MAD::NUT-fusion sarcoma: A sarcoma class with NUTM1, NUTM2A and NUTM2G fusions and possibly distinctive subtypes.

Abstract

NUT-fusion-associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. Here, we characterized 11 tumors harboring MAD::NUT-fusions (10/11 in females; median age: 48 yr; range: 1-67 yr), all histologically sarcomas. Eight cases were identified via sequencing database review and three were diagnosed prospectively. Eight patients (73%) presented with multifocal disease, including six with disseminated peritoneal tumors; three (27%) presented with solitary colonic, pulmonary, or orbital masses. Nine tumors (82%) harbored NUTM1 fusions, with MXI1 (5/9; 56%), MXD4 (2/9; 22%), and MGA (2/9; 22%). One tumor each harbored MXI1::NUTM2A and MXD4::NUTM2G. The nine MXD4/MXI1-rearranged sarcomas were high-grade, with epithelioid-to-spindle-cell cytomorphology, amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Histologic features included infiltrative growth (7/7 assessable tumors), rhabdoid morphology (7/9; 78%), prominent collagen (3/9; 33%), multinucleated tumor cells (2/9; 22%), and myxoid stroma (1/9, 11%). MXD4/MXI1-rearranged sarcomas expressed desmin (3/7; 43%), and keratin(s) (3/7; 43%), and not p63 (6 tumors), CD34 (5), or S-100 (5). The adult MGA::NUTM1-fusion sarcoma exhibited some cytologic overlap with MXD4/MXI1-rearranged sarcomas but showed lower-grade myxoid spindle cell regions, microcystic spaces, and S-100 expression. The pediatric MGA::NUTM1-fusion sarcoma was low-grade with CD34/S-100 co-expression. Immunohistochemistry (IHC) demonstrated NUTM1 expression in NUTM1-rearranged sarcomas (5/5), and weak and no expression in NUTM2A- and NUTM2G-rearranged sarcomas, respectively. Gene expression profiling demonstrated sarcomas with MXD4/MXI1::NUTM1/NUTM2A/NUTM2G fusions clustered separately from NUT carcinoma. Follow-up was available for nine patients (82%; median: 1.8 yr; range: 2 mo-8.2 yr). Four of seven patients with MXD4/MXI-rearranged sarcomas died of disease (median: 1.3 yr; range: 5 mo-4.8 yr), one entered hospice at two months, and one was alive with pericardial masses at 2.8 years. The adult with the MGA::NUTM1-fusion sarcoma died of other causes at 4.5 years; the child was alive without disease at 11 months. We conclude that MAD::NUT-fusions define a sarcoma class distinct from NUT carcinoma. Among this group, MGA::NUTM1-fusion sarcomas might represent a distinctive subset. NUTM1 IHC does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.