Hepatic epithelioid hemangioendothelioma (HEH) is extremely rare, occurring in 1 to 2 per 100,000, with chemotherapy options not well defined. Our case involved a 49-year-old female who had hepatic masses and metastasis to the lungs with a liver biopsy revealing HEH. After developing a rash from sorafenib, thalidomide was started with the progression of disease stabilized. Resection is only an option in 10% of the cases; therefore, chemotherapy is the only line of treatment. Newer chemotherapy alternatives are targeting angiogenesis via the vascular endothelial growth factor. Thalidomide was first used as an antiemetic, but, sadly, soon linked to phocomelia birth defects. Given the mechanism of action against angiogenesis, thalidomide has a valid role in vascular tumors. In conclusion, the use of thalidomide as chemotherapy is novel and promising, especially in the setting of a rare vascular liver tumor such as HEH.
Vascular in origin, hepatic epithelioid hemangioendothelioma (HEH) is an extremely rare diagnosis; therefore, treatment for this malignancy has not been well defined. Much of the data on HEH are in case studies and small case series with treatment usually confined to only a few options. Given the vascular nature of this cancer, thalidomide has been used with some degree of success. In the mid-twentieth century, thalidomide was used for morning sickness in pregnant women, and their babies developed well-documented phocomelia birth defects.
From those horrific malformations, continued investigation into the explanation of thalidomide involvement has led to a better understanding of its harmful effects on angiogenesis. With this discovery, the careful use of the medication has been employed as chemotherapy in cancers such as HEH. In this case report, we present a female diagnosed with metastatic HEH who has been successfully treated with thalidomide chemotherapy.
We present a 49-year-old Hispanic female originally seen in the ER for atypical chest pain needing cardiac evaluation. Patient presented months back with chest pain that started early the morning of admission, intermittent in nature, worsened with deep inspiration, and radiated to her back. No abdominal pain was noted, but she did complain of associated nausea, diaphoresis, fatigue, and dizziness. She also reported 30-pound weight loss in the last month with no change in appetite discussed. Past medical history was only significant for type 2 diabetes mellitus. Family history was significant for coronary artery disease in her father and stomach cancer in her mother. No pertinent surgical history was given. She denied any tobacco, alcohol, and illicit drug use.
Full cardiac evaluation, including EKG, cardiac marker testing, and chest X-ray, was negative. Upon further review of her chart, 3 years prior to this presentation, a computed tomography (CT) of the abdomen and pelvis was ordered by an urgent care physician secondary to abdominal pain. It showed multiple hypodense masses in the right and left lobe of the liver. The largest one showed a lobulated margin measuring 6.7 cm × 5.5 cm. The masses did not show typical characteristics of hemangioma or simple hepatic cyst. Also noted were fatty liver changes. There was no older study for comparison at that time. A short term repeat CT scan was recommended but she was lost to follow-up. During this admission, CT abdomen with intravenous contrast showed hepatic masses, largest being 12 cm × 5.5 cm, and development of small pulmonary nodules worrisome for metastasis (Figure
(a) Computed tomography (CT) of the abdomen showing a large hepatic mass, measuring 12 cm × 5.5 cm and designated by the blue arrow. (b) CT of the chest showing metastatic nodules, designated by yellow arrows.
Initial gastrointestinal evaluation revealed normal bilirubin, PT, PTT, and INR. Hepatitis B and hepatitis C were both negative. She did exhibit elevated alkaline phosphatase of 311 IU/L and elevated cancer markers, including CEA of 6.0 ng/mL, CA 19-9 of 74.8 units/mL, and CA 125 of 36.3 units/mL. Ultrasound guided liver biopsy was elected at this time and pathology was consistent with HEH (Figure
(a) Replacing hepatocytes is tumor with sometimes large, often spindled, aberrant nuclei amid abundant light pink, feathery matrixes (H&E, 100x). (b) Uniformly dark, cancerous nuclei, sometimes huge, lie in variably colored cytoplasm, often not evident. Cancer cells lie in isolation and in epithelioid groups. At the arrowhead, a group lies about a vacuole, which is a vascular lumen (H&E, 400x). (c) Cancer cell cytoplasm often expresses CD34, which emphasizes the epithelioid pattern (DAB, 400x). (d) Many cancer cell nuclei, often juxtaposed to vacuoles, express Factor XIIIa (DAB, 400x). Gold bars are 200
The term epithelioid hemangioma was coined by Weiss and Enzinger in 1982 to describe a distinct entity, a soft tissue vascular tumor of endothelial origin with a clinical course intermediate between benign hemangioma and malignant angiosarcoma [
In regard to treatment, resection is preferable with a 75% 5-year survival rate. However, resection is usually only an option in 10% of the cases [
In 1957, thalidomide was first released in West Germany. It was intended as a hypnotic and sedative medication but soon found favor working against nausea in morning sickness during pregnancy. Common side effects include somnolence, edema, hypotension, myelosuppression, peripheral neuritis, interstitial lung disease, and pneumonia. Sadly, thalidomide was also discovered to have a high association with birth defects such as phocomelia, a malformation of limbs. The phocomelia was severe with formation of the limbs appearing to be stunted and underdeveloped. 10,000 children were thought to be affected before it was taken off the market. One proposed teratogenic mechanism includes halting of angiogenesis by inhibition of fibroblastic growth factor (bFGF) and/or VEGF, which has been verified with in vivo studies [
Other than its effects on vascular growth, thalidomide also inhibits tumor necrosis factor (TNF)-
In conclusion, both the diagnosis of HEH and the use of thalidomide in a vascular mediated tumor are extremely rare. Given the mechanism of action against angiogenesis, thalidomide does show some benefit in treatment for such cancers. Furthermore, given the direction of cell receptor and/or growth factor guided chemotherapy, thalidomide may hold promising future derivatives that can better target malignant hepatic hemangiomas and other malignancies.
Informed consent was obtained from the patient.
The corresponding author guarantees the integrity and accuracy of this paper. There was no financial support provided for this paper and no conflict of interests.
Rashmi Verma provided editorial and writing assistance to the paper. Drew Payne provided editorial and writing assistance to the paper. Mitchell Wachtel provided writing assistance to the paper, especially regarding figures. Fred Hardwicke was the attending physician in the case and provided editorial assistance to the paper. Everardo Cobos provided editorial assistance to the paper.