Received: 13.10.2008 Accepted: 30.10.2008J Gastrointestin Liver DisMarch 2009 Vol.18 No 1, 103-108Address for correspondence: Larisa Săndulescu University of Medicine and Pharmacy Petru Rares Str. no 2 Craiova, Romania E-mail: larisasandulescu@yahoo.com

CLiNiCAL iMAGiNG

The Role of Real-time Contrast-Enhanced and Real-time Virtual Sonography in the Assessment of Malignant Liver LesionsLarisa Săndulescu, Adrian Săftoiu, Daniela Dumitrescu, Tudorel Ciurea

Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy Craiova, Romania

AbstractContrast enhanced ultrasound has recently been

introduced and is recommended in daily practice in many circumstances, mainly for the detection and characterization of focal liver lesions. Also, contrast enhanced ultrasound has the potential of becoming the primary liver-imaging modality, preceding CT or MR, for the diagnosis of hepatocellular carcinoma in patients with cirrhosis, detection of liver metastases in oncology patients and guidance and assessment of the outcome of percutaneous tumor ablation procedure. Recently, a new imaging technique that combines in real-time, transabdominal ultrasound with CT or MR, has been introduced in clinical practice. Real-time virtual sonography uses a magnetic positioning system attached to the ultrasound probe in order to calculate the spatial position and to display both imaging methods in real-time. Benefits include an increased diagnostic confidence, direct comparison of the lesions using different imaging modalities, more precise monitoring of interventional procedures and reduced radiation exposure. We describe the role of real-time contrast-enhanced and real-time virtual sonography in the assessment of malignant liver lesions.

Keywords Real-time contrast-enhanced ultrasound – malignant liver

lesions – hybrid imaging – real-time virtual sonography.

Contrast enhanced ultrasound (CEUS)The development of microbubble contrast agents has

had a major impact on the role of ultrasound in the liver, particularly for focal lesions. As a result of their double blood

supply provided by the hepatic artery and portal vein, focal liver lesions present a complex temporal and spatial picture of increased and reduced contrast [1].

The guidelines published in 2008 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) clearly defined the indication and recommendations for the use of contrast agents in liver ultrasound investigation [2]:

1. characterization of focal liver lesions (benign versus malignant);

2. guidance and monitoring local ablative treatment, and

3. measuring the hepatic transit time and studying the hepatic vessels.

1. Characterization of malignant liver lesions Hypo-enhancement of solid lesions (darker than

the surrounding liver) in the late phase characterizes malignancies [2].

Recognition of hepatocellular carcinomas (HCC) in liver cirrhosis is difficult if the echo texture is very inhomogeneous due to the presence of regenerative nodules and architectural changes caused by extensive fibrosis. The progression from a regenerative nodule to a frank HCC is characterized by loss of visualization of portal tracts and development of new arterial vessels, which become the dominant blood supply in HCC lesions [3-5]. This arterial neoangiogenesis is the landmark of HCC and is the key for imaging diagnosis [6-8]. Several reports have shown that CEUS is the perfect tool to detect arterial neoangiogenesis in HCC [9, 10-12]. Typical features of hepatocellular carcinoma in cirrhotic liver show strong, early, complete enhancement in the arterial phase [Fig. 1a], while macroregenerative nodules are iso-enhancing with liver parenchyma. In other cases, basket pattern, chaotic vessels or rim-like enhancement can be detected in HCC lesions. Selective arterial enhancement on CEUS has been observed in 91-96% of HCC lesions [13, 14]. In subsequent phases, most hepatocellular carcinomas have a wash-out pattern and become hypo-enhanced in the parenchimal phase (Fig. 1b,c). Both the 2005 EASL conference on HCC and the AASLD practice guidelines have recommended the further

104 Sandulescu et al

investigation of nodules detected during US surveillance with dynamic imaging techniques (including CEUS, multidetector CT or dynamic MR imaging) to highlight the different vascular supply of HCC versus non-malignant entities [15, 16]. The diagnosis of hepatic nodules depends on the lesion size. For lesions larger than 2 cm a single imaging technique showing the characteristic vascular profile of HCC (arterial hypervascularization with washout in the portal venous or the late phase) may confidently establish the diagnosis. In lesions ranging from 1 to 2 cm, AASLD guidelines have recommended that typical imaging findings should be

confirmed by two coincident dynamic imaging modalities for HCC diagnosis [15]. Currently, liver biopsy is recommended only if the lesion does not show typical features of HCC [15]. CEUS has been proven to be an effective noninvasive tool in the screening and diagnosis of HCC.

Metastases may be hypo- or hypervascular in the arterial phase or may have a peripheral rim enhancement (Fig. 2). All metastases have washout of the contrast and become hypo-enhanced in the portal and late phase (Fig. 3). Metastases of carcinomas are the most common malignant infiltration of the liver. In addition, the liver is the parenchymatous organ in which metastases are encountered most often. The introduction of CEUS in clinical practice has markedly improved the detection rate of liver metastases versus conventional ultrasound, especially for small size or isoechoic lesions, and also for metastases in difficult anatomical areas (e.g. in the superficial subdiaphragmatic areas and around the ligamentum teres) [17-19]. Some studies have shown that the accuracy in the detection of liver metastases is comparable to CT [20, 21]. It has also been demonstrated that CEUS can detect metastases not visible on CT [20, 22, 23], but can also miss lesions shown on CT. Current recommendations

Fig 1. HCC nodule that shows progressive and intense enhancement, with stelate pattern and central necrosis, in the arterial phase [a]. In subsequent portal and parenchymal phases, due to perfusion of surrounding liver parenchyma together with wash-out of the contrast agent from the nodule, it appears hypo-enhanced and less evident [b,c].

Fig 2. A 65- year-old male patient with a history of gastric cancer under chemotherapy and regular imaging follow-up. The non-enhanced B-mode US of the right liver lobe shows a liver metastasis with a strong peripheral rim enhancement in the arterial phase.

Fig 3. Contrast-enhanced US scan of the right lobe shows multiple metastases. The metastatic lesions are clearly delineated in the portal-venous and late phase as ‘black spots’, due to the lack of portal-venous blood supply.

Real-time contrast-enhanced and real-time virtual sonography 105

for the use of CEUS in liver imaging include the exclusion of liver metastases in oncology patients, even if the baseline scans do not show any abnormality [2]. In addition, CEUS is useful to assess the number and location of liver metastases, if it is important for treatment planning [2]. CEUS is also a promising modality to monitor chemotherapy for liver metastases [24], especially when antiangiogenic or targeted therapies are used [25].

2. Guiding and monitoring local ablative treatment Percutaneous ablation (radiofrequency ablation and

percutaneous ethanol injection) is currently the most used technique for both HCC and liver metastases [26-28]. The objective of this technique is to achieve complete necrosis of the tumoral tissue, including a sufficient safety margin. The use of contrast agents can provide many advantages [2, 29, 30]: evaluation of the number of lesions with the exclusion of patients initially enrolled for percutaneous treatment with unexpectedly large number of metastases detected; better delineation of lesions poorly visualized on baseline US scans; evaluation of ablation result with immediate detection of residual viable tumour area in the interventional room, not at a distance as CT or MRI, and with the same operator and the same US equipment used for the ablative procedure; additional percutaneous treatment application in the same session until no further residual enhancement is detectable; post-ablation follow-up (Figs. 4, 5). Recent studies have shown an accuracy of CEUS in the assessment of percutaneous treatment from 91 to 100% [31- 33]. Also, CEUS has almost the same sensitivity in the detection of residual HCC as CT [31-36]. Following these excellent results, some authors have suggested that CEUS should be used as the first imaging technique to evaluate the initial response to percutaneous treatment, thus avoiding the use of more expensive and time-consuming facilities [35].

3. Measuring the hepatic transit time and studying the hepatic vessels

Despite the major advances in imaging techniques, the detection of smaller (less than 1 cm) metastases is still very difficult. Several studies have revealed a significant shortening of the hepatic transit time (from hepatic artery to hepatic vein) in patients with liver metastases [37-39]. It was also demonstrated that a transit time of more than 10 seconds rules out metastases with a sensitivity of 100% and specificity of 91% [38].

CEUS is also useful for differential diagnosis between benign and malignant portal vein thrombosis. The malignant portal thrombus has arterial hypervascularity and marked late hypovascularity (Fig. 6) in contrast to benign thrombus which shows no arterial enhancement [40].

New prospect in contrast enhanced ultrasoundThe use of microbubbles for treatment may eventually

be even more important than their diagnostic uses. Microbubbles can aid drug delivery by themselves with

application in the emerging area of gene therapy or in other specific treatments as a minimally invasive means for treating pathologies via a targeted drug-delivery strategy. [41]. Further research is required to develop this technique into a clinically useful tool. CEUS can be used, also, for the quantification of tumoral perfusion in the early assessment and monitoring of the efficacy of antiangiogenic agents in quantitative terms based on changes in vascularity, before morphological changes become apparent [42, 43].

Fig 4. US of a 3-cm HCC in a 60-year-old woman correctly treated with percutaneous ethanol injection. Arterial phase of the HCC shows the typical hypervascularity before treatment [a]. CEUS scan of the same patient one month after the treatment shows absence of enhancement in the treated tumor compatible with a complete response [b].

Fig 5. Single HCC (2.5 cm) nodule in a cirrhotic patient. After percutaneous ethanol injection, CEUS shows in the arterial phase an area of hypovascularity replacing the treated tumor.

106 Sandulescu et al

Real-time virtual sonography (RVS)Real-time virtual sonography is a new imaging technique

that combines in real-time transabdominal ultrasound with CT or MR. This technique includes magnetic positioning sensors on the probe of the ultrasound scanner, for the creation of images with identical cross-sections in real time according to the position and angle of the probe in relation to the CT and MR volume data that has been acquired.

The actual procedure is: 1) first, the CT and MR volume data is transferred into the ultrasound machine; 2) the magnetic position sensor unit is prepared with attention to the positions of the orientation marks; 3) the transmitter (the instrument that produces magnetic waves) for the magnetic; position sensor unit is installed on the left flank of a patient; 4) the xyphoid process is selected as the reference point; 5) the first ultrasound section is sagital, with the left hepatic lobe. The virtual image (CT or MR and ultrasound) shows on the workstation monitor. Corrections are possible when the positions of virtual images and ultrasound images do not align.

Several studies have proved already the feasibility of the RVS module, especially for the percutaneous radiofrequency ablation of poorly visible or unidentifiable focal liver lesions during B-mode sonography [44-47] (Fig. 7). Improvement of the CT technique also allows the identification of the

relationship between the intrahepatic vessels and the HCC nodule during RVS (Fig. 8), consequently contributing to an accurate and safe performance of radio frequency ablation [48].

The real-time virtual sonography has some limitations. First, in patients in whom CT or MR is contraindicated (patients with known contrast medium allergies, renal insufficiency or metallic implant). Second, RVS does not show always the best synchronization of ultrasound and CT or MR image, but the discrepancy can be adjusted with neighboring portal and hepatic veins in most cases.

in conclusion, the RVS module displays the real-time ultrasound image simultaneously with the corresponding CT or MR virtual multi-planar view reconstructed from a stored volume data set. Benefits include an increased diagnostic confidence, direct comparison of the lesions using different imaging modalities, more precise monitoring of interventional procedures and reduced radiation exposure.

Acknowledgement This paper was supported through the research grant

number 2076/2007 „Staging diagnosis algorithm for the prediction of chronic hepatitis evolution using non-invasive ultrasound techniques, optimised through sthocastic imaging analysis – SONOFIBROCAST”, financed by the Romanian

Fig 6. Malignant portal vein thrombosis in a patient with HCC. The portal thrombus has arterial hypervascularity [a] and marked late hypovascularity [b]. Beside the portal vein a 2 cm HCC nodule is seen in the left liver lobe with the same contrast pattern.

Fig 7. Real-time virtual sonography showing multiple metastases, better depicted on contrast-enhanced CT, especially in the dome of the right liver lobe which is poorly visible [a]. Concomitant use of real-time virtual sonography and real-time contrast enhancement led to a better delineation of liver metastases [b].

Real-time contrast-enhanced and real-time virtual sonography 107

Ministry of Education and Research – National Authority for Scientific Research (MEdC – ANCS).

Conflicts of interestNothing to declare.

References 1. Dietrich CF. Characterisation of focal liver lesions with contrast

enhanced ultrasonography. Eur J Radiol 2004; 51 Suppl: S9-17. 2. Claudon M, Cosgrove D, Albrecht T, et al. Guidelines and good

clinical practice recommendations for contrast enhanced ultrasound (CEUS) - update 2008. Ultraschall Med 2008; 29: 28-44.

3. Ueda K, Terada T, Nakanuma Y, Matsui O. Vascular supply in adenomatous hyperplasia of the liver and hepatocellular carcinoma: a morphometric study. Hum Pathol 1992; 23: 619–626.

4. Kimura H, Nakajima T, Kagawa K, et al. Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry. Liver 1998; 18: 14–19.

5. Roncalli M, Roz E, Coggi G, et al. The vascular profile of regenerative and dysplastic nodules of the cirrhotic liver: implications for diagnosis and classification. Hepatology 1999; 30: 1174–1178.

6. Matsui O, Kadoya M, Kameyama T, et al. Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 1991; 178: 493–497.

7. Lencioni R, Cioni D, Della Pina C, Crocetti L, Bartolozzi C. Imaging diagnosis. Semin Liver Dis 2005; 25:162–170.

8. Lencioni R, Piscaglia F, Bolondi L. Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma. J Hepatol 2008; 48: 848-857.

9. Quaia E, Calliada F, Bertolotto M, et al. 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: 420-430.

10. Isozaki T, Numata K, Kiba T, et al. Differential diagnosis of hepatic tumors by using contrast enhancement patterns at US. Radiology 2003; 229: 798–805.

11. Chen MH, Dai Y, Yan K, et al. The role of contrast-enhanced ultrasound on the diagnosis of small hepatocellular carcinoma (</=3 cm) in patients with cirrhosis. Hepatol Res 2006; 35: 281–288.

12. Xu HX, Liu GJ, Lu MD, et al. Characterization of focal liver lesions using contrast-enhanced sonography with a low mechanical index mode and a sulfur hexafluoride-filled microbubble contrast agent. J Clin Ultrasound 2006; 34: 261–272.

13. Nicolau C, Catalá V, Vilana R, et al. Evaluation of hepatocellular carcinoma using SonoVue, a second generation ultrasound contrast agent: correlation with cellular differentiation. Eur Radiol 2004; 14: 1092-1099.

14. Gaiani S, Celli N, Piscaglia F, et al. Usefulness of contrast-enhanced perfusional sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography. J Hepatol 2004; 41: 421-426.

15. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208–1236.

16. Bruix J, Sherman M, Llovet JM, et al; EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421–430.

17. Yarmenitis SD, Karantanas A, Bakantaki A, Papantoniou Y, Gourtsoyiannis N. Detection of colorectal cancer hepatic metastases with contrast-enhanced ultrasound: comparison with conventional B-mode ultrasound. Dig Dis 2007; 25: 86-93.

18. Piscaglia F, Corradi F, Mancini M, et al. Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer. BMC Cancer 2007; 7: 171.

19. Konopke R, Kersting S, Bergert H, et al. Contrast-enhanced ultrasonography to detect liver metastases: a prospective trial to compare transcutaneous unenhanced and contrast-enhanced ultrasonography in patients undergoing laparotomy. Int J Colorectal Dis 2007; 22: 201-207.

20. Albrecht T, Blomley MJ, Burns PN, et al. Improved detection of hepatic metastases with pulse-inversion US during the liver-specific

Fig 8. Real- time virtual sonography of the HCC nodule with simultaneous display of the contrast-enhanced MR section and real-time ultrasound image: power Doppler [a] and dynamic Contrast Harmonic image [b, c]. The HCC nodule had rapid enhancement in the arterial phase [b], followed by wash-out in subsequent phases [c].

108 Sandulescu et al

phase of SHU 508A: multicenter study. Radiology 2003; 227: 361-370.

21. Dietrich CF, Kratzer W, Strobe D, et al. Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI. World J Gastroenterol 2006; 12: 1699-1705.

22. Harvey CJ, Blomley MJ, Eckersley RJ, et al. Hepatic malignancies: improved detection with pulse-inversion US in late phase of enhancement with SH U 508A-early experience. Radiology 2000; 216: 903-908.

23. Hohmann J, Albrecht T, Hoffmann CW, Wolf KJ. Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents. Eur J Radiol 2003; 46: 147-159.

24. Krix M. Quantification of enhancement in contrast ultrasound: a tool for monitoring of therapies in liver metastases. Eur Radiol 2005; 15 Suppl 5: E104-108.

25. Postema M, Gilja OH. Ultrasound-directed drug delivery. Curr Pharm Biotechnol 2007; 8: 355-361.

26. Nicolau C, Vilana R, Bianchi L, Brú C. Early-stage hepatocellular carcinoma: the high accuracy of real-time contrast-enhanced ultrasonography in the assessment of response to percutaneous treatment. Eur Radiol 2007; 17 Suppl 6: F80-88.

27. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228: 235-420.

28. Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005; 234: 961-967.

29. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197: 101-108.

30. Lencioni R, Della Pina C, Crocetti L, Bozzi E, Cioni D. Clinical management of focal liver lesions: the key role of real-time contrast-enhanced US. Eur Radiol 2007; 17 Suppl 6: F73-79.

31. Solbiati L, Ierace T, Tonolini M, Cova L. Guidance and monitoring of radiofrequency liver tumor ablation with contrast-enhanced ultrasound. Eur J Radiol 2004; 51 Suppl: S19-23.

32. Vilana R, Bianchi L, Varela M, et al. Is microbubble-enhanced ultrasonography sufficient for assessment of response to percutaneous treatment in patients with early hepatocellular carcinoma? Eur Radiol 2006; 16: 2454-2462.

33. Dill-Macky MJ, Asch M, Burns P, Wilson S. Radiofrequency ablation of hepatocellular carcinoma: predicting success using contrast-enhanced sonography. AJR Am J Roentgenol 2006; 186 (5 Suppl): S287-295.

34. Wen YL, Kudo M, Zheng RQ, et al. Radiofrequency ablation of hepatocellular carcinoma: therapeutic response using contrast-enhanced coded phase-inversion harmonic sonography. AJR Am J Roentgenol 2003; 181: 57-63.

35. Choi D, Lim HK, Lee WJ, et al. Early assessment of the therapeutic response to radio frequency ablation for hepatocellular carcinoma:

utility of gray scale harmonic ultrasonography with a microbubble contrast agent. J Ultrasound Med 2003; 22: 1163-1172.

36. Colagrande S, La Villa G, Bartolucci M, Lanini F, Barletta G, Villari N . Spiral computed tomography versus ultrasound in the follow-up of cirrhotic patients previously treated for hepatocellular carcinoma: a prospective study. J Hepatol 2003; 39: 93–98.

37. Bang N, Nielsen MB, Rasmussen AN, Osterhammel PA, Pedersen JF. Hepatic vein transit time of an ultrasound contrast agent: simplified procedure using pulse inversion imaging. Br J Radiol 2001; 74: 752-755.

38. Bernatik T, Becker D, Neureiter D, et al. Hepatic transit time of an echo enhancer: an indicator of metastatic spread to the liver. Eur J Gastroenterol Hepatol 2004; 16: 313-317.

39. Bernatik T, Strobel D, Häusler J, Hahn EG, Becker D. Hepatic transit time of an ultrasound echo enhancer indicating the presence of liver metastases - first clinical results. Ultraschall Med. 2002; 23: 91-95.

40. Venturi A, Piscaglia F, Silvagni E, et al. Role of real-time contrast-enhanced ultrasound in the assessment of metastatic portal vein thrombosis. Ultraschall Med 2007; 28: 75-78.

41. Blomley MJ, Cooke JC, Unger EC, Monaghan MJ, Cosgrove DO. Microbubble contrast agents: a new era in ultrasound. BMJ 2001; 322: 1222-1225.

42. Lassau N, Chami L, Benatsou B, Peronneau P, Roche A. Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification of tumor perfusion: a new diagnostic tool to evaluate the early effects of antiangiogenic treatment. Eur Radiol 2007; 17 Suppl 6: F89-98.

43. Lassau N, Brule A, Chami L, Benatsou B, Péronneau P, Roche A. Evaluation of early response to antiangiogenic treatment with dynamic contrast enhanced ultrasound. J Radiol 2008; 89: 549-555.

44. Minami Y, Kudo M, Chung H, et al. Percutaneous radiofrequency ablation of sonographically unidentifiable liver tumors. Feasibility and usefulness of a novel guiding technique with an integrated system of computed tomography and sonographic images. Oncology 2007; 72 Suppl 1: 111-116.

45. Kawasoe H, Eguchi Y, Mizuta T, et al. Radiofrequency ablation with the real-time virtual sonography system for treating hepatocellular carcinoma difficult to detect by ultrasonography. J Clin Biochem Nutr 2007; 40: 66-72.

46. Kitada T, Murakami T, Kuzushita N, et al. Effectiveness of real-time virtual sonography-guided radiofrequency ablation treatment for patients with hepatocellular carcinomas. Hepatol Res 2008; 38: 565-571.

47. Minami Y, Chung H, Kudo M, et al. Radiofrequency ablation of hepatocellular carcinoma: value of virtual CT sonography with magnetic navigation. AJR Am J Roentgenol 2008; 190: W335-341.

48. Tatsugami F, Matsuki M, Nakai G, et al. Hepatic computed tomography for simultaneous depiction of hepatocellular carcinoma, intrahepatic portal veins, and hepatic veins in real-time virtual sonography: initial experience. J Ultrasound Med 2007; 26: 1065-1069.