Variant WWTR1 gene fusions in epithelioid hemangioendothelioma-A genetic subset associated with cardiac involvement

Abstract

The genetic hallmark of epithelioid hemangioendothelioma (EHE) is a recurrent WWTR1-CAMTA1 fusion, which is present in most cases bearing a conventional histology. A subset of cases is characterized by a distinct morphology and harbors instead of YAP1-TFE3 fusion. Nevertheless, isolated cases lack these canonical fusions and remain difficult to classify. Triggered by an index case of a left atrial mass in a 76-year-old female with morphologic features typical of EHE, but which showed a WWTR1-MAML2 fusion by targeted RNA sequencing, we searched our files for similar cases displaying alternative WWTR1 fusions. A total of 6 EHE cases were identified with variant WWTR1 fusions, four of them presenting within the heart. There were three females and three males, with a wide age range at diagnosis (21-76 years, mean 62, median 69). The four cardiac cases occurred in older adults (mean age of 72, equal gender distribution); three involved the left atrium and one the right ventricle. One case presented in the vertebral bone and one in pelvic soft tissue. Microscopically, all tumors had morphologic features within the spectrum of classic EHE; two of the cases appeared overtly malignant. All cases were tested by FISH and four were investigated by targeted RNA sequencing. Two tumors harbored WWTR1-MAML2 fusions, one WWTR1-ACTL6A, and in three cases, no WWTR1 partner was identified. Of the four patients with follow-up, two died of disease, one was alive with lung metastases, and the only patient free of disease was s/p resection of a T11 vertebral mass. Our findings report on additional genetic variants involving WWTR1 rearrangements, with WWTR1-MAML2 being a recurrent event, in a small subset of EHE, which appears to have predilection for the heart.

Keywords: WWTR1; epithelioid hemangioendothelioma; fusion; heart.

Figure 1.. Morphologic spectrum of cardiac atrial tumors with WWTR1 variant fusions.

Bland epithelioid cells arranged in single files and cords within an abundant myxochondroid matrix (A, B, case 1). A more cellular lesion showing compact epithelioid cells with dense eosinophilic cytoplasm arranged in solid sheets with a less conspicuous fibrotic stromal component (C, D, case 5).

Figure 2.

A malignant EHE presenting as a right ventricular mass with lung metastases. Tumor was composed of sheets of enlarged epithelioid cells with abundant pale eosinophilic cytoplasm and enlarged nuclei with moderate atypia and prominent nucleoli. Mitotic figures were abundant. Tumor showed strong immunoreactivity for ERG (A-C, case 3).

Figure 3.

A malignant EHE with WWTR1 rearrangement only, presenting as a large pelvic mass in a 65-year-old male. The tumor is composed of large epithelioid to plump ovoid cells with abundant eosinophilic cytoplasm, arranged in cords (A), solid sheets (B), with variable nuclear pleomorphism, prominent nucleoli and intermixed inflammatory cells including eosinophils (C). Tumor cells show strong nuclear reactivity for ERG (D).

Figure 4.. Diagrammatic representation of 2 WWTR1 fusion variants identified on targeted RNA sequencing.

(A) Chromosomal location of WWTR1 gene locus in 3q25.1, ACTL6A in 3q26.33 and MAML2 in 11q21; red vertical lines depict the genomic breakpoint locus. Arrows show the direction of transcription of each gene. (B) WWTR1-ACTL6A transcript is composed of the first 4 exons of WWTR1 fused to most of ACTL6A (exons 2–14). (C) WWTR1-MAML2 transcript composed of the first 5 exons of WWTR1 gene fused to most of MAML2 gene (exons 2–5). The protein domains of each of the genes involved is also schematically depicted.