Primary pulmonary NFATC2::NUTM2-associated myoepithelial-like neoplasms: two hi-C-detected cases beyond routine targeted NGS and review of the literature

Rearrangements involving NFATC2 define a heterogeneous group of neoplasms, and NFATC2::NUTM2-associated tumors of the lung and salivary glands have recently emerged as a distinctive clinicopathologic entity. We report two primary pulmonary tumors that further refine the spectrum of this neoplastic group and highlight the diagnostic value of structural genomic analysis in morphologically characteristic but targeted sequencing-negative lesions. Both patients presented with small, slowly growing, contrast-enhancing pulmonary nodules and were free of disease at 12 and 18 months after resection. Histologically, both tumors were well circumscribed and composed of relatively monomorphic epithelioid to basaloid cells arranged in nests, cords, and trabeculae within densely sclerotic to hyalinized stroma, with a conspicuous peripheral lymphoid cuff. Immunohistochemically, both tumors showed an epithelial/basal phenotype with an atypical, non-lineage-definitive myoepithelial-like immunoprofile, expressing pan-cytokeratin, CK5/6, EMA, GATA3, calponin, and D2-40, while lacking S100, SOX10, p63, p40, and SMA. Targeted DNA- and RNA-based next-generation sequencing did not identify a driver alteration. Formalin-fixed paraffin-embedded Hi-C demonstrated the same recurrent t(10;20)(q22;q13) involving NUTM2E and NFATC2 in both cases. RNA-based analysis detected an NFATC2::NUTM2E fusion transcript in 1 case and additional breakpoint-level support in both. These findings expand the spectrum of primary pulmonary NFATC2::NUTM2-associated myoepithelial-like neoplasms and support morphology-guided structural genomic testing as a practical second-line diagnostic strategy.