Recurrent hepatic epithelioid hemangioendothelioma after orthotopic liver transplantation
Authors: Mary K. Rude, Rao Watson, Jeffrey S. Crippin
Journal: Hepatology (2013)

A 64-year-old female with no known liver disease presented with nonspecific abdominal pain and a 15-pound weight loss in 1999. Subsequent workup revealed multiple low-attenuation hepatic masses located along the surface of the liver on abdominal computed tomography (CT). A guided biopsy revealed hepatic epithelioid hemangioendothelioma (HEH). There was no evidence of extrahepatic disease. Orthotopic liver transplantation (OLT) was performed in 2000 without complication. She was maintained on tacrolimus with therapeutic levels and mycophenolate mofetil, with no evidence of rejection. Annual cross-sectional imaging for 5 years post-OLT showed no evidence of recurrence, and imaging in 2010 showed a normal-appearing transplanted liver (Fig. 1). Liver biochemistries were normal. She presented in 2012 with 1 week of nonspecific abdominal pain, jaundice, and pruritus. On examination, she was icteric and had mild right-upper-quadrant pain with palpation. Laboratory findings included aspartate aminotransferase (327 U/L), alanine aminotransferase (271 U/L), alkaline phosphatase (280 U/L), total bilirubin (8.3 mg/dL), direct bilirubin (7.0 mg/dL), and international normalized ratio (0.98). A complete blood count was normal. Viral hepatitis panel was negative. Doppler ultrasound (US) showed multiple round hypoechoic lesions throughout the liver and patent hepatic vasculature. Magnetic resonance imaging showed multiple enhancing lesions involving the liver and spleen, thought to be consistent with metastatic disease (Fig. 2,3). A US-guided core liver biopsy was performed. Rare atypical endothelial cells (ECs), some of which stained positive for CD34 and CD31, were noted. The biopsy was repeated and showed recurrent HEH (Fig. 4A,B). Shortly thereafter, she was started on palliative chemotherapy with thalidomide for recurrent HEH. She presented 6 months after diagnosis with an upper gastrointestinal bleed from esophageal varices, hypotension, renal failure, and progressive liver failure. She expired shortly thereafter. Epithelioid hemangioendothelioma (EH) is a neoplasm of vascular origin first described in 1982.1 The literature shows that EH may develop in the lung, bone, brain, soft tissue, and liver and have variable malignant potential. Given that HEH is quite rare, with an incidence of less than 1 in 1 million,2 little is known about its risk factors, disease course, or prognosis. Case reports show that patients with HEH tend to be females (female/male ratio: 3:2), with a peak incidence between 30 and 40 years of age.3 Presenting symptoms include weight loss, nonspecific abdominal pain occasionally localized to the right-upper quadrant, and hepatosplenomegaly. Laboratory findings tend to be nonspecific, but patients often have abnormal liver biochemistries. Multifocal peripheral hepatic nodules that coalesce and form capsular retraction are highly suggestive of HEH.4 Histological findings of HEH include epithelioid ECs infiltrating the surrounding sinusoids. Endothelial markers, such as CD31, CD34, and/or factor VIII–related antigen, are often positive.5 Because of its EC properties, agents targeted against vascular endothelial growth factor, including bevacizumab, thalidomide, cyclophosphamide, and sorafenib, have been shown to be successful in treating HEH in small case series.6, 7 OLT has become an acceptable treatment for HEH and is often the preferred therapy, given that 81% of patients have multifocal lesions at the time of diagnosis,8 making localized resection infeasible. The United Network for Organ Sharing reported a 5-year survival rate of 64% for 110 patients undergoing OLT for HEH between 1987 and 2005. Of these 110 patients, 12 (11%) died of recurrent HEH within 5 years.9 The literature reports an overall disease-free survival (DFS) ranging from 4 months to 10 years (mean, 59.2 months).3 A smaller study reviewed the outcomes of 30 patients with HEH treated with OLT resulting from unresectable disease versus liver resection and showed similar overall survival and DFS rates at 1, 3, and 5 years between the two treatment groups.10 There are no established recommendations for reimaging post-OLT when transplanted for HEH or for other indications for OLT; however, the American Association for the Study of Liver Diseases suggests that patients have an abdominal and chest CT every 6 months for 3 years post-OLT when transplanted for hepatocellular carcinoma.11 This case, treated with OLT, is the longest published interval between successful treatment with OLT and recurrence of likely metastatic HEH.