POU2F3-Expressing Small Cell Lung Carcinoma and Large Cell Neuroendocrine Carcinoma Show Morphologic and Phenotypic Overlap

Considering the differences in protein expression in small cell lung carcinoma (SCLC) by molecular classification, it is likely that there are differences in morphology, but the relationship between molecular classification and morphology has not been examined. Furthermore, there are limited reports concerning this molecular classification for large cell neuroendocrine carcinoma (LCNEC) and SCLC simultaneously. Therefore, we investigated the relationship between immunohistochemistry-based molecular classification and morphology, protein expression, and clinical features of 146 consecutive resection specimens of pulmonary neuroendocrine carcinoma (NEC), focusing mainly on POU2F3, the master transcription factor involved in tuft cell generation. POU2F3-dominant SCLC (n=24) and LCNEC (n=14) showed overlap in cytomorphology, while non-POU2F3-dominant SCLC (n=71) and LCNEC (n=37) showed distinct differences in cytomorphology. In addition, POU2F3-dominant NEC exhibited significantly more abundant tumor stroma, more prominent nest formation, more frequent bronchial intraepithelial involvement, and less frequent background fibrosis than non-POU2F3-dominant NEC. Immunohistochemically, POU2F3-dominant SCLC and LCNEC were characterized by lower expression of TTF-1, CEA, and neuroendocrine markers and higher expression of bcl-2, c-Myc, and c-kit. Clinically, POU2F3-dominant NEC had a significantly better prognosis than non-POU2F3-dominant NEC for recurrence-free survival. POU2F3-dominant NEC had a higher smoking index than non-POU2F3-dominant NEC. POU2F3-dominant NEC forms a unique population, exhibiting intermediate morphologic features between SCLC and LCNEC, with distinct protein expression as tuft cell-like carcinoma. Recognition of this unique subtype may provide clues for solving the long-standing issues of NEC and appropriate therapeutic stratification. It is important to accurately identify POU2F3-expressing carcinomas by immunohistochemistry and to analyze their clinicopathological features.