A novel WWTR1‐CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites

Abstract

The classification of epithelioid vascular tumors remains challenging, as there is considerable morphologic overlap between tumor subtypes, across the spectrum from benign to malignant categories. A t(1;3)(p36.3;q25) translocation was reported in two cases of epithelioid hemangioendothelioma (EHE), however, no follow-up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients. We undertook a systematic molecular analysis of 17 EHE, characterized by classic morphologic and immunophenotypic features, from various anatomic locations and with different malignant potential. For comparison we analyzed 13 epithelioid hemangiomas, five epithelioid angiosarcomas and four epithelioid sarcoma-like EHE. A fluorescence in situ hybridization (FISH) positional cloning strategy, spanning the cytogenetically defined regions on chromosomes 1p36.3 and 3q25, confirmed rearrangements in two candidate genes from these loci in all EHE cases tested. None of the other benign or malignant epithelioid vascular tumors examined demonstrated these abnormalities. Subsequent RT-PCR confirmed in three EHE the WWTR1-CAMTA1 fusion product. CAMTA1 and WWTR1 have been previously shown to play important roles in oncogenesis. Our results demonstrate the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue and visceral location (liver, lung) in keeping with a unique and specific pathological entity. Thus, FISH or RT-PCR analysis for the presence of WWTR1-CAMTA1 fusion may serve as a useful molecular diagnostic tool in challenging diagnoses.

Malignant vascular tumors—an update

“…7 Ten years later, two back-toback studies, using different methodologies, were able to clone the genes involved in the t(1;3)(p36.3;q25) translocation. 8,9 WWTR1 (also called TAZ), on 3q25, is a gene involved in 14-3-3 transcriptional factor activation and signaling in the hippo pathway that is normally highly expressed in endothelial cells. 10 WWTR1 fuses to CAMTA1, on 1p36, which belongs to a family of calmodulinbinding transcription activators, normally found only in brain.…”

“…The 1p36 region is frequently lost in neuroblastoma and gliomas, implicating CAMTA1 as a tumor suppressor gene. 11,12 Most cases with classic morphology (ie, lacking mature vascular channel formation) examined so far contain this translocation, 8,9 which is not directly targetable with present day therapeutics, but may reveal downstream targets in future studies.…”

Epithelioid Hemangioendothelioma of the Maxillary Sinus

“…Immunohistochemically, these tumors are positive for cytokeratin (especially CK18), and vascular markers including CD31, factor VIII-antigen, ERG and FLI-1. Recent studies have described a recurrent genetic fusion WWTR1-CAMTA1 in EHE [13], involving t(1;3) (p36;q25). This results in a reciprocal chromosomal translocation involving a fusion of the promoter of the WWTR1 gene with the carboxyl terminus CAMTA1 gene.…”

“…This results in a reciprocal chromosomal translocation involving a fusion of the promoter of the WWTR1 gene with the carboxyl terminus CAMTA1 gene. 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].…”

Epithelioid hemangioendothelioma of the spine: case report and review of the literature

“…Beyond morphologic assessment, EHE can be distinguished from other benign and malignant vascular lesions (including epithelioid angiosarcoma) by detection of the WWTR1-CAMTA1 gene fusion by either FISH or PCR-based methods. The use of a novel immunohistochemical stain for CAMTA1 has recently been studied (9,23,24).…”