NUTM1-rearranged Carcinoma of the Thyroid

Abstract

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non–NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell–derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non–NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non–NC-like morphology (P=0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3-NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.

Immunodetection of NUT Protein: Implementation, Indications, and Results in a Tertiary Reference Center

“…[10][11][12][13] Others depend on the description of novel sites of occurrence for NUTM1rearranged tumors, which justified testing some poorly differentiated tumors of the digestive tract 10,14 or the pelvic region. 10,15,16 Others are related to the description of distinctive NUT-expressing tumor entities, expanding the spectrum of NUT carcinoma, such as in the thyroid, 17 or belonging to other tumor spectrums, such as skin adnexal porocarcinomas. 18,19 In our hands, despite the relatively large indications and the important recruitment from the most frequent sites of occurrence, NUT carcinoma remained rarely diagnosed, with only 12 cases detected in 6 years out of the 382 tested (1.6%), with no case detected in the last 2 years of the study period.…”

“…Others depend on the description of novel sites of occurrence for NUTM1 -rearranged tumors, which justified testing some poorly differentiated tumors of the digestive tract 10,14 or the pelvic region 10,15,16 . Others are related to the description of distinctive NUT-expressing tumor entities, expanding the spectrum of NUT carcinoma, such as in the thyroid, 17 or belonging to other tumor spectrums, such as skin adnexal porocarcinomas 18,19 …”

NUT carcinoma and thoracic SMARCA4‐deficient undifferentiated tumour: facts and controversies

“…22 Some tumours arising in the lung parenchyma are positive for TTF1 (Figure 4C), 5,[22][23][24] focally or diffusely, even using the conventional 8G7G3/1 clone, and this is similar to occasional TTF1 and PAX8 expression in NUT carcinoma of the thyroid. 25 These findings create confusion with poorly differentiated adenocarcinoma and neuroendocrine carcinoma. CD34 can be expressed, unlike in most carcinomas.…”

“…[26][27][28] NSD3 fusion is overrepresented in the thyroid. 25 The fusion is considered to result via chromoplexy. 29 The karyotype is generally simple and secondary mutations are rare, 6,29 in contrast to ordinary carcinomas, but reminiscent of sarcoma or haematopoietic tumours.…”

“…Rarer partners include ZNF532 and ZNF592 26–28 . NSD3 fusion is over‐represented in the thyroid 25 . The fusion is considered to result via chromoplexy 29 .…”