Non‐small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours

Thyroid transcription factor 1 (TTF1) and p40 are widely-utilized diagnostic markers of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), respectively. Diffuse coexpression of TTF1 and p40 has been described in only rare case reports. In a multi-institutional study, we collected the largest cohort of these unusual tumours to-date (n = 14), with the goal of elucidating their clinicopathological and genomic characteristics. Lung tumours with diffuse coexpression (labelling 50-100% tumour cells) of TTF1 clone 8G7G3/1 and p40 clone BC28 were identified. Detailed clinicopathological and immunohistochemical parameters were analyzed. Eight tumours were analyzed by next-generation sequencing (NGS) and the results were compared to those in > 9 K LUAD and > 1 K LUSC. All tumours with diffuse TTF1/p40 coexpression were poorly differentiated non-small cell lung carcinomas (NSCLC), 42% of which had basaloid features. Some tumours exhibited focal keratinization (14%), napsin A and/or mucicarmine labelling (46%) or both squamous and glandular features (7%). NGS revealed a uniquely high rate of FGFR1 amplifications (70%) compared to either LUAD (0.7%, P < 0.0001) or LUSC (11%, P = 0.001). LUAD-type targetable driver alterations were identified in 38% of cases (one EGFR, two KRAS G12C). The tumours were clinically aggressive, exhibiting metastatic disease in most patients. Lung carcinomas with diffuse TTF1/p40 coexpression represent poorly differentiated NSCLCs with frequent basaloid features, but some show evidence of focal squamous, glandular or dual differentiation with a distinctly high rate of FGFR1 amplifications. The presence of targetable LUAD-type alterations (EGFR, KRAS G12C) emphasizes the importance of molecular testing in these tumours.