Malignant Undifferentiated Epithelioid Neoplasms with MAML2 rearrangements: a Clinicopathologic Study of Six Cases Demonstrating a Heterogenous Entity.

Among mesenchymal tumors, MAML2 gene rearrangements have been described in a subset of composite hemangioendothelioma and myxoinflammatory fibroblastic sarcoma (MIFS). However, we have recently encountered MAML2-related fusions in a group of 6 undifferentiated malignant epithelioid neoplasms that do not correspond to any established pathologic entities. The patients included 5 males and 1 female, aged 41-71 years old (median 61 years). The tumors involved the deep soft tissue of extremities (hip, knee, arm, hand), abdominal wall, and the retroperitoneum. Microscopically, the tumors consisted of solid sheets of highly atypical epithelioid cells with abundant cytoplasm and showed prominent mitotic activity and necrosis. In 3 cases, the cells displayed hyperchromatic nuclei or conspicuous macronucleoli and were admixed with background histiocytoid cells and a lymphoplasmacytic infiltrate. By immunohistochemistry (IHC), the neoplastic cells had a nonspecific phenotype. On targeted RNA sequencing, MAML2 was the 3' partner and fused to YAP1 (3 cases), ARHGAP42 (2 cases), and ENDOD1 (1 case). One case with YAP1::MAML2 showed strong and diffuse nuclear YAP1 immunostaining and harbored a concurrent RBMS3::RAF1 fusion. In 2 cases with targeted DNA sequencing, mutations in TP53, RB1 and PTEN were detected in 1 case, and PDGFRB mutations, CCNE1 amplifications and CDKN2A/2B deletion were detected in another case, which showed strong and diffuse PDGFRB expression by IHC. Of the 4 cases with detailed clinical history (median follow-up period 8 months), 3 developed distant metastatic disease (one of which died of disease); one case remained free of disease 3 years following surgical excision. In conclusion, we describe a heterogeneous series of MAML2-rearranged undifferentiated malignant epithelioid neoplasms, a small subset of which may overlap with a recently described MIFS variant with YAP1::MAML2 fusions, further expanding the clinicopathologic spectrum of mesenchymal neoplasms with recurrent MAML2 gene rearrangements. This article is protected by copyright. All rights reserved.