Abstract
BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma (NEC) with poor prognosis due to chemotherapy resistance. Molecular subtypes, including ASCL1, NEUROD1, YAP1 and POU2F3, have distinct clinical implications. POU2F3, linked to a tuft cell-like lineage, represents a non-neuroendocrine subtype found in SCLC and extrapulmonary NECs. However, its prognostic and clinical significance remain unclear. METHODS: A meta-analysis was performed to assess the relationship between POU2F3 expression and clinical outcomes in SCLC and NECs. Studies reporting clinicopathological or survival data related to POU2F3 expression, identified via immunohistochemistry, were included. This review was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered on the International Prospective Register of Systematic Reviews (registration number: CRD42023478789). RESULTS: Sixteen studies involving 2011 patients met inclusion criteria. Pooled analysis revealed that POU2F3 expression in SCLC significantly improved OS (HR = 0.74, 95% CI = 0.61-0.90, p < .01 and PFS/RFS (HR = 0.69, 95% CI = 0.53-0.90, p < .01). Subgroup analyses associated POU2F3 positivity with favourable survival when surgical specimen or whole slide analysis was used, or when studies with chemotherapy regimen were included. POU2F3 expression also correlated with younger age (p = .02) and male sex (p = .03) but not with smoking history, tumour stage, nodal involvement, or vascular invasion. CONCLUSION: POU2F3 expression is associated with improved survival and correlates with younger age and male sex in SCLC, highlighting distinct clinical and biological characteristics of this tuft cell-originated subtype. Data on extrapulmonary NECs were limited, precluding definitive conclusions for this population.