A 51-year-old woman presents to the ED with right upper quadrant abdominal pain. Contrast CT reveals four hypodense lesions in the right lobe of the liver. The largest lesion, measuring 1.7 cm in greatest dimension, is biopsied.
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Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm composed of epithelioid endothelial cells in a characteristic myxohyaline stroma. A vast majority of cases (>90%) are characterized by a t (1;3) (p36; q23-q25) resulting in a WWTR1-CAMTA1 fusion, which is demonstrated by CAMTA1 expression by immunohistochemistry. A small subset of EHE cases also undergo a separate translocation event, YAP1-TFE3, which shows a distinct morphology and expresses immunopositivity for TFE3 (which was negative in our case).
EHE most often arises in somatic soft tissue, but can occur in any visceral organ, often arising in liver and lungs. Clinically, it presents as a solitary, often painful mass. Tumors involving preexisting vessels can present with vascular occlusion-type symptoms such as edema and thrombophlebitis. It has a wide age distribution with a slight female predilection. It most commonly occurs in adults age 30-50 years, and rarely occurs in children. Interestingly, these tumors are often multifocal at presentation, which was the case here; our patient had four distinct tumors in the liver.
Morphologically, EHE shows an infiltrative growth pattern consisting of cords and nests of epithelioid cells in a variably myxoid and hyaline stroma. Angiocentric tumors grow outward from vessel walls and spread centrifugally into surrounding tissue. The tumor cells have moderate amounts of eosinophilic cytoplasm and round nuclei with inconspicuous nucleoli. Characteristic intracytoplasmic vacuoles (“blister cells”) representing primitive vascular lumina are often present and may contain erythrocytes.
EHE with YAP1-TFE3 fusion shows distinctive histology characterized by brightly eosinophilic cytoplasm with a solid growth pattern, and often form vascular channels. Notably, this latter feature is not seen in the classic form of EHE. Also, a small subset (<10%) of EHEs have atypical features such as nuclear pleomorphism, increased mitotic activity, solid sheet-like growth, and necrosis. This may resemble epithelioid angiosarcoma, and thus the diagnosis of EHE must be supported with ancillary studies.
The WWR1-CAMTA1 fusion can be demonstrated via immunohistochemistry with positive nuclear expression of CAMTA1, or via molecular testing. EHE also positively expresses endothelial markers CD31 and CD34, as well as ERG and FLI-1. Keratin markers are positive in up to 40% of cases, often with weak and/or focal expression. SMA, desmin, S100, and EMA are negative. As mentioned before, tumors harboring the YAP1-TFE3 fusion shows positive nuclear expression of TFE1.
Prognosis is largely dependent on anatomical location(s). EHE is indolent in most cases, but metastasis is observed in 20%-30% of patients. Tumors can also recur locally (10%-15%). Features that portend a more aggressive clinical course include tumor size >3 cm, elevated mitotic activity (>3 mitoses/50 HPF), severe cytologic atypia, spindled morphology, and the presence of necrosis. Treatment occurs by wide surgical excision with negative margins, and there is no proven role for adjuvant chemotherapy or radiation.
David Cook, M.D.
Resident, Anatomic Pathology/Neuropathology
Charles Sturgis, M.D.
Consultant, Anatomic Pathology
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science