Expanding the spectrum of non-canonical NUT carcinoma: clinicopathological and molecular characterization of BRD3::NUTM1 and WWTR1::NUTM1 fusion variants.

INTRODUCTION

Nuclear protein in testis (NUT) carcinoma (NC) is an extremely rare and highly aggressive tumor. Non-canonical NC patients frequently have unique clinicopathological characteristics in terms of location, molecular alteration, and outcome, with morphological overlap with other tumors. Here, we report and summarize the non-canonical clinicopathological features of three unusual NC patients harboring BRD3::NUTM1 or WWTR1::NUTM1 gene rearrangement.

METHODS

The data of three patients with NC who were diagnosed between 2019 and 2022 at the Department of Pathology at West China Hospital or the Sichuan Kingmed Center for Clinical Laboratory were collected. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and RNA sequencing were performed. A literature review was conducted for NC patients with non-canonical features.

RESULTS

All three NC patients were male and aged between 31 and 60 years. The primary sites were the gastric corpus, nasal cavity, and subcutaneous tissue of the calvaria vertex. Histologically, two patients harbored NC with glandular differentiation, and one harbored NC with small cell carcinoma-like morphology. IHC revealed positivity for Pan-CK (cytokeratin) (PCK) (3/3), Epithelial membrane antigen (EMA) (3/3), Cytokeratin 5/6 (CK5/6) (3/3), and P63 (2/3). The Ki-67 index ranged from 20% to 40%. The remaining IHC markers were negative. RNA sequencing revealed BRD3::NUTM1 fusion in two patients and WWTR1::NUTM1 fusion in one patient.

CONCLUSION

In our study, the clinicopathological features of NC in patients with rare molecular alterations are reported and summarized. As increasing numbers of NUTM1-rearranged tumors with diverse histologic phenotypes have been reported, the traditional classification of NC as a purely epithelial malignancy may warrant reconsideration. Non-canonical NC needs to be further reported, integrated, and classified to precisely guide targeted therapy.