Novel YAP1‐TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma

Abstract

Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong TFE3 immunoreactivity, FISH analysis for TFE3 gene rearrangement was applied to the index case as well as to 9 additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, 9 pseudomyogenic HE and 3 epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in 6 cases, lung in 3 and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and RT-PCR. YAP1 gene rearrangements were then confirmed in 7 of the remaining 9 TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.

Composite Hemangioendothelioma of the Submandibular Region

“…About half of EHE are associated with a medium-sized or large vessel. In addition to expressing vascular markers, EHE can express cytokeratins, and are associated with WWTR1-CAMTA1 [30] or YAP1-TFE3 [31] fusions, which have not yet been shown to be associated with other neoplasms. Kaposi sarcoma (KS) may be associated with immunosuppression, or with certain populations (e.g.…”

Malignant vascular tumors—an update

“…As the S127 14-3-3 binding site, WW domain and its C-terminal transactivation domain are not retained in the fusion, it is most likely that YAP1 provides a strong promoter to the oncogenic TFE3 function of the fusion protein. 14 The anatomic distribution of these lesions is mainly within soft tissue, ranging from head and neck, trunk and extremities, with only one case occurring in the bone (vertebral body). Additional cases were seen in the lung, with multifocal presentation.The tumors occurred in young adults, with a mean age of 30 years old, with no gender predilection.…”

Epithelioid Hemangioendothelioma of the Maxillary Sinus

“…These have not been seen in other vascular tumors and, hence, some authors have suggested that it could be used in difficult cases to distinguish EHE from its morphological mimics [13,14]. YAP1-TFE3 gene fusions have been identified in a subset of EHEs where WWTR1-CAMTA1 fusion was not identified [15]. Tumors with this fusion have been reported to demonstrate a strong expression of TFE3 (nuclear).…”