WHOLE EXOME SEQUENCING DETERMINES PLAUSIBLE VARIANTS IN AN ORAL COMPOSITE HEMANGIOENDOTHELIOMA WITH APPARENT YAP1-MAML2 FUSION

Abstract

<h3>Introduction</h3> Composite hemangioendothelioma (CHE) is considered a borderline malignant vascular tumor. Materials and Methods: 21-year-old female presented with painless left mandibular vestibular 1 cm mass of less than a year duration. H&E evaluation necessitated immunohistochemical studies that included CD31, CD34, D2-40, ERG, CAMTA1, and type IV collagen (COLIV). FISH was performed to investigate the presence of <i>YAP1</i> and <i>MAML2</i> aberrations and WES was performed to possibly identify causative gene variants. <h3>Results</h3> Non-encapsulated infiltrating tumor featured dilated vascular channels lined by cells exhibiting occasionally hobnail/matchstick-like arrangement. Intravascular cell proliferations and hyaline globules were also present. Lobular cell aggregates of spindle and epithelioid cells and slit-like spaces exhibiting a retiform or angiosarcomatous morphology were noted. Signet-ring and adipocyte-like cells were identified. Mitotic activity was exceptionally rare. Vascular spaces and the stroma featured lymphocytes and plasma cells. Neoplastic cells were positive for CD31, CD34, D2-40 and ERG, negative for CAMTA1 while COLIV highlighted the plasmalemma of most neoplastic cells, vessels and hyaline globules. FISH revealed inversion gaps supporting <i>YAP1MAML2</i> fusion. WES identified three missense mutations (a) <i>FLT1</i> [c.3046A>G; p.R1016G], (b) <i>PIK3CA</i> [c.3140A>T; p.H1047L], (c) <i>C11orf42</i> [c.910G>C; p.A304P], and one mitochondrial DNA frameshift insertion in <i>MT-ND4</i> [c.1107_1108insC; p.P370fs]. <h3>Conclusions</h3> 1. Histopathology and FISH support the diagnosis of CHE 2. FLT1 (VGFR1 precursor) and PIK3CA variants may be driver mutations. 3. Alternatively, PIK3CA may relate to tumor growth/enlargement 4. C11orf42 variant may be also tumorigenic 5. MT-ND4(NADH: Ubiquinone Oxidoreductase Core Subunit 4) variant possibly leads to altered reactive oxygen species hindering apoptosis.