Diagnostic efficacy of ultrasound in hepatocellular carcinoma diagnosis

KEYWORDS:

• Contrast-enhanced ultrasound
• diagnosis
• hepatocellular carcinoma
• surveillance
• ultrasound

1. Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death. Surviving HCC is mainly influenced by the stages of disease at the time of diagnosis [1,2]. Ultrasound (US) is a simple, noninvasive tool with no risk of radiation exposure. The advantages of US include being inexpensive, safe, and having high accessibility. Conventional US is usually used as the first choice for the surveillance of HCC. The development of contrast-enhanced US (CEUS) has promise in increasing the diagnostic accuracy of HCC. Based on current evidence, the authors review the diagnostic efficacy of US in HCC diagnosis.

2. The role of US in HCC surveillance

US has been used as the standard of care in high-risk groups for HCC surveillance every 6 months [1,2]. The major risk factors for HCC include chronic viral hepatitis B and C infection, nonalcoholic steatohepatitis, and liver cirrhosis. Some limitations could influence the sensitivity of US, such as quality of the US machine and experience of the operator, coarseness of liver parenchyma due to underlying cirrhosis, severe fatty liver background, and lesions located at the subdiaphragmatic area. A systematic review showed that the accuracy of US to detect HCC for patients with chronic hepatitis and cirrhosis with pooled sensitivity and specificity was 60% (95% confidence interval [CI]: 44–76) and 97% (95% CI: 95–98), respectively [3]. Another meta-analysis demonstrated that pooled sensitivity and specificity of US for cirrhotic patients was 94% and 94%, respectively. However, the sensitivity decreases to 63% for early-stage HCC [4].

The combination of US and alpha-fetoprotein (AFP) as surveillance modality increases the detection rate of HCC and has been widely used as a surveillance guideline in Asia-Pacific countries. The sensitivity of HCC detection has been increased to 90–99% with acceptable decreasing specificity [5]. AFP for HCC surveillance is not recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) practice guidelines [1,2]. The drop of AFP from the AASLD and EASL recommendations for HCC was the consequence of both suboptimal accuracy and a lack of standardized policy to treat AFP-positive patients lacking US detection of a nodule [1,2]. In fact, the increasing AFP levels might signal the risk of developing HCC clinically. For patients with regular surveillance, HCC survival has significantly improved due to increased detection rates of early-stage HCC and the potential to receive curative treatments.

3. Diagnostic efficacy of US in HCC

3.1. B-mode and Doppler US

The typical US images of HCC include hypoechoic or mixed echogenic nodules with halo indicating a capsule, and are affected by the presence of fat, calcium, and necrosis. Small HCC is usually homogeneous with hypoechoic echo texture. The growing tumor size may increase complexity of the nodule, which may become heterogeneous and more hyperechoic due to fatty degeneration or coagulation necrosis. Diffuse HCC may be difficult to identify or distinguish from background cirrhosis. Color Doppler US can detect blood flow signals in HCC without contrast medium; the tumor vascularity may present with arterial pulsating flows, such as a basket pattern flow [6]. However, detection of fine blood flow remains difficult due to a low signal-to-noise ratio and use of an estimate of the mean Doppler frequency shift. Power Doppler US has been more sensitive to fine blood flow in HCC, which displays the integrated power of the Doppler signals, and can depict more information of tumor vascularity in HCC than color Doppler US. For moderate to poorly differentiated HCC, there are no differences of tumor vascularity detection rates between power (93.3%) and color (86.7%) Doppler US. However, tumor vascularity detection rate of power Doppler US is superior to color Doppler US in well-differentiated HCC.

3.2. Contrast-enhanced US

3.2.1. General principles

US contrast agents have been developed during the recent two decades, and have increased the diagnostic accuracy of HCC. The advantage of CEUS is no adverse effect of contrast agent to thyroid and kidney functions. First-generation US contrast agents such as Levovist were introduced in 1996; however, the diagnostic efficacy is limited during continuous scanning due to early breakdown of the microbubbles.

Currently available second-generation contrast agents for CEUS are microbubbles consisting of gas bubbles stabilized by a shell, such as SonoVue, Definity, and Sonazoid. These contrast agents are 1–10 µm in size, with a low-mechanical index technique in US machines and mostly remain within the vascular space; this permits a continuous real-time evaluation of HCC. Similar to contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), contrast-enhancement patterns of CEUS include arterial, portal-venous, and late phases. HCC usually presents with hyperenhancement in the arterial phase and hypoenhancement in the portal-venous or delayed phases. Overall sensitivity of CEUS has been reported as 84.4% (95% CI: 79.8–87.5) [7]. A meta-analysis demonstrated that small HCC ≤2 cm diagnosed with CEUS (Sonovue and Levovist) has sensitivity of 81% (95% CI: 78–85) and specificity of 86% (95% CI: 82–89) [8].

Radiological diagnosis of HCC has been applied to cirrhotic patients and those with chronic hepatitis B only. A recent study evaluating the percentage of arterial hypervascularity of CEUS in HCC <2 cm showed that a total of 34% (55/119) of cases showed no arterial enhancement, while 18 (33%) of these cases were diagnosed as HCC. Most of these cases were well-differentiated HCC [9]. A study showed that the evaluation of the tumor vessel patterns during arterial-phase CEUS might be useful to differentiate between regenerative nodule and early-stage HCC or high-grade dysplastic nodule in patients with chronic liver disease [10]. Compared with other dynamic images, the sensitivity of CEUS is similar or even higher than dynamic CT for the detection of hypervascularity in early-stage HCC.

A previous study (n = 21) showed that the vascular pattern by CEUS (Sonovue) of intrahepatic cholangiocarcinoma may be similar to HCC and lead to false-positive diagnosis [11]. Thus, CEUS was removed as a diagnostic method in revised AASLD practice guidelines in 2011 [2]. However, validation power was limited due to the relatively small scale of patients included in the study. A larger study is needed to clarify this issue.

For contrast agent Sonazoid, there is an additional post-vascular phase, wherein contrast agent is taken up by Kupffer cells at 10–15 min after injection. Sonazoid was used as the defect reperfusion image by reinjection of Sonazoid during the Kupffer phase, as defect reperfusion imaging generates an excellent detectable rate of HCC that is unclear on conventional US [12]. Defect reperfusion imaging is also useful to identify recurrent area(s) followed by needle guidance for treatment, allowing the safety margin after radiofrequency ablation (RFA) to be identified accurately by determining the coagulation area in the Kupffer phase, and then assessing the adequate safety margin after reinjection of Sonazoid [12,13].

3.2.2. Treatment guidance and posttreatment evaluation

A fusion image has been developed that reconstructs high-resolution multiplanar images together with a position-tracking system using magnetic navigation. Real-time US can be fused and synchronized with corresponding planar images from contrast-enhanced CT or MRI. CEUS with or without fusion image could be used as treatment guidance for inconspicuous HCCs accurately when performing RFA or biopsy. The detectability rates of inconspicuous tumor are 93–100% by using CEUS.

CEUS has been widely used in posttreatment response evaluation for residual viable tumor after RFA or transcatheter arterial chemoembolization (TACE) [13,14]. In addition, the advantages of CEUS are more cost-effectiveness with no radiation exposure if compared with contrast-enhanced CT. A meta-analysis showed that the CEUS (Sonozoid, Sonovue, and Levovist) -evaluated success rate of RFA for HCCs was 91%. The result demonstrated that CEUS was a good comparable method with other contrast-enhanced imaging modalities in assessing the treatment effect of RFA in HCC [13]. The local tumor recurrence and local tumor progression rates were 4% and 8%, respectively. In the evaluation of treatment response of TACE, Xia et al. reported that the detection rates of the viable part of HCC after TACE was significantly more sensitive in CEUS than contrast-enhanced CT (58.1% vs. 39.5%; p < 0.01) [14].

4. Perspectives and conclusions

In the near future, efforts for the development of new contrast agents such as HCC molecular target-oriented microbubble shall certainly improve the diagnostic efficacy of HCC diagnosis. New technology of US instrumentation such as new nonlinear mode of US, faster US imaging, and high resolution and 3D US imaging can also increase HCC diagnostic rates. US elastography is a good noninvasive method in assessing the degree of liver fibrosis; it was currently used to predict the development of HCC in patients with chronic liver disease, as well as to predict the risk of HCC recurrence after curative therapies such as RFA and tumor resection [15]. Additionally, three-dimensional CEUS has been demonstrated to provide good depiction of tumors and vessels, high efficacy in evaluating post-ablating HCC, and is comparable with contrast-enhanced CT [16].

In conclusion, CEUS has high diagnostic efficacy for HCC diagnosis. It could also be used as treatment guidance for inconspicuous tumors and for evaluating local recurrence for posttreatment HCC. CEUS is highly recommended as the diagnostic algorithm and to be reintroduced in Western HCC guidelines. In addition, a study of HCC surveillance in cirrhotic patients showed that CEUS surveillance is a cost-effective strategy and gains the longest additional life-years [17]. CEUS should be considered as a surveillance tool in the near future to improve HCC survival, and is especially indicated for patients with cirrhosis and coarse hepatic parenchyma.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.