**6. Conclusions**

Ultrasound exploration using current technologies has excellent possibilities for practical use. Several elements related to the lack of standardization and reproducibility of ultrasound procedures as well as operator-dependent nature of the method require structured approach to its use in liver tumors pathology (Bolondi et al, 2007). Structuring these applications and description of their actual performance are included in successive recommendations made by expert groups, known as "EFSUMB guidelines" (Albrecht et al, 2004; Claudon et al, 2008). In the current stage the following applications in liver pathology, especially in tumors are accepted as valid and represent indications for CEUS:

a. *characterization of nodular lesions found on non-cirrhotic liver.* Ultrasound examination is often the first imaging procedure performed in patients with abdominal pathology. Quite often lesions are detected and their nature has to be further on defined. Ultrasound procedures that allow achieving this purpose are multiple and

*Targeted therapy using contrast agents*. The introduction of second generation contrast agents has been a great progress. Diagnostic performance is already proven. A step forward is tumor targeted therapy under ultrasound guidance. The principle is that of transporting chemotherapeutic agents to the target using microbubbles as vectors. Experiments have been made for binding different substances and/or genes to the lesion, with local release by "breaking" and intracellular penetration using the phenomenon of cellular membrane

*Image fusion*. Techniques for image fusion obtained by different imaging procedures allow the correlation of real-time ultrasound examination with CT or MRI images, enabling positioning of the needle in relation to the exact position of the tumor. The technique allows a better guidance both for biopsies and percutaneous ablative procedures, replacing CT guidance and thus avoiding irradiation. Combination with CEUS allows a better characterization of lesions as well as successful monitoring of percutaneous procedures or

*Elastography*. It was initially introduced in practice to assess the degree of fibrosis in chronic liver disease. In liver tumors it allows detection of liver nodules due to the difference of elasticity between the hepatic nodule and the parenchyma. There are few studies that try to assess the benign or malignant character of the lesion based only on elasticity. By combination with CEUS the method could be beneficial for early detection and

*High Intensity Focused Ultrasound (HIFU).* It is a new technique capable of destroying tumor tissue by hyperthermia, allowing percutaneous ablation without requiring tumor puncture. There are studies showing the efficacy of this technique in combination with TACE, with anti-tumor effect and better survival than using TACE alone (Wu, 2005). The method is expected to be an alternative to PEI and RFA because it avoids the puncture of the cirrhotic liver, but more studies are needed to prove its efficacy as a single therapy in the curative

Techniques for visualizing blood circulation independently from the angle of insonation based on transversal oscillation of red blood cells groups. This technique is now implemented on conventional transducers and can real time evidence different features of

Ultrasound exploration using current technologies has excellent possibilities for practical use. Several elements related to the lack of standardization and reproducibility of ultrasound procedures as well as operator-dependent nature of the method require structured approach to its use in liver tumors pathology (Bolondi et al, 2007). Structuring these applications and description of their actual performance are included in successive recommendations made by expert groups, known as "EFSUMB guidelines" (Albrecht et al, 2004; Claudon et al, 2008). In the current stage the following applications in liver pathology,

a. *characterization of nodular lesions found on non-cirrhotic liver.* Ultrasound examination is often the first imaging procedure performed in patients with abdominal pathology. Quite often lesions are detected and their nature has to be further on defined. Ultrasound procedures that allow achieving this purpose are multiple and

the blood flow visualized so far only on MRI angiography (Hansen et al, 2011).

especially in tumors are accepted as valid and represent indications for CEUS:

permeability called "sonoporation" (Lindner, 2004, Newman & Bettinger, 2007).

TACE effects (Sandulescu et al, 2011; Ewertsen et al, 2011).

characterization of HCC.

**6. Conclusions** 

treatment of HCC (Maruyama et al, 2008).

complementary: 2D/3D ultrasound and elastography for morphometric informations; Doppler ultrasound (with its variants) and CEUS allow hemodynamic information. CEUS examination is the most specific of them as it is based on different behavior of contrast agent transiting liver masses depending on their nature. CEUS accuracy for characterization of focal lesions detected on noncirrhotic liver is similar to that of CT/MRI, being of 94.5% for metastases, 97% for hemangiomas, and of 90% for focal nodular hyperplasia. The method has a performance superior to 2D ultrasound and a high rate of diagnosis confidence regardless of the operator in what concerns tumor characterization and nodules count (Quaia et al, 2004).

b. *characterization of nodular lesions found on the cirrhotic liver*. Ultrasound examination is a "screening" procedure used to detect early HCC (Bolondi et al, 2001). The cirrhotic liver during the restructuring process develops nodules that often raise questions regarding their nature. The criteria used to determine the nature of these nodules involve size, circulation pattern (Doppler evaluated) and vascular bed behavior (CEUS evaluated). In over 90% of cases, HCC has a characteristic behavior. CEUS exploration has a sensitivity of 92-94% and a specificity of 87-96% in characterizing HCC (Tanaka et al, 2001, Nicolau et al, 2004).

In a linear study, covering 36 months, (January 2006 – December 2008), made on a cohort of 379 patients with liver tumors, (fig. 15), we had similar results concerning the performances of CEUS compared to other imaging procedures such as CT/MRI and histopathology as other groups (personal experience; unpublished results from the project Angiotumor nr. 138/2006 financed by the Ministry of Education and Research from Romania) (fig. 16) (Badea et al, 2008).

Fig. 15. Types of liver focal lesions diagnosed by CEUS in our study (HCC=hepatocellular carcinoma, META=liver metastasis, CCC=cholangiocarcinoma, A-V FIST=arterio-venous fistula, FATTY-FREE=fatyy-free area, DISPL NOD=cirrhotic displastic nodule, FNH=focal nodular hyperplasia, HEMANG=liver hemangioma)

c. *Detection and characterization of liver metastases*. Ultrasound is a method widely used in the early detection of liver metastases in patients with cancer pathology. Beyond the known limitations of the method, the examination is used because it is accessible, nonirradiant and it can detect metastases of quite small sizes and allows their characterization using vascular criteria. CEUS examination increases the performance of conventional ultrasound to values comparable with CT/MRI, becoming an alternative to these procedures in certain well defined situations (Dietrich et al, 2006).

Fig. 16. The performance of CEUS in our study for the main malignant and benign lesions (HCC=hepatocellular carcinoma, META=liver metastasis, HEMANG=liver hemangioma, FNH=focal nodular hyperplasia, Se=sensitivity, Sp=specificity, PPV=positive predictive value, NPV=negative predictive value)

d. *Assessing therapeutic efficacy*. Using the vascular criteria allows the assessment of therapeutic efficacy under chemotherapy (Bolondi et al, 2007). Performing an interventional procedure (with diagnostic or therapeutic purpose) simultaneously with the administration of i.v. CAs increases the procedure's efficiency by a better visualization of the tumor and by correct guidance of the ablation needle in the active (vascularized) area of the tumor (Skjoldbye et al, 2002, Lencioni et al, 2004). After ablative procedures, or even better in one month after the procedure, the absence of the circulation bed in the tumor in arterial phase suggests an effective treatment (Solbiati et al, 2004; Vilana et al, 2006, Bartolotta et al, 2008). This principle is also true for chemotherapy with antiangiogenic agents. Even under these conditions combination of CEUS with i.v. contrast CT examination is required to detect small metastases between procedures (Bartolotta et al, 2008).
