Malignant epithelioid hemangioendothelioma is a rare vascular endothelial tumor with variable malignant potential, whose biological behavior lies between that of benign hemangiomas and highly aggressive angiosarcomas. This entity is exceptionally uncommon [1]. Its clinical course is unpredictable and may sometimes exhibit aggressive behavior. The tumor can originate from various organs including the liver, lungs, bones, breast, lymph nodes, skin, and head-and-neck regions. It most commonly occurs between the ages of 30 and 50 years [2].

Hepatic involvement is relatively rare, with approximately 200 cases reported in the literature. Because of its rarity, HEHE is frequently misdiagnosed on imaging as cholangiocarcinoma or metastatic disease, as in our patient, leading to diagnostic delay. According to the WHO 2002 classification, epithelioid hemangioendothelioma is considered a locally aggressive tumor with metastatic potential [3].

The exact cause of HEHE remains unknown. Suggested risk factors include exposure to vinyl chloride, polyurethane, and silica; oral contraceptive use; primary biliary cirrhosis; viral hepatitis; asbestos exposure; and alcohol consumption. A specific chromosomal translocation, t(1;3)(p36;q25), has been identified in HEHE, but the mechanism by which fusion transcripts contribute to tumorigenesis remains poorly understood [4].

Clinical presentation is usually non-specific, with weight loss and right upper quadrant discomfort being the most common symptoms. Less frequently, jaundice and hepatic failure may occur, typically related to massive tumor infiltration [3]. Liver function tests and tumor markers (AFP, CEA, CA 19-9) are often within normal ranges, limiting their diagnostic value [4].

On ultrasound, lesions are often hypoechoic. Contrast-Enhanced Ultrasound (CEUS) improves detection of multifocal lesions, typically demonstrating marked arterial phase enhancement followed by wash-out in the portal and delayed phases [5].

On CT, lesions are usually peripheral or subcapsular, hypodense compared with normal liver parenchyma. Capsular retraction and calcifications may be present. Post-contrast, three enhancement patterns are described:

• < 2 cm: homogeneous persistent enhancement,
• 2–3 cm: peripheral enhancement with progressive centripetal fill-in (“halo sign”),
• ≥ 3 cm: heterogeneous progressive enhancement.

Tumoral infiltration of hepatic or portal venous branches produces the characteristic “lollipop sign” [6].

MRI is more sensitive than CT for small lesions. Typically, lesions appear hypointense on T1, hyperintense on T2, and demonstrate the “target sign” in more than half of cases. Post-contrast, ring-like or target-like enhancement is observed. On hepatobiliary phase imaging, lesions appear hypointense or may show delayed central enhancement. Diffusion-weighted imaging (DWI) demonstrates peripheral hyperintensity with lower central signal, and ADC values are generally higher than those seen in hepatocellular carcinoma [1].

Definitive diagnosis relies on histopathology, which shows a mixture of epithelioid, dendritic, and intermediate cells with vacuolated cytoplasm sometimes containing erythrocytes, and hyperchromatic nuclei. Immunohistochemistry typically demonstrates positivity for CD31, CD34, and ERG, with Ki-67 useful for assessing proliferative activity. Keratin expression may also be present [8].

Lipiodol (Ethiodol) is an iodized oil known to localize selectively in hepatocellular carcinoma (HCC) cells and tumor vasculature for weeks to months following intra-arterial hepatic injection [9]. Its uptake in hepatic tumors is based on arterial vascularization and sinusoidal permeability. Being a lipophilic contrast medium, it preferentially accumulates in hypervascularized tumor tissues such as HCC, allowing precise visualization on CT or MRI after intra-arterial injection [10].

Lipiodol retention in tumors is more prolonged than in healthy liver parenchyma, making it useful for evaluating tumor necrosis after treatment, particularly following transarterial chemoembolization (TACE) [11]. Uptake varies by tumor type: it is usually intense and homogeneous in small HCCs, heterogeneous in larger lesions, minimal in hemangiomas, and variable in metastases depending on vascularization. For rare tumors such as hepatic epithelioid hemangioendothelioma, data on Lipiodol uptake are scarce, with no dedicated literature reviews, and its diagnostic or therapeutic role remains unclear [12].

In our case, the hepatic lesion was initially treated as HCC with Lipiodol-based chemoembolization. It was only after multidisciplinary tumor board review that a biopsy was recommended, which confirmed HEHE.

Between 60–80% of HEHE cases are initially misdiagnosed, with the most common differential diagnoses being metastases, angiosarcoma, sclerosing hepatocellular carcinoma, and cholangiocarcinoma [13].

First-line treatment is hepatic resection when technically feasible and when disease is localized [14]. In cases of diffuse, bilobar, or unresectable disease, liver transplantation is the treatment of choice, with reported 5-year survival ranging between 55–75%. For advanced or metastatic forms, systemic chemotherapy (doxorubicin, ifosfamide, gemcitabine, paclitaxel) has shown variable, mostly partial, responses [15]. Targeted anti-angiogenic therapies (sorafenib, pazopanib, bevacizumab) and immunotherapy with PD-1/PD-L1 inhibitors have provided encouraging results in small series and case reports. Transarterial embolization (TACE) may be used palliatively to slow disease progression or control symptoms [16]. Finally, in selected asymptomatic patients with indolent disease, close radiological surveillance may be considered.

In our case, the multiplicity and extent of the lesions led to a therapeutic approach combining capecitabine and bevacizumab chemotherapy, with liver transplantation planned as a subsequent option.