Non-small cell lung carcinomas with diffuse co-expression of TTF-1 and p40: Clinical, pathological and molecular characterization of a tumor subtype.

Lung cancer is typically classified based on morphological characteristics and immunoprofile. When histologic differentiation is difficult, immunohistochemical staining serves as a valuable diagnostic tool. Although most cases show distinct marker expression patterns, rare instances exhibit co-expression of both TTF-1 and p40. Moreover, for this particular subtype of non-small cell lung cancer (NSCLC), no clear demarcation is provided in the World Health Organization (WHO) classification system. In this study, we first conducted a comprehensive literature review to summarize previously reported cases and constructed survival curves for this rare subtype. Subsequently, we collected four additional cases of lung cancer exhibiting this uncommon co-expression pattern, along with four cases of adenosquamous carcinoma (ASC) for comparative analysis, aiming to further characterize their distinguishing clinicopathological features. Whole-exome sequencing (WES) was performed to establish a comprehensive mutational landscape of these tumors. Lung cancers with co-expression of TTF-1 and p40 exhibit a poorer prognosis compared with conventional adenocarcinoma (ADC) and squamous cell carcinoma (SCC). TP53 represents the most frequently mutated gene in this subtype. Notably, SYNE1, TMEM132C, and TNN were identified as characteristic mutations, defining a distinct mutational profile that sets this rare subtype apart from both SCC and ADC. Our findings highlight that NSCLC with diffuse co-expression of TTF-1 and p40 probably constitutes a distinct clinicopathological subtype with rapid clinical progression and poor prognosis, defined by unique morphological characteristics, a biphenotypic immunoprofile, and specific molecular alterations.