This multi-national study shows a relevant diagnostic benefit for the use of CEUS in a series of prospectively collected patients at risk for HCC, with liver observations categorized as indeterminate on CT or MRI. In nearly a third of cases originally deemed indeterminate on CT/MRI, CEUS achieved a definitive diagnosis with 100% PPV for CEUS LR-5 and LR-TIV and 100% NPV for CEUS LR-1 and LR-2.

Prior work attempting to resolve indeterminate liver findings focused primarily on repeating the CT/MRI, obtaining tissue sampling, or performing active surveillance. Abd Alkhalik Basha et al. conducted a study evaluating the diagnostic efficacy of LI-RADS with CT, categorizing small nodules detected in the cirrhotic liver at screening US. The study comprised 55 nodules, 14 of which were categorized as LR-3. Further investigation indicated that 7 of those nodules were finally confirmed as HCC, while the remaining lesions were benign [13]. Choi Se Jin et al. analyzed changes in size thresholds in CT/MRI according to LI-RADS v.2018 categorization and found 57 HCCs that were previously categorized as LR-3 (n = 3), LR-4 (n = 17), LR-5 (n = 31), and LR-M (n = 6). However, after the changes were implemented, it showed that the threshold had little impact on LI-RADS categorization for LR-5, although these changes showed that the observations that were initially categorized as LR-3 and LR-4 at CT/MRI could be re-categorized as LR-5 after 3–6 months imaging follow-up [14]. These findings agree with a 2018 study conducted by Mitchell et al. stating that the clinical outcome of nodules categorized as LR-3 with US evolves to HCC in a range of 6–69% [15]. Similarly, Darnell et al. evaluated 262 observations, of which 74 were categorized as LR-3 on MRI. Of these 74 LR-3 observations, with a median follow-up of 17 months, 51 nodules were diagnosed as HCC (68.9%), 2 were non-HCC malignant lesions (2.7%), and 21 remained as benign (28.37%) [16]. Shropshire et al. analyzed 141 lesions initially classified as LR-3 using the LI-RADS v2017 classification, with a mean follow-up imaging, either contrast-enhanced CT or MR, of 20.3 ± 13.4 months. From the initial classification, 40% (57/141) of the lesions remained as LR-3; 50% were downgraded to a benign classification (59 LR-1, 11 LR-2); 2% (3/141) were upgraded to LR-4; and 8% (11/141) was upgraded to LR-5 [17].

There are also clinical studies comparing inter-reader agreement and how their discrepancies can cause changes in management and outcomes. For instance, Yokoo et al. studied nodules categorized as LR-3, LR-4, LR-5, and LR-M and found that there was more discordance categorizing LR-3 and LR-4 observations than LR-5 observations and highlighted how this error may have affected management, including decisions regarding therapy and staging for organ transplantation [18]. In this study of 69 patients, 53 had discordant results, from which 30 had changes in clinical management. The reasons for discordance were detection (20/30), size (2/30), and LR category (8/30). In the detection discordance, the clinical change was type of follow-up imaging (between bi-annual screening US and shorter-term FU CT/MRI) (15/20), referral for biopsy (2/20), and eligibility for transplant (3/20). Discordance due to LR category consisted mainly in choosing imaging modality for follow-up (3/8), referral for biopsy (3/8), and changes between treatment modality (2/8). When the size classification was discordant the clinical changes made were between choosing locoregional vs systemic therapy and the eligibility of one patient to be considered for transplant.

Similarly, Smereka et al. studied LI-RADS in MRI, comparing the 2017 vs 2018 version between 3 radiologists. The combined data of all 3 radiologists showed that with the 2017 criteria, 42 out of 110 nodules (38.1%) categorized as LR-3 progressed to HCC, and while using the 2018 criteria, 144 out of 257 nodules (44.4%) categorized as LR-3 progressed to HCC. Additionally, the group showed that with the revised guidelines, several observations re-categorized as LR-3 had measurements between 10 and 19 mm [19].

Prior studies also compared the prognosis of LR-3 lesions identified by CEUS and CT/MRI. Zhou et al. conducted a meta-analysis comparing the proportion of HCC between the respective CEUS LI-RADS and CT/MRI LI-RADS categories and the proportion of HCC and non-HCC malignancies in each. They found that the proportion of HCC in CEUS LR-3 is lower than in CT/MRI (21% vs 35%). In addition, it outlined that there was more HCC categorized as LR-2, 3, and 4 in CT/MRI than in CEUS [20]. These data demonstrate the potential advantages of CEUS for indeterminate liver nodule categorization as both a primary and secondary diagnostic tool.

LR-NC category is assigned to those cases where there are technical or patient-related limitations that prevent the characterization of an observation, such as the complete lack of arterial phase images [21, 22]. Elsayes et al. recommended that nodules categorized as LR-NC may need repeat imaging tests in less than 3 months [23]. Kamath et al. reported one LR-NC case where the initial test was non-characterizable due to artifacts present on non-contrast images, and the inability to conclude the test with contrast. For this reason, the test modality was changed to multiphase CT, in which the observation was categorized as LR-5 [22].

Our study has several limitations, the most important of which is use of a composite imaging and histology reference standard. Ideally, HCC diagnosis should be established based on tissue sampling. However, the current clinical practice is based on imaging-based noninvasive diagnosis of HCC introduced by the Barcelona-2000 European Association for the Study of the Liver conference [2]. Therefore, obtaining histological diagnosis for every (or even most) HCC is no longer standard of care, making it practically impossible to use histology as reference in every case. Also, for this study, observations with persistent CT/MRI LR-3 categorization on 1-year follow-up imaging were considered non-malignant. However, since the growth rate of some well-differentiated HCC is relatively small, a 1-year follow-up may not be long enough to exclude malignancy. On the other hand, nodules followed for more than 1 year and initially categorized as non-malignant may eventually transform to malignancy. Another limitation is that similar to routine clinical practice, in most cases readers of CEUS were not blinded to the images/results of CT/MRI, since CT/MRI results commonly used to guide CEUS examinations. Although doing so might increase clinical applicability of our study findings. Also, despite the prospective multicenter design of our study, the relatively small sample size (75 liver lesions) of this sub-analysis may affect the generalizability and statistical power of the findings.

These findings have significant implications for patient management, and based on our data and the results of others, we believe that in patients at risk for HCC that CEUS should be recommended as an appropriate next step in management of focal liver observations with indeterminate CT/MRI categorization.