Pathological and molecular characterization of a four-component combined small cell lung carcinoma: a case report

Combined small cell lung carcinoma (SCLC) is a rare entity and characterized by the coexistence of SCLC and non-small cell lung cancer (NSCLC) components. We report the first known case of combined SCLC containing three distinct NSCLC components: squamous cell carcinoma, pleomorphic carcinoma, and adenocarcinoma (AD).

A 70-year-old man presented with right shoulder pain and underwent right upper lobectomy with en bloc chest wall resection and lymph node dissection. Histopathological examination of the resected specimen revealed four distinct histological components within the primary tumor. Comprehensive immunohistochemistry and molecular analyses, including RNA sequencing, were performed to characterize the tumor. A TP53 mutation was shared across all components, suggesting a common clonal origin, whereas additional genetic alterations were largely component specific. Clonal phylogenetic analysis indicated divergence from a common ancestral clone, supporting a structured multilineage evolutionary process. Transcriptomic profiling demonstrated lineage-associated expression patterns, and tumor microenvironment analysis revealed increased lymphocytic infiltration in the AD and pleomorphic carcinoma components, whereas proliferative signaling pathways were enriched in the SCLC component.

These findings highlight pronounced intratumoral molecular and immunological heterogeneity. Although combined SCLC with three NSCLC components is exceedingly rare, this case provides novel insights into lineage diversification and the clonal evolution and biological diversity of combined SCLC. Further accumulation of similar cases with integrated molecular analyses is warranted to improve understanding of this rare subtype and inform future therapeutic strategies.