Abstract
BACKGROUND: Non-small cell lung carcinoma (NSCLC) with co-expression of thyroid transcription factor-1 and p40 is an extremely rare and diagnostically challenging subtype. These tumors exhibit both glandular and squamous features, which reflect a dual-lineage differentiation pattern. CASE PRESENTATION: A 78-year-old male with a history of smoking and alcohol consumption was found to have a solid nodule in the right peripheral lung on CT. Postoperative pathology confirmed that the solid nodule was poorly differentiated NSCLC with diffused and strong positivity for both thyroid transcription factor-1 and p40 by immunohistochemistry. Next-generation sequencing identified somatic mutations of LRP1B and TP53, along with copy number amplification of TP63 and SOX2 as well as copy number loss of CDKN2A/B. CONCLUSIONS: NSCLC with co-expression of Thyroid Transcription Factor-1 and p40 is a rare and diagnostically challenging subtype, most frequently observed in older male patients with a history of smoking and predominantly arising in peripheral lung regions. The morphological, immunophenotypic and molecular features of these tumors suggest that they may originate from stem-like basal cells with dual-lineage differentiation. Literature review identified high-frequency alterations in TP53, FGFR1, CDKN2A, EGFR, KRAS, MYC, NF1 and AKT1. Next-generation sequencing-based genomic profiling facilitate the diagnosis and treatment of such cases.