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

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).

Case report: NUT carcinoma with MXI1::NUTM1 fusion characterized by abdominopelvic lesions and ovarian masses in a middle-aged female

“…Some reports of NUT carcinoma have shown some focal features of their possible origins. A recent rare report of an NSD3:NUTM1 fusion carcinoma arising in the thyroid showed retention of focal thyroglobulin production ( 16 ). In brief, the exact value of ER and PR expression in NUT carcinoma remains unclear, which may indicate a gynecologic origin and requires further investigation.…”

NUT midline carcinoma presenting initially as thyroid cancer: a case report and review of treatment

“…This patient underwent a total thyroidectomy and laryngopharyngectomy plus radiation and was alive 10 years after diagnosis, which is a clear outlier for survival [15] . A third recent case report described another NUTM1-BRD4 fusion in a 38-year-old male PD-L1 positive and TTF-1, P63, epithelial membrane antigen (EMA), and c-myc on immunohistochemistry [16] . Due to this patient being PD-L1 positive, similar to our patient, she was treated with chemotherapy followed by camrelizumab (a PD-1 inhibitor); however, she died 10 months after surgery.…”

NUTM1-rearranged Carcinoma of the Thyroid

“…Three cases in our cohort were previously published. 25,26,28 For each case, clinicopathologic characteristics were obtained from medical records and pathology reports, including patient age at diagnosis, gender, signs/ symptoms at presentation, extent of surgery, tumor size, presence of extrathyroidal extension, margin status, lymph node (LN) status, presence of distant metastases at diagnosis, IHC profile, NUTM1 fusion partner, treatment, and clinical outcome. OS was defined as time from initial diagnosis of cancer to death due to disease.…”

“…18 An emerging group of soft tissue sarcomas and cutaneous adnexal tumors harboring non-BRD4-associated NUTfusions also stain for NUT and should be distinguished clinically and pathologically from NC. 16,[19][20][21][22][23][24] Only rare, single case reports of NCs arising in the thyroid have been reported [25][26][27] ; therefore, the aim of this study was to comprehensively evaluate the clinicopathologic, immunophenotypic, and genetic characteristics of a series (n = 14) of NCs of the thyroid.…”