Case Report: transformation to SCLC from EGFR-mutated squamous cell lung carcinoma during osimertinib treatment.

Background: Somatic EGFR mutations are prevalent in lung adenocarcinoma but are exceptionally rare in primary squamous cell carcinoma (SCC). Consequently, while histologic transformation to small cell lung carcinoma (SCLC) is an established resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in adenocarcinoma, its occurrence in EGFR-mutated SCC remains virtually uncharacterized, representing a significant knowledge gap in thoracic oncology. Case description: We report the case of a 42-year-old male initially diagnosed with stage IIIA EGFR-mutated SCC. Following definitive chemoradiotherapy, the patient experienced disease recurrence and was sequentially treated with erlotinib plus ramucirumab, followed by osimertinib. Upon clinical progression during osimertinib therapy, a repeat biopsy was performed. Pathological and immunohistochemical evaluations revealed a complete phenotypic shift from the initial TTF-1-negative, p40-positive SCC to a TTF-1-positive SCLC, while retaining the original EGFR exon 19 deletion. The patient exhibited a favorable clinical response to a subsequent regimen of carboplatin, etoposide, and durvalumab. Conclusion: The retention of the EGFR mutation in the present case enabled the definitive diagnosis of histologic transformation from the original squamous cell carcinoma, confirming a shared clonal origin rather than a second primary malignancy. This case underscores the critical clinical necessity of routine resistance monitoring and repeat biopsies with comprehensive histological profiling at the time of TKI failure, regardless of the initial non-small cell lung cancer histology".