Epithelioid hemangioendothelioma (EHE), a rare malignant vascular neoplasm with variable morphologic features and unpredictable biologic behavior, was first described by Dail and Liebow in the lung in 1975 and was called “intravascular bronchioloalveolar tumor.” In 1982, Weiss and Enzinger described similar appearing tumors in the soft tissue that were of vascular origin, and proposed the term “epithelioid hemangioendothelioma.” Over time, it came to be known that these were the same lesion, and the term “epithelioid hemangioendothelioma” has been adopted.
These tumors can occur at virtually any site in the body, but most often occur in the liver, soft tissue, lung, and bone. Although most often affecting middle-aged adults, these tumors have been described over a broad age range (from 7 to 76 years). Generally, EHE are considered to be low- to intermediategrade malignancies; however, the clinical course of these tumors can be unpredictable and the life expectancy ranges from 1 to 15 years. The highest mortality rates are associated with lung involvement, and other poor prognostic factors include presence of respiratory symptoms at presentation, pleural effusion or pleural invasion, lymphatic spread, extensive intravascular spread, and hepatic metastases or metastasis to more than one site. Male sex has also been associated with poorer prognosis. Tumor size and mitotic activity have also recently been shown to be prognostic factors. Patients with tumors >3cm in diameter and >3 mitoses per 50 HPF have been shown to have a lower disease specific survival of 59% compared to about 100% survival in patients without those features.
While the etiology and pathogenesis of EHE remains unclear, several clonal chromosomal abnormalities have been identified, including a translocation involving CAMTA on chromosome 1 and WWTR on chromosome 3. Of interest, an association with Bartonella infection has also been suggested, with its role in development perhaps due to the organism’s characteristic chronic intraendothelial infection, its production of VEGF, and its suppression of endothelial cell apoptosis. Other studies have suggested an association with radiation and asbestos exposure, although smoking does not seem to be a contributory factor.
Although EHE is a rare malignancy, these tumors are fairly well described in the literature. However, only a handful of case reports have documented their cytomorphological features in fluid specimens. Histologically, EHE is an angiocentric tumor that expands the vessel wall, obliterates the vessel lumen, and extends into the surrounding tissue inducing a sclerotic response. These tumors are composed of epithelioid endothelial cells that are arranged in chains and cords that are found within a myxohyaline stroma. The cells may demonstrate a vesicular nuclear quality or nuclear grooves, and the cytoplasm may be eosinophilic with vacuolization, some of which may contain erythrocytes, characteristic features that are also seen in cytology specimens.
Immunostains can be used to help confirm a diagnosis of EHE; tumor cells are strongly and diffusely positive for vascular markers including CD31, CD34, Factor VIII, Fli-1, and ERG. About 20-40% of these tumors are positive for cytokeratins (including CK7, CK8, CK18) and EMA. Electron microscopy also is revealing, as characteristic findings such as Weibel-Palade bodies, cellular interdigitations with occasional tight junctions, pinocytotic vesicles, cytofilaments, and intracytoplasmic lumina support their vascular origin.