Pleural Fluid Cytology Detects Small Cell Carcinoma Transformation in EGFR ‐Mutant Lung Adenocarcinoma: A Case Report

BACKGROUND: Histological transformation of lung adenocarcinoma to small cell carcinoma is a rare but critical mechanism of acquired resistance to EGFR-TKIs. CASE: A 65-year-old woman with EGFR-mutant lung adenocarcinoma developed new-onset massive pleural effusion after an initial partial response to icotinib. Pleural fluid cytology revealed tumor cells with high nuclear-to-cytoplasmic ratio, finely granular chromatin, and nuclear molding, features suggestive of small cell carcinoma. Cell block immunohistochemistry confirmed small cell carcinoma (CD56+, Syn+, TTF-1+). Molecular testing demonstrated persistence of the original EGFR exon 19 deletion mutation, and single-cell sequencing supported clonal origin. CONCLUSION: Integrated cytological and molecular analysis of pleural fluid can provide compelling evidence supporting small cell transformation in EGFR-mutant lung adenocarcinoma. The shared EGFR mutation between the primary and transformed tumors is consistent with clonal evolution. This minimally invasive approach offers a practical alternative to tissue re-biopsy for monitoring acquired resistance to EGFR-TKIs.