Application Value of CEUS LI-RADS v.2017 in Focal Liver Lesions of Patients with a High Risk for Hepatocellular Carcinoma

doi:10.21203/rs.3.rs-4328061/v1

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Application Value of CEUS LI-RADS v.2017 in Focal Liver Lesions of Patients with a High Risk for Hepatocellular Carcinoma

https://doi.org/10.21203/rs.3.rs-4328061/v1

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Purpose

This goal of this research is to investigate the practical value with regards to the data system (LI-RADS) v.2017 as well as contrast-enhanced ultrasound (CEUS) liver imaging reporting for focal liver lesions (FLLs) in patients at high-risk of hepatocellular carcinoma (HCC).

Method

The research included 127 high risk patients with HCC, comprising a total of 148 FLLs. All lesions were verified through pathology. Relying on CEUS LI-RADS v.2017, two independent radiologists categorized the lesions and evaluated inter-observer agreement by Cohen’s kappa. Finally, the classification of inconsistent lesions was discussed and agreed upon. The diagnostic accuracy of each classification was calculated based on the pathological results.

Results

The cohort included 108 males and 19 females, aged 37–82 (mean = 59.93 ± 10.09) years, with a lesion size range of 0.8–15 (mean = 3.95 ± 2.88) cm. Through the Kappa test, the interobserver agreement was high in the classification of FLLs (ĸ = 0.670, P = 0.000). Of the 148 FLLs, 4 and 3 lesions were categorized as an LR-1 and LR-2, correspondingly, all of which were pathologically benign. 6 lesions were categorised as an LR-3, comprising 3 benign and 3 malignant lesions. The diagnostic accuracy of benign versus malignant lesions was approximately 50%. 18 lesions were categorised as LR-4 including 13 malignant lesions (13/18, 72.22%); 102 lesions were categorized as LR-5, with 101 pathologically confirmed malignant lesions (101/102, 99.02%); 8 lesions were categorized as LR-TIV and all of them were malignant; finally, 7 lesions were classified LR-M and with 5 confirmed malignancies (5/7, 71.43%).

Conclusions

LR1/2 and LR4/5/TIV/M demonstrated a high degree of diagnostic accuracy for the delineation between benign and malignant lesions respectively. The classification criteria demonstrated reliable interobserver consistency for the classification of FLLs.

Contrast-enhanced ultrasound

liver imaging reporting

data system

hepatocellular carcinoma

focal liver lesions

Liver cancer is ranked as the fifth most well-known cancer globally as well as stands as the second primary cause of cancer-related deaths. The HCC incidence constitutes around 90% of primary hepatocellular carcinoma (PHC), and the incidence worldwide has been steadily increasing. Currently, newly diagnosed cases of HCC have surged by 75% between 1990 and 2015, mainly due to the increase in human lifespan and population growth [1, 2]. Therefore, the monitoring of suspected HCC in high-risk patients is particularly important.

HCC is a unique malignancy. The difference in extracellular volume and blood flow between HCC and the surrounding non-neoplastic cirrhotic tissue results in the characteristic imaging manifestations during multiphase enhancement. This difference mainly depends on the enhancement characteristics of suspected tumors relative to the hepatic parenchyma across different phases, including the portal vein phase, hepatic artery phase, and subsequent phases, such as arterial phase hyperenhancement (APHE), subsequent washout appearance as well as capsule appearance, etc. In these high-risk patients with HCC, lesions with imaging characteristics of HCC can make a HCC diagnosis with high accuracy without the need for an invasive biopsy[3]. However, some lesions detected by ultrasound (US), magnetic resonance imaging (MRI) or computed tomography (CT) do not exhibit the common imaging characteristics of HCC. These lesions include non-HCC malignant tumors, non-malignant lesions, and HCC. Within these ambiguous cases, it can be challenging to develop a definite diagnosis.

Past clinical practice guidelines from the American Association for the Study of Liver Diseases (AASLD) suggest performing a biopsy for all lesions that are ≥ 1 cm detected by US and deemed to be undetermined by MRI and CT [4]. However, owing to the intricacy of treatment for suspected HCC and the constraints of biopsy[5, 6], alternative imaging or alternative methods such as follow-up, might be favored in certain instances. Hence, various societies including the Japan Society of Hepatology (JSH), the European Association for the Study of the Liver (EASL) as well as the AASLD have formulated guidelines in utilizing imaging tests for the HCC diagnosis [4, 7, 8]. These guidelines are constructed based on multiple factors, which includes APHE, size, nodular growth in follow-up examinations, washout, and/or histological diagnosis concerning HCC. While these criteria are beneficial for diagnosing HCC in several patients, in which they do not encompass a broad spectrum of imaging findings found in patients having focal nodules of the liver and chronic liver disease. Hence, the American College of Radiology (ACR) has assembled a team consisting of specialized radiologists to devise a novel integrated system. This system, also called the Liver Imaging Reporting and Data System (LI-RADS) was introduced in the year 2011 and subsequently updated in 2017 to interpret as well as report MRI and liver CT examinations in high-risk patients with HCC[9].

Given the widespread clinical application of Contrast-enhanced ultrasound (CEUS), the ACR assembled a panel of global experts in 2014 to establish the CEUS LI-RADS. CEUS offers several advantages, including real-time imaging, non-nephrotoxicity, high contrast resolution, as well as pure intravascular properties of microbubbles contrast agent, which allows the use of destructive complementary techniques and high precision. Therefore, the CEUS is becoming widely accepted in the clinical analysis of uncertain lesions in multiple organ systems, including renal masses or hepatic. Particularly for uncertain lesions on MRI or CT, US offers additional value after MRI and CT [10]. While the CT/MRI LI-RADS is well-established, concerns have been highlighted with regards the application of previous versions of the CEUS LI-RADS [11, 12]. Not long ago, the ACR introduced the CEUS LI-RADS version 2017 (v.2017), a recently established guideline aimed at standardizing the interpretation of CEUS of suspicious HCC lesions[11, 13, 14]. Currently, only few studies have validated the CEUS LI-RADS v.2017. Therefore, this research assessed the practical value of CEUS LI-RADS v.2017 for monitoring FLLs in high-risk HCC patients by examining its diagnostic accuracy.

Our retrospective study received approval from our institutional review board of Hangzhou Hospital for the Prevention and Treatment of Occupational Disease, which exempted the need for informed consent.

2.1. Study Participants

The study consecutively collected 282 patients with FLLs detected by CEUS from June 2016 to September 2019. Inclusion criteria were: 1) age older than 18; 2) presence of cirrhosis or chronic hepatitis, indicating a risk for HCC; 3) visible lesions examined by US; 4) the availability of CEUS data as well as 5) the availability of histological analysis of lesions. Exclusion criteria were: 1) Age under 18; 2) patients having cirrhosis because of special conditions (vascular disorders or congenital hepatic fibrosis, including cardiac congestion and Budd-Chiari syndrome); 3) personal a history of malignant tumors other than primary liver cancer; 4) patients with prior local or systemic ablative liver treatment. Following the exclusion and inclusion criteria, the study enrolled 127 consecutive participants (108 men and 19 women; range, 37–82 years) with 148 FLLs.

2.2. Ultrasound Technique

The standard CEUS and US examinations were conducted using a Mindary Resona 7 scanner (Mindary Medical Solutions; Shenzhen, China) equipped with a 1-5-MHz convex transducer. Here, the pulse inversion harmonic imaging was employed while the CEUS’s mechanical index was at 0.08. Before the CEUS examination, informed consent was acquired from all patients for the contrast’s. Firstly, conventional US scanning was performed, followed by the administration of contrast. SonoVue (SonoVue; Bracco SpA, Milan, Italy) 2.4 mL was injected into the antecubital vein, followed by a flush of 5 mL 0.9% saline. Moreover, the timer was initiated after the completion of SonoVue injection. Moreover, the target lesion as well as surrounding liver parenchyma were monitored for approximately 6–8 min.

2.3. Image Analysis

We conducted a retrospective assessment of the CEUS examination records of chosen patients who were treated between June 2016 and September 2019 at The First Affiliated Hospital of Ningbo University of Medicine. Prior to the review session, observers underwent training on the CEUS LI-RADS v.2017 instruction. The arterial phase (AP) was characterized as 10-20s to 30-45s following contrast injection. The portal venous phase (PVP) was characterized as 30–45 s to 2 min following contrast injection. Furthermore, late phase (LP) extended from the end of PVP until an unambiguous clearance of microbubbles from circulation at around 4 to 6 mins. Based on the imaging features of ultrasound image and video, and algorithm of CEUS LI-RADS v.2017, classification of observations was performed by two observers independently: LR-1 was defined as definitely benign, while LR-2 was characterized as probable benign lesion. Moreover, LR-3 as an intermediate probability for HCC, while LR-4 as a moderate probability of HCC as well as LR-5 as definitely HCC. LR-TIV is the tumor in vein, while LR-M as probably or definitely malignant but not specific for HCC. In addition, LR-NC is unable to be categorised due to image omission or degradation. Two observers, each with over 3 years of experience in the ultrasound medicine department and blinded to any pathological and clinical information, analyzed all images. In cases of differing opinions, the final LI-RADS categorization was determined by consensus.

2.4. Statistical Analysis

Quantitative variables were presented as a mean ± standard deviation (SD). Cohen’s kappa[15] was utilized for the assessment of the inter-observer agreement. The degrees of agreement were deemed as no agreement when Kappa value is less than equals to 0, none to slight when Kappa value is between 0.01 and 0.20, fair when Kappa value is between 0.21 and 0.40, moderate when Kappa value is between 0.41 and 0. 60, substantial when Kappa value is between 0.61 and 0.80, as well as almost perfect agreement when Kappa value is between 0.81 and 1. The data analysis was conducted by employing SPSS statistical analysis software (SPSS Inc., Chicago, Illinois, USA, 1999). At P < 0.05, the test was significant.

3.1. Participant Characteristics

This research enrolled 127 high-risk patients for HCC with 148 FLLs in the final study population. The relevant clinical characteristics of 127 enrolled patients were collected during the retrospective review and summarized in Table 1. Of the 127 patients, 85.04% (108 of 127 patients) were male, and their ages ranged from 37–82 years. All patients were diagnosed with either cirrhosis or chronic hepatitis. The longest diameter of observations ranged from 0.8–15 cm.

Table 1

Participant characteristics (n = 127)
Age [years] (range / mean ± SD)	37–82 (59.93 ± 10.09)
Gender (n, %)
Male	108 (85.04%)
Female	19 (14.96%)
Lesion size [cm] (range / mean ± SD)	0.8–15 (3.95 ± 2.88)
SD, standard deviation; n, number

3.2. Distribution and Interobserver Agreement of Categories

The LI-RADS frequencies categories as classified by observers are presented in Table 2. In total, 3 (2.03%) and 4 (2.70%) observations were categorized as LR-1 and LR-2 correspondingly by observer A. 101 (68.24%) observations were categorized as LR-5, 21 (14.19%) observations were categorised as LR-4, 8 (5.41%) observations were categorized as LR-TIV, 7 (4.73%) observations were categorized as LR-3, and 4 (2.70%) observations were categorized as LR-M by observer A. At the same time, 100 (67.57%) observations were categorized as LR-5, 20 (13.51%) observations were categorized as LR-4, 8 (5.41%) observations were classified as LR-TIV, 7 (4.73%) observations were classified as LR-M, 6 (4.05%) observations were classified as LR-3, 5 (3.38%) observations were categorised as LR-1, while 2 (1.35%) observations were categorised as LR-2 by observer B.

Table 2

LI-RADS categories of two observers
		Observer A
		LR-1	LR-2	LR-3	LR-4	LR-5	LR-TIV	LR-M	Total
Observer B	LR-1	3	2	0	0	0	0	0	5
	LR-2	0	0	2	0	0	0	0	2
	LR-3	0	2	4	0	0	0	0	6
	LR-4	0	0	1	12	7	0	0	20
	LR-5	0	0	0	8	92	0	0	100
	LR-TIV	0	0	0	0	0	8	0	8
	LR-M	0	0	0	1	2	0	4	7
	Total	3	4	7	21	101	8	4	148

LI-RADS, Liver Imaging Reporting and Data System; TIV, tumor in vein

According to the categories of two observers, Cohen’s kappa was conducted. The result indicated the inter-observer agreement for CEUS LI-RADS between observers A as well as observer B demonstrated substantial agreement (κ = 0.670, p = 0.000).

3.3. Diagnostic Accuracy

According to pathological results and final LI-RADS, categorization was achieved (Table 3). 118 of 148 (79.73%) observations were diagnosed as HCC, 6 of 148 (4.05%) observations were diagnosed as an intrahepatic cholangiocarcinoma (ICC), 5 of 148 (3.38%) observations were diagnosed as a combined hepatocellular cholangiocarcinoma (cHCC-CC) and 1 of 148 (0.68%) observation were classified as a sarcomatoid hepatocellular carcinoma (SHC). Hemangiomas, cirrhotic nodules, hyperplastic nodules, cysts, chronic inflammation, and focal nodular hyperplasia (FNH) accounted for 3.38% (5/148), 2.70% (4/148), 2.70% (4/148), 2.03% (3/148), 0.68% (1/148), and 0.68% (1/148) of lesions, respectively.

Table 3

The classified observations and corresponding pathological results.
	HCC	ICC	cHCC-CC	SHC	Cirrhotic nodule	Hyperplastic nodule	Chronic inflammation	Hemangioma	Cyst	FNH	Total^*
LR-1	0	0	0	0	0	0	0	1	3	0	4
LR-2	0	0	0	0	0	1	0	2	0	0	3
LR-3	2	1	0	0	0	3	0	0	0	0	6
LR-4	13	0	0	0	2	0	0	2	0	1	18
LR-5	90	5	5	1	1	0	0	0	0	0	102
LR-TIV	8	0	0	0	0	0	0	0	0	0	8
LR-M	5	0	0	0	1	0	1	0	0	0	7
Total	118	6	5	1	4	4	1	5	3	1	148
^*Final LI-RADS categorization was achieved by consensus in case of different opinions between two observers

HCC, Hepatocellular carcinoma; ICC, Intrahepatic cholangiocellular carcinoma; cHCC-CC, combined hepatocellular cholangiocarcinoma; SHC, Sarcomatoid hepatocellular carcinoma; FNH, focal nodular hyperplasia; TIV, tumor in vein.

Finally, 102 observations were categorized as LR-5, 101 (99.02%) were pathologically confirmed as malignant as well as 1 observation (0.98%) was histologically proved to be a cirrhotic nodule. The 101 malignant observations included 90 instances of HCC (88.24%, Fig. 1), 5 ICC (4.90%, Fig. 2), 5 cHCC-CC (4.90%) and 1 SHC (0.98%). For the 18 LR-4 observations, 13 cases (72.22%) were confirmed to be HCC. Cirrhotic nodules (Fig. 3), hemangioma, and focal nodular hyperplasia (FNH) accounted for 11.11% (2/18), 11.11% (2/18) and 5.56% (1/18) respectively. Seven observations were categorized as LR-M, which included 5 (71.43%, Fig. 4) HCC, 1 (14.23%) cirrhotic nodule and 1 (14.23%) episode of chronic inflammation. Eight observations were categorized as LR-TIV as well as all were confirmed HCC. Six observations were classified as LR-3 lesions including 3 hyperplastic nodules and 3 malignant (2 HCC [Figure 5] and 1 ICC), the diagnostic accuracy of benign and malignant tumors was about 50%. Also, 4 and 3 observations were categorized as LR-1 and LR-2, correspondingly, and pathologically proved to be benign.

Although the CT/MRI LI-RADS is well-established, CEUS was controversial and excluded from EASL and AASLD guidelines in 2011 and 2012. This study assessed the newly updated version of CEUS LI-RADS (v.2017), building upon previous versions. In this group, we found that middle-aged and elderly men were the most common demographic for liver cancer, a finding consistent with prior research^[16]. Studies have found variations in the age of liver cancer onset across geographical areas, sexes, and risk factors related to cancer development. Additionally, disparities in sex hormones are an essential risk factor for liver cancer. Testosterone acts as a positive regulator of hepatocellular cycle regulators, thereby accelerating the occurrence of HCC, while estradiol inhibits the development of HCC by inhibiting cell cycle regulators[16, 17].

Relying on the algorithm of CEUS LI-RADS v.2017, the inter-observer agreement among the two experienced radiologists was κ = 0.670, indicating that the categorisation of FLLs with CEUS LI-RADS can be reproduced with a significant agreement in high-risk patients having HCC. Of those observations, LR-1 was definitely benign. LR-1 classification targets include hepatic cysts, hemangiomas, and hepatic fat deposition. LR-2 was classified as probably benign, such as regenerative or low-grade dysplastic nodules. In this study, 4 observations were classified as LR-1, including 3 cysts and 1 hemangioma, while 3 observations were classified as LR-2, including 2 hemangiomas and 1 hyperplastic nodule. This indicated that CEUS LI-RADS v.2017 LR-1/2 had confirmed diagnostic accuracy for benign nodules.

CEUS LR-3 comprises discrete solid nodules < 10mm excluding the rim, without the presence of peripheral, discontinuous, globular APHE and washout of any type. LR-3 also encompasses nodules < 20 mm that do not exhibit APHE with or without late as well as mild washout. Finally, nodules greater than 20 mm not showing APHE and lack of any type of washout were also categorized as LR-3. These nodules indicate an intermediate probability of malignancy, typically necessitating follow-up or alternative imaging, and biopsy considered in cases selected from a multidisciplinary discussion. In the 6 LR-3 observations, 3 were benign and 3 were malignant tumors. The diagnostic accuracy of benign and malignant tumors was about 50%. Other authors[18, 19] have presented a similar incidence in these patients, highlighting the challenges in the differential diagnosis between early HCCs and benign nodules. LR-4 signifies probable HCC nodules, typically warranting a biopsy, however short-term (less than three months) imaging or alternative imaging follow-up may be considered if immediate treatment or biopsy is not pursued relying on a multidisciplinary discussion. Among these LR-4 lesions, 13 were HCC, 2 were cirrhotic nodules, 2 were hemangiomas and 1 was an FNH. Although most of them were malignant, nearly 30% (5/18) of benign lesions were classified into LR-4. Hemangiomas are usually classified as LR1/2 because of their typical features. It is presumed that some hemangiomas are classified as LR-4 because of their atypical manifestations. Meanwhile, we also found that cirrhotic nodules in benign lesions were relatively likely to be categorized as LR-4 or above. In this research, 4 cirrhotic nodules were included, 2 of which were categorized as LR-4, 1 LR-5 as well as 1 LR-M correspondingly. Bolondi et al [20] believed that HCC typically develops from cirrhotic nodules, which consist of regenerative as well as atypical hyperplastic nodules induced by hepatitis viruses. Li et al[21] discovered the absolute stiffness difference (ASD), stiffness value (SV), stiffness ratio (lesion/background liver) (SR) of small HCC as well as serum AFP were significantly higher than in cirrhotic nodules. Therefore, there may be image features of overlap between well-differentiated HCC or early HCC and cirrhotic nodules. Considering the multistage transition of HCC, identifying intermediate categories like LR-3 and 4 poses a significant challenge.

LR-5 is a crucial category as LR-5 nodules may be treated as HCC with no further imaging or biopsy. Among the 102 LR-5 lesions we analyzed, 101 were malignant lesions, including 90 cases of HCC, 5 cases of ICC, 5 cases of cHCC-CC, and 1 case of SHC. The diagnostic accuracy of malignancy was about 100%. The CEUS LI-RADS v.2017 also introduces a category for lesions that are either likely or definitely malignant, termed LR-M, which is inspecific for HCC. The imaging characteristics for LR-M encompass rim APHE, marked washout or early (lss than sixty seconds) washout. This category may encompass the possibility of cHCC-CC, ICC, or other malignancies. CEUS was eliminated from EASL and AASLD guidelines in 2011 and 2012 because of some ambiguities between ICC and HCC[18, 22, 23]. This edit was the result of a research[24] which formed a conclusion that ICC in cirrhosis exhibited a similar improvement pattern to that of HCC on CEUS, which could potentially yield a false-positive diagnosis with regards to HCC. Consequently, lesions are classified as LR-M are typically suspicious of ICC. However, in our classification, 5 of 7 LR-M lesions were HCC, 1 lesion was a cirrhotic nodule, 1 lesion was chronic inflammation, and there was no ICC. Meanwhile, in 6 cases of lesions diagnosed as ICC, 5 were LR-5 lesions, 1 was an LR-3 lesion and no LR-M lesions were categorized. These results were consistent with a previous study[25], which demonstrated that 7 out of 9 LR-M lesions were confirmed to be HCC, indicating a diagnostic accuracy of only 11.11%. Leoni et al[26] deduced that CEUS sensitivities improve when the wash-out time is omitted as a diagnostic criterion with early onset of wash-out (less than equals to 60s), which were frequently misclassified as LR-M. Hence, further validation is required to determine the threshold of wash out onset for categorizing LR-M lesions. In a current research, Li et al[27] showed that the specificity was substantially increased without affecting sensitivity. Here, the rate of HCCs misdiagnosed as ICCs drops from 12.3–4.4% when early washout onset was adjusted to < 45s. Additionally, Chen et al[28] showed that the modified LI-RADS with M-score had a greater specificity for diagnosing ICC and greater sensitivity for diagnosing HCC compared to ACR LI-RADS. The M score for ICC recognition is derived from a linear combination of chosen features weighted by their respective coefficients.

LR-TIV can be visually observed under CEUS as a formation of intravascular tumor thrombus due to tumor infiltration, allowing a coincidence rate of malignant diagnosis nearing 100%. Eight of the lesions in this study were LR-TIV, and all of them were proved to be malignant lesions by pathology.

Current limitations to the study are as follows. Firstly, this study is a retrospective study; and there are inevitable factors that interfere with data analysis and lead to deviation, such as operator dependency. Additionally, the sample size of this study needs to be further collected, especially for the LR-3 and LR-M lesions. Though this study is equivalent to the validation study regarding CEUS LI-RADS, additional efforts are required to improve and supplement CEUS LI-RADS compared to the current state of the CT/MRI LI-RADS. There remains quite a number of HCC or malignant liver tumors in non-high-risk HCC patients. Therefore, it is necessary to establish a more complete and applicable LI-RADS for all focal liver lesions.

Overall, CEUS LI-RADS v.2017 holds a substantial application value in the clinical assessment of FLLs in patients having greater risk of HCC. Moreover, LR-4/5/TIV/M and LR-1/2 demonstrate a high diagnostic accuracy in the classification of malignant as well as benign lesions respectively, and the classification criteria have good inter-observer consistency in the classification of FLLs. Due to the increasing worldwide prevalence and incidence of HCC, an accurate, early diagnosis is of utmost importance. The CEUS LI-RADS holds the potential to offer clinicians an additional modality to enhance the HCC diagnosis and aid in guiding further treatment options.

Author Contribution

Author 1 (First Author)( Chen Huihui): Conceptualization, Methodology, Software, Investigation, Formal Analysis, Writing - Original Draft,Funding Acquisition;Author 2 (Yang Dan): Data Curation, Validation,Methodology;Author 3(Wang Huihui) Resources, Software, Validation,Data curation;Author 4:(Corresponding Author)(Hu Jin Ming):Conceptualization, Resources, Supervision, Writing Review & Editing;

Data Availability

The anonymized imaging database can be obtained after the reasonable request is evaluated and approved by the institutional review board of Hangzhou Hospital for the Prevention and Treatment of Occupational Disease.

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No competing interests reported.

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Application Value of CEUS LI-RADS v.2017 in Focal Liver Lesions of Patients with a High Risk for Hepatocellular Carcinoma

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Abstract

Purpose

Method

Results

Conclusions

Figures

1. Introduction

2. Materials and methods

2.1. Study Participants

2.2. Ultrasound Technique

2.3. Image Analysis

2.4. Statistical Analysis

3. Results

3.1. Participant Characteristics

3.2. Distribution and Interobserver Agreement of Categories

3.3. Diagnostic Accuracy

4. Discussion

5. Conclusion

Declarations

Author Contribution

Data Availability

References

Additional Declarations

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