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Year : 2013  |  Volume : 9  |  Issue : 1  |  Page : 125-127

Malignant epithelioid hemangioendothelioma progressing after chemotherapy and Interferon treatment: A case presentation and a brief review of the literature

1 Department of Medical Oncology, Izmir Ataturk Training and Research Hospital, Ankara, Turkey
2 Department of Pathology, Izmir Ataturk Training and Research Hospital, Ankara, Turkey

Date of Web Publication10-Apr-2013

Correspondence Address:
Lutfiye Demir
Department of Medical Oncology, Izmir Ataturk Training and Research Hospital, Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.110386

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 > Abstract 

Epithelioid hemangioendothelioma is a rare, low-grade malignant vascular tumour. It is frequently seen in the liver, but can occur in the lungs, bones, and other soft tissues. Although survival time might be reasonable in cases that can undergo liver transplantation, there is no consensus on the treatment of metastatic patients. We report a 24-year-old female patient with rapidly progressing malignant epithelioid hemangioendothelioma that presented with acute abdominal distension. The patient was refractory to anthracycline and Interferon treatment and died 6.5 months after the diagnosis.

Keywords: Epithelioid hemangiendothelioma, hepatic, interferon, metastasis, treatment

How to cite this article:
Demir L, Can A, Oztop R, Dirican A, Bayoglu V, Akyol M, Kucukzeybek Y, Erten C, Somali I, Tarhan MO. Malignant epithelioid hemangioendothelioma progressing after chemotherapy and Interferon treatment: A case presentation and a brief review of the literature. J Can Res Ther 2013;9:125-7

How to cite this URL:
Demir L, Can A, Oztop R, Dirican A, Bayoglu V, Akyol M, Kucukzeybek Y, Erten C, Somali I, Tarhan MO. Malignant epithelioid hemangioendothelioma progressing after chemotherapy and Interferon treatment: A case presentation and a brief review of the literature. J Can Res Ther [serial online] 2013 [cited 2020 Jul 6];9:125-7. Available from: http://www.cancerjournal.net/text.asp?2013/9/1/125/110386

 > Introduction Top

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumour that was described for the first time as a clinical state between benign hemangioma and angiosarcoma by Weiss and Enzinger in 1982. [1] It originates from endothelial cells and generally occurs in the liver, lungs, and other soft tissues. Positivity of endothelial differentiation markers, such as factor VIII-dependent antigen, CD-34, and CD-31, as well as vascular invasion and an infiltrating growth pattern (except in the portal region) are important in the diagnosis of epithelioid hepatic hemangioendothelioma. [2]

As it is a rare tumour, there is no consensus regarding its treatment. Liver transplantation, hepatectomy, chemoembolization, radiotherapy, and chemotherapeutic agents such as Doxorubicin, Vincristine, Fluorouracil (5-FU), and Interferon (IF)-alpha 2b are reported treatment regimens. There are also reports about patients with EHE that were followed without any treatment. [2] Hemangioendothelioma is a vascular tumour with overexpression of vascular endothelial growth factor (VEGF) [3] and, as such, anti-angiogenic therapy together with systemic chemotherapy in the initial stages of treatment can increase the response rates and improve outcome.

Herein, we have reported a 24-year-old female patient with rapidly progressing malignant epithelioid hepatic hemangioendothelioma that presented with acute abdominal distension.

 > Case Report Top

A 24-year-old female presented to the emergency department with acute abdominal distension in November 2009. She immediately underwent exploratory laparotomy, which showed a bird-beak appearance of the ileum, multiple hemorrhagic spots in the omentum, multiple lymph nodes along the stomach and 2.5 litre of hemorrhagic liquid in the abdominal cavity. In addition, the liver had an irregular shape and some parts were quite small. Multiple biopsy specimens were obtained from suspicious areas of the liver and intestinal mesothelium. Pathologic examination revealed diffuse infiltration in adipose tissue [Figure 1], and immunohistochemical staining analysis was positive for CD-31 and CD-34, but negative for Heppar-1, cytokeratin 20, EMA, S-100, pancytokeratin, and WT-1 [Figure 2] and [Figure 3]. Based on these findings, the diagnosis was thought to be malignant EHE.
Figure 1: Epitheloid tumoural tissue in omental adipose tissue

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Figure 2: Tumour cells that are stained immunohistochemically with CD 31

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Figure 3: Tumour cells that are immunohistochemically stained membranous intense positive with CD 34

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Computed tomography (CT) imaging showed metastatic nodules in the lungs and pleural effusion in the right hemithorax. The liver was undersized and a 15 × 10-cm solid lobulated mass in left lobe, ascites, and para-aortic lymph nodes were observed [Figure 4]. Because of the metastatic involvement, liver transplantation was deemed an unsuitable treatment option following hepatobiliary consultation and, therefore, Doxorubicin 60 mg/m 2 (every 21 d) was started in January 2010. After the second cycle, the patient exhibited stabile radiological and clinical response; however, after the fourth cycle, new metastatic lesions in the spleen and liver were observed, and chemotherapy was stopped and IF alpha-2b (3 × 10 6 U t.i.w.) was started. During the first month of this therapy, the patient developed severe fatigue, cachexia, and unconsciousness; the disease progressed and the patient died 6.5 months after diagnosis.
Figure 4: Hypodense tumoural mass in the liver and diffuse perihepatic and intraabdominal fluid in computed tomography

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 > Discussion Top

EHE is a rare, endothelial vascular neoplasm. It arises from epithelioid and histiocyte cells and tends to be multifocal. The incidence of primary malignant hepatic hemangioendothelioma is >0.1/100,000; mean age at the time of diagnosis is 41.7 years and the male:female ratio is 2:3. [2]

Imaging studies have an important role in the diagnosis of EHE. Tumoural lesions appear as solid, non-homogenously hypodense nodules with a ring-like, low-density border, and a lower-density centre in contrast-enhanced CT imaging. Also, magnetic resonance imaging (MRI) shows non-homogenously hypointense lesions on T1-weighted images and hypertense lesions on T2-weighted images. [4] In this case, the tumoural masses were observed as hypodense nodules in the contrast-enhanced CT imaging.

The diagnosis of hepatic EHE must be verified by pathological examination of the tissue. Histopathological characteristics of hepatic EHE include an invasive growth pattern with preservation of the liver acinar composition and portal tracts. The tumour consists of epithelioid or dendritic cells, which are characterized by large eosinophilic cytoplasm in a fibromyxoid stroma. [5] Its vascular structure is discerned by immunohistochemical positive staining with endothelial cell markers, such as factor VIII-related antigen, CD-31 (platelet endothelial cell adhesion molecule 1 transmembrane glycoprotein), cytokeratin, and CD-34. Also, these tumours are positively stained with vimentin and negatively stained with CEA. [2],[5] In the current case, both typical tumour architecture and immunohistochemical positivity of endothelial cell markers (such as CD-31 and CD-34) supported the diagnosis of hepatic EHE.

Because of the heterogeneous nature of the tumour and its rarity, there is not any accepted treatment strategy for patients with hepatic hemangioendothelioma; the most common strategy is liver transplantation, followed by monitoring without treatment and chemotherapy or radiotherapy. [6] Although hepatectomy might be a treatment option, most patients are not eligible for the treatment due to the multicentric nature of the tumour. One study described a 33-year-old patient treated with a combination of doxorubicin, vincristine, and 5-Fluorouracil that had symptom-free survival of 10 years, another reported a patient with spleen and peritoneum involvement in whom endemic regression was observed after three cycles of Doxorubicin, and another patient was administered Epirubicin and Dacarbazine combination, but the metastases were not controlled. [7],[8]

Angiogenesis is an important process in the spread and growth of tumours. Fibroblast growth factor (FGF), hepatocyte growth factor (HGF), platelet-dependent growth factor (PDGF), and VEGF play major roles in this process. IF alpha has an immunomodulatory effect by regulating the cytokines that control the function and reproduction of tumour cells. It also reduces the sensitivity of vascular cells to VEGF and FGF, and diminishes vascularization. [9] In a case report, marked regression in pelvic metastases with IF alpha-2b was reported. [10] In another patient with lung metastases, a well-known anti-angiogenic drug, thalidomide, was found to be successful. [11] It was demonstrated that EHE tumour cells have VEGF expression, [3] and VEGF expression increased to a greater degree in patients with recurrent disease following liver transplantation. Bevacizumab together with chemotherapy was given to a 41-year-old patient with pulmonary EHE because of disease progression following Cisplatin-Etoposide treatment, which resulted in a partial response for 13 months. [12]

The presented case had diffuse peritoneal, lung, and spleen involvement. The disease progressed following single agent Doxorubicin. IF alpha-2b treatment was administered due to its anti-angiogenic and immunomodulatory effects, but there was no response to this treatment either. It is well-known that these tumours express high levels of VEGF; thus, preventing tumour spread with monoclonal antibody against VEGF (bevacizumab) together with chemotherapy or IF treatment in the early period can improve survival in patients with advanced-stage disease.

 > References Top

1.Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: A vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81.  Back to cited text no. 1
2.Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Schmied BM, Hallscheidt P, et al. Primary malignant hepatic epitheloid hemangioendotelioma: A comprehensive review of the literature with emphasis on the surgical therapy. Cancer 2006;107:2108-21.  Back to cited text no. 2
3.Park MS, Ravi V, Araujo DM. Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma and hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol 2010;22:351-5.  Back to cited text no. 3
4.Lin J, Ji Y. CT and MRI diagnosis of hepatic epithelioid hemangioendothelioma. Hepatobiliary Pancreat Dis Int 2010;9:154-8.  Back to cited text no. 4
5.Thin LW, Wong DD, De Boer BW, Ferguson JM, Adams L, Macquillan G, et al. Hepatic epithelioid haemangioendothelioma: Challenges in diagnosis and management. Intern Med J 2010;40:710-5.  Back to cited text no. 5
6.Langrehr JM, Peterson I, Pfitzmann R, Lopez-Hänninen E. Malignant epithelioid hemangioendothelioma of the liver. Results of surgical treatment strategies. Chirurg 2005;76:1161-7.  Back to cited text no. 6
7.Idilman R, Dokmeci A, Beyler AR, Bastemir M, Ormeci N, Aras N, et al. Successful medical treatment of an epitheloid hemangioendothelioma of liver. Oncology 1997;54:171-5.  Back to cited text no. 7
8.Morris JE, Malatjalian DA, Bodurthra A, Smith M, Koller O, Bhan J, et al. Epitheloid hemangioendothelioma of the liver: A report of two cases. Can J Gastroenterol 1993;7:530-4.  Back to cited text no. 8
9.Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, et al. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 1998;58:808-14.  Back to cited text no. 9
10.Kayler LK, Merion RM, Arenas JD, Magee JC, Campbell DA, Rudich SM, et al. Epitheloid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B. Transplantation 2002;74:128-30.  Back to cited text no. 10
11.Mascarenhas RC, Sanghvi AN, Friedlander L, Geyer SJ, Beasley HS, Van Thiel DH. Thalidomide inhibits the growth and progression of hepatic epitheloid hemangioendothelioma. Oncology 2004;67:471-5.  Back to cited text no. 11
12.Belmont L, Zemoura L, Couderc LJ. Pulmonary epitheloid hemangioendothelioma and Bevacizumab. J Thorac Oncol 2008;3:557-8.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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