Yi Dong, Zheng Zhu, Wen-Ping Wang, Feng Mao and Zheng-Biao JiShanghai, China

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Ultrasound features of hepatocellular adenoma and the additional value of contrast-enhanced ultrasound

Yi Dong, Zheng Zhu, Wen-Ping Wang, Feng Mao and Zheng-Biao Ji
Shanghai, China

Author Affiliations: Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, China (Dong Y, Wang WP, Mao F and Ji ZB); and Department of Ultrasound, Taicang First People’s Hospital, Taicang 215400, China (Zhu Z)

? 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

Published online December 30, 2015.

BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign tumor of the liver. It is of clinical importance to differentiate HCA from other liver tumors, especially hepatocellular carcinoma (HCC). This study aimed to evaluate the characteristic features of HCA by conventional ultrasound and contrast-enhanced ultrasound (CEUS) findings.

METHODS: Twenty-six patients (10 males and 16 females; mean age 36.2±5.0 years) with 26 histopathologically proven HCAs were retrospectively identified. According to the maximum diameter of HCAs, they were divided into three groups: <30 mm, 30-50 mm, and >50 mm. Ultrasound examinations were performed with C5-2 broadband curved transducer of Philips iU22 unit (Philips Bothell, WA, USA). For each lesion, a dose of 2.4 mL SonoVue? (Bracco Imaging Spa, Milan, Italy) was injected as a quick bolus into the cubital vein. Lesions’echogenicity, color-Doppler flow imaging and contrast enhancement patterns were recorded.

RESULTS: Grayscale ultrasound revealed that most of HCAs were hypoechoic (73.1%, 19/26). Spotty calcifications were detected in 26.9% (7/26) of the lesions. Color-Doppler flow imaging detected centripetal bulky color flow in 46.2% (12/26) of the HCAs. CEUS showed that 73.1% (19/26) of the HCAs displayed as rapid, complete and homogenous enhancement, and 53.8% (14/26) showed decreased contrast enhancement in the late phase. There was no significant difference in enhancement patterns among different sizes of HCAs (P>0.05). Centripetal enhancement with subcapsular tortuous arteries was common in larger HCAs.

CONCLUSIONS: CEUS combined with grayscale and color-Doppler flow imaging helped to improve preoperative diagnosis of HCAs. The characteristic imaging features of HCAs included: rapid homogeneous enhancement and slow washout pattern on CEUS; heterogeneous echogenicity on grayscale ultrasound; and centripetal enhancement with subcapsular tortuous arteries in large HCAs.

(Hepatobiliary Pancreat Dis Int 2016;15:48-54)

KEY WORDS:contrast-enhanced ultrasound; hepatocellular adenoma; ultrasound diagnosis

Introduction

Hepatocellular adenoma (HCA) is a rare benign tumor of the liver, which has a tendency of lifethreatening rupture with bleeding or malignant transformation.[1, 2]HCA is generally treated with surgery. However, conservative management such as observation may be considered for small HCA.[3]Thus it is of clinical importance to differentiate HCA from other liver tumors, especially hepatocellular carcinoma (HCC).

HCA is often incidentally diagnosed in asymptomatic patients. It is associated with right-upper abdominal pain (80%) and normal liver function.[4]With the development and wide application of various radiological techniques in recent years, the diagnosis rate of HCAs has been increased.[5-7]However, the noninvasive diagnosis of HCAs remains a challenge because of their varied appearances.[8]Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are used at present as the principal imaging methods, but they are not safe in patients with renal impairment because of potential contrast-induced nephropathy secondary to iodinated CT contrast or nephrogenic systemic fibrosis associated with gadolinium-chelated MR contrast media.[9]

Grayscale ultrasound and color-Doppler flow imaging (CDFI) are often the firstline imaging modalities forhepatic lesions because of the low cost and wide availability.[10]Unfortunately, the reliability of ultrasound and CDFI is limited in diagnosis of focal liver lesion (FLL).[11]Contrast-enhanced ultrasound (CEUS) is reliable for the assessment of FLL.[12]The advantages of CEUS includes relatively lower cost compared to CT or MRI, reduced time of examination, real-time observation over the whole period of enhancement, and lack of ionizing radiation. It has a good sensitivity and specificity in detection and characterization of benign and malignant hepatic lesions.[12-14]Dietrich et al and Kim et al[15, 16]reported the sensitivity and specificity in differentiating HCA from focal nodular hyperplasia (FNH), which ranged from 86% to 95% and from 74% to 79%, respectively. However, only a few reports focused on CEUS findings of HCA with a small number of cases.

In the present study, we retrospectively analyzed 26 HCAs in an attempt to identify the ultrasound features of HCA and to assess the value of CEUS in preoperative diagnosis.

Methods

Patients

This study was approved by the institutional ethics committee, and requirements for informed consents were waived. Between September 2004 and December 2012, 26 HCAs from 26 patients (10 males and 16 females; mean age 36.2±5.0 years, range 23-63) were retrospectively studied. HCAs with a diameter of at least 10 mm which allows reliable visualization and CEUS analysis were evaluated. In patients with multiple nodules, HCAs suitable for CEUS were those in which biopsies had been performed.

Examination technique

For each HCA, the examination protocol comprised three-steps: ultrasound, CDFI and CEUS. Two experienced physicians performed ultrasound scanning with Philips iU22 unit (Philips Bothell, WA, USA; C5-2 broadband curved transducer, 2-5MHz).

First, conventional ultrasound examinations, including ultrasond and CDFI, were performed. During the grayscale scan, optimized instrument settings were used to find the proper location of lesions and acquire the clear visualization, such as the adjustment of focal zones, depth, time gain compensation and application of harmonic imaging. CDFI was used to evaluate the blood flow signals inside the lesion. Flow parameters were adjusted to the lowest possible pulse repetition frequency (PRF <1000 Hz) and color flow sensitivity was adjusted to better detect the color signals and avoid aliasing.

CEUS was performed using contrast harmonic realtime imaging at a low mechanical index (MI) of 0.05-0.10. Each examination lasted about 5 minutes after the bolus injection of contrast agents. The contrast agent used in the present study was SonoVue? (Bracco Imaging Spa, Milan, Italy). For each lesion, a dose of 2.4 mL of SonoVue? was injected as a quick bolus via a 20-gauge intravenous catheter placed in the cubital vein, and followed by 5 mL of 0.9% normal saline flush. All examinations were digitally recorded. To characterize the lesion, SonoVue? enhancements during the arterial phase (15-30 seconds), portal venous phase (30-120 seconds) and late vascular phase (120-300 seconds) were evaluated.[13]

Image analysis

HCAs were divided into three groups according to the maximum diameter: <30 mm, 30-50 mm and >50 mm. They were evaluated by two independent experienced radiologists in terms of the number, location, maximum diameter, echogenicity (hyperechoic, hypoechoic or isoechoic HCAs; homogeneous or heterogeneous HCAs, which were compared with the intensity of the surrounding liver parenchyma), shape (regular or lobulated), margin (illor well-defined appearance) of the lesions in addition to the presence of anechoic region or calcification component. Using CDFI, we observed color flow signals inside the lesion and measured Doppler spectrums and resistance index (RI) of arteries. We also used CDFI to detect whether there is centripetal bulky color flow in the lesion. CEUS revealed patterns of SonoVue? enhancement of the lesion (hypo-enhancement, hyper-enhancement, and isoenhancement), the homogeneity of enhancement (homogeneous or heterogeneous) and special appearance of enhancement (intra-tumoral hypoechoic non-enhancing areas, subcapsule bulky and tortuous artery) when the arterial, portal venous and late phases were evaluated, as compared with the adjacent liver parenchyma. The time to enhancement, the time of beginning enhancement, the time to peaking, and the time of iso-enhancement and hypo-enhancement were recorded.

Statistical analysis

Data were expressed as mean±standard deviation. Statistical analyses were performed with SPSS 15.0 software package (SPSS, Chicago, IL, USA). The differences between the groups were evaluated using one-way ANOVA. A P<0.05 was considered statistically significant. Kappa statistics was used to assess inter-observer agreement. Agreement was reached as κ<0.20 poor; 0.20-0.39 fair; 0.40-0.59 moderate; 0.60-0.79 substantial; or 0.80-1.00 almost perfect.[17]

Results

Patient characteristics

All HCAs were pathologically confirmed by liver resection (n=18) and 18-gauge needle core biopsy (n=8). In this series, 20 patients had single nodule and 6 had multiple nodules (Table 1). The mean maximum diameter of HCAs was 49±26 mm (range 12-165). Ten of the 26 nodules were smaller than 30 mm (38.5%), 12 were 30-50 mm (46.2%), and 4 (15.4%) were larger than 50 mm. Twelve (46.2%) nodules were in the right lobe of the liver and 14 (53.8%) in the left lobe.

Clinical and general pathologic features

Oral contraceptive was used in a female patient. In 2 patients, acute abdominal pain was the main reason for imaging. The remaining lesions were incidentally discovered during radiologic examination of the abdomen with nonspecific symptoms.

Grayscale and CDFI features

Most HCAs were regular or round (23/26, 88.5%) and 3 were lobulated (11.5%). Most HCAs (24/26, 92.3%) appeared to be well-defined, whereas 2 HCAs (7.7%) showed ill-defined margins. Regarding echogenicity, most HCAs were hypoechoic (19/26, 73.1%), 5 (19.2%) hyperechoic and 2 (7.7%) isoechoic. Spotty calcifications were found in 26.9% (7/26) of the lesions (Fig. 1A). Two HCAs showed an intra-tumor in the anechoic region (7.7%).

Table 1. Baseline characteristics of patients (n=26)

Fig. 1. Hepatocellular adenoma with hemorrhage in a 27-year-old woman. A: Grayscale ultrasound showing a hypoechoic nodule with spotty hyperechoic calcifications in the right lobe of the liver (arrow); B: Arterial phase in CEUS: 17 seconds after injection of SonoVue ?, the nodule was heterogeneously enhanced with a bulky and tortuous artery under the capsule (arrow); C: Iso-enhancement was observed in the portal venous phase (arrow); D: Intra-tumoral hypoechoic areas were detected in the late phase (arrow); E: Axial contrastenhanced computed tomography showing multi low-density areas inner nodule (arrow); F: Low-power photomicrograph (hematoxylin-eosin staining; original magnification ×20) showing multiple hemorrhagic areas and dilated sinusoidal spaces.

CDFI detected arterial color flow in all lesions and Doppler spectrums were measured (Fig. 2). The meanvalue of RI was 0.47±0.02. Centripetal bulky color flow was detected in 46.2% (12/26) of the lesions (Table 2).

Fig. 2. Hepatocellular adenoma in a 45-year-old man. A: Grayscale ultrasound showing a hypoechoic nodule in the left lobe of the liver (arrow); B: Color-Doppler ultrasound detected centripetal bulky color arterial flow with low resistance index of 0.53; C: The nodule was centripetally and heterogeneously enhanced in the arterial phase, a bulky and tortuous artery was detected under the capsule (arrow); D: Iso-enhancement was observed in the portal venous phase (arrow); E: The nodule became partially hypo-enhanced in the late phase (arrow).

Table 2. Grayscale and CDFI features of HCAs (n=26)

CEUS features

After SonoVue? administration, all HCAs showed rapid and complete enhancement in the arterial phase. Of the lesions, 73.1% (19/26) displayed homogenous enhancement, and 26.9% (7/26) were heterogeneously enhanced (Fig. 1B). In the arterial phase, 46.2% (12/26) of the HCAs showed the patterns of centripetal filling enhancement. Bulky and tortuous arteries were detected under the capsules of the lesions (Fig. 2).

In the portal venous phase, 3 HCAs (11.5%) showed “wash-out” of contrast enhancement compared to the surrounding liver parenchyma. Eighteen (69.2%) of the HCAs showed iso-enhancement (Fig. 1C), and 5 (19.2%) showed persistent hyper-enhancement.

In the late phase, 53.8% (14/26) of the lesions showed hypo-enhancement (Fig. 2) and 46.2% (12/26) showed persistent enhancement (Fig. 3). The intra-tumoral hypoechoic areas can be detected in 23.1% (6/26) of the lesions, their maximum diameters ranged from 8 mm to 11 mm (Fig. 1D).

Since the lesions were divided into 3 groups according to their size, no significant difference was seen between the patterns of their enhancement (one-way ANOVA test, P>0.05). The median time of enhancement was 12.4±4.8 seconds (range 4-17), and peaked at 25.5± 7.6 seconds (range 17-34). Iso-enhancement occurred at87.2±41.7 seconds (range 45-128), and hypo-enhancement at 140.6±28.0 seconds (range 112-169), respectively. Centripetal enhancement with tortuous arteries under capsules was common in lesions larger than 50 mm. Most of smaller HCAs had homogenous enhancements (Table 3).

Fig. 3. Hepatocellular adenoma in a 19-year-old man. A: Grayscale ultrasound showing a hypo-echoic nodule in the right lobe of the liver (arrow); B: Color-Doppler ultrasound showing centripetal bulky color arterial flow around the lesion and inside of the lesion (arrow); C: Doppler spectrums measured with a low resistance index of 0.52; D: The nodule was centripetally enhanced with a bulky and tortuous artery under the capsule 14 seconds after SonoVue? administration (arrow); E: Hyper-enhancement was observed 34 seconds after injection of SonoVue? (arrow); F: The nodule was iso-enhanced in the late phase (arrow).

Table 3. CEUS features of 26 hepatocelluar adenomas in 26 patients

Substantial to almost perfect inter-reader agreement was achieved at CEUS (κ=0.819).

Discussion

Pathologically, HCAs are caused by benign proliferation of hepatocytes with high glycogens and fat contents, which are always lacking normal hepatic architecture.[2, 18]Distinctive histological features of HCAs include larger adenoma cells than normal hepatocytes, hypervascular nature with extensive sinusoids and feeding arteries, and absence of bile ducts.[5, 7, 19]HCAs carry risks of spontaneous bleeding or malignant transformation.[20]As the diagnosis of HCA is established, large, hemorrhagic or atypical HCAs should be removed operatively. Therefore, a definite diagnosis before surgery is of clinical importance.[11]

In the past decade, progress has been made in im-aging techniques of HCAs.[3, 20]However, it is still a challenge to differentiate HCAs from other benign or malignant liver tumors, such as FNH or HCC. Clinically suspected HCAs with atypical imaging features such as heterogeneous enhancement or increased size may require biopsy or even surgical resection.[2, 7]Among all imaging methods, ultrasound is always the first choice in liver imaging in consideration of its safety, availability and low cost.[10, 11]In our study, there were various appearances of HCAs on grayscale ultrasound, and most of them (73.1%, 19/26) were hypoechoic in comparison with normal liver parenchyma. Some HCAs were hyperechoic (19.2%, 5/26) or isoechoic (7.7%, 2/26), these may be caused by abundant fat, fibrosis, or bleeding inside.[21]26.9% (7/26) of the HCAs had calcifications as spotty hyperechoic foci with acoustic shadowing on grayscale ultrasound (Fig. 1A). Calcifications represented the nonspecific long-term evolution of intra-tumoral hemorrhage in HCAs.[22]Because of hemorrhagic areas, anechoic area was detected in 7.7% (2/26) of the HCAs, indicating multi low-density areas in nodule on contrastenhanced CT and multiple hemorrhagic areas and dilated sinusoidal spaces on histopathological photomicrograph (Fig. 1E and F). It was described that 25%-40% of the HCAs had a risk of rupture, which seems to be associated with hemorrhagic areas in HCA larger than 5 cm in diameter.[2, 23]We considered that grayscale ultrasound is helpful in accurately displaying the echogenicity and maximum diameter of HCAs, as well as showing calcification or inner lesion of anechoic areas. These features may help us to improve the preoperative diagnosis of intra-tumoral hemorrhage in HCAs (Fig. 2).

In our study, CDFI demonstrated centripetal bulky flow in 46.2% (12/26) of the HCAs with a relatively low RI (0.47±0.02). CEUS revealed that these lesions had centripetal enhancement in the arterial phase, with the presence of a large bulky and tortuous subcapsular feeding vessel. Pathologically, HCAs consisted of cordlike normal hepatocytes, and were structured in large plates and separated by dilated sinusoids. Thus, HCAs were perfused solely by arterial pressure derived from peripheral arterial feeding vessels, which may contribute to the centripetal enhancement pattern.[7, 19, 24]CDFI may be helpful in detection of centripetal blood flow signals, CEUS allows real-time assessment of liver vascularity, and displays the dynamic “wash-in” and “wash-out” of the lesion. CDFI combined with CEUS features will be helpful to observe real time blood filling mode of HCA, to detect the subcapsular feeding artery, and to make a differential diagnosis of HCA from FNH.[16, 25]

After SonoVue? administration, 73.1% (19/26) of the HCAs displayed rapid, complete and homogenous enhancement in the arterial phase (Fig. 3). Histologically, HCAs were characterized by extensive sinusoids and feeding arteries. Their architectural differences such as limited portal venous supply, with few terminal hepatic vein drainages might explain the fast “wash-in” in the arterial phase.[19, 23, 25-27]Contrast enhancement “washout” was noted in quite different ways in portal venous and late phases. A number of HCAs (88.5% in the portal venous phase and 46.2% in the late phase) demonstrated persistent enhancement (slightly hyperechoic or isoechoic), and three HCAs (11.5%) presented fast “wash-out”in the portal venous phase. According to a report,[28]different enhancements in the portal venous and late phases can be explained by different histological types of HCAs, absence of portal spaces and biliary ducts in HCAs, and cells similar to normal hepatocytes with few stroma. Thus we considered “slow wash-out” (persistent enhancement during portal venous and late phase) is a discriminant sign for HCAs in CEUS.

In the late phase, intra-tumoral hypoechoic areas can be detected in 23.1% (6/26) of the HCAs. HCA is a highly vascular tumor with multiple thin-walled sinusoids and poor connective tissue support. It is due to the presence of intra-tumoral materials such as fat, sinusoidal dilatation and necrotic or hemorrhagic components.[2, 28]

The ultrasonic features of HCA may be similar to its ultrasonographic features such as heterogeneous on grayscale ultrasound features, subcapsular tortuous arteries detected by CDFI with relatively low RI, and centripetal enhancement patterns with fast-enhanced subcapsular tortuous arteries. CEUS features of HCAs: rapid homogeneous enhancement and “slow wash-out”pattern may be helpful in the differential diagnosis of HCAs from HCCs.

There are some limitations in our study such as a limited number of lesions and pathologic subtypes of HCAs, but the benefits of CEUS are obvious. The diagnostic value will be increased when grayscale, CDFI and CEUS are combined.

Contributors: DY and ZZ wrote the first draft of this article. WWP made ultrasound analysis. MF and JZB made statistical analysis. All authors contributed to the intellectual context and approved the final version. DY and ZZ contributed equally to this article. WWP is the guarantor.

Funding: This study was supported by a grant from the National Natural Science Foundation of China (81371577).

Ethical approval: This study was approved by the Ethics Committees of Zhongshan Hospital, and requirements for informed consents were waived.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received March 13, 2015

Accepted after revision September 8, 2015

Original Article / Liver

doi:10.1016/S1499-3872(15)60039-X

Corresponding Author:Wen-Ping Wang, MD, PhD, Department of Ultrasound, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China (Tel: +86-21-64041990ext2474; Fax: +86-21-64220319; Email: puguang61@126.com)