Abstract
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).
Highlights
Nuclear protein of the testis (NUT) carcinoma is an aggressive carcinoma that was first described in single case reports beginning in 1991 with the description of an aggressive thymic carcinoma showing a gene translocation, t(15;19)(q15;p13) [1]
The NUTM1 break-apart probe FISH test was positive for rearrangement of the NUTM1 locus (Fig. 5). (FISH was performed as an alternate confirmatory method of the next-generation sequencing (NGS) results.). This case is the first reported of a thyroid carcinoma exhibiting thyrocyte differentiation and an NSD3::NUTM1 fusion
The unequivocal thyroid features by histology and immunophenotype suggest this carcinoma is better classified as a highgrade thyroid carcinoma than a variant NUT carcinoma
Summary
Nuclear protein of the testis (NUT) carcinoma (previously termed NUT midline carcinoma) is an aggressive carcinoma that was first described in single case reports beginning in 1991 with the description of an aggressive thymic carcinoma showing a gene translocation, t(15;19)(q15;p13) [1]. Approximately 200 cases of NUT carcinoma have been reported [3]. The typical NUT carcinoma harbors BRD4, BRD3, NSD3, or Z4 bromodomain complex (BDC) protein genes as fusion partners to NUTM1 and manifests histologically as an undifferentiated to poorly differentiated carcinoma [4]. NUT carcinoma has been considered a variant of high-grade squamous carcinoma. NUTM1::BRD4 (Exons 1–2 of NUTM1 and Exons 14–20 of BRD4). NSD3::NUTM1 fusion (Exon 7 breakpoint of NSD3 and Exon 3 breakpoint of NUTM1; transcript ID NM_017778.2/ NM_175741.2). Complete resection Local irradiation Cisplatin Etoposide Molibresib, a BETi (limited course). Complete resection thyroid tumor with gross Local irradiation extrathyroidal extension; Cisplatin. Pembrolizumab positive and mediastinal lymph node metastases.
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