DOI: 10.1148/radiol.2401032099
(Radiology 2006;240:295-298.)
© RSNA, 2006
Case 96: Hepatic Epithelioid Hemangioendothelioma1
Frank Earnest, IV, MD and
C. Daniel Johnson, MD
1 From the Department of Radiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. Received December 12, 2003; revision requested February 27, 2004; revision received April 2; final version accepted May 17.
Address correspondence to F.E. (e-mail: earnest{at}mayo.edu).
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HISTORY
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A 34-year-old woman was admitted to the hospital with a 1-year duration of intermittent discomfort in the right upper quadrant of the abdomen. An ultrasonographic (US) examination of the gallbladder was performed to evaluate suspected cholelithiasis; this examination revealed gallstones. An abnormal liver was visualized at the time of laparoscopic cholecystectomy. This woman had been in good health and had not undergone previous surgical procedures. She had had three normal-term pregnancies and took no regular medications. She had no known exposure to hepatotoxins and had not undergone previous transfusions. There was no history of regular tobacco or alcohol use and no family history of liver disease or familial neoplasia. She had elevated levels of serum aspartate aminotransferase (ie, 56 U/L; normal level, 12–31 U/L) and alkaline phosphotase (ie, 708 U/L; normal level, 37–98 U/L). Tumor marker levels—including 
-fetoprotein, carcinoembryonic antigen, and cancer antigen 19-9 levels—were normal. This patient was referred for further examination. US imaging, including Doppler examination of hepatic vessels, and computed tomography (CT) with late hepatic arterial phase and portal phase imaging were performed to allow further evaluation.
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IMAGING FINDINGS
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US images of the right hepatic lobe (Fig 1) demonstrated slightly lobulated confluent hypoechoic lesions that extended to the posterior aspect of the liver capsule. Contrast material–enhanced (Omnipaque 300; Nycomed Amersham, Princeton, NJ) CT images obtained through the upper abdomen (Fig 2) demonstrated multiple hypoattenuating lesions throughout the periphery of the liver that became confluent in the right hepatic lobe. One of the larger more discrete lesions demonstrated a target appearance with a peripheral zone of faint contrast enhancement. There were overlying areas of focal atrophy and capsular retraction.
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Figure 1a: US images of the right hepatic lobe in the (a) sagittal and (b) transverse planes demonstrate a lobulated, inhomogeneous, predominantly hypoechoic hepatic mass (arrowheads) that extends to the liver margin.
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Figure 1b: US images of the right hepatic lobe in the (a) sagittal and (b) transverse planes demonstrate a lobulated, inhomogeneous, predominantly hypoechoic hepatic mass (arrowheads) that extends to the liver margin.
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Figure 2a: Contrast-enhanced CT images of the liver (a) at the level of the hepatic venous confluence and (b, c) at the level of the liver hilum demonstrate multiple hypoattenuating hepatic nodules with areas of minimal heterogeneous enhancement (black arrowheads) that coalesce in the right hepatic lobe and are associated with areas of focal atrophy and capsular retraction (arrows). One of the larger nodules (visible in c) demonstrates a zone of peripheral enhancement (white arrowheads), with a more hypoattenuating central region.
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Figure 2b: Contrast-enhanced CT images of the liver (a) at the level of the hepatic venous confluence and (b, c) at the level of the liver hilum demonstrate multiple hypoattenuating hepatic nodules with areas of minimal heterogeneous enhancement (black arrowheads) that coalesce in the right hepatic lobe and are associated with areas of focal atrophy and capsular retraction (arrows). One of the larger nodules (visible in c) demonstrates a zone of peripheral enhancement (white arrowheads), with a more hypoattenuating central region.
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Figure 2c: Contrast-enhanced CT images of the liver (a) at the level of the hepatic venous confluence and (b, c) at the level of the liver hilum demonstrate multiple hypoattenuating hepatic nodules with areas of minimal heterogeneous enhancement (black arrowheads) that coalesce in the right hepatic lobe and are associated with areas of focal atrophy and capsular retraction (arrows). One of the larger nodules (visible in c) demonstrates a zone of peripheral enhancement (white arrowheads), with a more hypoattenuating central region.
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DISCUSSION
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Hepatic epithelioid hemangioendothelioma is a rare, low-grade malignant vascular tumor that, to our knowledge, was first described as a distinct entity by Weiss and Enzinger in 1982 (1). In 1984, a report by Ishak et al (2) detailed findings in 32 patients with hepatic epithelioid hemangioendothelioma. In 1999, Makhlouf et al (3) reported findings in a series of 137 patients with this tumor. The unusual imaging and pathologic findings and clinical course of this tumor are being recognized with increasing frequency.
Clinical manifestations of hepatic epithelioid hemangioendothelioma are uncommon and 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 and may die of liver failure (2). Results of analysis of pathologic specimens, including hepatic explants, suggest that hepatic failure is likely due to replacement of hepatic parenchyma by the tumor rather than to ductal obstruction (3); however, Miller et al (4) suggested that occlusion of peripheral bile ducts may cause focal atrophy and capsular retraction. There is a greater incidence of this neoplasm in women than in men (male-to-female ratio, 3:2), with peak incidence occurring between 30 and 40 years of age (3). The duration of symptoms prior to diagnosis ranges from 3 months to 2 years.
There are no known causes of or risk factors for hepatic epithelioid hemangioendothelioma. Physical examination findings are uncommon but may include hepatomegaly, a palpable mass, or jaundice. In most patients, liver function tests reveal mild elevation of serum bilirubin, alkaline phosphatase, and aspartate aminotransferase levels. Tumor marker levels, such as acute -fetoprotein and cancer antigen 19-9 levels, are almost always normal in patients with hepatic epithelioid hemangioendothelioma, unlike tumor marker levels in patients with other primary and metastatic hepatic tumors. Carcinoembryonic antigen levels may be elevated in a small number of patients.
Pathologic analysis in what is to our knowledge the largest reported series of patients demonstrated multiple hepatic nodules in 96 (82%) of 117 patients, with 21 patients (18%) having only one tumor (3). In the patients with only one tumor, tumors were found most commonly in the right hepatic lobe. Microscopic evaluation revealed an ill-defined growth pattern, with infiltrative margins. The tumor cells consisted of epithelioid and dendritic cells in variable proportions, with a propensity for invasion of terminal hepatic venules and portal vein branches. Although tumor invasion of peripheral hepatic venules and portal vein branches is a microscopic hallmark of hepatic epithelioid hemangioendothelioma (3), imaging studies demonstrate compression of peripheral portal and hepatic veins by the tumor rather than by the tumor thrombi in the central hepatic or portal veins more commonly associated with hepatocellular carcinoma. Growth within acini was associated with atrophy of hepatocytes. Immunohistochemical reactivity with factor VIII–related antigen was present in 99% of specimens, demonstrating the endothelial origin of these tumors.
US depicts hepatic lesions that are predominantly hypoechoic (5,6); however, hepatic lesions can also have mixed echotexture or be predominantly hyperechoic (4). To our knowledge, Doppler US findings have not been described. In this patient, Doppler US revealed no abnormalities in the hepatic arteries or veins. CT findings indicative of hepatic epithelioid hemangioendothelioma include multiple hypoattenuating tumors in both hepatic lobes that coalesce to form larger confluent hypoattenuating regions in a peripheral or subcapsular distribution and a halo or target pattern of enhancement in larger lesions (5,6). This patient underwent both hepatic arterial and portal venous phase scanning, and the arterial phase images did not demonstrate early phase enhancement or findings indicative of arteriovenous shunting. Radin et al (6) noted that the extent of lesions was best appreciated on unenhanced CT images. Miller et al (4) confirmed the previously noted CT findings and emphasized the presence of focal atrophy with retraction of the overlying liver capsule in nine of 13 patients. Kelleher et al (7) also noted the presence of capsular retraction or "umbilication" when examining liver explants. Calcification may be present in 20% of patients, as reported by Makhlouf et al (3). Magnetic resonance imaging reveals hypointense lesions relative to normal liver parenchyma on unenhanced T1-weighted images and heterogeneously increased signal intensity on T2-weighted images (4,8–11). Some lesions demonstrate either a peripheral halo or a target-type enhancement pattern after administration of a gadolinium-based contrast agent, with occasional observation of a thin peripheral hypointense rim (4). Ferumoxides-enhanced T2-weighted images may help physicians distinguish tumor margins (10).
At this time, there does not seem to be a correlation between morphologic tumor grading, clinical staging, and outcome (3). Surgical resection or transplantation is considered the treatment of choice (7,12,13). Because of the multifocal nature of this tumor, transplantation may be the optimal treatment (14). Metastatic lesions have been reported in 27% of patients at presentation and occur most commonly in the lungs. Other sites of metastases include the abdominal lymph nodes, omentum, mesentery, and peritoneum (3). The clinical course of these lesions is quite variable, and histologic analysis is of little value in predicting the clinical outcome. The roles of chemotherapy and radiation therapy are still unclear (12).
The clinical history of this patient, the results of laboratory tests, and the presence of multiple hypoattenuating hepatic masses that were associated with focal hepatic capsular retraction and that coalesced in the periphery of the liver and demonstrated target or halo-like enhancement suggest a diagnosis of epithelioid hemangioendothelioma. Although hepatic lesions can be associated with focal hepatic capsular retraction, this association is an infrequent occurrence with most benign or malignant hepatic tumors (15–17) and remains an important finding of hepatic epithelioid hemangioendothelioma. Conglomerate fibrosis in patients with cirrhosis most closely resembles this condition but is usually associated with morphologic changes of cirrhosis and regenerative nodules. Chronic biliary obstruction, which is commonly due to cholangiocarcinoma, can lead to lobar atrophy and capsular retraction; however, biliary dilatation is nearly always present. Treated metastases can lead to capsular retraction as the tumor shrinks, but a history of malignancy is usually present.
There are several important reasons that radiologists should be aware of the imaging findings associated with hepatic epithelioid hemangioendothelioma and should suggest this diagnosis in the proper clinical setting. First, the tumor has an intermediate malignant potential that is between that of hemangioma and that of hepatic angiosarcoma. Since it is a low-grade malignancy, it may be treated with resection or transplantation, even when metastatic disease is recognized (7,12–14,18,19). Second, the tumor can be confused with other lesions and is frequently misdiagnosed at initial histologic examination; it is most often diagnosed as a cholangiocarcinoma, angiosarcoma, hepatocellular carcinoma, or metastatic carcinoma (3). Demonstration of the vascular or endothelial origin of the tumor is critical for diagnosis and requires immunostaining for endothelial markers, including factor VIII–related antigen, CD31, and CD34. The radiologist may be the first physician to suggest the vascular origin of this neoplasm and the necessity of immunostaining for endothelial markers. Peripheral confluent masses with capsular retraction are hallmark features that should suggest a diagnosis of hepatic epithelioid hemangioendothelioma.
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FOOTNOTES
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| Part one of this case appeared 4 months previously and may contain larger images.
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References
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- Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for carcinoma. Cancer 1982;50:970–981.[CrossRef][Medline]
- Ishak KG, Sesterhenn IA, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol 1984;15(9):839–852.[Medline]
- Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999;85(3):562–582.[CrossRef][Medline]
- Miller WJ, Dodd GD 3rd, Federle MP, Baron RL. Epithelioid hemangioendothelioma of the liver: imaging findings with pathologic correlation. AJR Am J Roentgenol 1992;159(1):53–57.[Abstract/Free Full Text]
- Furui S, Itai Y, Ohtomo K, et al. Hepatic epithelioid hemangioendothelioma: report of five cases. Radiology 1989;171(1):63–68.[Abstract/Free Full Text]
- Radin DR, Craig JR, Colletti PM, Ralls PW, Halls JM. Hepatic epithelioid hemangioendothelioma. Radiology 1988;169(1):145–148.[Abstract/Free Full Text]
- Kelleher MB, Iwatsuki S, Sheahan DG. Epithelioid hemangioendothelioma of liver: clinicopathological correlation of 10 cases treated by orthotopic liver transplantation. Am J Surg Pathol 1989;13(12):999–1008.[Medline]
- Van Beers B, Roche A, Mathieu D, et al. Epithelioid hemangioendothelioma of the liver: MR and CT findings. J Comput Assist Tomogr 1992;16(3):420–424.[Medline]
- Lyburn ID, Torreggiani WC, Harris AC, et al. Hepatic epithelioid hemangioendothelioma: sonographic CT and MR imaging appearances. AJR Am J Roentgenol 2003;180(5):1359–1364.[Free Full Text]
- Kehagias DT, Moulopoulos LA, Antoniou A, Psychogios V, Vourtsi A, Vlahos LJ. Hepatic epithelioid hemangioendothelioma: MR imaging findings. Hepatogastroenterology 2000;47(36):1711–1713.[Medline]
- Ros LH, Fernandez L, Villacampa VM, Ros PR. Epithelioid hemangioendothelioma of the liver: characteristics on magnetic resonance imaging—case report. Can Assoc Radiol J 1999;50(6):387–389.[Medline]
- Lauffer JM, Zimmermann A, Krahenbuhl L, Triller J, Baer HU. Epithelioid hemangioendothelioma of the liver: a rare hepatic tumor. Cancer 1996;78(11):2318–2327.[CrossRef][Medline]
- Madariaga JR, Marino IR, Karavias DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma. Ann Surg Oncol 1995;2(6):483–487.[Abstract]
- Ben-Haim M, Roayaie S, Ye MO, et al. Hepatic epithelioid hemangioendothelioma: resection or transplantation—which and when? Liver Transpl Surg 1999;5(6):526–531.[CrossRef][Medline]
- Soyer P. Capsular retraction of the liver in malignant tumor of the biliary tract: MRI findings. Clin Imaging 1994;18(4):255–257.[CrossRef][Medline]
- Sans N, Fajadet P, Galy-Fourcade D, et al. Is capsular retraction a specific CT sign of malignant liver tumor? Eur Radiol 1999;9(8):1543–1545.[CrossRef][Medline]
- Blachar A, Federle MP, Brancatelli G. Hepatic capsular retraction: spectrum of benign and malignant etiologies. Abdom Imaging 2002;27(6):690–699.[CrossRef][Medline]
- Marino IR, Todo S, Tzakis AG, et al. Treatment of hepatic epithelioid hemangioendothelioma with liver transplantation. Cancer 1988;62(10):2079–2084.[CrossRef][Medline]
- Hung CF, Jeng LB, Lee WC, Lin DY, Tan PP, Chen MF. Liver transplantation for epithelioid hemangioendothelioma. Transplant Proc 1998;30(7):3307–3309.[CrossRef][Medline]
Congratulations to the 97 individuals and two resident groups that submitted the most likely diagnosis (hepatic epithelioid hemangioendothelioma) for Diagnosis Please, Case 96. The names and locations of the individuals and resident groups, as submitted, are as follows:
Individual responses
- Hisashi Abe, Osaka, Japan
- Albert J. Alter, Madison, Wis
- Alexandra Araújo, Lisbon, Portugal
- Javier Arnaiz, MD, Santander, Spain
- Lionel Arrivé, Paris, France
- Christian Arseneau, MD, Trois-Rivières, Quebec, Canada
- Dr Louisa Azizi, Paris, France
- H. Scott Beasley, MD, Pittsburgh, Pa
- Mark A. Bisesi, MD, Bloomington, Ind
- Gustav Blomquist, Houston, Tex
- Giuseppe Brancatelli, Palermo, Italy
- Ghislain Brousseau, MD, Charlesbourg, Quebec, Canada
- Douglas C. Brown, MD, Virginia Beach, Va
- Michael P. Buetow, MD, Okemos, Mich
- Peter C. Buetow, MD, Bellingham, Wash
- Stephen J. Buetow, MD, Evans, Ga
- Paula Campos, MD, Cascais, Portugal
- Dr Tirso Cascajares Murillo, Los Mochis, Mexico
- Neal R. Conti, MD, Seattle, Wash
- Anil Kumar Dasyam, Pittsburgh, Pa
- Marc G. de Baets, MD, Lugano, Switzerland
- Peter C. De Baets, MD, Damme, Belgium
- Manoel de Souza Rocha, Sao Paulo, Brazil
- Seena Dehkharghani, MD, Phoenix, Ariz
- Mustafa Kemal Demir, MD, Istanbul, Turkey
- Thaworn Dendumrongsup, MD, Songkla, Thailand
- Susana Dias, Porto, Portugal
- Seyed Emamian, MD, PhD, Rockville, Md
- Juliet H. Fallah, MD, Chicago, Ill
- Brett Ferdinand, Livingston, NJ
- Julio Fuentes Álvarez, MD, Tenerife, Spain
- Akira Fujikawa, MD, Tokyo, Japan
- Douglas Gardner, MD, Windsor, Ontario, Canada
- Gilles Genin, MD, Annecy, France
- Alvaro Gomez Naar, Salta, Argentina
- Francisco J. González, MD, Cantabria, Spain
- Daniel Gridley, MD, Phoenix, Ariz
- Horacio Gutierrez, MD, Longmont, Colo
- Ferris M. Hall, MD, Boston, Mass
- Srinivasan Harish, Hamilton, Ontario, Canada
- Rajapandian Ilangovan, MD, FRCR, London, United Kingdom
- Joao Rodrigues Inacio, Lisbon, Portugal
- Kiriakos Kalampoukas, MD, Kozani, Greece
- Myeong-Jin Kim, MD, PhD, Seoul, Korea
- Takuji Kiryu, MD, Gifu, Japan
- Steven A. Klein, MD, Shrewsbury, Mass
- Takashi Koyama, MD, PhD, Kyoto, Japan
- Hiroyuki Kumazoe, Fukuoka, Japan
- Yoshihisa Kurosaki, MD, Tokyo, Japan
- Stefanos Lachanis, MD, Athens, Greece
- Mario Laguna, West Allis, Wis
- Eugene Lin, MD, Seattle, Wash
- Marcio Lobo Guimaraes, MD, Brasilia, Brazil
- Patricia Lowry, MD, Richmond, Va
- Chikara Maeda, Wakayamashi, Japan
- N. B. S. Mani, MD, Nassau, Bahamas
- Waldir H. Maymone, Rio de Janeiro, Brazil
- Frank McKowne, MD, Vancouver, Wash
- Koen Mermuys, MD, Heverlee, Belgium
- Manabu Minami, MD, Tsukuba, Ibaraki, Japan
- Sankar Ranjan Mondal, MD, Nassau, Bahamas
- Tammam Nehme, East Wenatchee, Wash
- Michailidis Nikolaos, MD, Thessaloniki, Greece
- Hiroshi Nobusawa, Tokyo, Japan
- Marcos Nogueira Chagas, MD, Brasilia, Brazil
- Michael T. O'Loughlin, MD, West Hartford, Conn
- Hilton W. Pittman, Pensacola, Fla
- Shawn P. Quillin, MD, Charlotte, NC
- Enrique Remartínez Escobar, MD, Melilla, Spain
- Anna Patricia Riello, Rio de Janeiro, Brazil
- Jordi Rimola, MD, Barcelona, Spain
- Mathieu H. Rodallec, Paris, France
- Eloisa Santos Armentia, Vigo, Spain
- Steven Schepers, Herent, Belgium
- Anthony J. Scuderi, MD, Johnstown, Pa
- Robert H. Sherrier, MD, Boulder, Colo
- Taro Shimono, MD, Osaka, Japan
- Kouichi Sugiyama, Hamamatsu, Japan
- Amit Suri, MD, Kings Lynn, Norfolk, United Kingdom
- Kazuhiro Suzuki, Tokyo, Japan
- Norio Takahashi, MD, Fukui, Japan
- Eliko Tanaka, Yokohama, Japan
- Toyohiko Tanaka, MD, Shiga, Japan
- Kazuma Terauchi, Shizuoka, Japan
- William C. Torreggiani, Dublin, Ireland
- Hiroyuki Ueda, Kyoto, Japan
- Shigeaki Umeoka, MD, Wakayama, Japan
- Carlos Valls, MD, Barcelona, Spain
- Filiep Van Geluwe, Leuven, Belgium
- Joan C. Vilanova, MD, Girona, Spain
- Jesús I. Vivancos Garbayo, Tenerife, Spain
- Dr Silvio Alejandro Vollmer, Neuquen, Argentina
- Nicolaus A. Wagner-Bartak, MD, Houston, Tex
- Zhen Jane Wang, San Francisco, Calif
- Michael Weber, Berlin, Germany
- Kaneko You, MD, Gifu, Japan
- Joe Yut, Olathe, Kan
Resident group responses
- Hospital de Alzira and Consorcio Hospital General Universitario de Valencia Radiology Residents, Valencia, Spain
- Hospital of the University of Pennsylvania Radiology Residents, Philadelphia, Pa
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HISTORY
IMAGING FINDINGS
