Pulmonary mesenchymal cystic hamartoma with EWSR1::CREM fusion: molecular redefinition and diagnostic implications.

Pulmonary mesenchymal cystic hamartoma (MCH) is an exceptionally rare benign tumor characterized by cystic-solid architecture and biphasic epithelial-mesenchymal components. We report a 56-year-old woman with a 2.6-cm right lower lobe mass, histologically composed of pseudostratified ciliated epithelium, glandular components, and primitive mesenchymal cells with cartilaginous/adipose differentiation. Tumor cells showed diffuse moderate cytoplasmic BCL-2/CD56 staining, weak-moderate nuclear PR positivity, and a low Ki-67 index (< 2%). RNA sequencing identified a novel EWSR1::CREM fusion, involving exon 13 of EWSR1 and intron 5/exon 6 of CREM. This finding expands the molecular spectrum of FET::CREB-driven tumors and distinguishes MCH from mimics such as glomus tumor and pleuropulmonary blastoma. The patient remained recurrence-free at 4-year follow-up, underscoring the benign nature of this lesion. This study highlights three critical insights: (1) Molecular significance: The EWSR1::CREM fusion suggests shared oncogenic mechanisms with intracranial mesenchymal tumors and primary pulmonary myxoid sarcoma. (2) Diagnostic refinement: Integration of molecular profiling resolves diagnostic ambiguity in cystic lung lesions. (3) Clinical relevance: Routine molecular testing should be considered for ambiguous cystic lung lesions to refine classification. Conservative management is appropriate for molecularly confirmed MCH. Our findings emphasize the necessity of integrating histomorphology, immunohistochemistry, and molecular profiling in diagnosing rare pulmonary entities. Further studies are needed to elucidate the role of EWSR1::CREM in MCH pathogenesis and explore targeted therapeutic strategies.