The Role of Gene Fusions in Thymic Epithelial Tumors

Abstract

Thymic epithelial tumors (TET) are rare and large molecular studies are therefore difficult to perform. However, institutional case series and rare multi-institutional studies have identified a number of interesting molecular aberrations in TET, including gene fusions in a subset of these tumors. These gene fusions can aid in the diagnosis, shed light on the pathogenesis of a subset of tumors, and potentially may provide patients with the opportunity to undergo targeted therapy or participation in clinical trials. Gene fusions that have been identified in TET include MAML2 rearrangements in 50% to 56% of mucoepidermoid carcinomas (MAML2::CRTC1), 77% to 100% of metaplastic thymomas (YAP1::MAML2), and 6% of B2 and B3 thymomas (MAML2::KMT2A); NUTM1 rearrangements in NUT carcinomas (most commonly BRD4::NUTM1); EWSR1 rearrangement in hyalinizing clear cell carcinoma (EWSR1::ATF1); and NTRK rearrangement in a thymoma (EIF4B::NTRK3). This review focuses on TET in which these fusion genes have been identified, their morphologic, immunophenotypic, and clinical characteristics and potential clinical implications of the fusion genes. Larger, multi-institutional, global studies are needed to further elucidate the molecular characteristics of these rare but sometimes very aggressive tumors in order to optimize patient management, provide patients with the opportunity to undergo targeted therapy and participate in clinical trials, and to elucidate the pathogenesis of these tumors.

Hide-and-Seek With Spindle-Cell-Component-Poor Metaplastic Thymoma

“…A number of recurrent molecular aberrations in TET have already been identified, making molecular studies for TET a diagnostically important tool. Intriguingly, most of the recurrent gene fusions in TET involve mastermind-like transcriptional coactivator 2 (MAML2) gene, namely, MAML2::CRTC1 in mucoepidermoid carcinoma, MAML2::KMT2A in a subset of B2 and B3 thymomas, and importantly regarding the current case, YAP1::MAML2 in metaplastic thymoma [4]. Zhao et al in their study of 17 metaplastic thymoma cases proved that YAP1::MAML2 rearrangement is found in both epithelioid and spindle cell components, which again confirms the neoplastic origin of the spindle cell/stroma-like component [6].…”

“…The major hint leading to the correct diagnosis should be the unusual "stroma" with dense fibroblast-like cells, regardless of its proportion in the tumor. Another histological difference between the two types is the scattered thymocytes in type A thymoma which is typically lacking in the metaplastic type [4]. An unusual immunomarker expression in the stroma-like component, such as EMA, keratin, and Islet-1 could also be helpful.…”