The distinctive characteristics of the micro-vasculature and immune cell infiltration in cystic pancreatic neuroendocrine tumors.

Purpose: Hypervascularity is a main characteristic of pancreatic neuroendocrine tumors (PanNETs), and cystic PanNETs (CPanNETs) are unique type of PanNETs in which the microenvironment remains unknown. We aim to compare the micro-vasculature features and immune cell infiltration between CPanNETs and solid PanNETs (SPanNETs).

Methods: Data of 301 SPanNET and 36 CPanNET patients from a high-volume institution were evaluated. CD4, CD8, CD11c, CD15, CD20, CD68, CD34 and α-SMA expression levels were assessed by immunohistochemistry and immunofluorescent double staining. The microvessel density (MVD) and microvessel integrity (MVI) were examined.

Results: MVD and MVI expression levels in CPanNETs were significantly higher than those in SPanNETs (p = 0.025 and 0.0092, respectively). CPanNETs had higher proportions of T1 (p = 0.023) and G1 (p = 0.052) than SPanNETs. In SPanNETs, higher MVD occurred in stages T1, N0 and G1 than in the T2/T3, N1 and G2 subgroups. In CPanNETs, CD34-MVD was uncorrelated with the T stage or grade. Higher CD34-MVD, but not MVI, was associated with better DFS (HR 0.3209, 95% CI 0.1259-0.8176, p = 0.004). There were significantly more peritumoral infiltrating immune cells than their intratumoral counterparts (p < 0.001 for each) in CPanNETs and SPanNETs. The mean number of peritumoral CD68 + TAM in CPanNETs was significantly lower than that in SPanNETs (p = 0.008). The counts of other peritumoral immune cells did not significantly differ between CPanNETs and SPanNETs.

Conclusions: CPanNETs had a microenvironment distinct from that of SPanNETs, including higher CD34-MVD, higher MVI and lower TAM. This specific microenvironment structure may partially help predicting the prognosis of patients with PanNET.