Recurrent PDGFRB Mutations in Pulmonary Microcystic Fibromyxoma: A Clinicopathologic and Molecular Analysis of 3 Cases.

Pulmonary microcystic fibromyxoma (PMF), a rare benign mesenchymal neoplasm first described in 2006, remains diagnostically challenging due to histologic overlap with a variety of primary/metastatic myxoid tumors of the lung and absence of lineage-specific markers. Its molecular pathogenesis has been undefined. In this study, we analyzed 3 PMF cases (2 males, 1 female; age 48 to 63 y) presenting as solitary peripheral lung nodules (1.5 to 3.5 cm), incidentally detected or associated with cough. Histologically, tumors showed microcystic architecture with bland stellate/spindled cells in fibromyxoid stroma, devoid of mitoses or necrosis. Immunohistochemistry uniformly excluded epithelial, myoepithelial, myogenic, neural, and vascular differentiation. Targeted DNA-sequencing identified recurrent PDGFRB mutations in all cases: 2 exon 12 in-frame deletions (P.W566_I569del, P.R565_I569del) and 1 exon 14 missense mutation (P.N666K), validated by Sanger sequencing. PDGFRB immunohistochemistry in one case revealed diffuse cytoplasmic/membranous reactivity, supporting constitutive signaling. Targeted RNA-based NGS revealed no evidence of pathogenic gene fusions. All patients remained recurrence-free after resection (mean follow-up: 81 mo). Our findings establish PDGFRB mutations as a molecular hallmark of PMF, further confirming the neoplastic nature of PMF and broadening the spectrum of PDGFRB-activating alterations in mesenchymal tumors. These mutations, clustering in regions critical for kinase autoinhibition, may serve as potential diagnostic tools to distinguish PMF from histologic mimics.