SMARCA4-deficient thoracic malignancies with small cell lung cancer-like features: A clinicopathological and molecular study of a heterogeneous group.

[OBJECTIVES] To characterize SMARCA4-deficient thoracic malignancies with small cell lung cancer (SCLC)-like features as a heterogeneous disease spectrum.

[MATERIALS AND METHODS] We retrospectively reviewed our pathological archives and identified three cases that exhibited both immunohistochemical loss of SMARCA4 and "SCLC-like features," defined as the presence of characteristic SCLC histomorphology (per WHO criteria) along with immunohistochemical positivity for at least one neuroendocrine marker (synaptophysin, chromogranin A, or CD56). All cases underwent comprehensive immunohistochemical profiling, including CKpan, neuroendocrine markers, SCLC subtype-defining transcription factors (ASCL1, NEUROD1, POU2F3), as well as RB1 and p53, coupled with targeted next-generation sequencing.

[RESULTS] All tumors showed invasive growth, extensive necrosis, and uniform round-to-spindle cells with oat-shaped nuclei. Each case harbored a pathogenic truncating SMARCA4 mutation with complete loss of SMARCA4 protein expression, yet fell into distinct diagnostic categories: Case 1, located in the right upper lobe, was a SMARCA4-deficient SCLC-ASCL1 subtype, positive for CKpan, TTF-1, and neuroendocrine markers (synaptophysin, chromogranin A, CD56), and carried co-mutations in TP53 and RB1. Case 2, originating in the middle mediastinum, was a SMARCA4-deficient SCLC triple-negative (SCLC-TN) subtype, positive for CKpan, TTF-1, and synaptophysin but negative for all SCLC lineage-defining transcription factors, and also harbored TP53 and RB1 co-mutations. Case 3, a right pulmonary hilar mass, was diagnosed as a SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), lacking both CKpan and TTF-1 expression while showing synaptophysin positivity, with a TP53 mutation and retained wild-type RB1.

[CONCLUSION] Through multi-platform integrated analysis, this study confirms that thoracic malignancies with SCLC-like features and SMARCA4 deficiency constitute a heterogeneous group, forming a disease spectrum extending from classical SCLC-ASCL1 and SCLC-TN subtypes to SMARCA4-UT. These findings advocate for the adoption of a systematic, integrated diagnostic workflow in clinical practice and provides a theoretical foundation for developing subtype-specific treatment strategies across the different entities within this disease spectrum.