Modified LR-5 criteria based on gadoxetic acid can improve the sensitivity in the diagnosis of hepatocellular carcinoma

Abstract

BACKGROUND

Currently, only tumors classified as LR-5 are considered definitive hepatocellular carcinoma (HCC), and no further pathologic confirmation is required to initiate therapy. Previous studies have shown that the sensitivity of LR-5 is modest, and lesions enhanced by gadoxetic acid (Gd-EOB-DTPA) may exhibit lower sensitivity than those enhanced by Gd-DTPA.

AIM

To identify malignant ancillary features (AFs) that can independently and significantly predict HCC in Liver Imaging Reporting and Data System version 2018, and to develop modified LR-5 criteria to improve diagnostic performance on Gd-EOB-DTPA - enhanced magnetic resonance imaging.

METHODS

Imaging data from patients with HCC risk factors who underwent abdominal Gd-EOB-DTPA - enhanced magnetic resonance imaging were collected. Univariate and multivariate logistic regression analyses were performed to determine AFs that could independently and significantly predict HCC. The modified LR-5 criteria involved reclassifying LR-4/LR-3 lesions based on major features combined with independently significant AFs for HCC, or by substituting threshold growth with significant AFs. McNemar's test was used to compare the diagnostic performance of the modified LR-5 criteria.

RESULTS

A total of 244 lesions from 216 patients were included. Transitional phase hypointensity, mild - moderate T2 hyperintensity, and fat in mass (more than adjacent liver) were identified as significant independent predictors of HCC. Using the modified LR-5 criteria (e.g., LR-5-M1: LR-4 + transitional phase hypointensity; LR-5-M4: LR-5 by transitional phase hypointensity instead of threshold growth; LR-5-M5: LR-5 by mild - moderate T2 hyperintensity instead of threshold growth; LR-5-M8: LR-3/LR-4 + any two features of transitional phase hypointensity/mild - moderate T2 hyperintensity/fat in mass), sensitivities were significantly increased (88.5%-89.1%) compared to the standard LR-5 (60.6%; all P values < 0.05), while specificities (84.8%-89.9%) remained largely unchanged (93.7%; all P values > 0.05). The LR-5-M8 criterion achieved the highest sensitivity.

CONCLUSION

Mild - moderate T2 hyperintensity, transitional phase hypointensity, and fat in mass are independent and significant predictors of HCC malignant AFs. The modified LR-5 criteria can improve sensitivity without significantly reducing specificity.

Key Words: Hepatocellular carcinoma; Liver Imaging Reporting and Data System; Gadoxetic acid; Sensitivity; Specificity; Modified Liver Imaging Reporting and Data System

Core Tip: The LR-5 classification of Liver Imaging Reporting and Data System version 2018 can only be determined based on major features, which have high specificity but low sensitivity for the diagnosis of hepatocellular carcinoma. This study aims to identify independent and significant ancillary features and develop a modified LR-5 standard in Liver Imaging Reporting and Data System version 2018 based on gadoxetic acid. The modified LR-5 standard can improve the sensitivity of LR-5 without significantly reducing its original high specificity.

INTRODUCTION

East Asia experiences a significantly higher incidence of hepatocellular carcinoma (HCC) compared to other regions globally, primarily due to the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. This disease ranks second among causes of cancer-related mortality, imposing a substantial disease burden in the area[1,2]. HCC is unique in that it can be detected noninvasively using imaging criteria without confirmed pathology. This is partly because to the lesion's distinct morphological presentations and enhancement patterns[3]. Therefore, it is of great significance to construct a definitive imaging diagnostic system for HCC that can provide high sensitivity while maintaining high specificity. To achieve this, numerous medical professional committees and associations have developed their own HCC imaging diagnostic systems based on patient characteristics and medical backgrounds in various regions[4-9]. The American College of Radiology published the first version Liver Imaging Reporting and Data System (LI-RADS) in 2011, and the most recent version, LI-RADS version 2018 (LI-RADS v2018), has undergone four upgrades and has been fully incorporated into the American Association for the Study of Liver Disease guidelines[10,11]. With its continuous promotion and application, it has become an increasingly widely used imaging standard for monitoring and diagnosing HCC in high-risk populations[12,13].

Only tumors with a classification of LR-5 are now considered conclusive HCC, and no further pathologic confirmation is required to start therapy immediately[10,11]. Previous studies have shown that the sensitivity of LR-5 is modest[14]. The studies of other scholars have shown that the sensitivity of LR-5 lesions enhanced by gadoxetic acid (Gd-EOB-DTPA) may be lower than that of LR-5 lesions enhanced by Gd-DTPA[15,16]. The possible reason is that LI-RADS were originally developed based on Gd-DTPA, and LI-RADS incorporated GD-EOB-DTPA-related features into its diagnostic system in 2014[17,18]. In Gd-EOB-DTPA-magnetic resonance imaging (MRI) enhanced scanning, most HCC showed hypointense in hepatobiliary phase (HBP) compared to adjacent enhanced hepatic parenchyma. Previous studies have shown that Gd-EOB-MRI facilitates the detection of small HCC and helps distinguish between HCC and hyper vascular lesions containing normal liver cells[19,20], this may explain the inclusion of Gd-EOB-DTPA related features in LI-RADS. Previous studies have shown that LI-RADS v2018 has higher specificity than other imaging diagnostic systems[21,22], possibly because in western developed countries such as North America and Europe, the medical system allows more HCC patients to undergo liver transplantation, while in Asia, the diagnostic criteria for early liver cancer tend to be more sensitive. The medical environment in Asia focuses on early diagnosis of liver cancer and early local radiofrequency ablation/surgical treatment[23,24]. In addition, LI-RADS v2018 defines 21 types of ancillary features (AFs) (including 7 benign AFs and 14 malignant AFs), many of which are aimed at improving lesion detection, boost lesion classification confidence, and adjust LI-RADS category. However, LI-RADS did not specify the diagnostic efficacy or importance of each AFs[25,26]. Many AFs, according to some researchers, are not significant for the improvement of the diagnostic efficiency of LI-RADS, and some AFs can even be ignored under some conditions[27-30]. Additionally, prior study demonstrates that the frequency of each AF's occurrence may fluctuate depending on the contrast agent used[31]. Therefore, it is possible that the significance of some AFs is underestimated. Some studies have also shown that threshold growth of major features (MFs) may not be an important diagnostic indicator for HCC, and threshold growth is more common in non-HCC malignancies[29]. The purpose of this study is to find that LI-RADS v2018 based on Gd-EOB-DTPA enhanced MRI can independently and significantly predict the malignant AFs of HCC, and then try to develop a modified LR-5 standard to improve the sensitivity without significantly reducing the original high specificity of LR-5.

MATERIALS AND METHODS

Study population

This retrospective study was approved by the Institutional Review Board of our hospital (No. [2022] 21), and the need for patient informed consent was waived. We retrospectively collected data from patients who underwent dynamic contrast-enhanced MRI of the abdomen due to HCC risk factors at the Second Affiliated Hospital of Soochow University from January 2018 to January 2022. The inclusion criteria were as follows: (1) Patients aged ≥ 18 years; (2) Patients with chronic HBV hepatitis; (3) Patients with liver cirrhosis; (4) Potential recipients and donors for liver transplants; (5) Currently suspected of HCC or previous HCC patients; and (6) Intrahepatic lesions ≤ 3. The exclusion criteria were as follows: (1) Received any form of antitumor therapy or needle biopsy before dynamic contrast-enhanced MRI; (2)Secondary cirrhosis due to congenital liver fibrosis; (3) Cirrhosis due to vascular disease; (4) Poor image quality that affected interpretation or scanning protocol that did not meet the LI-RADS requirements; and (5) Patients with inadequate final diagnosis, such as suspected malignant tumor without pathological diagnosis due to immediate local treatment, suspected benign lesion without 24-month follow-up or pathological results, and interval between imaging examination and pathological sampling ≥ 2 months. The patient screening flowchart is shown in Figure 1.

Figure 1 Flowchart. HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; HBV: Hepatitis B virus; LI-RADS: Liver Imaging Reporting and Data System.

Image acquisition

MRI scans were performed using a 3.0-T scanner (Ingenia, Philips Healthcare, Best, Netherlands) with a 32-channel phased-array body coil. The unenhanced sequence included the respiration-triggered T2-weighted imaging (T2WI) spectral attenuated inversion recovery sequence along the horizontal axis, the coronal fat suppression sequence and the in-/out-of-phase T1-weighted imaging data collected by Dixon. The breath-triggered diffusion-weighted imaging included multiple b values of 0, 50, 800, 1000, and 1500. Enhanced images were acquired using a modified Dixon sequence, including seven dynamic enhancement phases: Pre-enhanced phase, early arterial phase, standard arterial phase, late artery phase, portal venous phase (PVP), transition phase (TP) and HBP. The slice thickness of the abovementioned sequence was 5 mm, the slice interval was 2-5 mm, the matrix was (224-512) × (224-512), the field of view was 400, and the inversion angle was 10°/90°. The contrast agent was disodium gadoxetate (Gd-EOB-DTPA; Primovist; Bayer Schering Pharma AG, Berlin, Germany). The contrast agent was intravenously administered via a power injector followed by a 25.0-mL saline flush. The contrast agent dosage was 0.1 mL/kg, and the flow rate was 1.0 mL/second. All acquisition technologies complied with LI-RADS v2018 technical requirements.

Image analysis

A radiologist with 9 years of experience in abdominal MRI performed lesion matching and labeling. The label matching method was used to determine the location of the lesion according to the treatment monitoring images, pathological results or follow-up images and identify the mass based on its size, serial number, and image number. The lesion size was measured three times on the HBP, TP/delay phase, PVP, and T2WI scans according to the measurement method required in LI-RADS, and the average value was taken and recorded in the stored electronic file.

Three intermediate - and senior-level radiologists (7-11 years of experience in MRI diagnosis) received systematic training of LI-RADS v2018. All 3 radiologists had applied LI-RADS v2018 clinically at least three months and passed the American College of Radiology LI-RADS case assessment. The LI-RADS features of all included lesions were assessed within the same month by three radiologists. During the evaluation process, the radiologists were blinded to each other's results. The radiologists were not informed of the clinical data and final results, but were informed the target population being studied had risk factors for HCC. MFs and AFs for each included lesion were evaluated and recorded by each radiologist, and each lesion was assigned to one of the following categories: LR-1, LR-2, LR-3, LR-4, LR-5, LR-M, and LR-TIV. LI-RADS v2018 classification was performed only through MFs. Any disputed results were resolved through negotiation at the final intragroup meeting. If the disagreement could not be resolved, the final result was that decided by a majority consensus.

Statistical analysis

Statistical analysis was performed by using version 26.0 SPSS (IBM, Armonk, NY, United States). The kappa test was used to analyze the consistency of features recognized between two radiologists. Kendall's W test was used to compare the consistency of features recognized among the three radiologists. The kappa values and Kendall's W values were interpreted as follows: Poor (0.00-0.20), fair (0.21-0.40), moderate (0.41-0.60), good (0.61-0.80), and excellent (0.81-1.00). Continuous variables were compared using the Shapiro-Wilk test; data conforming to a normal distribution were expressed as mean ± SD and analyzed using the independent samples t-test, while data conforming to a skewed distribution were expressed as median ± interquartile range and analyzed using the Mann-Whitney U test. Variables with P value < 0.1 in univariate analysis were included in multivariate Logistic regression analysis. The stepwise backward elimination method was used to determine the independent significant MFs and AFs that could independently significantly predict the malignancy of HCC. With pathological results as the gold standard, the diagnostic efficacy of standard LR-5 and modified LR-5 model for HCC, including sensitivity and specificity, were calculated respectively. McNemar test was used to compare the diagnostic efficacy of different diagnostic models.

RESULTS

Patients

A total of 216 patients were enrolled in this study, including 152 males (70.4%) and 64 females (29.6%). The age ranged from 20 to 84 years, with a mean of (58.69 ± 13.50) years. A total of 244 lesions were found in 216 patients, and the lesion size ranged from 0.6 cm to 18.9 cm, with an average of (4.51 ± 3.37) cm. The underlying liver-related causes were: HBV infection in 189 patients (87.5%), HCV infection with cirrhosis in 7 patients (3.2%), alcoholic cirrhosis in 8 patients (3.7%), non-alcoholic fatty liver disease with cirrhosis in 2 patients (0.9%), schistosomiasis cirrhosis in 5 patients (2.3%), and cirrhosis of other unknown causes in 5 patients (2.3%). The final diagnosis included 165 HCC lesions (67.6%), 24 non-HCC malignant lesions (9.8%), and 55 benign lesions (22.5%). Among the methods of obtaining final results, 117 (48.0%) were surgical pathology, 85 (34.8%) were puncture pathology, and 42 (17.2%) were follow-up results of at least 2 years. Detailed general information of other patients is shown in Table 1.

Table 1 Clinical and pathological characteristics of study patients, n (%).

Variables		Values
Number of patients		216
Age (years), mean ± SD		58.69 ± 13.50
Sex	Male	152 (70.4)
	Female	64 (29.6)
Cause of liver disease	HBV	189 (87.5)
	HCV	7 (3.2)
	ALD	8 (3.7)
	NAFLD	2 (0.9)
	SC	5 (2.3)
	Others	5 (2.3)
Number of lesions		244
Size of lesions (cm)		4.51 ± 3.37
Size subgroup	< 20 mm	76 (31.1)
	≥ 20 mm	168 (68.9)
Final diagnosis	HCC	165 (67.6)
	Non-HCC malignancy	24 (9.8)
	Intrahepatic cholangiocarcinoma	17 (7)
	NET G3	3 (1.2)
	Combined hepatocellular-cholangiocarcinoma	2 (0.8)
	Metastasis	2 (0.8)
	Benign lesion	55 (22.5)
	Hemangioma	19 (7.8)
	RN/DN	17 (6.9)
	FNH	9 (3.7)
	Liver abscess	6 (2.5)
	Angiomyolipoma	2 (0.8)
	Nodule of necrosis	1 (0.4)
	Hepatic schistosomiasis	1 (0.4)
Standard reference of diagnosis	Pathologic diagnosis of surgery	117 (48.0)
	Pathologic diagnosis of needle biopsy	85 (34.8)
	Typical imaging features with size stability (2 years)	42 (17.2)
LI-RADS category	LR-1	0 (0)
	LR-2	14 (5.7)
	LR-3	25 (10.2)
	LR-4	68 (27.9)
	LR-5	105 (43.0)
	LR-M	27 (11.1)
	LR-TIV	5 (2.0)

HBV: Hepatitis B; HCV: Hepatitis C; ALD: Alcoholic liver disease; NAFLD: Nonalcoholic fatty liver disease; SC: Schistosomal cirrhosis; NET: Neuroendocrine tumor; RN: Regenerative nodule; DN: Dysplastic nodule; FNH: Focal nodular hyperplasia-like nodule; LI-RADS: Liver Imaging Reporting and Data System.

LI-RADS features

Table 2 summarizes the consistency in the LI-RADS features assessed among different radiologists; excluding enhancing capsule (kappa value: 0.23-0.47, Kendall's W value: 0.52) and iron sparing in solid mass (kappa value: 0.31-0.37, Kendall's W value: 0.55), the consistency of the other features ranged from good to excellent, including nonperipheral washout (kappa value: 0.77-0.87, Kendall's W value: 0.79), transitional phase hypointensity (kappa value: 0.70-0.73, Kendall's W value: 0.87), mild-moderate T2 hyperintensity (kappa value: 0.71-0.75, Kendall's W value: 0.81), and fat in mass (kappa value: 0.73-0.83, Kendall's W value: 0.83).

Table 2 Liver Imaging Reporting and Data System features consistency of assessment among different radiologists, n (%).

LI-RADS features	Reader 1	Reader 2	Reader 3	Reader 1 vs reader 2, k value (95%CI)	Reader 1 vs reader 3, k value (95%CI)	Reader 2 vs reader 3, k value (95%CI)	Kendall's W
Nonrim APHE	204 (83.6)	174 (71.4)	203 (83.3)	0.67 (0.35-0.65)	0.81 (0.39-0.76)	0.73 (0.15-0.54)	0.81
Nonperipheral washout	163 (67.8)	155 (63.5)	150 (61.5)	0.83 (0.77-0.94)	0.87 (0.78-0.96)	0.77 (0.66-0.87)	0.79
Enhancing capsule	116 (47.5)	105 (43.0)	120 (49.2)	0.47 (0.33-0.66)	0.37 (0.31-0.51)	0.23 (0.11-0.27)	0.52
Threshold growth	7 (2.9)	5 (2.0)	6 (2.5)	1	1	1	1
Mosaic architecture	106 (43.4)	108 (44.3)	125 (51.3)	0.86 (0.83-0.97)	0.85 (0.71-0.94)	0.69 (0.67-0.83)	0.89
Non-enhancing capsule	21 (8.6)	21 (8.6)	21 (8.6)	0.71 (0.42-0.98)	0.71 (0.42-0.98)	0.71 (0.42-0.98)	0.79
Blood products in mass	100 (41.0)	82 (33.6)	76 (31.1)	0.87 (0.73-0.91)	0.89 (0.87-0.99)	0.90 (0.86-0.97)	0.93
Fat in mass-more than adjacent liver	82 (33.6)	86 (35.2)	90 (36.9)	0.83 (0.71-0.94)	0.81 (0.73-0.93)	0.73 (0.61-0.86)	0.83
Nodule-in-nodule architecture	83 (34.0)	78 (32.0)	72 (29.5)	0.71 (0.61-0.79)	0.67 (0.59-0.71)	0.59 (0.52-0.63)	0.65
Corona enhancement	42 (17.2)	56 (23.0)	53 (21.7)	0.81 (0.71-0.89)	0.83 (0.71-0.95)	0.78 (0.65-0.91)	0.83
Restricted diffusion	211 (86.5)	217 (88.9)	207 (84.8)	0.81 (0.65-0.91)	0.77 (0.61-0.89)	0.80 (0.66-0.95)	0.85
Mild-moderate T2 hyperintensity	213 (87.3)	200 (82.0)	202 (82.8)	0.75 (0.61-0.97)	0.71 (0.60-0.97)	0.73 (0.15-0.73)	0.81
Fat sparing in solid mass	15 (6.1)	29 (11.9)	31 (12.7)	0.61 (0.41-0.82)	0.64 (0.41-0.86)	0.45 (0.21-0.68)	0.71
Iron sparing in solid mass	44 (18.0)	38 (15.6)	40 (16.4)	0.31 (0.11-0.47)	0.33 (0.17-0.52)	0.37 (0.19-0.61)	0.55
Transitional phase hypointensity	229 (93.9)	225 (92.2)	230 (94.3)	0.73 (0.51-0.90)	0.71 (0.61-0.83)	0.70 (0.51-0.83)	0.87
Hepatobiliary phase hypointensity	223 (91.4)	225 (92.2)	225 (92.2)	0.81 (0.78-0.95)	0.82 (0.77-0.95)	0.87 (0.53-0.92)	0.89
Subthreshold growth	18 (7.4)	19 (7.8)	19 (7.8)	0.84 (0.67-1.01)	0.89 (0.74-1.04)	0.84 (0.67-1.01)	0.91

LI-RADS: Liver Imaging Reporting and Data System; CI: Confidence interval; APHE: Arterial phase hyperenhancement.

Univariate and multivariate logistic regression analysis of LI-RADS v2018 MFs and malignant AFs

In MFs, univariate analysis revealed statistically significant differences between HCC and non-HCC lesions in terms of lesion size, nonrim arterial phase hyperenhancement (APHE), nonperipheral washout, and enhanced capsule (all P values < 0.05). The mosaic architecture, blood products in mass, fat in mass and nodule-in-nodule architecture between HCC lesions and non-HCC lesions among the AFs favoring HCC in particular showed statistically significant differences (all P values < 0.05). Among the AFs favoring malignancy in general, there were statistically significant differences between HCC lesions and non-HCC lesions in restricted diffusion, mild-moderate T2 hyperintensity, transitional phase hypointensity and hepatobiliary phase hypointensity (all P values < 0.05).

Multivariate logistic regression analysis showed that Nonrim APHE [odds ratio (OR) = 18.913; 95% confidence interval (CI): 5.437-65.788; P = 0.000], nonperipheral washout (OR = 3.443; 95%CI: 0.920-12.887; P = 0.006), enhancing capsule (OR = 7.126; 95%CI: 1.209-42.004; P = 0.030), fat in mass (OR = 9.846; 95%CI: 2.042-47.467; P = 0.004) and mild-moderate T2 hyperintensity (OR = 13.516; 95%CI: 2.568-71.131; P = 0.002), transitional phase hypointensity (OR = 43.403; 95%CI: 10.479-179.770; P = 0.000), were independent and significant predictors of HCC (Table 3).

Table 3 Diagnostic performance and logistic regression analyses of major features and ancillary features favoring malignancy in Liver Imaging Reporting and Data System version 2018 for diagnosing hepatocellular carcinoma.

Features	Diagnostic performance (%)		Univariable analysis		Multivariable analysis
	Sensitivity	Specificity	OR (95%CI)	P value	OR (95%CI)	P value
Major features
Size of lesions (≤ 20 mm; > 20 mm)	73.3 (121/165)	40.5 (32/79)	1.872(1.063-3.299)	0.029a	0.969 (0.281-3.339)	0.960
Nonrim APHE	88.5 (146/165)	49.4 (39/79)	7.492(3.910-14.357)	0.000a	18.913 (5.437-65.788)	0.000b
Nonperipheral “washout”	58.8 (97/165)	88.6 (70/79)	11.095 (5.188-23.727)	0.000a	3.443 (0.920-12.887)	0.006b
Threshold growth	1.2 (2/165)	96.2 (76/79)	0.311(0.051-1.899)	0.395	-	-
Enhancing “capsule”	49.7 (82/165)	94.9 (75/79)	18.524 (6.475-52.991)	0.000a	7.126 (1.209-42.004)	0.030b
Malignant ancillary features favoring HCC
Mosaic architecture	51.5 (85/165)	74.7 (59/79)	3.134 (1.734-5.665)	0.000a	0.687 (0.188-2.516)	0.571
Nonenhancing “capsule”	4.2 (7/165)	96.2 (76/79)	1.122 (0.282-4.461)	1.000	-	-
Blood products in mass	38.2 (63/165)	91.1 (73/79)	6.353 (2.751-14.673)	0.000a	1.833 (0.385-8.730)	0.446
Fat in mass, more than adjacent liver	30.3 (50/165)	89.9 (71/79)	3.859 (1.729-8.612)	0.000a	9.846 (2.042-47.467)	0.004b
Nodule-in-nodule	30.3 (50/165)	93.7 (74/79)	6.435 (2.453-16.883)	0.000a	0.995 (0.200-4.949)	0.995
Favoring malignancy in general
Corona enhancement	15.2 (25/165)	84.8 (67/79)	0.997 (0.472-2.105)	0.994	-	-
Restricted diffusion	86.7 (143/165)	57.0 (45/79)	8.603 (4.571-16.190)	0.000a	0.697 (0.142-3.432)	0.658
Mild-moderate T2 hyperintensity	95.2 (157/165)	86.3 (50/79)	33.836 (14.535-78.766)	0.000a	13.516 (2.568-71.131)	0.002b
Fat sparing in solid mass	4.8 (8/165)	98.7 (78/79)	3.975 (0.488-32.344)	0.305	-	-
Iron sparing in solid mass	6.1 (10/165)	96.2 (76/79)	1.634 (0.437-6.113)	0.666	-
Transitional phase hypointensity	93.9 (155/165)	68.4 (54/79)	33.480 (15.103-74.219)	0.000a	43.403 (10.479-179.770)	0.000b
Hepatobiliary phase hypointensity	93.3 (154/165)	32.9 (26/79)	6.868 (3.177-14.848)	0.000a	0.999 (0.230-4.344)	0.999
Subthreshold growth	5.5 (9/165)	94.9 (75/79)	1.082 (0.323-3.626)	1.000	-	-

^aP < 0.2 in univariable analysis.

^bP < 0.05 in multivariable analysis.

OR: Odds ratio; CI: Confidence intervals; APHE: Arterial phase hyperenhancement; HCC: Hepatocellular carcinoma.

Efficacy analysis of the modified LR-5 model for HCC diagnosis

The modified LR-5: LR-5-M1: LR-4 + transitional phase hypointensity; LR-5-M2: LR-4 + mild-moderate T2 hyperintensity; LR-5-M3: LR-4 + fat in mass; LR-5-M4: Transitional phase hypointensity substitute threshold growth; LR-5-M5: Mild-moderate T2 hyperintensity substitute threshold growth; LR-5-M6: Fat in mass substitute threshold growth; LR-5-M7: LR-3/LR-4 + transitional phase hypointensity + mild-moderate T2 hyperintensity + fat in mass; LR-5-M8: LR-3/LR-4 + any two features of transitional phase hypointensity, mild-moderate T2 hyperintensity and fat in mass; LR-5-M9: LR-3/LR-4 + any one features of transitional phase hypointensity, mild-moderate T2 hyperintensity and fat in mass. Compared with the standard LR-5, LR-5-M1, LR-5-M4, LR-5-M5 and LR-5-M8 can improve the sensitivity without significantly reducing the specificity of LR-5, among which LR-5-M1 and LR-5-M8 have the highest sensitivity (both 89.1%). There was no significant difference in specificity (88.6%, 89.9%) compared with LR-5 (P = 0.385), as shown in Table 4, Figure 2, and Figure 3.

Figure 2 Axial images obtained with gadoxetic acid–enhanced magnetic resonance imaging in a 62-year-old man with cirrhosis by chronic B-viral hepatitis and surgically confirmed hepatocellular carcinoma. This lesion was assigned as LR-4 and could not be classified as LR-5 using Liver Imaging Reporting and Data System version 2018. In contrast, our modified LR-5 criteria or alternative criteria (LR-5-M1, LR-5-M2, LR-5-M8 and LR-5-M9) by utilizing independently significant ancillary features (nonrim arterial phase hyperenhancement, nonperipheral washout, mild-moderate T2 hyperintensity and transition phase hypointensity) helped achieve the correct diagnosis of hepatocellular carcinoma. A and B: In-/out-of-phase T1-weighted image showed a 0.9 cm-diameter mass in segment VIII of the liver (white arrow); C: T2-weighted image showed mild-moderate T2 hyperintensity in the lesion; D: Diffusion-weighted imaging showed restricted diffusion in the lesion; E: Pre-enhanced phase showed hypointensity in the lesion; F: Late artery phase showed nonrim arterial phase hyperenhancement in the lesion; G: Portal venous phase showed nonperipheral washout in the lesion; H and I: The transition phase and hepatobiliary phase showed hypointensity in the lesion (white arrow).

Figure 3 Axial images obtained with gadoxetic acid–enhanced magnetic resonance imaging in a 79-year-old man with cirrhosis by chronic B-viral hepatitis and surgically confirmed hepatocellular carcinoma. This lesion was assigned as LR-4 and could not be classified as LR-5 using Liver Imaging Reporting and Data System version 2018. In contrast, our modified LR-5 criteria or alternative criteria (LR-5-M1, LR-5-M2, LR-5-M3, LR-5-M4, LR-5-M5, LR-5-M6, LR-5-M7, LR-5-M8 and LR-5-M9) by utilizing independently significant ancillary features (nonrim arterial phase hyperenhancement, mild-moderate T2 hyperintensity, transition phase hypointensity and fat in mass, more than adjacent liver) helped achieve the correct diagnosis of hepatocellular carcinoma. A and B: T1-weighted image showed a 1.9 cm-diameter mass in segment VI of the liver (white arrow), signal loss (white arrow) in the leision of out phase imaging compared to that of in phase imaging indicated fat in mass, more than adjacent liver; C: T2-weighted image showed mild-moderate T2 hyperintensity in the lesion; D: Diffusion-weighted imaging showed restricted diffusion in the lesion; E: Pre-enhanced phase showed hypointensity in the lesion; F: Late artery phase showed nonrim arterial phase hyperenhancement and corona enhancement in the lesion; G: Portal venous phase showed no washout in the lesion; H: Transition phase showed hypointensity and enhancing capsule in the lesion; I: Hepatobiliary phase showed hypointensity in the lesion (white arrow).

Table 4 Diagnostic performances of various criteria using upgraded LR-5 for the noninvasive diagnosis of hepatocellular carcinoma.

Diagnostic criteria	Upgrade number	Total/final number	Sensitivity% (95%CI)	P value2	Specificity% (95%CI)	P value2
LR-5	-	105/244	60.6 (0.532-0.681)	-	93.7 (0.883-0.990)	-
LR-5-M11	51	156/244	89.1 (0.843-0.938)	0.000	88.6 (0.816-0.956)	0.263
LR-5-M2	54	159/244	87.9 (0.829-0.929)	0.000	82.3 (0.739-0.907)	0.028
LR-5-M3	16	121/244	67.9 (0.608-0.750)	0.168	88.6 (0.816-0.956)	0.263
LR-5-M41	50	155/244	88.5 (0.836-0.934)	0.000	88.6 (0.816-0.956)	0.263
LR-5-M51	53	158/244	88.5 (0.836-0.934)	0.000	84.8 (0.769-0.927)	0.072
LR-5-M6	17	122/244	68.5 (0.614-0.756)	0.135	88.6 (0.816-0.956)	0.263
LR-5-M7	11	116/244	67.3 (0.601-0.744)	0.207	93.7 (0.883-0.990)	1.000
LR-5-M81	50	155/244	89.1 (0.843-0.938)	0.000	89.9 (0.832-0.965)	0.385
LR-5-M9	70	175/244	91.5 (0.873-0.958)	0.000	69.6 (0.595-0.798)	0.000

¹By using these alternative criteria, the sensitivities were significantly increased in varying degrees, whereas specificities were not significantly different compared with the standard LR-5.

²In comparison with the standard LR-5 of LI-RADS v2018.

M: Modified; LR-5-M1: LR-4 by major features alone + TP hypointensity; LR-5-M2: LR-4 by major features alone + mild-moderate T2 hyperintensity; LR-5-M3: LR-4 by major features alone + fat in mass, more than adjacent liver; LR-5-M4: Transition phase (TP) hypointensity substitute threshold growth; LR-5-M5: Mild-moderate T2 hyperintensity substitute threshold growth; LR-5-M6: Fat in mass, more than adjacent liver substitute threshold growth; LR-5-M7: LR-3/LR-4 by major features alone + TP hypointensity + mild-moderate T2 hyperintensity + fat in mass, more than adjacent liver; LR-5-M8: LR-3/LR-4 by major features alone + any two features of TP hypointensity, mild-moderate T2 hyperintensity and fat in mass, more than adjacent liver; LR-5-M9: LR-3/LR-4 by major features alone + anyone features of TP hypointensity, mild-moderate T2 hyperintensity and fat in mass, more than adjacent liver; CI: Confidence intervals.

DISCUSSION

Our research demonstrates that Three MFs (nonrim APHE, nonperipheral washout and enhancing capsule), one AFs favoring HCC in particular (fat in mass), and two AFs favoring malignancy in general (transitional phase hypointensity and mild-moderate T2 hyperintensity) are LI-RADS features that can independently and significantly predict HCC on Gd-EOB-DTPA enhanced MRI. When the LR-4/ LR-3 lesions, which classified by MFs alone upgraded to LR-5 through independently and significantly malignant AFs of HCC, the sensitivity of the four modified LR-5 criteria for HCC diagnosis was higher than that of the standard LR-5, while the specificity was not significantly reduced.

Although some scholars have modified LI-RADS through malignant AFs, previous studies only explored a few features and modification modes[3,30,32-34]. In contrast, our study included all MFs and malignant AFs in LIRADS v2018, except for ultrasound visibility as discrete nodule, to identify the LI-RADS features that can independently and significantly predict HCC on Gd-EOB-DTPA enhanced MRI. Three malignant AFs (transitional phase hypointensity, mild-moderate T2 hyperintensity, and fat in mass) were discovered to be independently significant LI-RADS features that could predict HCC. This shows that the three malignant AFs mentioned above may be as important to MFs in the diagnosis of HCC. Furthermore, compared to other malignant AFs, the weight of these three AFs in the diagnosis of HCC may be underestimated in LI-RADS, these AFs can be used to upgrade lesions. Our research results are consistent with those of Xie et al[32], but the sensitivity of the modified LR-5 standard is higher than that of their study (70.7%). The possible reason is that the modification methods are different. Our study made an attempt to replace the threshold growth of MFs (LR-5-M4, 5, 6). And two of the modified LR-5 criteria can improve their sensitivity without significantly reducing the specificity of the original LR-5 criteria. Secondly, their study only included lesions of 10-19 mm size, and different inclusion criteria may also lead to differences in results. In addition, the threshold growth of MFs in our study did not show a high diagnostic value, which was consistent with the study of Park et al[29]. The possible reason is that the medical environment in our region emphasizes the early diagnosis and early local treatment of HCC, so there were fewer lesions showing this feature; in fact, just 2% (5/244) of lesions in our study showed threshold growth.

Our study shows that in AFs favoring malignancy, mild-moderate T2 hyperintensity and transitional phase hypointensity are LI-RADS features that can independently and significantly predict HCC on Gd-EOB-DTPA enhanced MRI. LI-RADS defined mild-moderate T2 hyperintensity as intensity on T2WI higher than liver, similar to or lower than non-ironoverloaded spleen, and lower than simple fluid. Mild-moderate T2 hyperintensity was considered to be positively correlated with arterial blood flow and negatively correlated with intrafocal portal blood flow[25]. It has been reported in the studies that up to 83% of HCC and 32%-53% of well-differentiated HCC showed mild-moderate T2 hyperintensity[35-37], and the occurrence of mild-moderate T2 hyperintensity was more frequently occurred in HCC with higher histopathological grade[38,39]. Previous studies have shown that a mild-moderate T2 hyperintensity helps to distinguish HCC lacking blood supply/ small HCC from a benign nodular/ vasogenic artifact[40,41], and most infiltrating HCC usually show mild-moderate T2 hyperintensity even without APHE[42]. The presence of mild-moderate T2 hyperintensity is highly suggestive of malignancy and is also seen in non-HCC malignancies[43]. Jeon et al[44] found that the sensitivity significantly increased but the specificity was not significantly altered when LR-3 was upgraded to LR-4 with mild-moderate T2 hyperintensity. The sensitivity of LR-4 was greatly increased and the specificity was also significantly reduced when other malignant AFs that could independently predict HCC significantly were utilized for upgrading. LI-RADS defined TP hypointensity as intensity in the transitional phase lower than liver, and the evaluation of this feature required TP 5-10 minutes after injection of Gd-EOB-DTPA. The liver parenchyma continued to enhancing after PVP as a result of liver cells uptake Gd-EOB-DTPA; hence, the hypointensity observed in TP may be caused by contrast agent clearance or by the lesion's absence of normal functional organic anion transport polypeptides. Due to the inability to distinguish between the two processes, LI-RADS believed that TP hypointensity did not have the same diagnostic importance as washout and could not be included in MFs[25]. However, many previous studies believed that TP hypointensity was an independent and significant predictor of HCC, and most HCC showed TP hypointensity[15,32,35]. Although the LI-RADS lexicon does not permit the interchange of image features among various image modalities, Lim et al[45], significantly improve the sensitivity without reducing the specificity of LR-5 by adding CT image washout features.

Neither mild-moderate T2 hyperintensity nor TP hypointensity is specific to HCC. Therefore, HCC cannot be diagnosed by mild-moderate T2 hyperintensity or TP hypointensity alone in the absence of MFs. Contrarily, in our study, by combining mild-moderate T2 hyperintensity and/or low TP hypointensity with LR-4/LR-3 lesions classified by MFs, the modified LR-5 criteria can significantly improve the sensitivity without significantly reducing the specificity. Our results are consistent with some previous studies[3,32,46], but inconsistent with those of Zhang et al[12]. Their study can improve the sensitivity of LR-5 lesions without affecting the specificity of LR-5 lesions by using HBP hypointensity as an additional MFs or replacing the enhanced capsule with HBP hypointensity as MFs. However, HBP hypointensity in this study did not become an independent and significant predictor of malignant AFs for HCC. The use of contrast agents may account for this difference. In the study of Zhang et al[12], gadobenate dimeglumine was used as a contrast agent, although it could be metabolized through both liver and kidney pathways at the same time as Gd-EOB-DTPA. However, Gd-EOB-DTPA was 50% hepatocellular specific, HBP was collected 15-20 minutes after injection, gadobenate dimeglumine was 5% hepatocellular specific, and HBP was collected 60 minutes after injection. Although Pan et al[47] found through the systematic review and meta-analysis of previous studies that using hypointensity on TP and HBP as an additional form of washout could improve the sensitivity of LI-RADS in the diagnosis of HCC, the original high specificity was decreased. By combining TP hypointensity with lesions classified as LR-4 by MFs as the modified LR-5 standard (LR-5-M1), our study found that the sensitivity could be significantly improved without significantly reducing the original high specificity of LR-5 standard. However, when mild-moderate T2 hyperintensity was combined with a lesion classified as LR-4 by MFs as a modified LR-5 standard (LR-5-M2), its sensitivity was significantly increased, but its specificity was also significantly decreased.

In our study, fat in mass (ancillary features favoring HCC in particular) is another important LI-RADS features that can independently and significantly predict HCC on Gd-EOB-DTPA enhanced MRI. LI-RADS defined fat in mass as excess fat within a mass, in whole or in part, relative to adjacent liver, which could be manifested as relative paucity of fat in a solid mass relative to steatotic liver or in inner nodule relative to steatotic outer nodule. The exact underlying mechanism of fat in HCC remains unclear. It may be that abnormal fat metabolism occurs during clonal expansion of dysplastic hepatocytes[25]. Moreover, as HCC develops and progresses, the primary blood supply shifts from the portal vein to the hepatic artery. This change in blood flow may result in cell metabolic abnormalities and ultimately cause steatosis. Lesions containing fat are commonly seen in small HCC, and the incidence is negatively correlated with the size of the lesion, and this feature can well distinguish intrahepatic cholangiocarcinoma from HCC[48]. Previous studies have proved that the detection of focal fat in high-risk HCC patients is beneficial to the diagnosis of HCC[49,50], and the presence of focal fat is considered to be a hallmark of the transformation from atypical hyperplasia to HCC[51,52]. The above reasons may explain why fat in mass is an important LI-RADS features that can independently and significantly predict HCC on Gd-EOB-DTPA enhanced MRI, and our study was mostly in accordance with those of Xie et al[32]. In our study, we found that the modified LR-5 standard (LR-5-M8) could produce a higher sensitivity (89.1%) without significantly lowering the original high specificity of the LR-5 standard when any two independently and significantly AFs (fat in mass, mild-moderate T2 hyperintensity, and low TP hypointensity) were combined with lesions classified as LR-4/3 by MFs. However, it was found that although the sensitivity was greatly improved, the specificity was also significantly reduced when fat in mass, mild-moderate T2 hyperintensity, and low TP hypointensity were combined with the lesions classified as LR-4/3 by MFs.

Furthermore, our study assessed the diagnostic performance of the modified LR-5 by substituting one or more independently significant malignant AFs for the threshold growth. Two modified LR-5 criteria (LR-5-M4: LR5 or TP hypointensity replaces the threshold growth; LR-5-m5: LR5 or mild-moderate T2 hyperintensity replaces the threshold growth) were also could significantly improve sensitivity without significantly reducing the original high specificity of the LR-5 standard.

There are some limitations in our study. First, this study is a single-center study, there may be potentially unavoidable selection bias. Second, the target population may different from that in other regions. Most of the patients in our study were previously infected with HBV or patients with HBV cirrhosis, which may limit its application in other regions. Further studies need to be conducted in international multicenter Settings that include more patients with HCV infection, alcoholic liver disease, or nonalcoholic fatty liver disease. Moreover, most of the final results of benign lesions were based on follow-up and clinical diagnosis rather than pathological diagnosis. The clinical practice in our region, it is not recommended to conduct invasive histopathological confirmation of highly suspected benign lesions in imaging and laboratory tests. Finally, the results demonstrated that TP hypointensity could independently and significantly predict malignant AFs of HCC, which was not applicable in Gd-DTPA enhanced LR-5 criteria.

CONCLUSION

In conclusion, we believe that LR-3/LR-4 can be upgraded to LR-5 in our region using independently and considerably malignant AFs (fat in mass, mild-moderate T2 hyperintensity, and low TP hypointensity). The modified LR-5 criteria can increase the sensitivity of LR-5 in the diagnosis of HCC while having minimal impact on its specificity.