A rare case of hepatic epitheliod hemangioendothelioma

Abstract

Hepatic epithelioid hemangioendothelioma (HEHE) is an extremely uncommon tumor of the liver. It typically lacks recognizable clinical signs and is diagnosed with the aid of imaging and histopathology combined with immunohistochemical analysis. We discuss the case of a 40-year-old woman with HEHE. The aim of this case report and literature review is to increase doctors’ knowledge of HEHE and reduce the incidence of missed clinical diagnoses.

Introduction

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor that develops from vascular endothelial or pre-endothelial cells [1]. While the World Health Organization classifies it as a malignant neoplasm, its clinical course is intermediate in the spectrum of vascular tumors, from benign hemangiomas to malignant angiosarcomas [2]. EHE can arise in multiple locations throughout the body, the most common sites of involvement being the liver, lungs, and bone [3]. Its presence in the liver often results in nonspecific abdominal symptoms. It is incidentally discovered on imaging as multifocal, heterogeneously enhancing nodules in both hepatic lobes. Depending on its histology, EHE can be misdiagnosed as hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, and metastatic carcinoma. Due to the rarity of hepatic EHE (HEHE) and its ambiguous symptoms and laboratory profiles, imaging and histologic evaluation are essential for its diagnosis.

This report presents the case of a 40-year-old female patient whose tumor was diagnosed as HEHE. Our aim is to increase the understanding and diagnosis of HEHE because, despite its histologic and immunohistochemical characteristics being distinct, it is frequently misinterpreted as a more clinically aggressive malignancy.

Case description

A previously healthy 40-year-old woman with no relevant family medical history presented at our hospital after experiencing abdominal pain in the right lower quadrant region. On physical examination, there were no abnormal findings or signs of chronic liver disease.

The laboratory data were as follows: hemoglobin 13.6 g/dL (normal, 13-17 g/dL), international normalized ratio 0.98, albumin 40 g/L (normal, 25-52 g/L), total bilirubin 11.2 μmol/L (normal, <15 μmol/L), glutamic oxaloacetate transaminase 19 U/L (normal, <34 U/L), glutamic-pyruvic transaminase 21 U/L (normal, <49 U/L). Serum alpha-fetoprotein, carbohydrate antigen 19-9, and carcinoembryonic antigen were within normal limits. The patient had negative test results for the hepatitis B core and surface antibodies and the hepatitis C antibody.

Abdominal ultrasound revealed a heterogeneous hypoechoic mass, 3 × 3 cm in size, in the left liver lobe (Fig. 1). In abdominal magnetic resonance imaging (MRI), the segment III of left liver lobe showed a round lesion with well-defined margin and the target sign in the axial T2-weighted image; the lesion consisted of concentric layers with a markedly hyperintense central tumor region and a moderately hyperintense peripheral zone (Fig. 2A). In an apparent diffusion coefficient map, the peripheral area of the tumor appeared hypointensive (Fig. 2B) and in dynamic contrast enhanced T1-weighted images, the pattern of enhancement was ring-like in noncontrast (Fig. 2C), arterial phase (Fig. 2D), and portal phase (Fig. 2E). The lesion also showed capsular retraction, that is, the adjacent liver surface was retracted toward the lesion (Fig. 2F). Another mass with similar characteristics appeared in segment IV of the left lobe (Figs. 2B, D, and E).

Fig. 1.

Abdominal ultrasonography shows a 3 × 3-cm heterogeneous hypoechoic mass in the left liver lobe.

Fig. 2.

Abdominal magnetic resonance imaging shows a round lesion with well-defined border and the target sign in segment III of the left liver lobe, on the axial T2-weighted image. The lesion consists of concentric layers, including a markedly hyperintense central tumor region and moderately hyperintense peripheral zone (A). In the apparent diffusion coefficient map, the peripheral area of the tumor appears hypointensive (B). In the dynamic contrast enhanced T1-weighted images, the pattern of enhancement is ring-like in noncontrast (C), arterial phase (D), and portal phase (E). The adjacent liver surface is retracted toward the lesion, that is, capsular retraction (F). Another mass with similar characteristics is seen in segment IV (B, D, and E).

We performed a percutaneous ultrasound-guided biopsy to obtain a clear diagnosis. Histologic examination indicated a malignant tumor with a carcinomatous and angiomatous component, but no cirrhosis. The tumor cells reacted positively to CD31, CD34, and CK, but negatively to arginase-1 (Fig. 3). Based on histopathological and immunochemical findings revealed HEHE. The patient was prescribed doxorubicin combined with ifosfamide and methotrexate. The patient was referred to our cancer center for continued follow-up.

Fig. 3.

Histologic findings of the liver biopsy of patient with hepatic epithelioid hemangioendothelioma. (A and B) Hematoxylin and eosin staining, 20× and 40×, respectively. Immunohistochemistry results were positive for CD31 (C), CD34 (D), and CK (E), and negative for arginase (F) (20×).

Discussion

The uncommon vascular tumor, EHE, has biological characteristics that are intermediate between hemangioma and hemangiosarcoma. Weiss and Enzinger [4] were the first to report a case of EHE in 1982. Although the tumor may occur elsewhere in the body, the liver is often affected. HEHE was first described by Ishak et al. [2] in their 1984 report. It is known to affect people of all ages (3-86 years in reported cases), with a peak incidence in the third and fourth decades of life and a higher frequency in women than in men (3:2) [5]. Its incidence is less than 1 in a million [6].

HEHE has no characteristic clinical manifestations. Right upper quadrant or epigastric discomfort (60%-70%), weight loss (20%), deteriorated overall condition (20%), or jaundice (10%) may be the only clinical signs of HEHE [7]. In the multicentric study by Sanduzzi-Zamparelli et al. [8], 17/27 patients (62.96%) were asymptomatic at the time of diagnosis. In Mehrabi et al.’s [9] study, 25% of the patients were asymptomatic and the most common symptoms were right upper quadrant pain, hepatomegaly, and weight loss. Increased alkaline phosphatase and γ-glutamyl transpeptidase and normal serum alpha-fetoprotein, carcinoembryonic antigen, and cancer antigen 19-9 are typical laboratory findings for patients with HEHE. In Mehrabi et al.’s [9] study, 15% of the HEHE patients did not have abnormal values in common laboratory tests.

Imaging and histologic examination are crucial for diagnosing HEHE because of uncommon tumor incidence and ambiguous symptoms and laboratory profiles. Paolantonio et al. [10] reported some specificity in the diagnostic performance of MRI, particularly T2-weighted imaging and dynamic studies, for HEHE. The most frequent presentation was peripheral distribution of lesions (72.7%), target appearance on T2-weighted images (63.6%), low signal intensity in T1-weighted images (63.6%), ring- or target-like enhancement in dynamic study (63.6%), and coalescence of nodules and capsular retraction (45.4%). In our case, the MRI findings were the target sign appearing in T2-weighted images and capsular retraction, which supported the diagnosis of HEHE.

EHE has been shown to have 3 types of cells: intermediate, dendritic, and epithelioid. Epithelioid cells are present in all cases. They are of endothelial origin and may have vacuoles, causing them to resemble the morphology of signet-ring cells. Dendritic cells are stellate and have multiple processes. Intermediate cells share features of both epithelioid and dendritic cells [2]. In immunohistochemical staining, the majority of vascular tumors, including HEHE, express CD31 and CD34. In contrast to HEHE, intrahepatic cholangiocarcinoma, metastatic carcinoma, and hepatocellular carcinoma frequently express cytokeratins, rather than CD34 or CD31 [11]. Furthermore, despite being helpful markers for distinguishing EHE from carcinomas in epithelial organs, CD31 and CD34 lack specificity. These endothelial cell markers are also expressed by other vascular tumors, such as angiosarcoma, angiomyolipoma, and hemangiomas, with overlapping morphologic and histologic characteristics, which sometimes makes it difficult to distinguish between them [12]. In our case, the patient's tumor tested positive for CD31, CD34, and CK but was negative for arginase-1.

There are no set standards for managing HEHE. Chemotherapy, ablation, surgery, and liver transplantation are among several therapeutic options with variable outcomes. In fact, a previous study found that there was no discernible difference in the 5-year survival rate between the various therapies [13].

Conclusion

HEHE is a malignant tumor, with a vascular origin and no recognized etiology and has an uncertain course. Imaging and histologic study are essential for diagnosing HEHE. There are no established guidelines for the care of patients with this tumor due to its rarity.

Author's contributions

Dau QL and Tran NA contributed equally to this article as first authorship. Dau QL and Tran NA: Case file retrieval and case summary preparation. Dau QL and Nguyen MD: preparation of manuscript and editing. All authors read and approved the final manuscript.

Availability of data and materials

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

Ethics approval and consent to participate

Our institution does not require ethical approval for reporting individual cases or case series. Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.

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Not applicable.

Patient consent

Informed consent for patient information to be published in this article was obtained.