Squamous transformation of EGFR-mutant lung adenocarcinoma after EGFR-TKI therapy: clonal continuity, tissue-based diagnosis, and therapeutic evidence gaps.

Assessment at progression after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy in EGFR-mutant non-small cell lung cancer requires more than identifying a single resistance mechanism. It also requires attention to lineage plasticity, tumor heterogeneity, the pattern of progression, and tissue-based findings. In a subset of patients, rebiopsy may reveal squamous histological transformation, sometimes with retention of the founder EGFR mutation. When present, retention of the founder EGFR mutation supports a shared clonal origin but does not, by itself, determine treatment. Confirmation of squamous transformation also changes the evidentiary context, because results from histologically unselected post-EGFR-TKI populations cannot always be applied directly to patients with confirmed transformation. This review focuses on squamous transformation and related basal/squamous reprogramming detected at EGFR-TKI progression, with particular emphasis on histological and molecular reassessment. We distinguish between direct clinical evidence from histologically confirmed transformed tumors and supportive translational evidence from EGFR-mutant resistance models and related lineage-transition systems. Plasma circulating tumor DNA can identify selected resistance alterations and track molecular evolution, but it cannot define morphology or lineage identity. When transformation is suspected, repeat tissue biopsy remains central, and reassessment should integrate morphology, immunohistochemistry, and paired molecular comparison with the original tumor. Integrated pathological and molecular reassessment may also uncover coexisting actionable alterations and help clarify whether progression is driven mainly by the transformed component, residual EGFR-dependent disease, or mixed resistance. Current evidence does not support a transformation-specific treatment sequence, so management remains individualized. Future studies should combine prospective rebiopsy cohorts, paired tissue-plasma profiling, and clinically annotated models to identify predictors of transformation and develop lineage-informed treatment strategies.