Epithelioid hemangioendothelioma (EHE) is a sarcoma that is characterized by vacuolated endothelial cells distributed in a distinctive myxohyaline stroma; most such tumors harbor WWTR1::CAMTA1 gene fusions. There is an uncommon, distinctive EHE subset that shows frank vasoformation and harbors YAP1::TFE3 gene fusions. 

EHE occurs across a wide age distribution, with a median age at presentation of around 50 years.¹ YAP1::TFE3 fusions tend to occur in younger patients than WWTR1::CAMTA1 fusions.²

EHE has a variable disease course that depends in part on body site. Tumors occurring in skin and soft tissue tend to be solitary, while those occurring in bone, lung, and liver tend to be multifocal at presentation.^3-6 

EHE is comprised of endothelial cells dispersed singly or in small clusters in a characteristic myxohyaline stroma. Neoplastic cells are frequently vacuolated. There are often injured blood vessels in the tumor, and sometimes these vessels are plugged by clusters of neoplastic endothelial cells. EHE with YAP1::TFE3 rearrangement has a similar myxohyaline stroma, but, in contrast to conventional EHE, tumor cells are nested and exhibit frank vasoformation.

EHE is positive for vascular markers, including ERG, CD31, and CD34.⁷ In addition, CAMTA1 immunohistochemistry is about 85% sensitive and 100% specific for the diagnosis (Fig. 1); this sensitivity is in keeping with the underlying frequency of WWTR1::CAMTA1 gene fusions.⁸ TFE3 immunohistochemistry (Fig. 2) is highly sensitive for YAP1::TFE3-rearranged EHE;² however, it has suboptimal specificity and also can be positive in WWTR1::CAMTA1-rearranged tumors.⁹ Immunohistochemistry directed against the C-terminus of YAP1 demonstrates loss of expression in YAP1::TFE3-rearranged EHE.¹⁰

Figure 1. CAMTA1 immunohistochemistry in epithelioid hemangioendothelioma (EHE). Nuclear CAMTA1 expression correlates with underlying CAMTA1 gene rearrangement and is seen in about 85% of EHE, including the example shown here.

Figure 2. TFE3 immunohistochemistry in epithelioid hemangioendothelioma (EHE). This example of TFE3-rearranged EHE demonstrates nuclear positivity for TFE3. TFE3 rearrangements are present in about 5% of EHE.

EHE was initially proposed to have intermediate biologic potential, but, with the benefit of more robust follow-up data, it is now known to be a sarcoma with significant metastatic potential, ranging from 20-40% depending on primary site.^3,6,11 Primary visceral lesions have a worse prognosis, with around 40% metastatic potential and an over 40% mortality rate in one long-term follow-up study.⁶ In comparison, primary soft tissue EHE has a better prognosis, with roughly 20% metastatic and mortality rates;³ EHE of the skin has an excellent prognosis.¹² Patients with YAP1::TFE3-rearranged EHE have a roughly 50% chance of developing metastases, commonly long after the initial diagnosis.^2,13

• EHE has t(1;3)(p36;q23-25) in 85% of tumors, identified by karyotype in 2001,¹⁴ which corresponds to the WWTR1::CAMTA1 gene fusion.^9,14,15 This fusion is not present in angiosarcoma, and so it distinguishes  between these two entities when present.¹⁶

• YAP1::TFE3 fusion occurs in approximately 5% of tumors.² YAP1 C-terminus IHC is a useful marker that supports the diagnosis of EHE with YAP1::TFE3.

• The WWTR1 and YAP1 proteins are regulated by Hippo pathway; in conditions of confluent cell growth, these proteins are phosphorylated and degraded. In contrast to native WWTR1, the fusion protein localizes to the nucleus, where it is not subject to Hippo pathway-induced degradation and where it drives a WWTR1-like transcriptional program.¹⁷