European Radiology

, Volume 28, Issue 5, pp 2077–2088 | Cite as

Contrast-enhanced US for characterization of focal liver lesions: a comprehensive meta-analysis

Original Article
  • 186 Downloads

Abstract

Objectives

This meta-analysis was performed to evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in differentiating malignant from benign focal liver lesions (FLLs).

Methods

Cochrane Library, PubMed and Web of Science databases were systematically searched and checked for studies using CEUS in characterization of FLLs. Data necessary to construct 2×2 contingency tables were extracted from included studies. The QUADAS tool was utilized to assess the methodologic quality of the studies. Meta-analysis included data pooling, subgroup analyses, meta-regression and investigation of publication bias was comprehensively performed.

Results

Fifty-seven studies were included in this meta-analysis and the overall diagnostic accuracy in characterization of FLLs was as follows: pooled sensitivity, 0.92 (95%CI: 0.91–0.93); pooled specificity, 0.87 (95%CI: 0.86–0.88); diagnostic odds ratio, 104.20 (95%CI: 70.42–154.16). Subgroup analysis indicated higher diagnostic accuracy of the second-generation contrast agents (CAs) than the first-generation CA (Levovist; DOR: 118.27 vs. 62.78). Furthermore, Sonazoid demonstrated the highest diagnostic accuracy among three major CAs (SonoVue, Levovist and Sonazoid; DOR: 118.82 vs. 62.78 vs. 227.39). No potential publication bias was observed of the included studies.

Conclusion

CEUS is an accurate tool to stratify the risk of malignancy in FLLs. The second-generation CAs, especially Sonazoid may greatly improve diagnostic performance.

Key Points

CEUS shows excellent diagnostic accuracy in differentiating malignant from benign FLLs.

The second-generation CAs have higher diagnostic accuracy than first-generation CAs.

Sonazoid demonstrates the highest diagnostic accuracy among three major CAs.

Keywords

Ultrasonography Contrast media Liver neoplasms Diagnosis Meta-analysis 

Abbreviations

CEUS

Contrast-enhanced ultrasound

FLLs

Focal liver lesions

CAs

Contrast agents

CA

Contrast agent

QUADAS

Quality Assessment of Diagnostic Accuracy Studies

TP

True positive

TN

True negative

FP

False positive

FN

False negative

DOR

Diagnostic odds ratio

PLR

Positive likelihood ratio

NLR

Negative likelihood ratio

CIs

Confidence intervals

HSROC

Hierarchical summary receiver operating characteristic

AUC

Area under the curve

RDOR

Relative diagnostic odds ratio

UL

Upper limit

LL

Lower limit

HCCs

Hepatocellular carcinomas

RES

Reticuloendothelial system

Notes

Compliance with ethical standards

Guarantor

The scientific guarantor of this publication is Xuening Zhang.

Conflict of interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was not required for this study because the study concerns a meta-analysis.

Ethical approval

Institutional review board approval was not required because the study concerns a meta-analysis.

Methodology

• diagnostic study

• performed at one institution

Supplementary material

330_2017_5152_MOESM1_ESM.docx (12.6 mb)
ESM 1 (DOCX 12873 kb)
330_2017_5152_MOESM2_ESM.doc (73 kb)
ESM 2 (DOC 73 kb)

References

  1. 1.
    Gatos I, Tsantis S, Spiliopoulos S et al (2015) A new automated quantification algorithm for the detection and evaluation of focal liver lesions with contrast-enhanced ultrasound. Med Phys 42:3948–3959CrossRefPubMedGoogle Scholar
  2. 2.
    Salvatore V, Borghi A, Piscaglia F (2012) Contrast-enhanced ultrasound for liver imaging: recent advances. Curr Pharm Des 18:2236–2252CrossRefPubMedGoogle Scholar
  3. 3.
    Lencioni R, Piscaglia F, Bolondi L (2008) Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma. J Hepatol 48:848–857CrossRefPubMedGoogle Scholar
  4. 4.
    Deng H, Shi H, Lei J, Hu Y, Li G, Wang C (2016) A meta-analysis of contrast-enhanced ultrasound for small hepatocellular carcinoma diagnosis. J Cancer Res Ther 12:C274–C276CrossRefPubMedGoogle Scholar
  5. 5.
    Yoon JH, Park JW, Lee JM (2016) Noninvasive Diagnosis of Hepatocellular Carcinoma: Elaboration on Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guidelines Compared with Other Guidelines and Remaining Issues. Korean J Radiol 17:7–24CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Guang Y, Xie L, Ding H, Cai A, Huang Y (2011) Diagnosis value of focal liver lesions with SonoVue®-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis. J Cancer Res Clin Oncol 137:1595–1605CrossRefPubMedGoogle Scholar
  7. 7.
    Ignee A, Atkinson NS, Schuessler G, Dietrich CF (2016) Ultrasound contrast agents. Endosc Ultrasound 5:355–362CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Paefgen V, Doleschel D, Kiessling F (2015) Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery. Front Pharmacol 15:197Google Scholar
  9. 9.
    Maruyama H, Sekimoto T, Yokosuka O (2016) Role of contrast-enhanced ultrasonography with Sonazoid for hepatocellular carcinoma: evidence from a 10-year experience. J Gastroenterol 51:421–433CrossRefPubMedGoogle Scholar
  10. 10.
    Kondo S, Takagi K, Nishida M et al (2017) Computer-Aided Diagnosis of Focal Liver Lesions Using Contrast-Enhanced Ultrasonography With Perflubutane Microbubbles. IEEE Trans Med Imaging 36:1427–1437CrossRefPubMedGoogle Scholar
  11. 11.
    Seitz K, Strobel D (2016) A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA. Ultraschall Med 37:229–232CrossRefPubMedGoogle Scholar
  12. 12.
    Hohmann J, Skrok J, Basilico R et al (2012) Characterisation of focal liver lesions with unenhanced and contrast enhanced low MI real time ultrasound: on-site unblinded versus off-site blinded reading. Eur J Radiol 81:e317–e324CrossRefPubMedGoogle Scholar
  13. 13.
    Shan QY, Chen LD, Zhou LY et al (2016) Focal Lesions in Fatty Liver: If Quantitative Analysis Facilitates the Differentiation of Atypical Benign from Malignant Lesions. Sci Rep 6:18640CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Quaia E, De Paoli L, Angileri R, Cabibbo B, Cova MA (2014) Indeterminate solid hepatic lesions identified on non-diagnostic contrast-enhanced computed tomography: assessment of the additional diagnostic value of contrast-enhanced ultrasound in the non-cirrhotic liver. Eur J Radiol 83:456–462CrossRefPubMedGoogle Scholar
  15. 15.
    Ryu SW, Bok GH, Jang JY et al (2014) Clinically useful diagnostic tool of contrast enhanced ultrasonography for focal liver masses: comparison to computed tomography and magnetic resonance imaging. Gut Liver 8:292–297CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sporea I, Badea R, Popescu A et al (2014) Contrast-enhanced ultrasound (CEUS) for the evaluation of focal liver lesions - a prospective multicenter study of its usefulness in clinical practice. Ultraschall Med 35:259–266CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang P, Zhou P, Tian SM, Qian Y, Li JL, Li RZ (2014) Diagnostic performance of contrast-enhanced sonography and acoustic radiation force impulse imaging in solid liver lesions. J Ultrasound Med 33:205–214CrossRefPubMedGoogle Scholar
  18. 18.
    Jacob J, Deganello A, Sellars ME, Hadzic N, Sidhu PS (2013) Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice. Ultraschall Med 34:529–540CrossRefPubMedGoogle Scholar
  19. 19.
    Streba CT, Ionescu M, Gheonea DI et al (2012) Contrast-enhanced ultrasonography parameters in neural network diagnosis of liver tumors. World J Gastroenterol 18:4427–4434CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Anaye A, Perrenoud G, Rognin N et al (2011) Differentiation of focal liver lesions: usefulness of parametric imaging with contrast-enhanced US. Radiology 261:300–310CrossRefPubMedGoogle Scholar
  21. 21.
    Bartolotta TV, Taibbi A, Midiri M, Matranga D, Solbiati L, Lagalla R (2011) Indeterminate focal liver lesions incidentally discovered at gray-scale US: role of contrast-enhanced sonography. Investig Radiol 46:106–115CrossRefGoogle Scholar
  22. 22.
    Giorgio A, Calisti G, di Sarno A et al (2011) Characterization of dysplastic nodules, early hepatocellular carcinoma and progressed hepatocellular carcinoma in cirrhosis with contrast-enhanced ultrasound. Anticancer Res 31:3977–3982PubMedGoogle Scholar
  23. 23.
    Strobel D, Bernatik T, Blank W et al (2011) 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. Ultraschall Med 32:593–597CrossRefPubMedGoogle Scholar
  24. 24.
    Beaton C, Cochlin D, Kumar N (2010) Contrast enhanced ultrasound should be the initial radiological investigation to characterise focal liver lesions. Eur J Surg Oncol 36:43–46CrossRefPubMedGoogle Scholar
  25. 25.
    Ooi CC, Low SC, Schneider-Kolsky M et al (2010) Diagnostic accuracy of contrast-enhanced ultrasound in differentiating benign and malignant focal liver lesions: a retrospective study. J Med Imaging Radiat Oncol 54:421–430CrossRefPubMedGoogle Scholar
  26. 26.
    Rognin NG, Arditi M, Mercier L et al (2010) Parametric imaging for characterizing focal liver lesions in contrast-enhanced ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control 57:2503–2511CrossRefPubMedGoogle Scholar
  27. 27.
    von Herbay A, Westendorff J, Gregor M (2010) Contrast-enhanced ultrasound with SonoVue: differentiation between benign and malignant focal liver lesions in 317 patients. J Clin Ultrasound 38:1–9Google Scholar
  28. 28.
    Inoue T, Kudo M, Maenishi O et al (2009) Value of liver parenchymal phase contrast-enhanced sonography to diagnose premalignant and borderline lesions and overt hepatocellular carcinoma. AJR Am J Roentgenol 192:698–705CrossRefPubMedGoogle Scholar
  29. 29.
    Jang HJ, Kim TK, Wilson SR (2009) Small nodules (1-2 cm) in liver cirrhosis: characterization with contrast-enhanced ultrasound. Eur J Radiol 72:418–424CrossRefPubMedGoogle Scholar
  30. 30.
    Liu GJ, Xu HX, Xie XY et al (2009) Does the echogenicity of focal liver lesions on baseline gray-scale ultrasound interfere with the diagnostic performance of contrast-enhanced ultrasound? Eur Radiol 19:1214–1222CrossRefPubMedGoogle Scholar
  31. 31.
    Moriyasu F, Itoh K (2009) Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial. AJR Am J Roentgenol 193:86–95CrossRefPubMedGoogle Scholar
  32. 32.
    Quaia E, Alaimo V, Baratella E, Medeot A, Midiri M, Cova MA (2009) The added diagnostic value of 64-row multidetector CT combined with contrast-enhanced US in the evaluation of hepatocellular nodule vascularity: implications in the diagnosis of malignancy in patients with liver cirrhosis. Eur Radiol 19:651–663CrossRefPubMedGoogle Scholar
  33. 33.
    Sugimoto K, Shiraishi J, Moriyasu F, Doi K (2009) Computer-aided diagnosis of focal liver lesions by use of physicians' subjective classification of echogenic patterns in baseline and contrast-enhanced ultrasonography. Acad Radiol 16:401–411CrossRefPubMedGoogle Scholar
  34. 34.
    Trillaud H, Bruel JM, Valette PJ et al (2009) Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI. World J Gastroenterol 15:3748–3756CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang WP, Wu Y, Luo Y et al (2009) Clinical value of contrast-enhanced ultrasonography in the characterization of focal liver lesions: a prospective multicenter trial. Hepatobiliary Pancreat Dis Int 8:370–376PubMedGoogle Scholar
  36. 36.
    Zuber-Jerger I, Schacherer D, Woenckhaus M, Jung EM, Schölmerich J, Klebl F (2009) Contrast-enhanced ultrasound in diagnosing liver malignancy. Clin Hemorheol Microcirc 43:109–118PubMedGoogle Scholar
  37. 37.
    D'Onofrio M, Faccioli N, Zamboni G et al (2008) Focal liver lesions in cirrhosis: value of contrast-enhanced ultrasonography compared with Doppler ultrasound and alpha-fetoprotein levels. Radiol Med 113:978–991CrossRefPubMedGoogle Scholar
  38. 38.
    Hatanaka K, Kudo M, Minami Y, Maekawa K (2008) Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignancies: comparison with contrast-enhanced CT. Oncology 75:42–47CrossRefPubMedGoogle Scholar
  39. 39.
    Shiraishi J, Sugimoto K, Moriyasu F, Kamiyama N, Doi K (2008) Computer-aided diagnosis for the classification of focal liver lesions by use of contrast-enhanced ultrasonography. Med Phys 35:1734–1746CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Strobel D, Seitz K, Blank W et al (2008) Contrast-enhanced ultrasound for the characterization of focal liver lesions--diagnostic accuracy in clinical practice (DEGUM multicenter trial). Ultraschall Med 29:499–505CrossRefPubMedGoogle Scholar
  41. 41.
    Wang ZL, Tang J, Weskott HP et al (2008) Undetermined focal liver lesions on gray-scale ultrasound in patients with fatty liver: characterization with contrast-enhanced ultrasound. J Gastroenterol Hepatol 23:1511–1519CrossRefPubMedGoogle Scholar
  42. 42.
    Catala V, Nicolau C, Vilana R et al (2007) Characterization of focal liver lesions: comparative study of contrast-enhanced ultrasound versus spiral computed tomography. Eur Radiol 17:1066–1073CrossRefPubMedGoogle Scholar
  43. 43.
    Celli N, Gaiani S, Piscaglia F et al (2007) Characterization of liver lesions by real-time contrast-enhanced ultrasonography. Eur J Gastroenterol Hepatol 19:3–14CrossRefPubMedGoogle Scholar
  44. 44.
    Dai Y, Chen MH, Yin SS et al (2007) Focal liver lesions: can SonoVue-enhanced ultrasound be used to differentiate malignant from benign lesions? Investig Radiol 42:596–603CrossRefGoogle Scholar
  45. 45.
    Jung EM, Clevert DA, Schreyer AG et al (2007) Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: a prospective controlled two-center study. World J Gastroenterol 13:6356–6364CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Quaia E, D'Onofrio M, Cabassa P et al (2007) Diagnostic value of hepatocellular nodule vascularity after microbubble injection for characterizing malignancy in patients with cirrhosis. AJR Am J Roentgenol 189:1474–1483CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Xu J, Wu Y, Dong F (2007) Clinical value of contrast-enhanced ultrasound in differentiating benign and malignant focal liver lesions. J Huazhong Univ Sci Technolog Med Sci 27:703–705CrossRefPubMedGoogle Scholar
  48. 48.
    Leen E, Ceccotti P, Kalogeropoulou C, Angerson WJ, Moug SJ, Horgan PG (2006) Prospective multicenter trial evaluating a novel method of characterizing focal liver lesions using contrast-enhanced sonography. AJR Am J Roentgenol 186:1551–1559CrossRefPubMedGoogle Scholar
  49. 49.
    Nicolau C, Vilana R, Catalá V et al (2006) Importance of evaluating all vascular phases on contrast-enhanced sonography in the differentiation of benign from malignant focal liver lesions. AJR Am J Roentgenol 186:158–167CrossRefPubMedGoogle Scholar
  50. 50.
    Wang JH, Lu SN, Hung CH et al (2006) Small hepatic nodules (< or =2 cm) in cirrhosis patients: characterization with contrast-enhanced ultrasonography. Liver Int 26:928–934CrossRefPubMedGoogle Scholar
  51. 51.
    Wu W, Chen MH, Yin SS et al (2006) The role of contrast-enhanced sonography of focal liver lesions before percutaneous biopsy. AJR Am J Roentgenol 187:752–761CrossRefPubMedGoogle Scholar
  52. 52.
    Xu HX, Liu GJ, Lu MD et al (2006) Characterization of small focal liver lesions using real-time contrast-enhanced sonography: diagnostic performance analysis in 200 patients. J Ultrasound Med 25:349–361CrossRefPubMedGoogle Scholar
  53. 53.
    Kim SH, Lee JM, Lee JY et al (2005) Value of contrast-enhanced sonography for the characterization of focal hepatic lesions in patients with diffuse liver disease: receiver operating characteristic analysis. AJR Am J Roentgenol 184:1077–1084CrossRefPubMedGoogle Scholar
  54. 54.
    Bryant TH, Blomley MJ, Albrecht T et al (2004) Improved characterization of liver lesions with liver-phase uptake of liver-specific microbubbles: prospective multicenter study. Radiology 232:799–809CrossRefPubMedGoogle Scholar
  55. 55.
    Dietrich CF, Ignee A, Trojan J et al (2004) Improved characterisation of histologically proven liver tumours by contrast enhanced ultrasonography during the portal venous and specific late phase of SHU 508A. Gut 53:401–405CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Klein D, Jenett M, Gassel HJ, Sandstede J, Hahn D (2004) Quantitative dynamic contrast-enhanced sonography of hepatic tumors. Eur Radiol 14:1082–1091CrossRefPubMedGoogle Scholar
  57. 57.
    Peschl R, Werle A, Mathis G (2004) Differential diagnosis of focal liver lesions in signal-enhanced ultrasound using BR 1, a second-generation ultrasound signal enhancer. Dig Dis 22:73–80CrossRefPubMedGoogle Scholar
  58. 58.
    Quaia E, Calliada F, Bertolotto M et al (2004) Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 232:420–430CrossRefPubMedGoogle Scholar
  59. 59.
    Suzuki S, Iijima H, Moriyasu F et al (2004) Differential diagnosis of hepatic nodules using delayed parenchymal phase imaging of Levovist contrast ultrasound: comparative study with SPIO-MRI. Hepatol Res 29:122–126CrossRefPubMedGoogle Scholar
  60. 60.
    von Herbay A, Vogt C, Willers R, Häussinger D (2004) Real-time imaging with the sonographic contrast agent SonoVue: differentiation between benign and malignant hepatic lesions. J Ultrasound Med 23:1557–1568CrossRefGoogle Scholar
  61. 61.
    Isozaki T, Numata K, Kiba T et al (2003) Differential diagnosis of hepatic tumors by using contrast enhancement patterns at US. Radiology 229:798–805CrossRefPubMedGoogle Scholar
  62. 62.
    Karabacakoglu A, Karakose S, Cil AS, Kaya A (2003) Contrast media-enhanced power Doppler sonography for evaluation of hemangiomas and malignant tumors in the liver. J Gastroenterol Hepatol 18:92–98CrossRefPubMedGoogle Scholar
  63. 63.
    Strobel D, Raeker S, Martus P, Hahn EG, Becker D (2003) Phase inversion harmonic imaging versus contrast-enhanced power Doppler sonography for the characterization of focal liver lesions. Int J Color Dis 18:63–72CrossRefGoogle Scholar
  64. 64.
    Beissert M, Delorme S, Mutze S et al (2002) Comparison of B-mode and conventional colour/power Doppler ultrasound, contrast-enhanced Doppler ultrasound and spiral CT in the diagnosis of focal lesions of the liver: Results of a multicentre study. Ultraschall Med 23:245–250CrossRefPubMedGoogle Scholar
  65. 65.
    von Herbay A, Vogt C, Häussinger D (2002) Late-phase pulse-inversion sonography using the contrast agent levovist: differentiation between benign and malignant focal lesions of the liver. AJR Am J Roentgenol 179:1273–1279CrossRefGoogle Scholar
  66. 66.
    Fracanzani AL, Burdick L, Borzio M et al (2001) Contrast-enhanced Doppler ultrasonography in the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis. Hepatology 34:1109–1112CrossRefPubMedGoogle Scholar
  67. 67.
    Perera RH, Hernandez C, Zhou H, Kota P, Burke A, Exner AA (2015) Ultrasound imaging beyond the vasculature with new generation contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol 7:593–608CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Yanagisawa K, Moriyasu F, Miyahara T, Yuki M, Iijima H (2007) Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol 33:318–325CrossRefPubMedGoogle Scholar
  69. 69.
    Claudon M, Cosgrove D, Albrecht T et al (2008) Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) -. update 2008. Ultraschall Med 29:28–44CrossRefPubMedGoogle Scholar
  70. 70.
    Jang HJ, Yu H, Kim TK (2009) Contrast-enhanced ultrasound in the detection and characterization of liver tumors. Cancer Imaging 9:96–103PubMedPubMedCentralGoogle Scholar

Copyright information

© European Society of Radiology 2017

Authors and Affiliations

  1. 1.Radiology DepartmentSecond Hospital of Tianjin Medical UniversityTianjinChina
  2. 2.Department of Medical ImagingSecond Hospital of Tianjin Medical UniversityTianjinChina

Personalised recommendations