CEUS has improved the characterization of focal liver lesions showing comparable results to those with CT and MRI and when performed by experienced operators, it significantly improves overall diagnostic accuracy by more than 30% compared with unenhanced ultrasound [12].
This study was conducted on 60 patients with 70 hepatic focal lesions. CEUS and triphasic CT were done to all patients. No adverse events occurred after the administration of SonoVue. From 70 focal lesions assessed, CEUS missed 4 lesions (2 HCCs and 2 hemangiomas). That was due to either very small size or deeply situated lesions or those lesions seated within hepatic dome hindered by the costal margin and was not easily accessible. Thus, in this study that investigated the role of CEUS in characterization of malignant from benign hepatic focal lesions, the sensitivity, specificity, PPV, NPV, and accuracy of CEUS in the differentiation between benign and malignant hepatic focal lesions were 94.2%, 88.9%, 91%, 94.1%, and 92.3%, respectively, and for triphasic CT were 100%, 81.8%, 84%, 100%, and 90.7%, respectively. There was no statistically significant difference between CEUS and triphasic CT.
The two most important multi-center studies regarding CEUS application for the characterization of focal liver lesions were the German Society of Sonography (DEGUM) multi-center study and a French study, showed good value for CEUS for focal liver lesion characterization [13, 14]. The DEGUM study included 1349 patients with focal liver lesions on ultrasound. A total of 1328 focal liver lesions (755 malignant and 573 benign) were assessed. The reference standard diagnosis was made by means of liver biopsy in 75% of cases and by contrast-enhanced CT or contrast-enhanced MRI in the other cases. The accuracy of CEUS for the diagnosis of focal liver lesions was 90.3%. CEUS showed 95.8% sensitivity and 83.1% specificity, with 95.4% positive predictive value and 95.9% negative predictive value for differentiating benign versus malignant lesions. The French study assessed the clinical value of CEUS using SonoVue for the characterization of focal liver lesions discovered in patients with a cancer history or in those with chronic liver disease. The study included 1034 focal liver lesions undiagnosed on ultrasound alone. The reference standard methods were contrast-enhanced CT, contrast-enhanced MRI, or liver biopsy and CEUS had 79.4% sensitivity and 88.1% specificity in differentiating benign versus malignant focal liver lesions. These findings are also approximate to the study done by Sporea and Sirli, included 573 benign lesions and 755 malignant lesions, who investigated if CEUS ready for use in daily practice for evaluation of focal liver lesion. The overall accuracy of CEUS for the diagnosis of HFLs was 90.3%. CEUS had 95.8% sensitivity and 83.1% specificity, with 95.4% positive predictive value (PPV) and 95.9% negative predictive value (NPV) for differentiating benign versus malignant lesions [15]. Another study by Trillaud et al. for characterization of focal liver lesions with SonoVue enhanced sonography in comparison to CT in which 68 focal liver lesions were benign and 55 were malignant showed sensitivity, specificity and accuracy of 95.5%, 75.0%, and 90.0% for CEUS and 72.7%, 37.5%, and 63.3% for CT. In comparison, CT was significantly less sensitive (p < 0.0001), less specific (p < 0.029), and less accurate (p < 0.0001) than SonoVue enhanced ultrasound unlike our study [16]. Although our results using SonoVue enhanced ultrasound were near from this study regarding the sensitivity, specificity and accuracy, but we did not find any statistically significant difference between the different imaging modalities (p < 0.452).
In this study, CEUS using SonoVue correctly characterized 30 (83.3%) HCC lesions, 16 (72.7%) benign lesions, and 12 (100%) metastatic lesions and showed atypical enhancement pattern in 4 (11.1%) HCC lesions, 4 (18.2%) benign lesions, and none of metastatic patients while CT correctly characterized 28 (77.8%) HCC lesions, 22 (100 %) benign lesions, and 10 (83.3%) metastatic patients and showed atypical enhancement in 8 (22.2%) HCC lesions, none of benign lesions, and 2(16.7%) of metastatic lesions. Thus, there was no statistically significant difference between both modalities. Our findings are in agreement with Martie et al. and Laroia et al. who studied the role of CEUS using SonoVue in the characterization of 100 and 50 patients with HCCs, respectively. CEUS using SonoVue correctly characterized 75.7% and 88% of the lesions, respectively [17, 18].
In this study, 8 patients with HCC had associated portal vein thrombosis, of which 2 were malignant thrombi. CEUS and triphasic CT detected and correctly characterized 8/8 thrombi (100%). There is no statistically significant difference between them. These findings are in disagreement with a study conducted by Rossi et al. who compared CEUS and triphasic CT in the detection and characterization of PVT complicating HCC in 50 patients, in which 44 thrombi were pathologically diagnosed as malignant and 6 were benign. CEUS detected 50/50 (100%) thrombi and correctly characterized 49/50 (98%) while CT detected 34/50 (68%) thrombi and correctly characterized 23/ 34 (68%), So, CEUS outperformed triphasic CT in terms of both thrombus detection and characterization in this study [19].Another study by Sorrentino et al. who investigated CEUS versus biopsy for the differential diagnosis of PVT in 108 HCC patients, 58 patients (53.7%) with malignant PVT and 50 (46.3%) with benign PVT. Sensitivity, specificity, positive and negative predictive value of biopsy and CEUS were the same for both: 89.6%, 100%, 100% and 89.2%, respectively [20].
Regarding the role of CEUS in the assessment of HCC after therapeutic intervention, this study showed that CEUS correctly identified 8 (40%) ablated HCC and 8 incompletely ablated HCC (40%) but misdiagnosed 4 incompletely ablated HCC (20%) as ablated. These findings are in agreement with a multi-center study by Lu et al. to evaluate the ability of CEUS using SonoVue in monitoring percutaneous thermal ablation procedure in patients with HCC in comparison with contrast-enhanced CT and/or MRI. One hundred eighteen patients were monitored to assess the tumor response to treatment within 1 month after the ablation procedure by radiofrequency or microwave ablation. No enhancement was seen in 110/118 (93.2%) both on CEUS and CECT/CEMRI. The specificity and accuracy of CEUS in detecting tumor vascularity were 98.2% and 96.6%, respectively. The study concluded that, in the detection of HCC tumor vascularity and assessment of response to thermal ablation, real-time CEUS provided results comparable to those obtained with CT and MRI [21]. These findings are also in agreement with Salvaggio et al. who evaluated the ability of CEUS with second-generation contrast agent in monitoring RFA and TACE treatments of 148 HCCs. In RFA treatment, CEUS showed a sensitivity of 83.3% and a specificity of 100% using CT as reference standard with no statistical difference. CEUS detected all cases of incomplete response in HCCs treated with TACE using angiography as reference standard [22].
In this study, no adverse events occurred after SonoVue administration to any of the patients. The safety profile of SonoVue in this study is in agreement with Sporea et al. who used CEUS using SonoVue to evaluate hepatic focal lesions in 294 patients and reported no adverse events in any of their patients [23].
The principal limitation of this study was the limited lesion number, mainly due to the exclusion of patients with suboptimal US scan due to the patient body habitus or intervening bowel gas which should be considered a major limitation in the applicability of the technique. In Cantisani et al. study, CEUS still presents the same important drawbacks of every US examination, including operator dependency, obese patients, and non-compliant subjects. For these reasons, if the B-mode US is unsatisfactory, the subsequent CEUS examination will be suboptimal. A specific limitation of CEUS in studying the liver is that limited spatial resolution and, as such, very small lesions may be missed. The US study of the subdiaphragmatic liver by subcostal scanning is sometimes inadequate, especially in patients with a high lying diaphragm [24]. Also, SonoVue role in percutaneous ablation is limited because of its short-lasting enhancement effect and thus, a new second-generation sonographic contrast agent, Sonazoid, with post-vascular phase is more useful as a contrast agent during thermal ablation of HCCs [25]. Sonazoid allows real-time vascular imaging, stable Kupffer phase imaging lasting up to 60 min (which is not possible with SonoVue), its use is tolerable for multiple scanning and enables the detection of B-mode ill-defined nodules, facilitating correct staging of HCC before treatment [26].