Gd-EOB-DTPA-enhanced hepatobiliary phase MRI characteristics of inflammatory hepatic adenoma

Purpose

To investigate the imaging characteristics of the hepatocyte-specific contrast agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in inflammatory hepatocellular adenoma.

Methods

The clinical data and magnetic resonance imaging (MRI) manifestations of 13 patients with pathologically confirmed I-HCA were retrospectively analyzed. There were 10 males and 3 females with an average age of 33.1 ± 10.7years. All patients underwent enhanced MR examination with Gd-EOB-DTPA (a hepatocyte-specific contrast agent). Image analysis included the number, location, size, morphology, plain scan signal, enhancement characteristics, and hepatobiliary-specific phase (HBP). The apparent diffusion coefficient (ADC) values of the lesions and surrounding normal liver parenchyma were measured on the ADC map, and the difference was compared by paired sample t-test.

Results

In this study, CRP showed a high rate of positive results; there was positive reactivity for CD34 in all patients. Among the 13 cases, 8 cases were single and 5 were multiple, for a total of 26 lesions. The margins of the lesions were all clear, and mostly round or oval; T1WI showed equal or high signal, T2WI showed high signal, DWI showed high signal, the arterial phase was highly enhanced, and the portal phase was not clear. 21 lesions in the hepatobiliary-specific phase had no uptake. The atoll sign was present in only 12% of cases. There was no significant difference between the average ADC value of the lesion and the average ADC value of the adjacent normal liver parenchyma (P = 0.620). The study revealed positive reactivity for C-reactive protein (CRP) and CD34.

Conclusion

The Gd-EOB-DTPA-enhanced hepatobiliary phase MRI of I-HCA exhibits certain characteristic features, which serve as an aid in the diagnosis of the disease.

Hepatocellular adenoma (HCA) is a rare benign monoclonal liver tumor that can be categorized into four subtypes based on genotype and immunophenotypic characteristics:1) Inflammatory hepatocellular adenoma (I-HCA), accounting for about 40–45%; 2) HNF1α-inactivated HCA (H-HCA), comprising approximately 35%; 3) β-catenin-activated HCA (β-HCA), about 20%; and 4) unclassified HCA (U-HCA), representing less than 10% [1, 2]. In 2017, a further classification into eight subtypes was proposed, based on Sonic Hedgehog pathway activation and exon mutation status [3]. The primary complications associated with HCA include hemorrhage and malignant transformation, with non-H-HCA subtypes exhibiting a higher risk of malignancy compared to H-HCA. I-HCA, constituting the majority of non-H-HCA, is shown to have a higher risk of bleeding due to histological features such as inflammatory infiltration, sinusoidal dilation, thick-walled arteries, and biliary reactions [2, 4]. Early diagnosis of I-HCA is crucial. Routine tissue biopsy for suspected HCA lesions may lead to nonspecific results and increase the risk of bleeding. Therefore, non-invasive imaging techniques, particularly magnetic resonance imaging (MRI), play a key role in the diagnosis of HCA [3, 5]. However, current evidence regarding the use of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI in the assessment of hepatocellular adenoma remains limited. This study aims to address this knowledge gap by offering additional details about the diagnostic utility of this imaging technique.

Clinical data

This retrospective study was approved by the ethical committee of our institution (Approval number: B2021-366), and the requirement for obtaining informed consent was waived because of the retrospective nature of the study. This retrospective study covers 13 patients with I-HCA diagnosed at our institution from June 2015 to August 2024. These patients had a total of 47 lesions. Inclusion criteria were patients who had not undergone radiotherapy, chemotherapy, or immunotherapy, and whose histological characteristics of multiple lesions were essentially similar to those of solitary lesions. 21 lesions were excluded based on the following criteria: (1) lesions in multifocal cases that were not biopsied or surgically resected (n = 6); (2) lesions < 6 mm in size and/or located subcapsularly where accurate apparent diffusion coefficient (ADC) values could not be measured (n = 10); (3) lesions not visible or unclear on MRI images (n = 4); (4) lesions post-interventional procedures (n = 1). All patients underwent blood testing at our institution.

Imaging examination methods

In this study, a total of 13 patients with I-HCA were included. All of them underwent MRI scans using the Siemens Aera 1.5 T superconducting MRI from Germany. Abdominal coils were used, and the main scanning sequences included fat-suppressed fast spin-echo T2-weighted imaging, in-phase and opposed-phase gradient echo T1-weighted imaging, diffusion-weighted imaging (DWI), and 3D-VIBE dynamic contrast-enhanced scanning.

All patients received Gd-EOB-DTPA, marketed as Primovist by Bayer Schering Pharma in Germany and known as Eovist in the United States, for contrast-enhanced scans. The total volume of the contrast agent was 10 ml, injected into the elbow vein at a rate of 1 ml/s, followed by a 20 ml saline flush. Post-contrast imaging was performed to obtain arterial phase, portal venous phase, and transitional phase images at 25–30 s, 60–80 s, and 180 s after the injection, respectively. Hepatobiliary phase scanning was conducted 10–30 min after the injection. All imaging examinations for this case group utilized respiratory gating and were scanned at the end of expiration. The specific scanning parameters of Gd-EOB-DTPA are shown in Supplementary Table 1.

Image analysis

The images were independently reviewed by two radiologists, each with over 10 years of experience in liver MRI diagnostics, using the GE PACS system. The final interpretation was reached in consensus. The following features were recorded: (1) Lesion Characteristics: Number, location, size, shape, borders, signal intensity, and signal changes on in-phase and opposed-phase imaging. The T1WI/T2WI signal of the lesions was compared with the surrounding normal liver tissue and categorized as low signal, isointense, or high signal. (2) Dynamic Enhancement Features and Hepatobiliary Phase (HBP) Signal: The signal intensity of the lesions in the arterial phase, portal venous phase, transitional phase, and hepatobiliary phase was analyzed, with the enhancement level of the liver parenchyma in the same phase serving as a reference. (The criterion for high enhancement in the arterial phase was a signal clearly higher than the liver parenchyma, with a net enhancement amplitude clearly higher than the liver parenchyma.) (3) ADC Measurement: The ADC values of the lesions and the surrounding normal liver parenchyma were measured. To avoid large vessels, hemorrhage, and artifacts, three different, similarly sized circular regions of interest (ROIs) were selected in each lesion. The average value of these measurements was taken as the final ADC value. (4) Observation of Accompanying Signs: Hemorrhage, cystic changes, necrosis, central scar, capsule, and halo signs were noted. The data presented in this study represent the final consensus set.

Pathological analysis

All samples underwent hematoxylin and eosin (H&E) staining as well as immunohistochemical staining for markers including serum amyloid A (SAA) and CD34. Additionally, the surrounding liver parenchyma was assessed for fatty infiltration and cirrhosis.

Statistical methods

Statistical analysis was conducted using SPSS software version 26.0. The Shapiro-Wilk test was employed to determine whether the quantitative data followed a normal distribution. Continuous variables were expressed as mean ± standard deviation (x ± s). Paired-sample t-tests were used to compare the differences in ADC values between the lesions and surrounding liver parenchyma. A P-value of less than 0.05 was considered statistically significant.

Clinical and pathological characteristics

Among the 13 patients, there were 10 males and 3 females, aged 20 to 59 years, with an average age of 33.1 ± 10.7 years. Six patients were classified as obese, defined by a body mass index (BMI) of 28 kg/m² or higher, while five patients were classified as overweight (BMI > 24 kg/m² or < 28 kg/m²). One patient had a history of hypertension and diabetes, with a daily history of smoking and alcohol consumption for over 10 years; 2 had a history of hypertension. 8 patients had solitary lesions, and 5 had multiple lesions. 10 patients had concurrent fatty liver disease. All patients denied a history of steroid medication, and female patients denied a history of oral contraceptive use. Laboratory tests revealed 1 case of hepatitis B and 1 case of slightly elevated alpha-fetoprotein (AFP), while tumor markers including AFP, carcinoembryonic antigen (CEA), and CA-199 were negative in other patients; C-reactive protein (CRP) was not tested in 5 cases, elevated in 6 cases, and normal in 2 cases. There was positive reactivity for CD34 in all patients. 12 cases showing positive SAA. Clinical and pathological characteristics are shown in Table 1.

Gd-EOB-DTPA enhanced scanning

In the 13 patients with 26 lesions, all lesions had well-defined borders; 22 lesions were round or oval, and 4 were slightly lobulated. The average length of the lesions was 29.0 ± 23.3 mm (range 9.0–120.0 mm). On T1WI sequences, 18 lesions appeared hyperintense (including one with a patchy low signal and one with a ring-like pattern of central low and peripheral high signal). On T2WI sequences, 88% of the lesions showed high signal intensity (including one with a distinct stellate high signal on T2WI, one with a patchy low signal, and one with a ring-like central high and peripheral isointense signal). On DWI sequences, 84.6% of the lesions showed high signal intensity. The atoll sign is present in only 12% of cases. All lesions exhibited high enhancement during the arterial phase, with most showing obvious homogeneous enhancement. In the HBP, most lesions did not show uptake. Specific imaging features are presented in Fig. 1; Table 2.

Images a to f are from the same patient. a: Slightly high signal on T2-weighted imaging (T2WI); b and e: Volume interpolated breath-hold examination (VIBE) sequence showing low signal in the center and high signal at the edges in pre-contrast images. In the arterial phase, there is significant enhancement in the center and moderate ring-like enhancement at the edges. In the portal venous and transitional phases, the enhancement in the center fades while the edges continue to enhance. In the hepatobiliary phase (HBP), there is ring-like uptake around the lesion, but no uptake in the center. The criterion for HBP assessment is the presence of contrast agent in the bile ducts

Full size image

ADC value analysis

The average ADC value for the 26 lesions was 1.126 ± 0.402 × 10^-3 mm/s, while the average ADC value for the adjacent normal liver parenchyma was 1.293 ± 0.196 × 10^-3 mm/s. The difference between the two was not statistically significant (P = 0.620, P > 0.05, as shown in Fig. 2).

The average apparent diffusion coefficient (ADC) value for the 26 lesions was 1.126 ± 0.402 × 10^-3 mm/s, whereas the average ADC value for the adjacent normal liver parenchyma was 1.293 ± 0.196 × 10^-3 mm/s. The difference between the two was not statistically significant (P = 0.620 > 0.05)

Full size image

I-HCA is one of the primary pathological subtypes of liver adenomas. Since the 1970s, its association with oral contraceptive pills (OCPs) has been reported [6]. Historically, middle-aged women with a history of OCP use were considered a high-risk group for liver adenomas. Recent studies have shown significant epidemiological disparities in liver adenomas between Western and Eastern patients due to the widespread use of second- and third-generation OCPs (which contain lower levels of hormones), changes in contraceptive methods, and lifestyle differences. Notably, in Asian countries, liver adenomas are more common in men, and cases in women without a history of OCP use are more frequent [7,8,9]. Additionally, high BMI, metabolic syndrome, and alcohol intake have been identified as new associated factors for I-HCA [5, 9]. In this study, the ratio of male to female participants was 10:3, with overweight and obese patients accounting for 11 out of 13 cases, and one patient with a history of alcohol abuse, aligning with these new associated factors. I-HCA patients often lack specific clinical symptoms and are predominantly diagnosed incidentally. Tumor markers in these patients are typically negative, with normal liver enzyme levels. This study demonstrated elevated expression of acute inflammatory markers, including CRP and SAA, in the serum of I-HCA patients. This finding is consistent with the results reported by Bioulac-Sage et al. [1, 2, 5].

The atoll sign, defined in international literature as a ring of high T2WI signal around the lesion’s margin, shows enhancement in the arterial and portal venous phases but no uptake in the HBP. This sign has high specificity for diagnosing I-HCA [10, 11]. However, its sensitivity is lower in Asian populations [8, 12], which aligns with the findings of this study. Additionally, I-HCA often appears hyperintense on diffusion-weighted imaging (DWI), but there is no statistically significant difference in ADC values compared to the surrounding normal liver parenchyma. Researchers believe that the DWI hyperintensity in I-HCA might be related to the T2 shine-through effect. I-HCA pathologically exhibits sinusoidal dilatation, polymorphous inflammatory cell infiltration, petechiae, and distorted thick-walled blood vessels. These features lead to its unique imaging characteristics, particularly the delayed enhancement in the high signal areas on T2-weighted images (T2WI) [13, 14]. In this study, all 26 I-HCA lesions showed no washout and exhibited a “fast in, slow out” enhancement pattern, consistent with existing literature [12, 14].

About 20% of I-HCA lesions displayed varying degrees of iso- or hyperintensity in the HBP, which could even be observed in multiple lesions within the same patient [15,16,17]. Grazioli et al. [18] in 2005 found that the studied HCAs were hypointense relative to normal liver in the hepatobiliary phase, even in samples containing I-HCA subtypes. However, this study’s findings differed, noting that some I-HCA can present varying degrees of iso- or hyperintensity in the hepatobiliary phase. One possible explanation is that some lesions were previously considered focal nodular hyperplasia (FNH) and now are reclassified as I-HCA. The specific mechanism behind the iso- or hyperintensity of I-HCA in the hepatobiliary phase remains unclear. Some scholars believe it may be due to the inherent high signal on T1WI images and potential steatosis in the tumor [19], while others suggest it could be related to changes in cellular architecture and absence of bile duct structures, which impairs the excretion of contrast agents in I-HCA [11]. Despite this, the uptake and excretion of Gd-EOB-DTPA largely depend on transport proteins on the hepatocyte surface; hence, most I-HCA still appear as low signal in HBP.

I-HCA has the highest incidence and bleeding rate among all liver adenoma subtypes. In contrast, H-HCA ranks second in terms of incidence but has the lowest invasiveness. Despite having a lower incidence, β-HCA carries the highest risk of malignant transformation. Therefore, accurate subtyping is crucial for clinical decision-making. In magnetic resonance (MR) chemical shift imaging, H-HCA is characterized by a diffuse, uniform signal drop within the tumor, offering high sensitivity and specificity for its diagnosis [17]. According to literature, H-HCA has the lowest signal intensity in the HBP among all liver adenoma subtypes [7, 11,12,13]. β-HCA, with the highest rate of malignant transformation among all subtypes, exhibits imaging characteristics similar to hepatocellular carcinoma (HCC) and is significantly associated with a history of chronic hepatitis B and central scarring. Studies suggest that the “fast in, fast out” enhancement pattern and low ADC values of β-HCA may be linked to its potential for malignant transformation [8, 11, 13]. Unfortunately, there are no detailed studies on the characteristic imaging features of U-HCA, and the new subcategories such as βI-HCA and sh-HCA remain unsolved puzzles in the field of radiology [3].

Although the atoll sign has been demonstrated to exhibit high specificity in diagnosing I-HCA, our study indicates that this sign has lower sensitivity in the Asian Homo sapiens population. Therefore, for the Asian Homo sapiens population, diagnosis requires combining other imaging features with the atoll sign, particularly for lesions detected via CT or other examinations but displaying atypical adenoma characteristics. The hepatobiliary-specific MR enhancement of I-HCA presents some uncommon manifestations, which is the focus of this study. Unlike previous research, our study summarizes the pathological features of I-HCA and, for the first time, reports that I-HCA can exhibit varying signal intensities during the HBP. We can even observe this phenomenon among different lesions within the same patient, thereby deepening our understanding of I-HCA.

The limitations of this study include the following: firstly, as a retrospective study, the number of cases involved is relatively small, which may have some impact on the results. Secondly, our study may have selection bias and does not cover all I-HCAs. Finally, this study only analyzed and summarized the characteristics of Gd-EOB-DTPA-enhanced MRI in I-HCA and did not compare it with other types of vascular-rich liver lesions. These limitations will be addressed and refined in future research.

In summary, Gd-EOB-DTPA-enhanced MRI is of significant value in the diagnosis of I-HCA in the Asian population. Particularly in non-HCC high-risk groups, such as obese young males, the diagnosis of I-HCA should be highly suspected when there are single or multiple liver occupancies with normal tumor markers, elevated serum CPR, and multifaceted hepatobiliary signal characteristics.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Not applicable.

Not applicable.

1. Yiheng Zheng and Ermin Cai contributed equally to this work.

Authors and Affiliations

1. Zhuji People’s Hospital of Zhejiang Province, Shaoxing, 311800, China

   Yiheng Zheng & Ermin Cai

2. Department of Radiology, Shanghai Geriatric Medical Center, Shanghai, 201104, China

   Mingliang Wang

3. Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

   Mengsu Zeng & Mingliang Wang

Contributions

MLW took charge of the study design; YHZ, EMC took charge of data extraction; YHZ, EMC performed statistical analyses and interpretation. YHZ, EMC, MLW, MSZ were responsible for manuscript drafting; YHZ, EMC, MLW, MSZ took charge of the modification. The final manuscript has been read and approved by all authors.

Corresponding author

Correspondence to Mingliang Wang.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee of Zhongshan Hospital of Fudan University because of the retrospective nature of the study. Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent. The study is approved by Zhongshan Hospital of Fudan University institutional review board (Approval number: B2021-366). All experiments were performed in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions