Synchronous Small Cell and Adenocarcinoma of the Lung Integrating Morphology and Molecular Profiling: A Case Report

Combined small cell lung carcinoma (SCLC) is not uncommon, though the combination with a second primary adenocarcinoma is less frequent. Molecular profiling can clarify clonal relationships and identify potentially actionable alterations, but interpretation requires careful integration with histologic and clinical findings. We report a 61-year-old woman with 2 synchronous right upper lobe tumors: a poorly differentiated combined SCLC with an adenocarcinoma component (cribriform 40%, acinar 30%, solid 30%) and a separate invasive adenocarcinoma (60% acinar, 40% lepidic), both staged pT1bN0M0. Core biopsy of the combined SCLC initially showed only adenocarcinoma morphology, highlighting the diagnostic limitations of undersampling in combined tumors. Molecular profiling revealed overlapping truncal alterations (TP53 C135Y, RB1 Q344, and KRAS G12C) at markedly discordant variant allele frequencies (VAF) of ∼46% in Tumor 1 versus ∼3% in Tumor 2, alongside a dominant KRAS G12V mutation unique to Tumor 2, a finding strongly associated with separate primary lung carcinomas rather than intrapulmonary metastasis. These molecular findings, interpreted in the context of field cancerization, favor independent primary tumors over clonal spread. The SCLC component dictated adjuvant cisplatin-etoposide regardless of the accompanying adenocarcinoma histology. This case report exemplifies the importance of integrated histologic and molecular evaluation, and the need to recognize potentially actionable mutations in combined SCLC. Comprehensive profiling not only clarifies clonal relationships and may guide therapeutic strategies, including in the context of recurrence or combined presentations.