Non-small cell lung carcinomas with diffuse co-expression of TTF-1 and p40: clinicopathologic and molecular characterization of a rare phenotype.

Non-small cell lung carcinomas showing co-expression of TTF-1 and p40 in sampled tumor tissue are rare, diagnostically challenging, and not formally recognized in the current WHO classification of thoracic tumors. We analyzed 15 pulmonary carcinomas with TTF-1/p40 co-expression to characterize their clinicopathologic features and molecular alterations. The cohort consisted predominantly of male patients and was composed mainly of high-grade, poorly differentiated tumors. All cases demonstrated diffuse nuclear co-expression of TTF-1 and p40 by immunohistochemistry. Whole-exome sequencing, performed in 12 cases, revealed frequent TP53 alterations (9/12), occasional concurrent RB1 alterations, and a rare FGFR3::TACC3 fusion, which was further validated by FISH. Two tumors with prominent lymphoid stroma were positive for Epstein-Barr virus-encoded RNA and lacked TP53 alterations, suggesting additional biological diversity within this phenotype. Follow-up data were available for 13 patients (range, 1-29 months); 4 died of disease and 9 were alive at last follow-up. Two additional patients were lost to follow-up. Collectively, these findings suggest that pulmonary carcinomas showing TTF-1/p40 co-expression in sampled tissue comprise a heterogeneous clinicopathologic and molecular group rather than a currently definable distinct entity. Despite the small sample size and the inclusion of several biopsy-only cases, this study provides a descriptive basis for future investigation of this unusual immunophenotypic pattern.