Original Article  /  Liver

CT and MRI diagnosis of hepatic epithelioid hemangioendothelioma Jiang Lin and Yuan Ji Shanghai, China

BACKGROUND: Hepatic epithelioid hemangioendothelioma (EHE) is a rare, low-grade malignant vascular tumor. Although its unusual imaging and pathologic findings are being recognized with increasing frequency, diagnosis is still difficult. This study aimed to analyze the CT and MRI features of hepatic EHE with a pathological study in order to improve the diagnostic accuracy and knowledge of this disease in daily practice.

a signet ring-like structure. Immunohistochemically, all patients were positive for CD34, 4 were positive for CD31, and 3 were positive for factor Ⅷ-related antigen.

CONCLUSIONS:  Hepatic EHE may manifest as solitary or diffuse nodular lesions with a predilection for peripheral subcapsular growth and nodular confluence, together with the "halo" and "capsular retraction" signs. These imaging findings can help to improve the diagnostic accuracy of this rare hepatic METHODS: Nine patients with hepatic EHE confirmed pathologi- tumor. cally underwent plain and dynamic contrast-enhanced multi(Hepatobiliary Pancreat Dis Int 2010; 9: 154-158) detector row CT examination. Of these patients, four underwent additional MRI (plain T1-weighted imaging (T1WI), T2- KEY WORDS: liver neoplasm; weighted imaging (T2WI), and dynamic contrast-enhanced epithelioid hemangioendothelioma; scanning) and one had selective hepatic arteriography. The computed tomography; imaging findings were reviewed retrospectively together with MR imaging the pathological results.

RESULTS: A total of 79 lesions, ranging from 3.0 to 44.6 mm in maximum diameter, with an average of 16.8±7.1 mm, were found in various segments of the liver. Thirty of the 79 lesions grew adjacent to the hepatic capsule. In the 4 patients receiving MRI, 39 lesions were found with low signal intensity on unenhanced T1WI and intermediate to high signal intensity on T2WI. The "capsular retraction" sign was found in all the 4 patients. Nine of the 39 lesions showed the "halo" sign after contrast enhancement on MRI. Of the 79 lesions (hypodense nodules) in the 9 patients shown by unenhanced plain CT, 26 were confluent. Calcification was found in 2 patients and the "capsular retraction" sign in 7. Thirty-eight of the 79 lesions demonstrated the "halo" sign after contrast enhancement on CT, and this sign was more clearly demonstrated in the portal venous phase. In one patient, selective hepatic arteriography showed patchy stain in the peripheral liver parenchyma with small vessels around them. Histology in all patients revealed proliferation of abnormal fibrous tissue and vessel-like structures scattered with irregular epithelioid cells having

Author Affiliations: Department of Radiology (Lin J) and Department of Pathology (Ji Y), Shanghai Zhongshan Hospital, Fudan University, Shanghai 200032, China Corresponding Author: Jiang Lin, MD, Department of Radiology, Shanghai Zhongshan Hospital, Fudan University, Shanghai 200032, China (Tel: 8621- 64041990; Fax: 86-21-64038472; Email: [email protected]) © 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.

Introduction

E

pithelioid hemangioendothelioma (EHE) is a rare, low-grade malignant vascular tumor first described as a distinct entity by Weiss and Enzinger in 1982.[1] It is an uncommon tumor of vascular origin that may develop in the soft tissue, lung, bone, brain, and small intestine.[2] Rarely it occurs in the liver. Imaging, pathologic, and clinical diagnosis of hepatic EHE are difficult.[3-9] Because it is usually defined as a low- to intermediate-grade malignancy, it may be treated successfully by resection or transplantation.[10] Familiarity with the imaging and pathologic findings of hepatic EHE may allow recognition of this rare hepatic tumor at an early stage. We retrospectively analyzed the imaging features of 9 patients with hepatic EHE treated from January 2004 to August 2009 at our institution. The objective was to demonstrate the CT and MRI findings of this disease together with a pathological study and a literature review, in order to improve the diagnostic accuracy and knowledge of this disease in daily practice.

Methods Nine patients with hepatic EHE were retrospectively reviewed. They were 4 men and 5 women with age ranged

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from 25 to 62 years (mean 46 years). Four patients presented with right abdominal incipient pain as the onset symptom, and 5 had no remarkable chief complaints. All patients were incidentally found to have hepatic lesions by ultrasound screening. Laboratory tests showed their alpha-fetoprotein, carcinoembryonic antigen, and cancer antigen 19-9 within normal limits. Their HBsAg and HCV were also negative. The imaging diagnosis was confirmed pathologically by 18-gauge needle biopsy in 5 patients and surgery in 4. Four patients with hepatic EHE underwent 1.5 T MRI examination, including unenhanced axial fatsuppressed turbo-spin echo (TSE), T2-weighted imaging (T2WI), and breath-hold fast low angle shot (FLASH) T1-weighted imaging (T1WI). Then MRI contrast medium, gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma, Germany), was used at a dose of 2 ml/kg. It was administered through an antecubital vein at a rate of 2 ml/s. Dynamic breath-hold FLASH T1WI acquisitions were obtained at 20-25, 60-70, and 90-120 seconds after contrast enhancement. The effective slice thickness used was 5 mm in all acquisitions. All 9 patients with hepatic EHE underwent multidetector row CT examination, including unenhanced plain scans and dynamic contrast-enhanced scans with a non-ionic contrast medium (Omnipaque 300, GE Healthcare, USA). The volume of 80-100 ml contrast medium was injected at a rate of 3 ml/s via an antecubital vein. An arterial phase scan was obtained 25-35 seconds after the start of the contrast injection.

This was followed by the portal venous phase at 75-85 seconds. All slice thicknesses were 5-7 mm. One patient with hepatic EHE had selective hepatic arteriography with the Seldinger technique via femoral arterial catheterization to the common hepatic artery. Thirty to forty-five ml of a non-ionic contrast medium (Omnipaque 300, GE Healthcare, USA) was infused into the common hepatic artery at 5 ml/s. Angiography was started 3 seconds after contrast medium injection and 12 angiograms were taken consecutively within 30 seconds. The pathologic diagnosis of hepatic EHE was based on HE-stained sections,[4] which presented with a fibrosclerotic center and cellular periphery. Tumor cells showed epithelioid differentiation and had characteristic intracytoplasmic lumina, occasionally containing red blood cells, resembling signet ring-like stuctures. Immunohistochemically, tumors were positive for at least one endothelial marker i.e., factor Ⅷ-related antigen (FⅧRAg), CD34, or CD31.

Results Altogether 79 lesions were found in the 9 patients with hepatic EHE. Eight patients had multiple lesions while the remaining one had a solitary lesion. The maximum diameter of the lesions ranged from 3.0 to 44.6 mm (mean 16.8±7.1 mm). They distributed in various hepatic segments with the majority in segment Ⅵ followed by segments Ⅳ and Ⅷ. All 79 lesions were

Fig. 1. A 26-year-old female with multifocal hepatic EHE. A, B: T2WI MRI at two different levels showing intermediate to high signal intensity lesions; C, D: Corresponding contrast-enhanced MRI showing inhomogenously enhanced lesions. E, F: Portal venous phase CT at two different levels showing multiple inhomogenously enhanced lesions with partial coalescence, peripheral subcapsular distribution, and ring-like enhancement, presenting as the halo sign. Both the findings of CT and MRI are diagnostic of EHE. Hepatobiliary Pancreat Dis Int，Vol 9，No 2 • April 15，2010 • www.hbpdint.com • 155

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located within a 3-cm zone (i.e., the shortest distance lower density layers. The solitary lesion in 1 patient was from the border of the lesion to the hepatic capsule or misdiagnosed as hepatic inflammatory pseudotumor porta hepatis) beneath the hepatic capsule, including 30 (Fig. 2A). In 8 patients with multiple lesions, two were diagnosed with EHE but the other 6 were misdiagnosed very close to the capsule. with hepatic cavernous hemangioma or metastasis. MRI manifestations In 4 patients undergoing MRI, 39 lesions were found. Selective hepatic arteriography Twenty-seven lesions were found in one patient. No On T1WI, the lesions were hypointense with lower signal intensity in the center. They demonstrated intermediate enlargement or dilatation of the common hepatic artery to high sinal intensity on T2WI (Fig. 1 A, B) and some and intrahepatic arterial branches was shown. At the with local invagination of the nearby hepatic capsule arterial phase, irregular patchy stains appeared in the presenting with the "capsular retraction" sign. Peripheral hepatic parenchyma adjacent to the hepatic capsule ring-like enhancement occurred in all lesions during of the right and left lobes. These stains persisted in the arterial phase with even stronger enhancement the parenchymal phase with small tortuous vessels in the portal venous phase (Fig. 1 C, D). Nine of the around the tumor. This patient was misdiagnosed with lesions presented the characteristic "halo" sign which metastasis by hepatic arteriography. consisted of a hypointense center and periphery with an intermingled hyperintense layer in between. Three Pathologic findings patients were misdiagnosed with liver metastasis and Nine lesions were detected by fine needle biopsy in another with hepatic cavernous hemangioma. 5 patients. Microscopically, proliferated fibrous tissue intermingled with epithelioid cells was observed in CT manifestations these lesions. Four patients were subjected to surgical Plain unenhanced CT revealed 79 lesions in the 9 resection, including resection of solitary lesion in 1 patients. They were multiple in 8 patients and solitary patient. In the other three patients multiple lesions in one. All lesions presented as solid, inhomogenously were seen in segments Ⅱ-Ⅷ, some of which had hypodense nodules with a ring-like low density border coalescence. Segment Ⅳ alone was resected in these or lower density center. Twenty-six of the 78 lesions patients. Eight lesions were resected in these 4 patients. appeared to be coalesced. Calcification was found in Macroscopically, the cross-section of gross specimens 2 lesions. The "capsular retraction" sign was shown in in multiple lesions showed an ill-defined tumor border 7 patients. At the arterial phase, 9 lesions in 2 patients with peripheral gray and red consistency and central gray revealed no enhancement while 70 lesions in 7 patients and yellow rigidity. On the contrary, the solitary lesion showed slight peripheral enhancenment. At the portal presented with clear-cut demarcation, gray and white venous phase, all lesions demonstrated various degrees consistency of the cross-section surface. Microscopically, of enhancement, predominantly at the periphery (Fig. 1 the patient with multiple lesions demonstrated proliE, F). Thirty-eight lesions showed the "halo" sign with feration of abnormal fibrous tissue and vessel-like inner low density, in-between high density, and outer structures. And the patient with a solitary lesion showed a predominantly dense fibrous stroma. All the surgical specimens demonstrated epithelioid tumor cells with characteristic intracytoplasmic lumina, containing red blood cells, resembling signet ring-like structures (Fig. 2B). Immunohistochemically, 14 lesions in the 9 patients were positive for CD34, 10 lesions in the 4 patients were positive for CD31, and 7 lesions in 3 patients were positive for FⅧRAg.

Fig. 2. A 51-year-old man with right-lobe hepatic EHE. A: Portal venous phase CT showing an inhomogenously enhanced lesion in peripheral subcapsular location with typical halo sign; B: Photomicrograph showing epithelioid cells with signet ringlike structures and proliferated fibrous tissue (HE, original magnification ×100).

Discussion Hepatic EHE is a rare vascular tumor that has a low to intermediate malignant potential between hepatic hemangioma and hepatic angiosarcoma. In 1984, primary hepatic EHE was first reported by Ishak et

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al[2] as a rare occurrence in the liver. There are no known causes of or risk factors for hepatic EHE, which has a predilection for middle-aged females. Clinical manifestations of hepatic EHE are nonspecific and include right upper quadrant pain, weight loss, or both. Many patients are asymptomatic when the tumor is discovered. A few patients present with jaundice, portal hypertension, and liver failure.[4] Hepatic EHE is classified pathologically into solitary nodular and diffuse nodular types (probably evolving from the former). The nodular lesions in a predominantly peripheral distribution under the hepatic capsule are sometimes coalesced. The occurrence of multiplicity and coalescence always indicates a late stage of the disease. The cross-section of the nodule is often gray and white with a hard consistency and sometimes shows an infiltrative growth pattern. The surrounding liver parenchyma is always normal in the solitary nodular type. But in the diffuse nodular form, compensatory hepatic hypertrophy is a common complication and cirrhosis or focal nodular hyperplasia may develop in a few cases. Microscopically, hepatic EHE possesses two characteristics.[3-6] First, the tumors are composed of dendritic and epithelioid cells with intracytoplasmic lumina, containing red blood cells, resembling signet ring-like stuctures. Second, the tumors consist of large amounts of mucinous and dense stroma in the center and rich cellular zones in the periphery. In addition, progressive sclerosis or calcification may occur in 23% of cases. The diagnosis can be suggested immunohistochemically if the tumors are positive for at least one endothelial marker i.e., FⅧRAg, CD34, or CD31. The prognosis of hepatic EHE is generally favorable. The characteristic imaging findings of hepatic EHE in this study were basically in agreement with those published in the literature.[3, 5-8] CT and MRI findings indicative of hepatic EHE included single or multiple nodules in both hepatic lobes that may coalesce to form larger confluent masses in a peripheral or subcapsular distribution and a "halo" and "capsular retraction" sign. MRI showed inhomogenously hypointense lesions on T1WI and inhomogenously hyperintense lesions on T2WI. The lesions demonstrated peripheral ringlike enhancement at the arterial phase and stronger enhancement at the portal venous phase with some lesions having the "halo" sign. Unenhanced CT revealed hepatic EHE as solid, inhomogenously hypodense nodules with a ring-like low density border and a lower density center. After contrast enhancement, the lesions showed no enhancement or slight peripheral enhancement at the arterial phase. But at the portal

venous phase, the "halo" sign became conspicuous. The "capsular retraction" sign occurred in the vicinity of the lesions. According to the literature,[4, 9] calcification may be seen in this tumor, but was only found in 2 lesions, probably due to the small sample in our series. Selective hepatic arteriography revealed an intermediate blood supply for the tumor and inhomogenous staining at the parenchymal phase. This finding is similar to those of other tumors with no specific manifestations. In correlation with pathologic classification, the tumors in this study could be divided into diffuse nodular and solitary nodular types based on the imaging findings. Pathologically, hepatic EHE occurs mainly in the solitary type at the early stage but with a propensity for invasion of terminal hepatic venules and portal vein branches.[3, 4] As it progresses, the tumor nodules become multifocal and confluent, especially in the subcapsular regions. Histologically, tumor cells and stroma are in variable proportions. At the periphery of the tumor, there is active proliferation of tumor cells which often invade and obliterate sinusoids and the tributaries of the portal and hepatic veins. On the contrary, fibrosclerotic tissue of hypovascularity occurs in the tumor center. For the "halo" sign in nodules demonstrated on both CT and MRI, the hypodense/ hypointense inner center represents coagulative necrosis, calcification, and tiny hemorrhages; and the in-between hyperdense/hyperintense layer corresponds to viable tumor cells and edematous loose connective tissue.[5, 6] Sometimes, an outer layer with lower density/ intensity may be found, which histologically stands for an avascular zone between tumor and normal liver.[5, 9] The "capsular retraction" sign is caused by the fibroproliferative reactions of the tumor, which lead to invagination of the nearby liver capsule.[5, 9-12] Hepatic EHE should be differentiated from metastatic carcinoma, hepatocellular carcinoma, angiosarcoma, and atypical hepatic cavernous hemangioma. According to the literature,[3, 5, 6, 9] it is often confused with or sometimes indistinguishable from these disorders based on imaging findings alone; as a result, the final diagnosis depends on pathological findings. But on the basis of this retrospective analysis, we believe that peripheral confluent masses with capsular retraction and the halo sign are hallmark features that should suggest a diagnosis of possible hepatic EHE. Furthermore, the relevant medical history, symptoms and signs, as well as laboratory tests are also helpful for the differential diagnosis. Radiologists and clinicians should be aware of these imaging findings associated with hepatic EHE and should suggest this diagnosis in the proper clinical setting.

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Funding: None. Ethical approval: Not needed. Contributors: LJ proposed the study, analyzed the data and wrote the paper. JY provided pathologic analysis. LJ is the guarantor. 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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