Hepatic epithelioid hemangioendothelioma (HEHE) is an extraordinarily rare vascular tumor^1-3 and the optimal clinical management has not been clearly defined yet. We report a new case of HEHE managed with liver transplantation (LT). We also discuss the therapeutic options.

A 60-year-old male patient presented with anorexia, asthenia, weight loss (5 kg) and abdominal bloating. The laboratory tests showed total bilirubin of 3.9 mg/dL, ALT 127 U/L, GGT 191 U/L, ALP 684 U/L, CA125: 3600 U/mL and INR 1.17. The patient underwent abdominal ultrasound, computed tomography (CT) scan (Fig. 1AB), magnetic resonance imaging (MRI) and positron emission tomography computed tomography (PET-CT) which showed multiple nodules in both hepatic lobes with diffuse involvement of the hepatic parenchyma, ascites without portal thrombosis, and absence of extrahepatic disease. The pathology examination after fine needle aspiration (FNA) biopsy made the diagnosis of HEHE. The patient developed portal thrombosis with worsening of the clinical and laboratory findings and anticoagulation was started with enoxaparin 100 mg subcutaneously every 24 hours. Two months after the onset of symptoms, he was evaluated by the Transplantation Committee and put on the waiting list with MELD (model for end stage liver disease) score of 21, and MELD-Na score of 28 (creatinine: 1.13 mg/dL, INR: 1.07; total bilirubin: 9.2 mg/dL, sodium: 126 mmol/L).

Figure 1 CT scan in axial and coronal planes. HEHE with diffuse liver involvement 

In July 2021, after 1 month on the waiting list, he underwent LT from a brain-dead donor [donor risk index (DRI) of 1.96], with preservation of the vena cava. Cold ischemia time was 275 minutes, warm ischemia time was 32 minutes and total operative time was 288 minutes (Fig. 2). Eversion thrombectomy was performed for partial portal thrombosis (grade II) in addition to hilar lymph node resection. Immunosuppression was started with corticosteroids, mycophenolate and a single dose of basiliximab due to impaired glomerular filtration rate according to our usual protocol. Advagraf^® was started on day 3. He was discharged on post-transplant day 11 without Clavien-Dindo complications ≥ grade IIIa.

Figure 2 Surgical field 

The pathology examination reported diffuse HEHE with invasion of intrahepatic veins and gallbladder wall, portal vein tumor thrombus and metastases in 5 of 23 nodes excised. The tumor was positive for CD31 and CD34 markers and negative for CKAE1/AE3. The Ki-67 proliferation index was low (3%). Hepatic epithelioid hemangioendothelioma is a vascular endothelial cell tumor composed of epithelial-like cells and dendritic cells in mucus or fibrotic matrix². The tumor cells express the endothelial markers CD31, CD34, vimentin and factor VIII antigen^2,4. Translocation t(1;3)(p36.3;q25) and WWTR1-CAMPTA1 mutation are specific of HEHE^2,3. The World Health Organization (WHO) defines HEHE as a malignant tumor with metastatic potential and variable clinical course (indolent to progressive)^1-5. It is extremely rare, with and estimated incidence of 1-2 cases per 1 million people^2,3,5,6. Mean age of patients is 30-50 years and is more common in women with a female-to-male ratio of 3:2^1,2. It is classified into three types: solitary (13-18% of HEHE), multiple, the most common type, and diffuse with coalescence of different nodules^2,3. Thirtyfive percent of HEHE patients present metastases in the lung, peritoneum, spleen, lymph nodes and bones at the moment of diagnosis^1-3.

The etiology of HEHE is still unclear. Several possible risk factors have been identified, such as exposure to chloroethylene, polyurethane, asbestos or silica, oral contraceptive use, sarcoidosis, Crohn’s disease, liver trauma, primary biliary cirrhosis, viral hepatitis, and alcohol use^2,3. Our patient did not present any of these factors. The three most common symptoms of HEHE are abdominal pain, liver enlargement and weight loss, but 20-40% of patients may be asymptomatic^1,3,6. Diffuse HEHE, as in our case, can progress rapidly to ascites, portal hypertension, jaundice, Budd-Chiari syndrome, Kasabach-Merritt syndrome and acute liver failure^1,2,4.

Liver function and tumor markers are usually normal². The imaging features of HEHE are nonspecific² and include the peripheral location of the nodules, the contraction of the capsule, the tendency of multiple nodules to coalesce and calcifications⁴. The “halo sign” and the “lollipop sign” on CT scan and MRI (T2 imaging) may be present in some cases of HEHE^2,3. Forty percent of patients present portal vein thrombosis before LT¹. The differential diagnoses are liver metastases, sclerosing hepatocellular carcinoma, cavernous hemangioma, hemangiosarcoma/ angiosarcoma, or intrahepatic cholangiocarcinoma^2,3. Due to the absence of specific characteristics in signs and symptoms, laboratory tests and radiological findings, biopsy still plays a decisive role in its diagnosis². There are no international guidelines for the management of HEHE^1,5. Several treatments have been used, as waiting strategy, medical treatment (propranolol/corticosteroids), chemotherapy, radiotherapy, techniques and surgery^2,3,5. The management of hepatic EHE depends on tumor size, location, extrahepatic extension, and patients’ medical status³. Liver resection or LT is the treatment of choice, if feasible^2,4,6. Liver transplantation is indicated in those patients suitable for surgery with unresectable multifocal, diffuse tumors¹. The presence of extrahepatic disease is not an absolute contraindication for LT if these metastases can be resected^1-5. Hepatic epithelioid hemangioendotheliomas account for 0.1% of all the LT performed in the United States⁵.

Survival of HEHE at 1 and 5 years after LT is 88.6% and 79.5%, respectively, according to the European registry, and 80% and 64%, respectively, in the United States². Recurrence occurs in 25% of patients undergoing LT (median: 18 years)¹. Risk factors for recurrence include tumor size > 10 cm, advanced age and macrovascular and lymph node involvement¹. Lai et al. developed the HEHE-LT Score to predict the risk of post-LT recurrence; disease-free survival at 5 years ranged between 94% for a score < 2 and 38.5% for a score > 6¹.

In conclusion, HEHE is an extremely rare tumor, with difficult clinical and radiological diagnosis, and its treatment, if feasible, is liver resection or LT. The results obtained with LT are good, but the risk of recurrence is not negligible.