Epithelioid Hemangioendothelioma: Treatment Landscape and Innovations for an Ultra-Rare Sarcoma

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma with a paucity of data on best practices for management. Pathogenic translocations involving the YAP or TAZ genes lead to constitutive activation of TEAD and TEAD-associated pathways. As our understanding of the molecular drivers of EHE has advanced, investigational treatment strategies have shifted away from cytotoxic chemotherapy toward more targeted approaches. This review focuses on the historical context and evolving landscape of systemic therapies for patients with EHE. For newly diagnosed patients, we recommend consultation at a high-volume sarcoma center whenever possible. If the disease is localized and resectable, surgical excision by a sarcoma-focused surgical oncologist is preferred. When the disease is unresectable, we first assess for disease progression to determine whether active surveillance is appropriate. Some patients may experience indolent, asymptomatic disease for years-or even decades-without requiring intervention. In patients with progressive or symptomatic unresectable disease, systemic therapy is warranted. Setting realistic expectations about the goals of treatment is essential, as no current systemic therapies reliably reduce tumor burden. However, molecular profiling and ongoing correlative studies from clinical trials may soon identify more effective therapeutic targets. For this reason, we encourage referral to centers that routinely perform molecular profiling and offer clinical trials with eligibility criteria for EHE, even to be considered as a first-line approach. Outside of a clinical trial, cytotoxic chemotherapy remains the frontline standard of care for patients who require systemic treatment. Importantly, treatment decisions must incorporate patient preferences and recognition that symptomatic improvement alone can be a meaningful outcome for preserving quality of life.