Abstract Background In the era of targeted and immune therapy, histologic transformation has emerged as a key mechanism of therapeutic resistance in non-small cell lung cancer (NSCLC). While transformation of adenocarcinoma to small-cell carcinoma following targeted or immune therapy is increasingly recognized, conversion of squamous cell carcinoma (SCC) to large-cell neuroendocrine carcinoma (LCNEC) or mixed adeno-neuroendocrine phenotypes is exceptionally rare. Case Presentation A 75-year-old man with heavy tobacco exposure was diagnosed with stage IIB (cT1aN1M0) right upper lobe SCC with biopsy-proven hilar nodal metastasis. Molecular testing revealed EGFR/ALK wild type and no actionable alterations. PD-L1 immunostaining showed 100% tumor proportion score (TPS). The patient received neoadjuvant carboplatin, paclitaxel, and nivolumab, achieving improvement in FDG avidity of the right upper lobe nodule and partial resolution of the previously seen FDG-avid right hilar lymph node. Following three cycles, he underwent right upper lobectomy with mediastinal lymph-node dissection. Pathology revealed a combined adenocarcinoma and LCNEC, with pleural invasion, and no residual squamous cell carcinoma was present. Repeat molecular profiling demonstrated KRAS amplification (8.8 copies), and PD-L1 immunostaining showed only 1% TPS. Discussion This patient represents, to our knowledge, the first documented dual transformation from SCC to combined adenocarcinoma and LCNEC following chemo-immunotherapy. The transformation from pure SCC to combined adenocarcinoma and LCNEC with a new KRAS amplification may represent therapy-induced clonal evolution and lineage plasticity. Under the dual selective pressure of chemotherapy and nivolumab, the tumor’s dominant squamous clone was eradicated, and minor subclones with distinct differentiation and molecular features expanded, leading to a new histologic and molecular phenotype. Most likely our patient’s tumor exhibited both interclass and intraclass plasticity—transforming not only across lineages (from squamous to glandular and neuroendocrine) but also differentiating into two distinct histologic phenotypes simultaneously, an observation not previously reported. While adenocarcinoma-to-small-cell conversion is well established and squamous-to-small-cell transformation has been described after immune checkpoint inhibition (Zeng et al., 2023), squamous-to-LCNEC or mixed adeno-neuroendocrine conversion remains exceedingly rare. Prior reports describe only a spontaneous SCC-to-LCNEC transformation (Li et al., 2023) and de novo mixed tumors (Agrawal et al., 2025). Conclusion This case underscores the remarkable tumor plasticity induced by combined cytotoxic and immune therapy. Recognition of such dual lineage transformations is essential, as dynamic histologic and molecular evolution may profoundly alter prognosis and therapeutic strategy in the era of neoadjuvant immunotherapy. This abstract is funded by: none
Umar et al. (Fri,) studied this question.