Case Report: squamous transformation after long-term osimertinib in EGFR-mutant lung adenocarcinoma with retained EGFR/TP53 alterations.

Histological transformation is an important mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer. Compared with small cell transformation, acquired squamous transformation is uncommon and remains less well characterized. We report a 52-year-old woman who underwent thoracoscopic left upper lobectomy and wedge resection of the left lower lobe for lung adenocarcinoma in April 2021. Molecular testing identified an EGFR exon 19 deletion and a TP53 c.713G>T (p.C238F) mutation. She received osimertinib, and the interval from treatment initiation to the first clinically and radiologically suspected disease progression was approximately 39 months. After this clinically suspected progression, pemetrexed plus cisplatin achieved a partial response. In August 2025, an enlarged left supraclavicular lymph node was detected, and re-biopsy confirmed squamous cell carcinoma. Systemic evaluation did not reveal evidence of a second primary malignancy. Molecular testing of the squamous lesion identified the same EGFR exon 19 deletion and TP53 mutation as those in the primary lung adenocarcinoma, providing molecular evidence consistent with a shared tumor origin and favoring acquired squamous histological transformation over a second primary squamous cell carcinoma. The patient subsequently received carboplatin, nanoparticle albumin-bound paclitaxel, and tislelizumab, achieving a radiologic partial response followed by stable disease during maintenance tislelizumab. This case highlights acquired squamous histological transformation as a rare resistance pattern after long-term osimertinib treatment. Re-biopsy and molecular comparison are important for distinguishing histological transformation from a second primary tumor. The observed response to platinum-taxane chemotherapy combined with tislelizumab should be interpreted cautiously because the relative contributions of chemotherapy and immunotherapy cannot be determined from a single case.