POU2F3 in Small Cell Lung Cancer (SCLC): Diagnostic Utility in Neuroendocrine-Low/Negative SCLC and Discrimination From Other Thoracic Malignancies and Other Small Blue Round Cell Tumors.

POU2F3 is a newly identified immunohistochemical marker specific for the chemosensory tuft cell-related subtype of small cell lung cancer (SCLC) (SCLC-P). The characteristics of SCLC-P remain incompletely defined, and POU2F3 expression patterns across different organs and tissue types are poorly documented. We assessed POU2F3 expression in 253 SCLCs, with comprehensive clinicopathological and genomic characterization of POU2F3-positive tumors. POU2F3 expression profiles were investigated in other major lung cancer types (n = 2537) and other tumors across different organs and tissue types (n = 195). POU2F3 was expressed in 10.28% (26/253) of all SCLC cases and was strongly associated with low expression of standard neuroendocrine (NE) markers (Syn, CgA, CD56, and INSM1). In NE-low/negative SCLC and NE-high SCLC, the POU2F3 positive rates were 83.33% (20/24) and 2.62% (6/229), respectively. Additionally, POU2F3 was detected in squamous cell carcinoma (2.35%) and large cell NE carcinoma (25%) but was negative in lung adenocarcinoma, NUT carcinoma, large cell carcinoma, pleomorphic carcinoma, SMARCA4-deficient thoracic undifferentiated tumor, atypical carcinoid, and adenoid cystic carcinoma. Notably, the highly heterogeneity of POU2F3 expression was observed in 7.3% (3/41) of surgical SCLC specimens. In extrapulmonary tumors, POU2F3 was positive in 37.5% (6/16) of extrapulmonary small cell NE carcinomas, 16.67% (5/30) of thymic tumors, 1 of 2 extrapulmonary large cell NE carcinomas, and 1 of 1 nasopharyngeal carcinoma. SCLC-P tends to be more prevalent in surgical specimens (P = .009) and earlier TNM stage (P = .045). Next-generation sequencing revealed that SCLC-P (n = 6) exhibited enrichment in MYC gene amplification and lower mutation rate of RB1 but similar rates of TP53 and PTEN alterations as POU2F3-negative SCLC (n = 13). This study establishes POU2F3 as a critical diagnostic biomarker for NE-low/negative SCLC, demonstrating high specificity in distinguishing SCLC-P from other thoracic malignancies and small blue round cell tumors. We delineate the distinct clinicopathological and genomic profile of POU2F3-driven SCLC (SCLC-P), providing a foundation for its diagnostic application. Further validation in expanded cohorts is warranted to confirm its clinical utility.