胸部SMARCA4欠損未分化腫瘍およびSMARCA4欠損非小細胞肺癌の臨床病理学的および分子遺伝学的展望

SMARCA4-deficient tumors of the thoracic cavity represent a newly emerging group of aggressive neoplasms driven by inactivation of the SMARCA4 gene, a key member of the SWI/SNF chromatin remodeling complex. These tumors are broadly classified into thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) and SMARCA4-deficient non-small cell lung carcinomas (SMARCA4-dNSCLC). Despite some overlap in genomic alterations, especially smoking-related mutations like TP53, KRAS, and KEAP1, these entities differ in histomorphology, immunoprofile, and biological behavior. SMARCA4-UTs are undifferentiated, often rhabdoid in appearance, with loss of epithelial markers and gain of stem cell markers such as SOX2 and SALL4, while SMARCA4-dNSCLCs retain some epithelial differentiation. Radiologically, these tumors often present as large central thoracic masses with high metabolic activity and early metastases. Both tumor types show poor prognosis, with limited response to conventional therapies. Immunotherapy, particularly immune checkpoint inhibitors, shows promise even in PD-L1-negative cases, and emerging epigenetic and molecular targeted therapies are under investigation. It is crucial to distinguish SMARCA4-UT and SMARCA4-dNSCLC by appropriate use of histopathology, immunohistochemistry, and molecular studies, considering the prognosis and treatment response. Our review focuses on the advancement of understanding the clinicopathological spectrum of both entities, their genetic landscape, and current treatment options.