Diagnostic performance of intravascular perfusion based contrast-enhanced ultrasound LI-RADS in the evaluation of hepatocellular carcinoma
BACKGROUND: The contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) is a relative new algorithm for hepatocellular carcinoma (HCC) assessment. OBJECTIVE: To validate the diagnostic efficiency of the intravascular perfusion based CEUS LI-RADS for HCC. METHODS: Archives of 873 patients with focal liver lesions (FLLs) undergoing CEUS were reviewed, and target images were read by two sonologists independently according to the CEUS LI-RADS. The diagnostic performance was calculated and compared. RESULTS: Assessment with reference to CEUS LI-RADS, 87 of 218 FLLs (39.9%) were categorized as LR-5, 131 of 218 FLLs (60.1%) were categorized as non-LR-5, 19 of 99 HCCs were categorized as non-LR-5, and 7 of 119 non-HCCs were categorized as LR-5. The sensitivity, specificity, AUROC, positive and negative predictive values of CEUS LI-RADS for diagnosing HCC were 80.81%(95%CI: 71.7%–88.0%), 94.1%(95%CI: 88.3%–97.6%), 0.87 (95%CI: 0.82–0.92), 91.9%(95%CI: 84.1%–96.7%), and 85.5%(95%CI: 78.3%–91.0%), respectively. CONCLUSIONS: The diagnostic efficiency of the intravascular perfusion based CEUS LI-RADS for the evaluation of HCCs is very good.
Keywords: Liver; focal liver lesion (FLL); hepatocellular carcinoma (HCC); contrast-enhanced ultrasound (CEUS); liver imaging reporting and data system (LI-RADS)
1 Introduction
Focal liver lesions (FLLs) are common in general adult population, among them hepatocellular carcinoma (HCC) represents a significant international public health concern [[1], [3]]. Accurate diagnosis of FLLs is essential for appropriate treatment, especially the imaging evaluation of HCC [[3]]. Color Doppler ultrasound (US) and contrast agent enhanced ultrasound (CEUS) exhibit an important role in the liver assessment, can characterize the FLLs with preliminary information [[5], [7]]. In clinical practice, dichotomic categorization of FLLs for benign and malignant lesion is a usual consideration for diagnosis, and some pathologies of FLLs can be established, with reference standard from the World Federation for Ultrasound in Medicine & Biology (WFUMB) guidelines, including vascular perfusion features that the pattern and degree of enhancement in arterial phase, the presence or absence of washout in portal venous phase and late phase, the degree of washout, and washout timing, together with reference to risk factors [[5]]. However, some small HCCs, hypovascular HCCs, and other tumors with unusual manifestations at dynamic perfusion imaging present overlapping CEUS features with other pathologies, which makes the diagnosis challenging [[5], [7]]. To improve diagnosis, professionals continuously probe new methods. The contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) is a relative new algorithm endorsed by American College of Radiology (ACR) to improve standardization and consensus with regard to performance, interpreting, and reporting CEUS assessment of patients with risk factors of cirrhosis of various causes, chronic hepatitis B or C, alcohol induced liver disease, and nonalcoholic steatohepatitis, or other risk factors of the pathogenesis of HCC [[7]]. In this algorithm the lesions are assigned into different categories of the probability that the lesion is a benign entity or HCC according to CEUS findings. In LI-RADS, FLLs categorized as LR-1 indicates benign, LR-2 indicates probably benign, LR-3 indicates intermediate probability for HCC, LR-4 indicates probably HCC, LR-5 indicates HCC, LR-M indicates probably malignant but not specific for HCC, and LR-T indicates treated observation. LR-5V is a subcategory of LR-5, indicating an HCC lesion with tumor in vein [[7], [9]]. FLLs in patients at risk of HCC are common too, some of the FLLs are HCC or other malignant lesions, so CEUS is used widely for the evaluation of inconclusive FFLs. The CEUS LI-RADS has been reported turning out improving diagnostic efficiency in the patients at risk of HCC [[10], [12], [14], [16], [18], [20]]. However, the diagnostic efficiency is discordance, the advantages of CEUS LI-RADS for HCC in our district has not been sufficiently investigated, and further study is beneficial. The aim of the present study was to validate the diagnostic efficiency of the intravascular perfusion based CEUS LI-RADS for HCCs.
2 Materials and methods
2.1 Patients selection
During this retrospective study, achieves of 873 consecutive patients with FFLs undergoing CEUS examinations in a tertiary central hospital from January 2017 to May 2020 were reviewed. All FLLs had been examined using conventional US before undergoing CEUS. The inclusion criteria were: routine and incidental US evaluation positive for FLLs in patients at risk of HCC. Risk factors for HCC referred to that patients with cirrhosis of various causes, chronic hepatitis B or C, alcohol induced liver disease, and nonalcoholic steatohepatitis [[14], [16]]. FLLs at non-contrast CT or MRI assessed for other clinical aims; inconclusive FLLs after contrast enhanced CT or MRI assessment. Patients with benign FLLs at previous CEUS returned to routine follow-up. Patients with inconclusive FLLs or suspicious HCC at CEUS or CT or MRI were referred to further evaluation and/or management (follow-up, biopsy, etc). The exclusion criteria were: patients without contrast-enhanced CT/MRI or biopsy or other data for the determination of FLLs; patients losing follow-up; patients with diffuse HCCs; patients with FLLs of maximal diameter > 8cm (compromising visualization); patients had undergone transcatheter arterial chemoembolization, radiofrequency ablation, chemotherapy, and radiotherapy; and patients with poor quality of CEUS for the FLLs. 215 patients with 218 FLLs were included, and 658 patients with 674 FLLs were excluded. The patients selection flowchart is shown on Fig. 1. The baseline characteristics for patients and lesions are shown in Table 1.
Graph: Fig. 1 The patients selection flowchart.
Table 1 The baseline characteristics for patients and focal liver lesions
| Characteristic | Hepatocellular carcinoma | Intrahepatic cholangiocarcinoma | Other malignant lesion | Benign lesion |
| Number | 99 | 10 | 17 | 92 |
| Male (n, %) | 86(86.9) | 8(80) | 13(76.5) | 44(47.8) |
| Female (n, %) | 13(13.1) | 2(20) | 4(23.5) | 48(52.2) |
| Age (year) | (32–88) | (55–83) | (43–83) | (31–90) |
| Lesion size (mm) | 35.4±17.6 (median 30.5) | 35.5±16.9 (median 28.5) | 26.7±8.9 (median 26) | 24.9±17.1 (median 19) |
| Underlying liver diseases | Chronic hepatitis B and/or cirrhosis. | 9 chronic hepatitis B; 1 biliary lithiasis. | 14 chronic hepatitis B and/or cirrhosis, 3 nonalcoholic steatohepatitis. | 78 chronic hepatitis B and/or cirrhosis, 11 nonalcoholic steatohepatitis, 2 alcoholic steatohepatitis, 1 immune-hepatitis. |
2.2 US examination
Gray scale US, color Doppler flow imaging and CEUS were performed by using GE Logiq E9 ultrasound system (GE Healthcare, Milwaukee, WI, USA) and Mindray Resona 7(Shenzhen Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China), using a multifrequency curved array transducer. The CEUS examinations were performed in the light of WFUMB guidelines [[5]]. The FLL was selected as the region of interest using conventional US, select the abdomen model, the gain, dynamic range, depth gain compensation, depth, and focus were adjusted to optimize imaging, then shift the model to contrast imaging, using the default parameter (MI 0.1). The contrast agent used was the sulphur hexafluoride microbubbles (Shanghai Bracco Sine Pharmaceutical Corp. Ltd., Shanghai, China). During the procedure, 2.4 mL suspension liquid of sulphur hexafluoride microbubbles was administered by bolus injection from the antecubital vein via a 20-gauge catheter, and a flush of 5 mL 0.9%sodium chloride solution was followed. The imaging timer was started simultaneously with the injection of the sulphur hexafluoride microbubbles. The target lesion was imaged and observed for 5 minutes or longer. The CEUS imaging and representative images were saved in the US system and the Picture and Archiving and Communication Systems (PACS), and the dynamic video were exported to computer late for detailed analysis.
2.3 Image study and LI-RADS category assignment
All conventional US and CEUS images and examination application forms were assorted out from the PACS and marked by assistants. If a patient with several FFLs, only the target lesion (one or two representative lesions) was selected; if a patient underwent two and more times of CEUS, only the latest one was enrolled. The CEUS LI-RADS category assignment was performed by two sonologists (six years and eight years experiences in the liver CEUS assessment, respectively) who were blinded to the previous diagnosis in the PACS. They read the US and CEUS images with reference to CEUS LI-RADS (2017 version) independently; if no consensus was reached, they discussed to get a consensus [[5], [7]]. Inter-reader agreement of two sonologists was assessed by reading images of 60 FLLs selected randomly from the previous included patients. The CEUS features of FFLs were characterized as follows: (1) the number of lesions; (2) maximum diameter of the target lesion; (3) shape; (4) margin; (5) enhancement intensity (hyper-/iso-/hypo-) in different phases (time); (6) enhancement patterns of the lesion in the arterial phase (rim/homogeneous/heterogeneous/mosaic architecture, or nodule in nodule architecture; or/and tumor in vein); (7) onset time of enhancement; (8) washout time (≤60 s refers to early washout); (9) (if the lesion presented hyperenhancement and then washout) enhancement duration (washout time subtracts onset time); (10) tumor feeding artery; (11) boundary of non-enhanced area in the tumor (if it was present); and (12) substantial washout [[5], [7]]. HCC was defined as maximal diameter greater than 10 mm or more, typical hyperenhancement in arterial phase (not rim enhancement or peripheral discontinuous enhancement), and late washout (≥60 seconds) and mild degree of washout, which is also the definition of CEUS LR-5 [[7]].
2.4 Reference standards
Reference criteria for patients with FFLs categorized as CEUS LR-1 and LR-2 was contrast enhanced CT or MRI, and FFLs categorized as LR-1 and LR-2 were considered benign. FFLs categorized as CEUS LR-3 and LR-4 were evaluated with imaging follow-up or biopsy. FFLs that did not progress to a higher CEUS LR category at 3 times follow-up in 12 months were considered as benign; if FFL increased greater than 20%in size at follow-up, CEUS, further assessment with contrast enhanced CT or MRI, or biopsy was done. Inconclusive FFLs that developed to LR-5 at follow-up CEUS and contrast enhanced CT or MRI were considered to be HCC. Biopsy and histological analysis was used as reference criterium for patients with FFLs of CEUS LR-M. Patients with FFLs of CEUS LR-3 and LR-4 without histological diagnosis that remained inconclusive at follow-up contrast enhanced CT or MRI were ruled out (counted as exclusion patients). All FFLs categorized LR-5 after contrast enhanced CT and/or MRI assessment were considered to be HCC.
2.5 Statistical analysis
Noncontinuous parameters are presented as numbers and percentage. Continuous parameters are presented as mean±standard deviation. The diagnostic efficiencies of differentiating HCC from other FLLs [intrahepatic cholangiocarcinoma (ICC), other malignant lesions, and benign lesions] according to CEUS LI-RADS were assessed, the sensitivity, specificity, area under the Receiver Operating Characteristics curve (AUROC), positive predictive value, and negative predictive value were determined. The interobserver agreement between the two sonologists for rating of FLLs according to CEUS LI-RADS was calculated. The level of agreement was interpreted in accordance to the ranks for kappa value as follows: 0.0–0.20, poor agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; and 0.81–1.00, excellent agreement [[21]]. A level of p value of < 0.05 was considered statistically significant. MedCalc version 19. 0.4 (MedCalc Software bvba, Ostend, Belgium) was used for the statistical analyses.
3 Ethics approval and consent to participate
The procedures followed at clinical practice were in accordance with the ethical standards of the institutional committee on human experimentation and with the World Medical Association Declaration of Helsinki (revised in 2000). Approval was obtained by the ethics committee of our hospital (2020–009) and written informed consent from patients was waived due to the retrospective design of the study.
4 Results
Assessment with reference to CEUS LI-RADS, 87 of 218 FLLs (39.9%) were categorized as LR-5, 131 of 218 FLLs (60.1%) were categorized as non-LR-5, 19 of 99 HCCs were categorized as non-LR-5, and 7 of 119 non-HCCs were categorized as LR-5, as shown in Table 1. The sensitivity, specificity, AUROC, positive and negative predictive values of CEUS LI-RADS for diagnosing HCC were 80.81%(95%CI: 71.7%–88.0%), 94.1%(95%CI: 88.3%–97.6%), 0.87 (95%CI: 0.82–0.92), 91.9%(95%CI: 84.1%–96.7%), and 85.5%(95%CI: 78.3%–91.0%), respectively. Distribution of CEUS LI-RADS categories and different FLLs are shown in Table 2. 12 of 99 HCCs (12.1%) and six of 10 ICCs (60%) occurred early washout (within 60 second). The inter-reader agreement between the two readers for rating of FLLs according to CEUS LI-RADS was excellent, with k values of 0.81 and 0.82, respectively. Figure 2 and 3 show CEUS features of FLLs and CEUS LI-RADS.
Table 2 Distribution of LI-RADS categories and different focal liver lesions
| Benign lesions | HCC | ICC | Other malignant lesions |
| LR-1 (n = 10) | 10 | 0 | 0 | 0 |
| LR-2 (n = 64) | 64 | 0 | 0 | 0 |
| LR-3 (n = 16) | 16 | 0 | 0 | 0 |
| LR-4 (n = 22) | 2 | 17 | 0 | 4 |
| LR-M (n = 18) | 0 | 2 | 8 | 8 |
| LR-5 (n = 87) | 0 | 80 | 2 | 5 |
| Total focal lesion (n = 218) | 92 | 99 | 10 | 17 |
HCC: hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma.
Graph: Fig. 2 A 45-year-old man with chronic hepatitis B and a focal liver lesion. On sonography, the focal lesion in the VI segment of the liver presents ovoid shaped, with ill-defined margin, homogeneous isoechogenicity, and the sectional size is 58 mm×55 mm (Fig. 2a, arrow). CEUS shows rapid arterial phase hyperenhancement (Fig. 2b and c, arrows, 9 s and 11 s), portal venous phase hypoenhancement (Fig. 2d, arrow, 55 s), and late phase slight hypoenhancement (Fig. 2e, arrow, 198 s). It was categorized as LI-RADS 5, and was assumed hepatocellular carcinoma (HCC). Contrast-enhanced CT and MRI verified it was LI-RADS 5 (HCC).
Graph: Fig. 3 A 61-year-old man with a focal liver lesion. On sonography, the focal lesion in the V segment of the liver presents ovoid shaped, with ill-defined margin, heterogeneous isoechogenicity, and the sectional size is 44.1 mm×33.8 mm (Fig. 3a, arrow). CEUS shows arterial phase rim hyperenhancement, central hypoenhancement and no-enhancement (Fig. 3b and c, arrows, 22 s and 38 s), portal venous phase rim slight hypoenhancement, and central hypoenhancement and no-enhancement (Fig. 3d, arrow, 89 s), and late phase rim slight hypoenhancement and central hypoenhancement and no-enhancement (Fig. 3e, arrow, 176 s). It was categorized as LI-RADS M, and was assumed hepatic sarcoma. Histopathology and immunohistochemistry confirmed it is intrahepatic cholangiocarcinoma.
5 Discussion
In the present study, CEUS LI-RADS demonstrated higher sensitivity, specificity, accuracy, and positive and negative predictive values for HCC evaluation; which is consistent with the study by Schellhaas et al., and does not agree with the study by Li et al. and Huang et al. [[10], [13], [15]]. The reasons may be that the sample population and lesion size are disparity. According to WFUMB guidelines, hypervascular perfusion is the predominant characteristic for HCC, and there is no consensus on diagnosis for hypovascular and atypical lesions [[10], [12], [14], [16]]. In routine practice, radiologists usually interpret the major features of FLLs and establish the diagnosis depending dominantly on WFUMB guidelines, however, some CEUS features of FLLs overlapped frequently with those of other pathologic lesions. The features of contrast agent imaging between well-differentiated HCC and high-grade dysplastic nodule may overlap [[25]]. The development of HCC is thought by several steps, and dysplastic nodule of high grade is usually a precursor of HCC [[26]]. Therefore, some dysplastic nodules may have similar enhancement patterns as that the well-differentiated small HCC. Some HCCs are primarily hypovascular and present atypical CEUS patterns mimicking regenerative nodules, and it's a challenge for diagnosis [[23]]. Some patients of ICC with chronic hepatitis B, if the lesions present CEUS features of annul iso-enhancement in arterial phase and mild washout in portal venous and late phases, it may be mistaken as a category of LR-5. The LR-M category indicates malignancy not specific for HCC, which usually requires biopsy for histological analysis, so if ICC can be accurately categorized as LR-M, the diagnostic value of CEUS LI-RADS is high, as is illustrated by Fig. 3. Compared with HCCs, ICCs exhibit less intense enhancement in the arterial phase and early washout (< 60 s) compared with the typically late and mild washout in HCCs [[5], [18], [25], [27]]. Our study findings that 12 of 99 HCCs (12.1%) and six of 10 ICCs (60%) occurred onset of washout before 60 second were partially agreed with it (Fig. 2 and 3). CEUS LR-4 was categorized those FLLs with high probability of HCC but not defined. Terzi et al. and Huang et al. reported a percentile of HCC of 48%(11 of 23) and 85.6%in LR-4 [[11], [15]]. However, our study showed a lower HCC percentile of 17.2%(17/99) in LR-4, the causes are probably that differences in the examined study sample (number, diameter) and/or underlying liver disease. Washout is an important feature of HCC, ICC and many other malignant lesions, however, some FLLs present atypical washout pattern, and this may lead to incorrect categorizing [[18], [20], [25], [28], [30]].
There were two caveats to this study. Firstly, the retrospective design, which may lose some CEUS features of FLLs. However, we took CEUS for FLLs seriously in routine practice, and the CEUS features of FLLs had been recorded as detail as possible, so little information was overlooked. Secondly, many FLLs had not got histopathologic results, especially for the FLLs of the LR-3, which might compromise the reference standards strength. Fortunately, no malignant lesion was found from lesions of LR-3 at follow-up.
Collectively, we conclude that ACR CEUS LI-RADS has very high diagnostic efficiency for FLLs of patients at risk of HCC. Nevertheless, the present diagnostic performance is still not perfect, and further study should be conducted in the future, e.g., to investigate CEUS LI-RADS in a larger patient cohort, with focus on the role of LR-4 and LR-M in the differential diagnosis of HCC; to determine features of HCC microvascularization using quantitative perfusion analysis of CEUS [[31]]; to validate and optimize tumor targeting contrast agents like BR55 [[32]].
Conflict of interest
The authors declare they have no conflict of interests.
Acknowledgments
This project was supported by the National Natural Science Foundation of China (Grant No. 81560290).
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By Dongsheng Zuo; Kefeng Yang and Size Wu
Reported by Author; Author; Author
