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

Abstract

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 on the distribution and state of nerve fibers in PDAC tissue and their clinicopathological impacts. The aim of the present 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 a 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 .980‐2.114) were prognostic factors of shorter OS in the multivariate analysis. These findings suggest low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose a simple, practical and reproducible method (to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC ), which has been validated using another cohort (n = 81).

Nerve fibers in the tumor microenvironment in neurotropic cancer—pancreatic cancer and cholangiocarcinoma

“…An increased density of nerve fibers in the tumor lesion is correlated with high-grade disease and increased pathological stage, including for cancers of head and neck [ 68 ], breast [ 69 ], lung [ 70 ], stomach [ 71 ], prostate [ 26 , 62 ], colon and rectum [ 72 ]. For PDAC it is suggested to be the other way around: a low nerve fiber density correlates with a poorer survival [ 73 ]. In another study, a high nerve fiber density of the parasympathetic nerve fibers correlated with tumor budding and a poor survival [ 74 ].…”

“…Interestingly, lower intrapancreatic neural density in the tumor area was linked to shorter OS with multivariate analysis [ 73 ]. Related research in CCA mainly focused on PNI prevalence and patient survival [ 45 , 99 , 104 ].…”

Nerves and Pancreatic Cancer: New Insights into A Dangerous Relationship

“…Although PNI is almost omnipresent in PDAC patients, a clear consensus in terms of the profound impact of perineural invasion on overall survival, disease free survival, early tumor recurrence is still missing. Numerous studies have reported a correlation between PNI and tumor recurrence and/or patients’ survival [8,9,12,18,19,20,21,22,23,24]; however, few studies failed to show PNI as an independent predictor of tumor recurrence (overall and early) and of patient survival [25,26]. These differences are most likely due not only to the retrospective design of the majority of these studies but also to the high variance in histological evaluation of PNI.…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…Postganglionic sympathetic fibers mostly run with blood vessels (561,562). Innervation is increased in PaCa (563, 564), nerve fibers forming a dense network that interacts with tumor cells and supports tumor growth and dissemination (565)(566)(567). In fact, PaCa metastasize by PNI.…”