Pulmonary and Pleural Epithelioid Hemangioendothelioma

Pulmonary epithelioid hemangioendothelioma is a rare vascular neoplasm of endothelial or pre-endothelial cell origin, characterized by markedly variable clinical behavior, ranging from decades-long indolence to rapidly progressive, fatal disease. Although epithelioid hemangioendothelioma can arise at virtually any site, thoracic involvement—most commonly in the lung and, less often, in the pleura—presents distinctive diagnostic and management challenges. The presence of pleural involvement is associated with a poor prognosis. On imaging, chest radiography is nonspecific; CT typically shows bilateral nodules (frequently <2 cm) arranged in a perivascular distribution, with occasional ground-glass, calcification, cavitation, and pleural thickening or effusion. Fluorodeoxyglucose positron emission tomography/computed tomography demonstrates variable avidity, depending on tumor size, and is helpful for staging purposes. Thoracic MRI, although not diagnostic, helps better delineate pleural involvement, chest-wall or mediastinal invasion, and bone marrow involvement. Pathologically, pulmonary epithelioid hemangioendothelioma exhibits cords and nests of epithelioid cells within a myxohyaline stroma, characterized by intracytoplasmic vacuoles. Immunophenotyping confirms endothelial differentiation (e.g., CD31, ERG/FLI1), and nuclear CAMTA1 expression coincides with the classical WWTR1-CAMTA1 fusion gene. Molecular testing for WWTR1-CAMTA1 or YAP1-TFE3 fusion genes is the most specific ancillary discriminator from morphologic mimics. Bronchoalveolar lavage is essentially nondiagnostic, and transbronchial biopsies have low yield. Image-guided core biopsy or surgical lung biopsy is often required for definitive diagnosis. Management is individualized: Observation is appropriate for asymptomatic, indolent disease. Resection of solitary or limited lesions can be performed via wedge resection. Systemic therapy (e.g., sirolimus, VEGFR-TKIs such as pazopanib, or MEK inhibition with trametinib) is favored for progressive, symptomatic, multifocal, or pleural disease. Prognosis is influenced by tumor phenotype.