Reduction of intrapancreatic neural density in cancer tissue predicts poorer outcome in pancreatic ductal carcinoma

Summary

Neural invasion is one of the malignant features contributing to locally advanced and/or metastatic disease progression in patients with pancreatic ductal adenocarcinoma (PDAC). Few studies exist about the distribution and state of nerve fibers in PDAC tissue and about their clinicopathological impacts. The aim of this study was to investigate the clinicopathological characteristics and prognostic value of intrapancreatic neural alterations in patients with PDAC. We retrospectively analyzed 256 patients with PDAC who underwent macroscopic curative surgery. Nerve fibers, immunolabeled with specific neural marker, GAP‐43, were digitally counted and compared among PDAC, chronic pancreatitis (CP), and normal pancreatic tissues. Interlobular nerve fibers were apparently hypertrophic in both CP and PDAC, although intrapancreatic neural density and nerve number decreased characteristically in PDAC. They tended to decrease toward the center of the tumor. Kaplan‐Meier survival analyses revealed a statistically significant correlation between low neural density and shorter overall survival (OS) (P = 0.014), and between high neural invasion and shorter OS (P = 0.017). Neural density (P = 0.04; HR = 1.496; 95% CI 1.018‐2.199) and neural invasion ratio (P = 0.064; HR = 1.439; 95% CI 0.980‐2.114) were prognostic factors of shorter OS at multivariate analysis. These findings suggest the low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose the simple, practical, and reproducible method (to measure neural density and neural invasion ratio at the conventional histopathological diagnosis of PDAC), which has been validated using another cohort (n=81).

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