AIM: To analyze contrast-enhanced ultrasound (CEUS) features of histologically proven hepatic epithelioid hemangioendothelioma (HEHE) in comparison to other multilocular benign focal liver lesions (FLL).

METHODS: Twenty-five patients with histologically proven HEHE and 45 patients with histologically proven multilocular benign FLL were retrospectively reviewed. Four radiologists assessed the CEUS enhancement pattern in consensus.

RESULTS: HEHE manifested as a single (n = 3) or multinodular (n = 22) FLL. On CEUS, HEHE showed rim-like (18/25, 72%) or heterogeneous hyperenhancement (7/25, 28%) in the arterial phase and hypoenhancement (25/25, 100%) in the portal venous and late phases (PVLP), a sign of malignancy. Eighteen patients showed central unenhanced areas (18/25, 72%); in seven patients (7/25, 28%), more lesions were detected in the PVLP. In contrast, all patients with hemangioma and focal nodular hyperplasia showed hyperenhancement as the most distinctive feature (P < 0.01).

CONCLUSION: CEUS allows for characterization of unequivocal FLL. By analyzing the hypoenhancement in the PVLP, CEUS can determine the malignant nature of HEHE.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular neoplasm of endothelial origin with primary liver involvement and is characterized by the presence of epithelioid endothelial cells[1]. Weiss and Enzinger first reported 41 patients with this unique tumor in 1982[2]. This tumor is histologically characterized by an epithelial appearance and the endothelial nature of the tumor cells[3]. Currently no more than 200 patients with HEHE have been reported since its first description, and most of the studies were small series[4,5].

No definite etiopathogenetic factors, apart from an association with oral contraceptives, trauma, and exposure to vinyl chloride, have to date been ascribed to HEHE[1,6]. The tumor generally affects adults, with a strong female predominance and a peak incidence occurring between 30 and 40 years of age. The clinical manifestations and laboratory data of HEHE are nonspecific, usually presenting with general symptoms, such as right upper quadrant pain or weight loss. Some patients may present with liver failure, Budd-Chiari syndrome, or portal hypertension, while others may be asymptomatic. Its clinical course and prognosis are variable and unpredictable[7]. Due to its nonspecific clinical manifestations and prolonged clinical course, establishing diagnosis even with histopathological findings can often be challenging[8].

HEHE carries intermediate malignant potential, and transplantation may provide a long term cure[9]. Therefore, the recognition of the imaging features of this rare neoplasm may be helpful for the detection and further surgical treatment of this potentially curable disease. In addition, it is important to distinguish HEHE from other primary and secondary benign and malignant hepatic tumors, such as atypical (multilobulated) hemangioma and hemangiomatosis, hepatocellular adenoma and hepatocellular carcinoma, intrahepatic cholangiocarcinomas, lymphoma, and liver metastases[10]. Radiologists should be aware of its imaging findings and raise suspicion in the proper clinical setting[8,11].

Conventional ultrasound is the most commonly used imaging method for real time diagnosis of FLL. However, the most frequent imaging findings of multilocular HEHE are nonspecific[11]. Often, multiple HEHE on conventional ultrasound might be difficult to differentiate from other atypical multilocular FLLs[12,13]. As a result, the final diagnosis of HEHE depends on biopsy and histological findings[14,15].

Contrast enhanced ultrasound (CEUS) allows for the differentiation of most benign and malignant liver tumors in the portal venous and late phases (PVLP). This finding was summarized in the European Federation of Societies for Ultrasound in Medicine and Biology guidelines and recommendations for the use of CEUS in liver[16,17]. Benign FLLs are typically iso- or hyperenhancing in the PVLP; whereas malignant primary and secondary liver tumors almost always show hypoenhancement in the PVLP, since they do not contain the respective specific hepatic vessels. This hypoenhancement in the PVLP is decisive for determining if a lesion should be biopsied[18,19]. In addition, CEUS findings of HEHE have not been well addressed. Therefore, the aim of our study is to analyze the CEUS features of histologically proven HEHE and to compare these features to those of other multilocular benign FLLs, including hemangiomas and focal nodular hyperplasia (FNH), since they are the most important for differential diagnosis. We assessed the clinical value of CEUS to define the malignant nature of the disease with hypoenhancement in the PVLP. To our best knowledge, this is the first report on the CEUS features of HEHE.

To the best of our knowledge, CEUS features of HEHE have not been well characterized. To date, only a few imaging studies have investigated HEHE, and most of them were limited patients series[4,15,21], and CEUS features of HEHE have been described only in a few patients[15,21,22]. In many patients, CEUS is the first and decisive imaging technique for detecting and characterizing liver tumors[23-25]. The use of ultrasound contrast agents improved detection and made it possible to assess the benign or malignant nature of liver tumors in most patients[13,26-28]. Previously, three forms of HEHE have been described: single nodular, multifocal nodular, and the diffuse type[1]. Consistent with our current study, most HEHE present as multiple FLL. After CEUS, more lesions could be detected in 7/25 (28%) patients[29]. As HEHE has ill-defined margins on grayscale ultrasound, CEUS may be helpful to detect more lesions with sharper and clearer margins.

In our current retrospective study, we discovered that CEUS reliably showed typical signs of HEHE in most patients with hyperenhancement in the arterial phase and hypoenhancement in the PVLP, which might be useful in determining whether a biopsy is necessary for suspected malignant lesions. In correlation with pathologic classification, histologically, HEHE possesses two distinctive characteristics, which are directly related to the echogenicity and enhancement pattern of HEHE on ultrasound images[1,20,30,31]. First, HEHE are composed of dendritic and epithelioid cells with intracytoplasmic lumina containing red blood cells. However, the peripheral proliferation remains active and forms numerous arterial-venous shunts, which could account for the fast rim-like enhancement in the arterial phase and quick washout in the PVLP during CEUS[7]. Second, tumor cells and stroma of HEHE exist in variable proportions, and the central stromal portion of the lesion can vary from myxoid to densely fibrotic. With the growth of the tumor, the central stroma degenerate gradually and become sclerotic as the blood supply decreases[20]. In our results, hypoenhancement with central unenhanced area at PVLP of CEUS was mostly common in HEHE. Moreover, additional lesions were detected at CEUS, leading to improvements in liver staging.

Alomari et al[32] first described the lollipop sign as a new cross-sectional sign of HEHE on computed tomography (CT) and magnetic resonance imaging (MRI): a well-defined peripherally enhancing (or non-enhancing) lesion with an avascular core on enhanced images (the candy in the lollipop) and a histologically occluded vein (the stick). Concerning the CT imaging, focal calcifications were reported in 20% of patients; capsular retraction was in 10%-25% of patients[20]. The lesions demonstrated peripheral rim-like hyperenhancement in the arterial phase with even stronger enhancement in the portal venous phase by contrast enhanced MRI. Central areas of reduced signal may correspond to areas of hemorrhage, coagulation necrosis, and calcification[7]. We showed that peripheral rim-like hyperenhancement in the arterial phase and hypoenhancement in the PVLP with central unenhanced areas could be detected in 72% HEHE patients. Therefore, the contrast enhanced image modalities demonstrate a similar enhancement pattern of this disease. CEUS can be considered at least equal to, and in some ways (real time observation, no radiation, less expensive) superior to, CT and MRI as a diagnostic tool[33].

Most of the HEHE lesions were multinodular (88%) and hypoechoic (92%) in our current study. As set out in the current literature and in textbooks, the origin of hypoechoic lesions is considerably more varied and confusing than other lesions[13,23]. All hypoechogenic lesions should be investigated using a contrast enhanced imaging technique[16,18]. Evaluation with CEUS in the PVLP is determinant in this context, and contrast medium hypoenhancement in the late phase is a decisive indication for liver biopsy[23].

HEHE has a variable clinical and biological course compared to benign endothelial tumors (hemangiomas) and malignant angiosarcomas with a slowly progressive phenotype. The tumor can even be difficult to diagnose based on biopsy specimens[34]. CEUS differentiation of different liver tumors is essential because of different therapeutic approaches[35]. HEHE should be differentiated from atypical multilocular liver hemangioma and FNH, because both of them could demonstrate as multilocular hypoechoic liver lesions. Although benign FLLs are commonly iso- or hyperenhancing in the PVLP, malignant primary and secondary liver tumors almost always show hypoenhancement in the PVLP[18,19]. Based on results of our retrospective analysis, we believe that peripheral rim-like hyperenhancement at the arterial phase and quick washout at the PVLP with central unenhanced area are hallmark features that suggest a diagnosis of possible HEHE. In contrast, both multilocular hemangiomas and FNH showed hyperenhancement and remained iso or hyperenhanced in PVLP.

Furthermore, in the clinical setting, factors helpful for the differential diagnosis of HEHE are a medical history without extrahepatic malignant tumor, patients with no symptoms, and laboratory tests[35].

In conclusion, CEUS imaging findings reliably compile typical signs of HEHE, allowing for effective differentiation with other multilocular hypoechoic hepatic lesions, including liver hemangioma and FNH. CEUS can help to improve the diagnostic confidence of HEHE, a rare hepatic tumor, and the liver staging of the disease to guide additional diagnostic work-up.