NFATC2::NUTM2A/B Fusions Characterize a Novel Indolent Myoepithelial-Like Neoplasm of the Lungs and Salivary Glands.

With the increasing use of next-generation sequencing, the classification of heretofore unclassified neoplasms is evolving rapidly. Specifically, gene fusions have emerged as context-specific defining genetic markers for an increasing number of entities, mostly of soft tissue, bone, and salivary gland origin. We describe four myoepithelial-like neoplasms of salivary (two) and pulmonary (two) origin, carrying recurrent NFATC2 fusions involving NUTM2B (three) and NUTM2A (one) as fusion partners. Patients were two females and two males aged 24-67 years (median, 33). The tumor size ranged from 1 to 4.5 cm. Treatment was surgery without (three) or with (one) adjuvant radiochemotherapy. No metastases or other primary tumors were found at the time of diagnosis. Three patients with follow-up (two with salivary, one with pulmonary tumor) were disease-free at 9, 11, and 31 months. Original diagnoses were "unclassified neoplasm" with consideration of adamantinoma-like Ewing sarcoma and myoepithelial neoplasm. Histology revealed infiltrating monotonous epithelioid to basaloid cells arranged into lobular aggregates, nests, and cords within variably sclerosed stroma containing extensive basement membrane-like hyaline material. Frankly malignant features (malignant cytology, high mitotic activity, necrosis, perineural or lymphovascular invasion) were absent. IHC showed coexpression of low and high molecular weight keratins (AE1/AE3 and CK5/6; 4/4), EMA (2/2), and CD99 (2/2). Negative markers included p63 (0/4), NUT (0/4), S100 (0/4), SOX10 (0/4), p40 (0/2), and SMA (0/2). This study introduces a novel salivary and lung tumor entity driven by NFATC2::NUTM2A/B fusions and displaying myoepithelial-like morphology but imperfect myoepithelial immunophenotype. Report of more cases should shed light on the biological properties and appropriate therapeutic strategies of this novel neoplasm.