Role of Contrast-Enhanced Ultrasound as a Second-Line Diagnostic Modality in Noninvasive Diagnostic Algorithms for Hepatocellular Carcinoma

Abstract

Objective: To investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) and its role as a second-line imaging modality after gadoxetate-enhanced MRI (Gd-EOB-MRI) in the diagnosis of hepatocellular carcinoma (HCC) among at risk observations.

Materials and methods: We prospectively enrolled participants at risk of HCC with treatment-naïve solid hepatic observations (≥ 1 cm) of Liver Imaging Reporting and Data System (LR)-3/4/5/M during surveillance and performed Gd-EOB-MRI. A total of one hundred and three participants with 103 hepatic observations (mean size, 28.2 ± 24.5 mm; HCCs [n = 79], non-HCC malignancies [n = 15], benign [n = 9]; diagnosed by pathology [n = 57], or noninvasive method [n = 46]) were included in this study. The participants underwent CEUS with sulfur hexafluoride. Arterial phase hyperenhancement (APHE) and washout on Gd-EOB-MRI and CEUS were evaluated. The distinctive washout in CEUS was defined as mild washout 60 seconds after contrast injection. The diagnostic ability of Gd-EOB-MRI and of CEUS as a second-line modality for HCC were determined according to the European Association for the Study of the Liver (EASL) and the Korean Liver Cancer Association and National Cancer Center (KLCA-NCC) guidelines. The diagnostic abilities of both imaging modalities were compared using the McNemar's test.

Results: The sensitivity of CEUS (60.8%) was lower than that of Gd-EOB-MRI (72.2%, p = 0.06 by EASL; 86.1%, p < 0.01 by KLCA-NCC); however, the specificity was 100%. By performing CEUS on the inconclusive observations in Gd-EOB-MRI, HCCs without APHE (n = 10) or washout (n = 12) on Gd-EOB-MRI further presented APHE (80.0%, 8/10) or distinctive washout (66.7%, 8/12) on CEUS, and more HCCs were diagnosed than with Gd-EOB-MRI alone (sensitivity: 72.2% vs. 83.5% by EASL, p < 0.01; 86.1% vs. 91.1% by KCLA-NCC, p = 0.04). There were no false-positive cases for HCC on CEUS.

Conclusion: The addition of CEUS to Gd-EOB-MRI as a second-line diagnostic modality increases the frequency of HCC diagnosis without changing the specificities.

Keywords: Contrast enhanced ultrasound; Hepatocellular carcinoma; Liver; Magnetic resonance imaging.

Fig. 1. Flow diagram of the participants included in the study.

^*Inconclusive histopathologic diagnosis (n = 2), or lack of long term follow up (≥ 2 years) to assure benignity (n = 2). CEUS = contrast-enhanced ultrasound, Gd-EOB-MRI = gadoxetate-enhanced MRI, HCC = hepatocellular carcinoma, LI-RADS = Liver Imaging Reporting and Data System, LR = LI-RADS

Fig. 2. A 66-year-old man with chronic hepatitis B.

(A) In the arterial phase of Gd-EOB-MRI, there was a 1.4-cm isoenhancing observation (arrow) in segment 8 of the liver. This observation (arrow) presented washout on (B) the portal venous phase, which was inconclusive for a diagnosis of HCC. On CEUS, (C) a 1.6-cm APHE observation (arrow) was noted with mild washout at 87 seconds after contrast agent injection (D, arrow). This observation was concluded to reflect HCC, based on dynamic computed tomography images (APHE with portal washout) and elevated alpha fetoprotein level. APHE = arterial phase hyperenhancement

Fig. 3. A 56-year-old man with pathologically confirmed HCC in segment 6 of the liver.

On Gd-EOB-MRI, (A) a 3.2-cm APHE observation (arrows) in segment 6 of the liver showed no washout in (B) the portal venous phase (arrows), which was thus inconclusive for diagnosing HCC. On CEUS, (C) a 3.2-cm APHE observation (arrows) was noted with a mild washout at 221 seconds after contrast agent injection (D, arrows).

Fig. 4. A 58-year-old woman with chronic hepatitis B and a pancreatic neuroendocrine tumor.

On Gd-EOB-MRI, (A) a 1.2-cm APHE observation (arrow) in segment 8 of the liver presented no washout (B) the portal venous phase (arrow) and hypointensity in (C) the hepatobiliary phase (arrow). Thus, this observation was noninvasively diagnosed as HCC using the Korean Liver Cancer Association and the National Cancer Center guidelines. On CEUS after real-time ultrasound image fusion with magnetic resonance image, (D) a 1.2-cm APHE observation (arrow) was noted early (48 seconds) and marked washout (E, arrow), which suggested malignancy other than HCC. This observation was confirmed as a hepatic metastasis from a pancreatic neuroendocrine tumor.