Value of Contrast-Enhanced Ultrasound in Differential Diagnosis of Focal Liver Lesions

Purpose: to evaluate the diagnostic value of contrastenhanced ultrasound (CEUS) with SonoVue in differential diagnosis of focal liver lesions (FLL) in a multidisciplinary clinic in Russian Federation.
Materials and methods. Bolus intravenous administration of 1.2 ml of SonoVue (Bracco Swiss CA, Switzerland) followed with 5ml saline flush was used for liver CEUS. We utilized the scanners Mindray DC-8 (Mindrаy, China), Logiq S8 (GE, USA), Philips Epiq 7 (Philips, Holland), SonoScape S9 (SonoScape, China), Hitachi Ascendus (Hitachi, Japan) with 3.0–5.0 MHz convex probes in specialized “contrast” mode with low mechanic index (MI 0.08–0.1). The study conferred 73 patients in the age between 18 and 84 years (mean age 49 years) with FLL. CEUS was performed in 22 patients with previously verified diagnosis, while the rest of patients underwent CEUS before the final diagnosis. Contrast-enhanced liver CT was performed in all patients. In 49 (67.12%) of 73 cases, a pathology was performed after a targeted core-needle biopsy or autopsy. Qualitative features of US contrast enhancement of FLL were evaluated.
Results. Qualitative aspects of CEUS for differentiation of FLL were defined. The principal sign for diagnosis between benign and malignant masses with CEUS was hypoenhancement of malignant lesions in comparison to surrounding normal parenchyma in portal and late venous phase (p ≤ 0.01). Alternatively, hyper- or isoenhancement throughout late venous phase was characteristic for benign FLL. Diffuse heterogeneous contrast enhancement was indicative of malignant FLL, and homogeneous – for benign. Additional diagnostic feature (p ≤ 0.05) was the type of contrast enhancement in the arterial phase. Heterogeneous diffuse contrast enhancement was observed in malignant FLL, while homogeneous – in benign FLL. Peripheral nodular contrast enhancement with centripetal filling was characteristic for liver hemangioma, centrifugal filling with “spoke-wheel” vascular pattern – for FNH, and peripheral rim-like hyperenhancement with rapid achievement of hypoenhancement at the beginning of the portal phase – for liver metastasis.
Conclusion. Complex analysis of qualitative characteristics of CEUS with SonoVue is a promising option for differential diagnosis of FLL (sensitivity 92.85%, specificity 91.3%, diagnostic accuracy 92.15%) and can be utilized in daily practice.

1. Зубарев А.В. Методы медицинской визуализации – УЗИ, КТ, МРТ – в диагностике опухолей и кист печени. М.: Видар, 1995: 10–14. Zubarev A.V. Methods of medical visualization – Ultrasound, CT, MRI – in diagnosis liver tumors and cysts. M.: Vidar, 1995: 10–14. (In Russian)

2. Бондаревский И.Я., Бордуновский В.Н., Кинзерский А.Ю. Возможности ультразвуковой диагностики в выявлении очаговых образований печени. Медицинская визуализация. 2011; 5; 19–24. Bondarevsky I.Ya., Bordunovsky V.N., Kinzersky A.Yu. Possibilit0ies of Ultrasound Diagnosticsin Revealing of Focal Formations of Liver. Medical Visualization. 2011; 5: 19–24. (In Russian)

3. Колганова И.П., Осипова Н.Ю., Сидорова Е.Е., Шипулева И.В., Кармазановский Г.Г. Очаговые образования печени. Вопросы лучевой диагностики. Классика. Будущее. Медицинская визуализация. 2008; 5: 131–134. Kolganova I.P., Osipova N.Yu., Sidorova E.E., Shipuleva I.V., Karmazanovsky G.G. FocalLesionsofaliver. The Questions of Diagnostic Imaging. Routine and Future. Medical Visualization. 2008; 5: 131–134. (In Russian)

4. Зогот С.Р., Акберов Р.Ф. Частота, лучевая семиотика метастазов в печень опухолей различной локализации по результатам комплексного лучевого исследования. Практическая медицина. 2013; 2 (67): 119–122. Zogot S.R., Akberov R.F. Frequency and x-ray semiotics of liver metastasis of various location tumors on the results of a comprehensive radiologic study. Practicheskaya meditsina. 2013; 2 (67): 119–122. (In Russian)

5. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015; 136 (5): 359–386. DOI: 10.1002/ijc.29210.

6. Palmucci S. Focal liver lesions detection and characterization: The advantages of gadoxetic acid-enhanced liver MRI. Wld J. Hepatol. 2014; 6 (7): 477–485. DOI: 10.4254/wjh.v6.i7.477.

7. Roche V., Pigneur F., Tselikas L., Roux M., Baranes L., Djabbari M., Costentin C., Calderaro J., Laurent A., Rahmouni A., Luciani A. Differentiation of focal nodular hyperplasiafrom hepatocellular adenomas with lowmechanical index contrast-enhanced sonography (CEUS): effects of size on diagnostic confidence. Eur. Radiol. 2015; 25 (1): 186–195. DOI: 10.1007/s00330-014-3363-y.

8. Trillaud M., 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 SonoVueenhanced sonography: international multicenter-study in comparison to CT and MRI. Wld J. Gastroenterol. 2009; 15 (30): 3748–3756. DOI: 10.3748/wjg.15.3748.

9. Ophir J., Parker K.J. Contrast agents in diagnostic ultrasound. Ultrasound Med. Biol. 1989; 15 (4): 319–333. PMID: 2669297.

10. Solbiati L., Martegani A., Leen E., Correas J.M., Burns P.N., Becker D. Contrast-Enhanced Ultrasound of Liver Diseases. Italia: Springer-Verlag, 2003. 123 p.

11. Albrecht T., Blomley M., Bolondi L., Claudon M., Correas J.M., Cosgrove D., Greiner L., Jäger K., Jong N.D., Leen E., Lencioni R., Lindsell D., Martegani A., Solbiati L., Thorelius L., Tranquart F., Weskott H.P., Whittingham T.; EFSUMB Study Group. Guidelines for the use of contrast agents in ultrasound. January 2004. Ultraschall Med. 2004; 25: 249–256. DOI: 10.1055/s-2004-813245.

12. Claudon M., Cosgrove D., Albrecht T., Bolondi L., Bosio M., Calliada F., Correas J.M., Darge K., Dietrich C.F., D'Onofrio M., Evans D.H., Filice C., Greiner L., Jäger K., Jong N.D., Leen E., Lencioni R., Lindsell D., Martegani A.,Meairs S., Nolsoe C., Piscaglia F., Ricci P., Seidel G., Skjoldbye B., Solbiati L., Thorelius L., Tranquart F., Weskott H.P., Whittingham T. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008. Ultraschall Med. 2008; 29: 28–44. DOI: 10.1055/s-2007-963785.

13. 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. Ultraschall Med. 2013; 34: 11–29. DOI: 10.1055/s-0032-1325499.

14. Weskott H.-P. Контрастная сонография. Бремен: UNIMED , 2014. 284 c. Weskott H.-P. Contrast-enhanced sonography. Bremen. UNI-MED, 2014. 284 p. (In Russian)

15. D’Onofrio M., Crosara S., de Robertis R., Canestrini S., Cantisani V., Morana G., Pozzi Mucelli R. Malignant focal liver lesions at contrast-enhanced ultrasonography and magnetic resonance with hepatospecific contrast agent. Ultrasound. 2014; 22 (2): 91–98. DOI: 10.1177/1742271X13513888.

16. Cantisani V., David E., Meloni F.M., Dietrich C.F., Badea R., Messineo D., D'Ambrosio F., Pisgalia F. Recall strategies for patients found to have a nodule in cirrhosis: is there still a role for CEUS? Med Ultrason. 2015; 17 (4): 515–520. DOI: 10.11152/mu.2013.2066.174.rsp.

17. Wang W., Liu J.-Y., Yang Z., Wang Y.-F., Shen S.-L., Yi F.-L., Huang Y., Xu E.-J., Xie X.-Y., Lu M.-D., Wang Z., Chen L.-D. Hepatocellular adenoma: comparison between real-time contrast-enhanced ultrasound and dynamic computed tomography. Springerplus. 2016; 5 (1): 951. DOI: 10.1186/s40064-016-2406-z.

18. Зубарев А.В. Трехмерная и эхоконтрастная ангиография. Медицинская визуализация. 1997; 4: 3–8 Zubarev A.V. 3-dementional and contrast-enhanced angiography. Medical Visualization. 1997; 4: 3–8. (In Russian)

19. Камалов Ю.Р., Сандриков В.А., Гаврилов А.В. Использование ультразвукового контраста Levovist при обследовании больных опухолями печени, портальной гипертензией и при ортотопической трансплантации печени. Клиническая физиология. Диагностика – новые методы; Под ред. Сандрикова В.А. М.: Аир-Арт, 1998: 144–149. Kamalov Yu.R., Sandrikov V.A., Gavrilov A.V. The use of ultrasound contrast Levovist when examine patients with tumors of the liver portal hypertension and orthotopic liver transplantation. Klinicheskaya fiziologiya. Diagnostica – novye metody. Ed. Sandrikov V.A. M.: Air-Art, 1998: 144–149. (In Russian)

20. Щербакова С.В., Кунцевич Г.И., Чебышева Э.Н., Журенкова Т.В. Оценка результатов исследования кровотока у больных хроническим панкреатитом и раком поджелудочной железы с помощью Левовиста. Диагностика – новые методы; Под ред. Сандрикова В.А. М.: Аир-Арт, 1998: 149–150. Scherbakova S.V., Kuncevich G.I., Chebysheva E.N., Zhurenkova T.V. Evalution results of the study of blood flow in patients with chronic pancreatitis and pancreatic cancer using Levovist. Diagnostika – novyemetody. Ed. Sandrikov V.A. M.: Air-Art, 1998: 149–150. (In Russian)

21. Гажонова В.Е., Зубарев А.В., Кислякова М.В. Эхо-контрастная ангиография предстательной железы с Левовистом для улучшения визуализации кровотока. Диагностика – новые методы; Под ред. Сандрикова В.А. М.: Аир-Арт, 1998: 151–156. Gazhonova V.E., Zubarev A.V., Kislyakova M.V. Contrastenchanced angiography with Levovist of prostate. Diagnostica – novye metody. Ed. Sandrikov A.V. M.: AirArt, 1998: 151–156. (In Russian)

22. Сенча А.Н., Могутов М.С., Патрунов Ю.Н., Пеняева Э.И., Кашманова А.В., Сенча Е.А. Ультразвуковое исследование с использованием контрастных препаратов. М.: ВИДАР, 2015. 144 c. Sencha A.N, Mogutov M.S., Patrunov Yu.N., Peniaeva E.I., Kashmanova A.V., Sencha E.A. Contrast-enhansed ultrasound. M.: Vidar, 2015. 144 p. (In Russian)

23. Аскерова Н.Н., Кармазановский Г.Г. Контрастное усиление изображения препаратом SonoVue®: пути усовершенствования ультразвуковой диагностики очаговой патологии органов брюшной полости и забрюшинного пространств. Медицинская визуализация. 2015; 1: 115–125. Askerova N.N., Karmazanovsky G.G. Contrast-enhanced imaging with Utilisation of SonoVue: Ways of improvement of ultrasonic diagnosis of foca lliver lesions in parenchymal organs and retroperitoneal. Medical Visualization. 2015; 1: 115–125. (In Russian)

24. Феоктистова Е.В., Белякова Л.А., Варфоломеев С.Р. Ультразвуковое исследование с контрастным усилением у детей – возможности применения в онкологической практике. Ультразвуковая и функциональная диагностика. 2016; 5: 22–32. Feoktistova E.V., Belyakova L.A., Varfolomeeva S.R. Contrast-enhansced ultrasound (CEUS) inpediatric oncology (literarure review). Ultrasound and functional diagnostic. 2016; 5: 22–32. (In Russian)

25. Агеев А.С., Чекалова М.А., Патютко Ю.И., Поляков А.Н., Маргарян А.Г. Ультразвуковое исследование с контрастным усилением в диагностике метастатического поражения печени. Ультразвуковая и функциональная диагностика. 2016; 2: 9–16. Ageev A.S., Chekalova M.A., Patutko Yu.I., Polyakov A.N., Margaryan A.G. Contrast-enhansed ultrasound in liver metastases diagnosis. Ultrasound and functional diagnostic. 2016; 2: 9–16. (In Russian)

26. Ветшева Н.Н., Фисенко Е.П., Степанова Ю.А., Камалов Ю.Р., Тимина И.Е., Киселева Т.Н., Жестовская С.И. Ультразвуковое исследование с контрастным усилением: терминология, технические и методологичекие аспекты. Медицинская визуализация. 2016; 4: 132–140. Vetsheva N.N., Fisenko E.P., Stepanova Yu.A., Kamalov Yu.R. Contrast-enhanced ultrasound: terminology, technical and methodologicial aspects. Medical Visualization. 2016; 4: 132–140. (In Russian)

27. Bernatik T., Seitz K., Blank W., Schuler A., Dietrich C.F., Strobel D. Unclear Focal Liver Lesions in ContrastEnhanced Ultrasonography – Lessons to be Learned from the DEGUM Multicenter Study for the Characterization of Liver Tumors. Ultraschall Med. 2010; 31 (6): 577–581. DOI: 10.1055/s-2008-1027806.

28. Von Herbay A., Westendorff J., Gregor M. Contrastenhanced ultrasound with SonoVue: Differentiation between benign and malignant focal liver lesions in 317 patients. J. Clin. Ultrasound. 2010; 38 (1): 1–9. DOI: 10.1055/s-0042-120272.

29. Quaia E., Calliada F., Bertolotto M., Rossi S., Garioni L., Rosa L., Pozzi-Mucelli R. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology. 2004; 232 (2): 420–430. DOI: 10.1148/radiol.2322031401.

30. 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. Am. J. Roentgenol. 2006; 186: 1512–1519. DOI: 10.2214/AJR.05.0943.

31. Iavarone M., Sangiovanni A., Forzenigo L.V., Schiff E.R., Maddrey W.C., Sorrell M.F. Diagnosis of hepatocellular carcinoma in cirrhosis by dynamic contrast imaging: the importance of tumor cell differentiation. Hepatology. 2010; 52 (5): 1723–1730. DOI: 10.1002/hep.23903.

32. Xu H.X., Liu G.J., Lu M.D., Xie X.Y., Xu Z.F., Zheng Y.L., Liang J.Y. Characterization of focal liver lesions using contrast-enhanced sonography with a low mechanical index mode and a sulfur hexafluoride-filled microbubble contrast agent. Clin. Ultrasound. 2006; 34 (6): 261–272. DOI: 10.1002/jcu.20234.

33. Xu H.X., Liu G.J., Lu M.D., Xie X.Y., Xu Z.F., Zheng Y.L., Liang J.Y. Characterization of small focal liver lesions using real-time contrast-enhanced sonography: diagnostic performance analysis in 200 patients. J. Ultrasound Med. 2006; 25 (3): 349–361.

34. Xu H.X., Xie X.Y., Lu M.D., Liu G.J., Xu Z.F., Zheng Y.L., Liang J.Y., Chen L.D. Contrast-enhanced sonography in the diagnosis of small hepatocellular carcinoma < or = 2 cm. J. Clin. Ultrasound. 2008; 36 (5): 257–266. DOI: 10.1002/jcu.20433.

35. Xu X.H., Lu M.D., Liu L.N., Zhang Y.F., Guo L.H., Xu J.M., Liu C. Discrimination between neoplastic and nonneoplastic lesions in cirrhotic liver using contrastenhanced ultrasound. Br. J. Radiol. 2012; 85: 1376–1384. DOI: 10.1259/bjr/19932596.

36. 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. Am. J. Roentgenol. 2007; 189: W7–W12. DOI: 10.2214/AJR.06.1060.

37. Burns P.N., Wilson S.R. Focal Liver Masses: Enhance ment Patterns on Contrast-enhanced Images – Concordance of US Scans with CT Scans and MR Images. Radiology. 2007; 242 (1): 162–174. DOI: http://dx.doi.org/10.1148/radiol.2421051006.

38. Grazioli L., Federle M.P., Brancatelli G., Ichikawa T., Olivetti L., Blachar A. Hepatic adenomas: imaging and pathologic findings. Radiographics. 2001; 21: 877–892. DOI: 10.1148/radiographics.21.4. g01jl04877.

39. Dietrich C.F., Schuessler G., Trojan J., Fellbaum C., Ignee A. Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound. Br. J. Radiol. 2005; 78: 704–707. DOI: 10.1259/bjr/88181612.

40. Seitz K., Strobel D., Bernatik T., Blank W., FriedrichRust M., Herbay A.V., 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, Davos. Ultrashall Med. 2009; 30 (4):383–389. DOI: 10.1055/s-0028-1109673.

41. 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 contrastenhanced ultrasound (CEUS). Ultrashall Med. 2009; 30 (4): 376–382. DOI: 10.1055/s-0028-1109672.

42. 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. Ultraschall Med. 2010; 31 (3): 276–282. DOI: 10.1055/s-0028-1109852.

43. Matsui O. Detection and Characterization of Hepatocellular Carcinoma by Imaging. Clin. Gastroenterol. Gepatol. 2005; 3 (2): S136–S140. DOI: 10.1016/S1542-3565(05)00707-X.

44. Dietrich C.F., Mertens J.C., Braden B., Schuessler G., Ott M., Ignee A. Contrast-enhanced ultrasound of histologi cally proven liver hemangiomas. Hepatology. 2007; 45 (5): 1139–1145. DOI: 10.3748/wjg.v22.i19.4741.

45. Xu H.X., Lu M.D. The current status of contrast-enhanced ultrasound in China. J. Med. Ultrason (2001). 2010; 37 (3): 97–106. DOI: 10.1007/s10396-010-0264-9.