Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3. Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient’s tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to < 2% reactivity for proteins typically diffusely expressed in NUT carcinoma: p40, p63, and cytokeratins 5/6. NUT protein expression was equivocal, but fluorescence in situ hybridization confirmed a NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).