Diffuse co-expression of TTF-1 and p40 (ΔNp63) defines a distinct biphenotypic non-small cell lung carcinoma: clinicopathologic and molecular characterization of 19 cases.

[BACKGROUND] The diffuse co-expression of thyroid transcription factor-1 (TTF-1) and p40 defines a rare and diagnostically challenging subtype of non-small cell lung carcinoma (NSCLC). Due to its extreme rarity, the clinicopathologic and molecular characteristics of this entity remain poorly characterized.

[METHODS] We conducted a comprehensive analysis of the largest single-institution cohort to date ( = 19) of NSCLCs with diffuse TTF-1/p40 co-expression. All cases underwent detailed histopathologic review. Immunohistochemistry (IHC) utilized specific antibody clones (TTF-1: 8G7G3/1; p40). Molecular profiling was performed via next-generation sequencing in a subset of cases, including multi-region analysis for select tumors.

[RESULTS] The cohort mainly consisted of elderly male smokers (median age 65; 84.2% male; 73.7% smokers). Anatomically, 84.2% of tumors were located in the right lung, mainly in the upper lobe, with no clear preference for central or peripheral distribution. Histologically, all were poorly differentiated NSCLCs, classifiable into two patterns: a basaloid/squamous-like pattern and an inflammatory/plasmacytoid pattern. Molecular profiling revealed a hybrid genomic landscape, with individual tumors harboring alterations linked to both adenocarcinoma and squamous cell carcinoma, along with a high prevalence(58.8%) of mutations. In an index case, multi-region sequencing revealed a shared mutation across regions, with a mutation confined to the high-grade TTF-1/p40-positive area. Most patients (66.7%) presented with Stage III or IV disease, and 61.1% developed metastases, including four with distant spread and seven involving thoracic or supraclavicular lymph nodes or the pleura. Three patients died from the disease within 10–64 months after diagnosis. However, all patients with Stage I or II disease who underwent resection remained disease-free.

[CONCLUSIONS] NSCLC with diffuse TTF-1/p40 co-expression constitutes a distinct biphenotypic entity with unique clinicopathologic and molecular features. We suggest specific diagnostic criteria to ensure proper identification. Given the presence of targetable drivers and frequent PD-L1 expression, an integrated diagnostic approach is crucial for guiding personalized therapy and enhancing patient outcomes.