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.
The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.
Thus, we undertook a molecular analysis of six samples from two patients with multicentric hepatic EHE to test our hypothesis that the presence of identical breakpoints in WWTR1 and CAMTA1 support the monoclonal nature of multifocal EHE.
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.
Fourteen of 18 informative cases were positive for WWTR1-CAMTA1 fusion transcripts, four of which showed higher-grade cytological features termed by some as 'malignant EHE'.
Genetic characterization of several soft tissue tumour types that occur in the skin has resulted in the identification of diagnostically useful markers: ALK gene rearrangement with corresponding ALK protein expression by immunohistochemistry in epithelioid fibrous histiocytoma; the WWTR1-CAMTA1 fusion gene with CAMTA1 protein expression in epithelioid haemangioendothelioma; MYC amplification and overexpression in radiation-associated angiosarcoma; and EWSR1 gene rearrangement in cutaneous myoepithelial tumours.
Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses.
Interestingly, we observed CAMTA1 gene break-apart in all of the five TFE3-positive EHEs via FISH assays, and four out of the five TFE3-positive EHEs exhibited WWTR1-CAMTA1 gene fusions via RT-PCR.
A recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1-negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver.
Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future.
The 10% of EHEs that lack the TAZ⁻CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3).
We point out the telltale immunophenotypes: angiolymphoid hyperplasia with eosinophilia and EH (FOS-B/others negative), PM-HAE (FOS-B/AE1/AE3/others negative), epithelioid hemangioendothelioma (CAMTA-1 or TFE-3/others negative).
Care should be taken to identify such cells in limited biopsies; immunohistochemistry for CAMTA1, a specific and sensitive marker for EHE, can be confirmatory.
A WWTR1-CAMTA1 fusion is present in most classic epithelioid hemangioendothelioma, regardless of their clinical behavior, suggesting that additional genetic abnormalities might be responsible in driving a more aggressive biology.