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.

Keywords: EWSR1; MAML2; NTRK; NUTM1; YAP1.

Figure 1

Mucoepidermoid carcinoma. (A). This circumscribed neoplasm (right side) is focally invading (arrow) into the surrounding thymic gland tissue (left side). (B,C). The tumor is composed of squamous and intermediate cells which express p40 (D) and of mucus-containing cells. (E). Mucicarmine highlights cytoplasmic mucin. Magnification, H&E × 12.5 (A), ×200 (B), ×400 (C), p40 × 400 (D), mucicarmine × 400 (E).

Figure 2

Metaplastic thymoma. (A) This well-circumscribed neoplasm shows a biphasic morphology composed of darker and paler areas. (B) The paler component (upper part) contains spindle cells with ample pale cytoplasm. The darker component (lower part) is composed of bland, slightly elongated epithelial cells that harbor oval nuclei. (C,D) Break-apart fluorescence in situ hybridization studies reveal MAML2 rearrangement using MAML2 3′ (green)/5′ (red) (11q21) probe (arrows point towards cells that show disruption of one red and green signal) in the spindle (C) and in the epithelioid (D) component. Magnification, H&E x scanned (A), ×400 (B), MAML2 FISH × 1000 (oil immersion) (C,D). Figure 2C,D contributed by Dr. Rhett P. Ketterling, MD and Jamie V. Berg, Mayo Clinic Rochester.

Figure 3

NUT carcinoma. (A) Irregular nests of tumor cells are surrounded by a desmoplastic stroma. Areas of necrosis are present (arrow). (B) The tumor cells are monotonous, round, with a high nuclear-to-cytoplasmic ratio and prominent nucleoli. High mitotic activity is present. The arrow points towards abrupt squamous differentiation. The neoplastic cells express p40 (C), TTF-1 (clone SPT24; weaker expression; note TTF-1 is diffusely expressed by the same population of neoplastic cells that also expresses p40) (D), and NUT protein (E). The NUT immunohistochemical test shows the characteristic stippled nuclear expression in the tumor cells ((E) insert). Magnification, H&E × 40 (A), ×400 (B), p40 × 400 (C), TTF-1 × 400 (D), NUT × 400 (E), × 600 ((E) insert).

Figure 4

NUT carcinoma. (A) Medium-sized neoplastic cells with prominent nucleoli are associated with numerous neutrophils. The neoplastic cells are focally positive for TTF-1 (clone SPT24, staining of scattered tumor cells) (B), synaptophysin (C), and NUT (D). Although NUT shows the characteristic nuclear speckled staining pattern, the overall expression is weak. (E). Therefore, break-apart fluorescence in situ hybridization studies using NUTM1 (15q14) 3′ (red)/5′ (green) probe were performed which confirmed NUTM1 rearrangement (arrows point towards cells that show 1 red, 1 green, and 1 green/red dot, indicating the separation of 5′NUTM1 and 3′NUTM1 signals). Magnification, H&E × 400 (A), TTF-1 × 400 (B), synaptophysin × 400 (C), NUT × 400 (D), ×600 ((D) insert), FISH NUTM1 × 1000 (oil immersion). Figure 4E was contributed by Daniel Sill, Mayo Clinic Rochester.