MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes.

NUT fusion-associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. In this study, we characterized 11 tumors harboring MAD::NUT fusions (10/11 in female patients; median age: 48 years; range: 1-67 years), all histologically different from NUT carcinoma. Eight cases were identified via sequencing database review and 3 were diagnosed prospectively. Eight (73%) patients presented with multifocal disease, including 6 with disseminated peritoneal tumors; 3 (27%) presented with solitary colonic, pulmonary, or orbital masses. Nine (82%) tumors harbored NUTM1 fusions, with MXI1 (5/9; 56%), MXD4 (2/9; 22%), and MGA (2/9; 22%). One tumor each harbored MXD4::NUTM2G and MXI1::NUTM2A fusions. The 9 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 tumors), or S-100 (5 tumors). 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 coexpression. Immunohistochemistry 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 9 patients (82%; median length: 1.8 years; range: 2 months to 8.2 years). Four of 7 patients with MXD4/MXI1-rearranged sarcomas died of disease (median survival: 1.3 years; range: 5 months to 4.8 years), 1 entered hospice at 2 months, 1 was alive with pericardial masses at 2.8 years, and 1 was alive with no evidence of disease at 8.2 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 immunohistochemistry does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.