March 19, 2008
Hepatic Malignant Epithelioid Hemangioendothelioma: A Case Report and Review of the Literature
By Woodall, Charles E Scoggins, Charles R; Lewis, Angela M; McMasters, Kelly M; Martin, Robert C G
Malignant epithelioid hemangioendothelioma is a rare hepatic tumor of vascular origin. It is most commonly found in young to middle aged women, and the tumors vary in reported malignant potential. Compounds such as oral contraceptive pills, poly vinyl chloride, and Thorotrast have been identified as risk factors for subsequent disease development. Radiologic ("lollipop" sign, capsular flattening) and pathologic (Factor-VIII antigen staining positive) evaluation aids in the diagnosis. As with most mesenchymal tumors, surgical resection is the most effective means of controlling local disease and preventing distant metastasis, though adjuvant therapies have been offered for those that are unresectable or not transplant candidates. We present our case of a hepatic malignant epithelioid hemangioendothelioma and a review of the English-language literature. Case PresentationA 69-YEAR-OLD WHITE female complained of vague abdominal pain with some generalized fatigue and a 10 pound weight gain. The clinical evaluation was otherwise negative. Specifically, she had no history of hepatitis or cirrhosis, and no history of exposure to environmental agents potentially associated with malignant epithelioid hemangioendothelioma (EHE).
Computed tomography of the abdomen demonstrating a 4.0 x 5.0 x 3.0 cm mass confined to the right lobe of the liver in segments 7 and 8, suggested a malignancy, rather than focal nodular hyperplasia or hepatic adenoma given its morphology, hypervascularity, and absence of significant fat content. Liver function tests, carcinoembryonic antigen, and alpha fetal protein, were all within normal limits, and a viral hepatitis panel was negative. Upper and lower endoscopy were normal. A percutaneous core needle biopsy of the mass suggested a tumor of vascular origin likely a malignant epithelioid hemangioendothelioma because immunohistochemical stains for Factor VIII antigen, cluster of differentiation molecule (CD) 31, and CD 34 were positive.
An arteriogram confirmed the vascular nature of the mass and defined normal vascular anatomy. She underwent cholecystectomy and right hepatic lobectomy. Malignant EHE was confirmed (Figs. 1, 2). The patient tolerated the procedure well; she received no adjuvant therapy and remains well without evidence of disease at 7 years postoperatively.
Malignant EHE represents a rare (
FIG. 1. High power photomicrograph showing the vascular channels of the tumor.
FIG. 2. Midpower photomicrograph of the tumor demonstrating the vascularity next to normal liver parenchyma.
The relative obscurity and heterogeneity of this tumor makes diagnosis via imaging difficult, though some recent reports have expanded the knowledge base in regards to radiologic findings. The lesions are most frequently peripheral in location. Malignant EHE may manifest as a single nodule or diffuse bilobar disease, which can coalesce into a larger dominant mass. This coalescence was first described by Fumi et al.18 when they proposed a two tiered classification system based on nodular or diffuse disease status. Plain abdominal x-rays frequently show right upper quadrant calcifications (Table 1 ).7 The tumors are heterogeneous by ultrasound; they may be hyper-, hypo-, or isoechoic.19 Cross sectional modalities such as computed tomography and magnetic resonance imaging can reveal the recently described "lollipop sign," with a hepatic or portal vein terminating at the periphery of the mass giving rise to a unique imaging characteristic not commonly seen with other hepatic malignancies.20 Capsular retraction from peritumoral fibrosis may also cause "flattening" of the surface of the liver. Computed tomography may note a hypervascular periphery; additionally, the MR technique of administering superparamagnetic iron oxide has been proposed as a test to furthermore delineate these tumors because of their avid uptake of this contrast medium.21
TABLE 1 Useful Adjuncts in Diagnosing Epithelioid Hemangioendothelioma
Laboratory data is usually nondiagnostic. Tumor markers, such as carcinoembryonic antigen and afetoprotein are generally normal. A recent case series identified serum thyrotropin elevation in seven patients, apparently from a thyrotropin analogue secreted from the tumor.22 This was also reported in a separate case report of a woman before she was treated with transplantation, and was suggested as a postoperative tumor marker to follow patients for early evidence of recurrence.23 Liver function tests may be mildly abnormal, including gamma-GTP (glutamyl transpeptidase).24 Patients may also have an elevated plasma Factor VIII level.
TABLE 2. Review of Cases and Outcomes of Malignant Epithelioid Hemangioendothelioma
Pathologically, the tumors have vascular invasion, a finding that is not surprising given their vascular origins, with the endothelial cells being "epithelioid" or "histiocytoid" in nature.2 Immunohistochemical staining for epithelial markers such as factor VHI-related antigen, CD-31, and CD-34 aid in the diagnosis and confirm its endothelial origin, a pathognomonic feature. Like many mesenchymal tumors, the determination of malignancy is indirect, by such factors as mitotic index and cellularity, as well as clinical behavior.7
Because the hepatic variant of the tumor is more aggressive, up to 60 per cent of patients get metastatic disease, most commonly in the lungs as is the case with most sarcomatous tumors.5 Advanced local dis ease can be problematic as well. Complications such as spontaneous rupture25 and adult Kasabach-Merritt syndrome (a vascular lesion that triggers platelet trapping and subsequent consumptive thrombocytopenia)26 have been reported. In advanced disease, Budd-Chiari may be encountered.27
Similar to other mesenchymal neoplasms, operative therapy remains the mainstay of treatment for patients with malignant EHE.28 Though one case report does identify spontaneous regression in an elderly female with biopsy proven disease,29 most authors recommend definitive operative intervention. As with other hepatic malignancies, the type of operative therapy being recommended is shifting. Resection for localized disease is the generally accepted modality, though some papers report a more fulminant course complicated by recurrence after curative resection.30 Orthotopic liver transplantation for diffuse disease has shown durable success, with survival rates of 75 per cent at 5 years and 60 per cent disease free rates,1 similar to that of patients who undergo transplantation for other hepatic tumors.31 The disease can return in the allograft.5 Despite this, some authors have even recommended it for patients with extrahepatic disease,32 followed by chemotherapy, usually doxorubicin or 5-fluorouracil. Adjuvant therapies, such as arterial chemo-embolization have been reported as a viable bridge to transplantation.33 Radio-frequency ablation, commonly used in the liver for other malignancies, has been used successfully in bone disease34 and would likely serve some purpose in hepatic manifestations of disease. Antineoplastic drugs such as thalidomide have shown benefit as adjuvant therapies or primary treatment for unresectable disease35 and interferon alpha-2B has been used in combination with bilobar hepatic resection with success in case reports.36 Therapeutic devascularization has been attempted in patients with nonresectable disease, with poor results.15 Because of the rarity of the tumor and nonuniform treatment of patients, as well as the varied nature of the disease, predicting prognosis is somewhat challenging. Most publications seem to suggest somewhere between 40 and 75 per cent 5-year survival,15 though there are certainly case reports of patients at both extremes of this spectrum. Whereas some may succumb early, many reports suggest long survival after resection, and a successful term pregnancy has even been described after extirpation of widespread metastatic disease.37 Less is known about truly long-term (greater than 5 year) outcomes. Malignant hepatic epithelioid hemangioendothelioma remains a rare entity, addressed in the literature mostly by case reports (Table T). Its variable nature and clinical course make standardized staging, therapy, and prognosis difficult. While multiple causative factors have been suggested, these remain little more than loose associations. Most authors recommend surgical therapy as standard of care, and this seems appropriate given that most other mesenchymal tumors are best treated operatively. Transplantation has been effective, with survivals in line with other hepatic malignancies treated by this therapy. A large clinical series seems unlikely given the infrequency with which this tumor is encountered; case series and reports such as this one will likely remain as the sole source of reported clinical literature for this malignancy.
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CHARLES E. WOODALL, M.D., CHARLES R. SCOGGINS, M.D., ANGELA M. LEWIS, M.D.,
KELLY M. MCMASTERS, M.D., PH.D., ROBERT C.G. MARTIN, M.D.
From the Department of Surgery, Division of Surgical Oncology, James Graham Brown Cancer Center,
University of Louisville School of Medicine, Louisville, Kentucky
Address correspondence and reprint requests to Robert C.G. Martin, M.D., University of Louisville School of Medicine, 315 East Broadway Suite 312, Louisville, KY 40202. E-mail: [email protected]
Copyright Southeastern Surgical Congress Jan 2008
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