VEGF pathway signalling across pulmonary neuroendocrine tumours: associations with histological subtypes in a multicentre study

Abstract The current classification of pulmonary neuroendocrine neoplasms (NENs) is primarily based on histomorphological criteria, which do not fully capture their underlying biological heterogeneity. This limitation is particularly evident among pulmonary carcinoids, a subgroup characterized by highly variable clinical behaviour and prognostic outcomes despite similar morphological features. Angiogenesis is a hallmark of NENs, yet the role of the vascular endothelial growth factor (VEGF) pathway in pulmonary NENs remains incompletely defined. In this multicentre retrospective study, 109 pulmonary NENs (67 typical carcinoids, 22 atypical carcinoids, and 20 high-grade NENs) were analysed. VEGF, VEGFR1, VEGFR2, and VEGFR3 expression was assessed by immunohistochemistry and correlated with clinicopathological features and outcome. VEGF pathway components showed subtype-specific expression patterns. VEGFR1 was reduced in high-grade tumours and displayed a bimodal distribution, while VEGFR2 and VEGFR3 were higher in atypical carcinoids and high-grade tumours. Survival and recurrence were driven by histological subtype, whereas VEGF pathway expression lacked independent prognostic significance. The higher expression of VEGFR2 and VEGFR3 observed in atypical carcinoids and high-grade neuroendocrine carcinomas suggests a possible involvement of the VEGF signalling pathway in tumour biology. These findings contribute to the biological characterization of pulmonary NENs and provide a rationale for future studies investigating whether VEGF pathway markers may have predictive relevance for anti-angiogenic therapies.