Significance of YAP1–MAML2 rearrangement and GTF2I mutation in the diagnosis and differential diagnosis of metaplastic thymoma

Abstract

Background Metaplastic thymoma (MT) is a very uncommon thymoma type, with biphasic differentiation as one of its histological characteristics. This histological pattern, however, can also be mistaken for type A thymoma and the A component in type AB thymoma. Methods Postoperative specimens were collected from five MT and four type A thymomas with a retrospective analysis involving immunohistochemistry, fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Results The histological morphology of the MT overlapped with that of the type A thymoma. With immunostains, the former’s spindle cell components expressed vimentin and EMA, but not CD20. In MT, 3/5 cases had the nuclear expression of YAP1. The spindle cell component of the type A thymoma was found to express CD20. In all five cases of MT, FISH detection revealed YAP1–MAML2 fusion, which was not found in any type A thymoma cases. NGS sequencing confirmed YAP1–MAML2 rearrangement in all five cases of MT, and mutations in POLE and HRAS were also found in two cases, respectively. GTF2I c.74146970 T > A mutations were found in all cases of type A thymoma, and HRAS and NRAS mutations were found in two cases, but no YAP1–MAML2 rearrangement was evident. Conclusions For the diagnosis and differential diagnosis of challenging cases, the YAP1–MAML2 rearrangement and GTF2I mutation were both significant molecular events specific to MT and type A thymoma, respectively.

The Role of Gene Fusions in Thymic Epithelial Tumors

“…More recently, MAML2 rearrangements have been observed in both the epithelial and spindle cell component (Figure 2C,D) suggesting that both components are at least clonal and likely neoplastic [6]. Mutations in POLE, HRAS, ALK, CDK4, PTEN, and BRAF were also identified in a number of metaplastic thymomas [6,8]. No other genetic alterations, including GTF2I mutation, have been found in these neoplasms [5,7,25].…”

“…For instance, in mucoepidermoid carcinomas, the reported fusion gene is cysteine-rich C-terminal 1 (CRTC1) leading to MAML2::CRTC1 fusions [2]. In metaplastic thymomas the fusion partner is Yes associated protein 1 (YAP1), leading to YAP1::MAML2 fusion genes [5,6,8]. In a subset of B2 and B3 thymomas the fusion partner is lysine methyltransferase 2A (KMT2A), resulting in KMT2A::MAML2 fusions [9].…”

“…P40 marks only the epithelial component and is negative in the spindle cell component. MAML2 rearrangements have been identified in 77 to 100% of these tumors (Figure 2C,D) [5][6][7][8]. In metaplastic thymomas the fusion partner is YAP1, resulting in YAP1::MAML2 fusion genes fusing exon 1 or exons 1-5 on YAP1 with exons 2-5 on MAML2 [5,6].…”

“…Reports of sarcomatoid carcinomas arising in metaplastic thymoma suggest that a small subset of these tumors may develop into a high-grade tumor [27,28]. The majority of patients do not develop metastases, recurrence, or mortality from the disease [5][6][7][8]25]. Only one patient has been reported to develop a recurrence and pleural metastases 14 months after resection of the primary tumor [26].…”

“…In TET, recurring gene fusions have been identified involving mastermind transcriptional coactivator 2 (MAML2), Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1 (EWSR1), NUT midline carcinoma family member 1 (NUTM1), and neurotrophic tyrosine kinase receptor (NTRK). MAML2 gene rearrangements have been detected in mucoepidermoid carcinomas [2][3][4], metaplastic thymomas [5][6][7][8], and occasional B2 and B3 thymomas [9]. Interestingly, fusion partners of MAML2 vary depending on the subtype of the TET.…”