Simple SummaryPancreatic cancer, one of the most aggressive forms of cancer, is a lethal disease. Although nerves infiltrate the tumor microenvironment and they are even present in pancreatic tumors, the role of innervation, especially sympathetic innervation, remains unclear. Moreover, neurotransmitters can modulate the evolution of pancreatic cancer through various processes, such as carcinogenesis, invasions, proliferation, or metastasis. Here, we assess pancreatic neoplastic tissue, examining the sympathetic nerve fibers and the density of beta 2 adrenoreceptors, both intratumoral and peritumoral. These were correlated with the clinical outcome. If the intratumoral sympathetic nerves registered a structural alteration, and the peritumoral nerves were not structurally altered, they could not be associated with prognosis; the same was not observed regarding beta 2 adrenoreceptors. Increased immunoreactivity of beta 2 adrenoreceptors in pancreatic peritumoral tissue was associated with poor prognostic factors in pancreatic cancer.AbstractBackground: The aim of our study was to evaluate sympathetic neuronal remodeling in patients with pancreatic cancer, together with its correlation with clinical outcomes. Methods: In this descriptive, retrospective study, we analyzed pancreatic cancer specimens and peritumoral pancreatic tissue from 122 patients. We also investigated tyrosine hydroxylase immunoreactivity for the analysis of sympathetic nerve fibers and beta 2 adrenoreceptors immunoreactivity. To investigate the potential interaction between tyrosine hydroxylase (TH), beta 2 adrenoreceptors (B2A) immunoreactivity, and clinicopathological outcomes, we used the median to classify each case as TH+, respectively, B2A+ (if it presented a value higher than the median). Results: Firstly, the overall survival was analyzed according to TH and B2A immunoreactivity, in both intratumoral and peritumoral tissue. Only B2A immunoreactivity in the peritumoral pancreatic tissue influenced overall survival at 5 years of follow-up; thus, B2A+ patients recorded a 5-year survival of only 3% compared to B2A− patients who recorded an overall survival at 5 years of follow-up of 14% (HR = 1.758, 95% CI of ratio 1.297 to 2.938,p= 0.0004). Additionally, the increased immunoreactivity of B2A in the peritumoral tissue was also associated with other factors of poor prognosis, such as moderately or poorly differentiated tumors, the absence of response to first-line chemotherapy, or metastatic disease. Conclusions: The increased immunoreactivity of beta 2 adrenoreceptors in pancreatic peritumoral tissue represents a poor prognostic factor in pancreatic cancer.