Epithelioid hemangioendothelioma (EHE) are rare tumors, accounting for less than 1% of vascular tumors. Due to their rarity and varied presentations, they are often misdiagnosed. These tumors have been shown to harbor recurrent gene translocations, resulting in different gene fusions. EHE most commonly occur in liver alone (21%), in both liver and lung (18%) as a synchronous primary, bone alone (14%) and lung alone (12%). A classic presentation of a solitary or multiple pleural-based thickening/mass that closely mimics malignant mesothelioma clinically has also been described. Besides these sites of origin, EHE has been described in various other organs of head and neck, breast, lymph nodes, limbs and mediastinum in varied frequency and presentations. In many instances, pleural effusion is the first sign of pleural invasion in cases of primary lung EHE. Multi-centric primary tumors are also a common occurrence and due to their tendency to lose vascular and epithelial markers, it is difficult to distinguish simultaneous primary tumors at different sites from metastatic lesions. The median age of onset for EHE is 36 years but can be seen in all age ranges including children and the elderly. EHE is reportedly more common in females, however; pleural EHE is more frequent in males.
The 2013 WHO classifications of tumors of soft tissue classifies EHE as a malignant soft tissue tumor, locally aggressive with metastasis and mortality seen in up to 25% and 15% respectively. Morphologically, typical EHE expressing the hallmark WWTR-CAMTA1 fusion gene demonstrates nests and cords of tumor cells with epithelioid morphology embedded in a myxoid-hyaline stroma. The characteristic “blister cells” with intracytoplasmic lumina are frequently observed in epithelioid cells. Morphologic features of EHE expressing YAP1-TFE3 fusion gene are voluminous eosinophilic cytoplasm with mild to moderate cytologic atypia, more overt vascular channels formation and metastases potential. The vascular channels are not frequently observed in WWTR-CAMTA1 fusion or classic EHE. The age range of EHE with YAP1-TFE3 fusion is 14-50 years, median being 30 years, which is slightly younger than the classic EHE. It is also associated with increased metastases potential. High risk features of EHE are > 3 mitotic figure/ 50 HPF and > 3 cm in size. The 5-year disease specific survival of high risk is 59% versus 100% for low risk. Cytologic features that are helpful for the diagnosis and guiding the work up include moderately cellular preparations, predominantly single cells, and occasional cohesive cell clusters, sometimes arranged in pseudopapillary configuration with prominent stroma. The individual cells exhibit epithelioid cytomorphology, dense cytoplasm with well-defined cytoplasmic borders and mild nuclear atypia, scant mitotic activity, and rare or no necrosis. Intracytoplasmic lumina (ICLs), with or without erythrocytes (blister cells) can be seen along with intranuclear pseudo-inclusions and nuclear grooves. The background is frequently bloody with hemosiderin laden macrophages. Myxoid stromal fragments or scant stroma can also be observed. Inflammatory infiltrate, occasionally forming germinal centers, and multinucleated giant cells can also be seen. In general, EHE is positive for ERG, FLI-1, CD34 and CD31 and frequently expresses cytokeratin. WWTR-1-CAMTA1 fusion EHE stains for CAMTA1 immunohistochemical stain, and nuclear TFE3 positivity is helpful in supporting the diagnosis of YAP1-TFE3 fusion mutated EHE variants.