The Feature of Solitary Small Nodular Type of Hepatic Epithelioid Hemangioendothelioma Open Access

Epithelioid hemangioendothelioma was first described by Weiss and Enzinger [1] in 1982 as a vascular tumor of endothelial origin that originates from soft tissue, visceral organs, bone, lung, brain, and the small intestine. Hepatic epithelioid hemangioendothelioma (HEHE) was first described as a low- to intermediate-grade malignancy [2]. It is a rare tumor with an incidence of 1 per 100,000 population [3]. HEHE commonly develops between 30 and 50 years of age, and the male-to-female ratio of incidence is 2: 3 [3]. The solitary nodular form has been reported in only 13.5–18% of patients [3]. Prognosis is favorable compared to other hepatic malignancies. Long-term survival is possible with successful liver resection or liver transplantation [3, 4]. Metastases have been reported in 27–37% of patients at presentation and occur mostly in the lungs (17%) [3]. Laboratory analysis has shown that while liver enzymes may be moderately elevated, tumor markers are usually normal [5], making the clinical diagnosis of HEHE difficult [5]. Imaging findings of HEHE show some typical features and size-dependent patterns with contrast enhancement, on both computed tomography (CT) and magnetic resonance imaging (MRI) [5]. The small size of HEHE makes it difficult to diagnose, resulting in a misdiagnosis of cholangiocellular carcinoma or metastatic tumor. We describe here a case of small and solitary HEHE that was previously diagnosed as a metastatic tumor from renal cell carcinoma.

A 74-year-old man underwent surgical resection for left renal cell carcinoma 20 years ago. During follow-ups, multidetector CT was performed at each checkup, every year. A nodule (1.3 cm in diameter) at liver segment VIII with a suspicion for invasion into the vein of segment VIII was detected that showed isodensity in the arterial phase, low density in the portal venous phase, and homogeneous enhancement in the late phase (Fig. 1a–c). Contrast-enhanced ultrasound with perflubutane (Sonazoid, Daiichi-Sankyo, Tokyo, Japan) showed low signal intensity at segment VIII during the Kupffer phase (Fig. 1d). 18-Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) showed no abnormal uptake at segment VIII of liver or other organs. MRI showed the tumor with low intensity on T1-weighted images and high intensity on T2-weighted images (Fig. 2a, b). Dynamic MRI with Gd-EOB-DTPA-enhanced MRI showed that the tumor was not enhanced in the early phase, had low intensity relative to normal liver at 30 and 120 s after injection, and showed low signal intensity in the hepatobiliary phase (Fig. 2c–f). The patient tested negative for hepatitis B surface antigen and hepatitis C virus antibody. Serum tumor markers like carcinoembryonic antigen, carbohydrate antigen 19-9, α-fetoprotein, and PIVKA-2 were normal. Partial hepatectomy on the gross specimen revealed a yellowish-white mass with irregular margins (Fig. 3a). Hematoxylin-eosin staining revealed spindle- and oval to polygonal shaped cells with acidophilic cytoplasm (Fig. 3b). Tumor cells stained positive for endothelial markers (CD31, CD34, and factor VIII) (Fig. 4a–c). Tumor cells were negative for hepatocyte antigen, cytokeratin, and D2-40 (Fig. 4d–f). Based on the above data, a histological diagnosis of HEHE was made. The postoperative course was normal. The patient was discharged at 16 days post-surgery and has been relapse-free for 4 months.

HEHE is rare tumor often misdiagnosed as cholangiocellular carcinoma or a metastatic tumor. It does not have characteristic symptoms or tumor markers, making diagnosis difficult. Common symptoms include right upper quadrant pain (48.6%), hepatomegaly (20.4%), and weight loss (15.6%) [3]. In our case, the patient was asymptomatic; the tumor was detected incidentally by CT, during a clinical follow-up. HEHE often presents as an advanced-stage, diffuse multifocal type and rarely as the solitary nodular type that represents an early stage [3, 4, 6]. It is important to distinguish HEHE from other hepatic tumors and to detect it before it becomes a multifocal lesion because long-term survival is possible after successful liver resection or transplantation, even in the presence of distal metastasis [7]. HEHE is difficult to diagnose using preoperative radiology techniques as seen in our study where radiological images showed a tumor, 1.3 cm in diameter, at liver segment VIII. A preoperative diagnosis of metastatic tumor was made. However, a pathological diagnosis subsequently revealed a small and solitary type of HEHE.

Some reports suggest the use of CT [5], MRI [8-10], and US [11] images in the preoperative diagnosis of HEHE. Zhou et al. [5] report imaging findings of HEHE that show some typical features and size-dependent patterns with contrast enhancement on both CT and MRI. Okano et al. [10] show that apparent diffusion coefficient maps may be useful in revealing the malignant potential of the tumor. Lee et al. [8] have examined the characteristic features of HEHE, divided into core and non-core groups, on MRI using Gd-EOB-DTPA. Alomari [12] first described the lollipop sign: 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, as a new cross-sectional sign of HEHE on CT and MRI. The lollipop sign rarely occurs in benign or malignant hepatic tumors; hence, it is considered a characteristic of HEHE [5]. Lesions smaller than 2.0 cm mostly demonstrate mild homogeneous enhancement in the arterial phase [5]. In our case, the tumor was revealed to be approximately 1.3 cm in diameter on CT images and showed isodensity in the arterial phase, low density in the portal venous phase, and homogeneous enhancement in the late phase. The enhanced effect of the tumor was equal to that reported by Zhou et al. [5] for a tumor when it was less than 2 cm. In this case, the lollipop sign was unclear. Dong et al. [11] report that by analyzing hypo-enhancement in the portal venous and late phases, contrast-enhanced ultrasound can determine the malignant nature of HEHE. The role of FDG-PET in HEHE has been evaluated in previous studies. In a study of six patients, Dong et al. [13] found that 18-fluoro-2-deoxyglucose uptake in lesions of HEHE depends on tumor cellularity, not on tumor size. Dual-time-point imaging may not be useful in differentiating benign lesions from HEHE. However, the utility of FDG-PET in monitoring the effect of radiation therapy and chemotherapy has been reported [14, 15]. These image features of HEHE are detailed in Table 1.

A diagnosis of HEHE can be made with confidence by fine needle aspiration and small biopsy with immunohistochemical staining [16]. In our case, the small tumor was located at segment VIII, between hepatic veins. Biopsy of the tumor was difficult. Therefore, the final diagnosis of HEHE required histopathological confirmation with immunohistochemical staining for endothelial markers like CD31 and CD 34, and factor VIII.

Surgical treatment options for HEHE include liver resection or transplantation; prognosis is more favorable than for other hepatic malignancies [3]. The disease-free survival rate is 83.3% at 1 year and 44.4% at 3 years in liver resection patients [17]. The survival rate at 1 year and 5 years, respectively, was 100 and 75% after liver resection, and 96 and 54.5% after liver transplantation [3]. Non-surgical treatment options include transcatheter arterial chemoembolization when the tumor is located only in the liver [18], and antitumor medication when the tumor has metastatic lesions with the lung or other organs. Sorafenib is a therapeutic option for unresectable HEHE. It is a tyrosine kinase inhibitor associated with this signaling pathway [19]. It is reported that, with the administration of thalidomide, the progression of diffuse metastatic HEHE is hindered successfully [20, 21].

HEHE is difficult to diagnose because it is a rare tumor with nonspecific symptoms and lack of tumor markers. It is important to detect the tumor early before it enters the multifocal nodule pattern stage. We found a small tumor that was treated with hepatectomy. Despite a small-sized tumor, we believe a preoperative diagnosis for HEHE to be possible by characteristic image features, as has been reported previously.

The authors thank to Yuki Saka for her secretarial assistance.

The patient has provided permission to publish these features of his case, and his identity has been protected.

The authors declare no conflict of interest. This study received no funding.

N.K. is the first author of this manuscript and K.A. is the corresponding author. All the authors contributed to performing the surgeries, data collection, and data analysis. All authors read and approved the final manuscript.