Epithelioid hemangioendothelioma (EHE) is a rare and low-grade malignant endothelial sarcoma. Based on disease-defining mutations, approximately 95% of EHEs have the conventional WWTR1::CAMTA1 gene fusion, while approximately 5% are the Yes-associated protein-1 (YAP1):: transcription factor binding to IGHM enhancer 3 (TFE3) fused tumor subtype according to the World Health Organization classification. Although this tumor type is well recognized, EHE, especially the YAP1::TFE3 fused tumor subtype, represents a diagnostic challenge in routine practice due to its rarity and morphologic overlap with other epithelioid tumors, including other benign and malignant epithelioid vascular neoplasms or carcinomas. Here, we highlight the loss of YAP1 C-terminus expression from the nucleus and cytoplasm of tumor cells along with TFE3 positivity and CAMTA1 negativity as a panel of sensitive markers for detecting lung EHE with YAP1::TFE3 fusion. We also briefly describe the clinicopathological characteristics of this tumor subtype and detail its relevant differential diagnosis.
