The diagnostic performance of contrast-enhanced ultrasound (CEUS) for evaluating hepatocellular carcinoma (HCC) juxtaposed to MRI findings; a retrospective single-center analysis of 292 patients

BACKGROUND: HCC is the most frequent primary liver cancer entity. Major risk factors comprise chronic HBC and HCV infections, ALD or NAFLD. Apart from the anamnesis, the clinical examination and serologic analysis, an essential part of the diagnostic HCC work-up is due to imaging findings from sonography, CT or MRI scans. HCC lesions feature a distinct vascularization pattern: hyperenhancement during early arterial and hypoenhancement/wash-out during portal venous or delayed phases. CEUS facilitates dynamic assessment of microperfusion patterns of suspicious liver lesions. PURPOSE: The purpose of the present retrospective single-center study was to determine the diagnostic value of CEUS for assessing HCC by comparison with findings from MRI scans. MATERIALS AND METHODS: Between 2004-2018 292 patients with suspicious liver lesions underwent CEUS and MRI. All patients underwent native B-mode, Color Doppler and CEUS after given informed consent. The applied contrast agent was a second-generation blood pool agent (SonoVue®, Bracco, Milan, Italy). Every CEUS examination was performed and interpreted by a single experienced radiologist (EFSUMB Level 3). RESULTS: CEUS was performed on all included patients without occurrence of any adverse effects. CEUS showed a sensitivity of 96%, a specificity of 91%, a PPV of 95% and a NPV of 94% for analyzing HCC in comparison with MRI as the diagnostic gold standard. CONCLUSION: With a distinguished safety profile CEUS shows a high diagnostic accuracy in assessing HCC compared to corresponding results from MRI scans.

Keywords: Hepatocellular cancer; HCC; liver; CEUS; MRI

Hepatocellular carcinoma (HCC) represents the most frequent primary hepatic tumor entity and the second most lethal cancer [[1], [3]]. HCC is more common among men with a global male: female-ratio of 2,4 : 1. Patients typically present between the 3rd and 5th decade [[4]]. Major risk factors for HCC development are chronic liver diseases, such as hepatitis B and C virus infections (HBV, HCV), alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) or hereditary syndromes like hemochromatosis and congenital metabolic disorders.

The rising prevalence of NAFLD, which is linked to diabetes, obesity and metabolic syndrome, will result in increasing liver cancer development in Western countries [[5]]. Up to 90% of HCC develop in underlying liver cirrhosis [[6]]. Nevertheless, HCC may even develop in non-cirrhotic patients.

Multiple clinical trials depicted the benefit and cost-effectiveness of HCC surveillance [[7]] which is recommended by leading hepatology societies at semiannual intervals [[9]] [[11]]. A timely diagnosis within screening programs allows for initiating curative therapeutical options which in case of a delayed diagnosis could not have been conducted. Operator-dependent ultrasonography is the favored imaging modality for HCC screening with a diagnostic sensitivity up to 80% and a specificity of more than 90% [[13]]. Additionally, alpha-fetoprotein levels, as the most common tumor marker, are assessed for HCC surveillance.

A high diagnostic accuracy can be yielded by monitoring the distinct vascularization pattern of HCC lesions due to supply by arterial vessels compared to adjacent unaffected liver parenchyma which is supplied by portal venous branches [[14]]. Hence hyperenhancing during early arterial phase and hypoenhancing/wash-out during venous or delayed phases can be registered on computed tomography (CT) and magnetic resonance imaging (MRI) scans. Non-ionizing contrast-enhanced ultrasound (CEUS) can also be applied to visualize the typical tumor microperfusion [[15], [17]].

Standardized screening, surveillance, diagnosing and treatment response assessment of HCC by applying CT, MRI or contrast-enhanced ultrasound (CEUS) is facilitated by the Liver Imaging Reporting and Data System (LI-RADS) [[19]]. In indeterminate cases, biopsy and histopathological analysis need to complement the diagnostic work-up.

In the present retrospective single-center study, we evaluated the diagnostic performance of CEUS in assessing HCC lesions compared to findings from corresponding MRI scans.

This retrospective single-center study was approved by the local institutional ethical committee of the institutional review board and all contributing authors followed the ethical guidelines for publication in Clinical Hemorheology and Microcirculation. All study data were gathered according to the principles expressed in the Declaration of Helsinki/Edinburgh 2002. Oral and written informed consent of all patients were given before CEUS examination and their associated risks and potential complications have been carefully described. All CEUS examinations were performed and analyzed by a single skilled radiologist with experience since 2000 (EFSUMB level 3). All included patients underwent native B-mode, Color Doppler and CEUS scans. Up-to-date high-end ultrasound systems with adequate CEUS protocols were utilized (GE Healthcare LOGIQ L9, Chicago, Illinois, USA; Siemens Ultrasound Sequoia, ACUSON Sequoia, Mountain View, California, USA; Philips Ultrasound iU22, EPIQ 7, Seattle, Washington, USA). A low mechanical index was used to avoid early destruction of microbubbles (<0, 2). For all CEUS examinations, the second-generation blood pool contrast agent SonoVue® (Bracco, Milan, Italy) was used [[15]]. 1,2–1,5 ml of SonoVue® were applied. It is a purely intravascular contrast agent that does not diffuse into the interstitial space, thus allowing for dynamic assessment of microcirculation. After contrast agent was applied, a bolus of 5–10 ml sterile 0,9% sodium chloride solution was given. No adverse side effects upon administration of SonoVue® were registered. All CEUS examinations were successfully performed and image quality was sufficient in every single case. The patient files and imaging records were collected from the archiving system of our institution.

A total of 292 patients on whom CEUS was performed between 2004-2018 underwent additional MRI scans and were included in this retrospective single-center study. In total, 308 examinations were analyzed. CEUS and MRI data were retrieved from the Picture Archiving and Communication System (PACS) of our institution.

Between 2004-2018 292 patients HCC patients underwent CEUS examination and subsequent MRI scan with a predilection in men (211 male vs. 81 female patients, 72% vs. 28%, respectively). The mean age of the patients at the time of CEUS examination was 60 years (range: 20–87 years). With MRI as the reference imaging modality, CEUS showed a sensitivity of 96% and a specificity of 91%, a positive predictive value (PPV) of 95% and a negative predictive value (NPV) of 94%. Kappa coefficient between CEUS and MRI showed a value of 0,881 (p < 0,001). Figure 1 depicts the morphological correlates in CEUS and corresponding MRI scan of a representative case of HCC.

Graph: Fig. 1 Morphological correlates of HCC in CEUS and MRI. A. Native B-mode shows subcapsular hyperechoic lesion in liver segment VII (red arrow). B. No detection of hypervascularization in Color Doppler. C. Early arterial hyperenhancement of the lesion in CEUS (left, red arrow), right native B-mode. D. Discrete wash-out of the lesion in portal venous phase in CEUS (left), right native B-mode. E. Corresponding hyperenhancing liver lesion in MRI, arterial phase (Gadovist) in axial reformation (red arrow). F. Partial retention deficit of the lesion during hepatocyte-specific sequence in MRI (red arrow), coronal reformation.

Conventional ultrasound still is the imaging modality of first choice when it comes to HCC surveillance in high-risk patients. The leading hepatology societies recommend surveillance at semiannual intervals.

CEUS facilitates differentiation between hepatic lesions of varying entity, like hemangioma, focal nodular hyperplasia (FNH), metastases, HCC, arteriovenous malformation or echinococcal manifestations [[20], [22], [24]] at a lower rate of adverse effects compared to more elaborate imaging modalities. On the other hand, one must consider the limitations of CEUS over CT and MRI: restricted ability of staging, limited diagnostic accuracy in obese, cirrhotic patients due to poor sonic window, risk of misdiagnosing intrahepatic cholangiocarcinoma as HCC [[26]].

The goal of the present retrospective single-center study was to analyze the diagnostic value of CEUS in evaluating HCC compared to findings from corresponding MRI scans as the gold standard. Our results demonstrate that CEUS has a high diagnostic accuracy in assessing HCC and go in line with prior reports [[28], [30], [32]]. The kappa coefficient between CEUS and MRI findings was 0,881 which is considered to be a strong degree of agreement between CEUS and MRI findings.

An equal diagnostic value of CEUS compared to MRI scans for liver tumor differentiation and specification could be demonstrated within the framework of a multi-center trial [[28]]. To date, CEUS is not recommended as a primary imaging modality by the major hepatology societies [[9], [34]]; but except for the American Association for the Study of Liver Diseases (AASLD) it is considered a secondary imaging option. In case MRI findings of suspicious liver lesions are inconclusive, supplemental CEUS can shed light on the underlying tumor entity [[36]].

Furthermore, therapeutic response in HCC lesions upon radiofrequency ablation (RFA) or microwave ablation (MWA) could be monitored by using CEUS [[37]]. Post-therapeutical perfusion defects were detected by performing quantitative perfusion analysis [[39]]. Advanced surveillance programs, the introduction of new therapies, the rising number of NAFLD patients and the increasing age of HCV-infected patients due to improved therapies leads to an increasing incidence of HCC [[40], [42]].

The performance of conventional ultrasound is of inferior value when compared to CEUS [[44]]. Benign and malignant lesions might share sonomorphological features [[46]], thus leading to potential misdiagnosis. Interestingly, CEUS already depicted to be a cost-effective tool for HCC surveillance [[47]]. Despite the known diagnostic superiority of CEUS juxtaposed to conventional sonography, no recommendation for the utilization of CEUS in the context of HCC surveillance in patients with chronic liver disease has been pronounced by the leading hepatology societies. It needs to be further evaluated whether CEUS might be a feasible diagnostic tool for HCC surveillance.

The accessibility, repeatability, its sparkling safety profile and the cost-effectiveness renders CEUS appealing in the context of HCC surveillance. In addition, CEUS enables to dynamically visualize parenchymal and tumor microperfusion at a more accurate temporal and spatial resolution than MRI scans [[48], [50], [52]].

A critical cohort of patients with chronic liver disease do also have compromised renal function or intracorporeal devices –not MRI-conditional - thus meaning contraindication for more elaborate MRI scans. Of note, the safe use of CEUS in pediatric patients had already been described in several clinical trials and eventually led to its approval for pediatric liver imaging by the Food and Drug Administration (FDA) [[53]].

In a nutshell, CEUS constitutes a directly accessible efficient diagnostic tool for evaluating HCC lesions and may be utilized with less hesitations in renal impairment, pregnancy and in pediatric patients compared to MRI scans. The role of CEUS as a first-line imaging modality for characterizing HCC lesions and in the context of cancer surveillance still needs to be ascertained in future clinical studies.

The authors have no conflict of interest to report.