim YK, Kim SH, et al. Comparison of super-resolution US and contrast material-enhanced US in detection of the spoke wheel sign in patients with focal nodular hyperplasia. Radiology. 2021; 298:82–90.
38. Chernyak V, Fowler KJ, Kamaya A, Kielar AZ, Elsayes KM, Bashir MR, et al. Liver imaging reporting and data system (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology. 2018; 289:816–830.
39. Saito A, Yamamoto M, Katagiri S, Yamashita S, Nakano M, Morizane T. Early hemodynamics of hepatocellular carcinoma using contrast-enhanced ultrasound with Sonazoid: focus on the pure arterial and early portal phases. Glob Health Med. 2020; 2:319–327.
40. Hwang JA, Jeong WK, Kang HJ, Lee ES, Park HJ, Lee JM. Perfluorobutane-enhanced ultrasonography with a Kupffer phase: improved diagnostic sensitivity for hepatocellular carcinoma. Eur Radiol. 2022; 32:8507–8517.
41. Inoue T, Kudo M, Hatanaka K, Takahashi S, Kitai S, Ueda T, et al. Imaging of hepatocellular carcinoma: qualitative and quantitative analysis of postvascular phase contrast-enhanced ultrasonography with sonazoid. Comparison with superparamagnetic iron oxide magnetic resonance images. Oncology. 2008; 75 Suppl 1:48–54.
42. Kudo M, Hatanaka K, Inoue T, Maekawa K. Depiction of portal supply in early hepatocellular carcinoma and dysplastic nodule: value of pure arterial ultrasound imaging in hepatocellular carcinoma. Oncology. 2010; 78 Suppl 1:60–67.
43. Takahashi M, Maruyama H, Ishibashi H, Yoshikawa M, Yokosuka O. Contrast-enhanced ultrasound with perflubutane microbubble agent: evaluation of differentiation of hepatocellular carcinoma. AJR Am J Roentgenol. 2011; 196:W123–W131.
44. Mita K, Kim SR, Kudo M, Imoto S, Nakajima T, Ando K, et al. Diagnostic sensitivity of imaging modalities for hepatocellular carcinoma smaller than 2 cm. World J Gastroenterol. 2010; 16:4187–4192.
45. Goto E, Masuzaki R, Tateishi R, Kondo Y, Imamura J, Goto T, et al. Value of post-vascular phase (Kupffer imaging) by contrastenhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma. J Gastroenterol. 2012; 47:477–485.
46. Hsiao CY, Chen PD, Huang KW. A prospective assessment of the diagnostic value of contrast-enhanced ultrasound, dynamic computed tomography and magnetic resonance imaging for patients with small liver tumors. J Clin Med. 2019; 8:1353.
47. Wang F, Numata K, Chuma M, Miwa H, Moriya S, Ogushi K, et al. A study on the inconsistency of arterial phase hypervascularity detection between contrast-enhanced ultrasound using sonazoid and gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid magnetic resonance imaging of hepatocellular carcinoma lesions. J Med Ultrason (2001). 2021; 48:215–224.
48. Hatanaka K, Kudo M, Minami Y, Maekawa K. Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignancies: comparison with contrast-enhanced CT. Oncology. 2008; 75 Suppl 1:42–47.
49. Hatanaka K, Kudo M, Minami Y, Ueda T, Tatsumi C, Kitai S, et al. Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid. Intervirology. 2008; 51 Suppl 1:61–69.
50. Luo W, Numata K, Kondo M, Morimoto M, Sugimori K, Hirasawa K, et al. Sonazoid-enhanced ultrasonography for evaluation of the enhancement patterns of focal liver tumors in the late phase by intermittent imaging with a high mechanical index. J Ultrasound Med. 2009; 28:439–448.
51. Kudo M, Ueshima K, Osaki Y, Hirooka M, Imai Y, Aso K, et al. Bmode ultrasonography versus contrast-enhanced ultrasonography for surveillance of hepatocellular carcinoma: a prospective multicenter randomized controlled trial. Liver Cancer. 2019; 8:271–280.
52. Park JH, Park MS, Lee SJ, Jeong WK, Lee JY, Park MJ, et al. Contrast-enhanced US with perfluorobutane for hepatocellular carcinoma surveillance: a multicenter diagnostic trial (SCAN). Radiology. 2019; 292:638–646.
53. Tanaka H, Iijima H, Nouso K, Aoki N, Iwai T, Takashima T, et al. Cost-effectiveness analysis on the surveillance for hepatocellular carcinoma in liver cirrhosis patients using contrast-enhanced ultrasonography. Hepatol Res. 2012; 42:376–384.
54. Minami Y, Kudo M, Hatanaka K, Kitai S, Inoue T, Hagiwara S, et al. Radiofrequency ablation guided by contrast harmonic sonography using perfluorocarbon microbubbles (Sonazoid) for hepatic malignancies: an initial experience. Liver Int. 2010; 30:759–764.
55. Dohmen T, Kataoka E, Yamada I, Miura K, Ohshima S, Shibuya T, et al. Efficacy of contrast-enhanced ultrasonography in radiofrequency ablation for hepatocellular carcinoma. Intern Med. 2012; 51:1–7.
56. Lee MW, Lim HK, Rhim H, Cha DI, Kang TW, Song KD, et al. Percutaneous radiofrequency ablation of small (1-2 cm) hepatocellular carcinomas inconspicuous on B-mode ultrasonographic imaging: usefulness of combined fusion imaging with MRI and contrast-enhanced ultrasonography. Can J Gastroenterol Hepatol. 2018; 2018:7926923.
57. Inoue T, Kudo M, Hatanaka K, Arizumi T, Takita M, Kitai S, et al. Usefulness of contrast-enhanced ultrasonography to evaluate the post-treatment responses of radiofrequency ablation for hepatocellular carcinoma: comparison with dynamic CT. Oncology. 2013; 84 Suppl 1:51–57.
58. Sugimoto K, Moriyasu F, Saito K, Rognin N, Kamiyama N, Furuichi Y, et al. Hepatocellular carcinoma treated with sorafenib: early detection of treatment response and major adverse events by contrastenhanced US. Liver Int. 2013; 33:605–615.
59. Takizawa K, Numata K, Morimoto M, Kondo M, Nozaki A, Moriya S, et al. Use of contrast-enhanced ultrasonography with a perflubutane-based contrast agent performed one day after transarterial chemoembolization for the early assessment of residual viable hepatocellular carcinoma. Eur J Radiol. 2013; 82:1471–1480.
60. Funaoka A, Numata K, Takeda A, Saigusa Y, Tsurugai Y, Nihonmatsu H, et al. Use of contrast-enhanced ultrasound with sonazoid for evaluating the radiotherapy efficacy for hepatocellular carcinoma. Diagnostics (Basel). 2021; 11:486.
Full Text Links
  • JLC
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr