Tumor-induced Lymphangiogenesis And Lymphatic Vessel Invasion: An Important Mechanism Of Extrapancreatic Nerve Plexus Invasion Of Pancreatic Adenocarcinoma

Background and Objective:Neural invasion is a special feature and an independent prognostic factor of pancreatic cancer. Furthermore, extrapancreatic nerve plexus invasion is responsible for the high recurrence in curatively resected cases. The authors carried out a histopathologic study of resected pancreatic adenocarcinoma to elucidate the mechanism of extrapancreatic nerve plexus invasion via the pathways of tumor-induced newborn lymphatic vessels, an important invasive pattern in pancreatic cancer, for the better treatment of this disease.Methods:We investigated 70 patients with pancreatic adenocarcinoma who had undergone pancreatic resection with various systemic regional dissection of lymph node and extra-pancreatic neural plexus, accroding to the location of tumor lesion, at our department. Histopathological examination of the serial sections were made in the cases that were made up of pancreatic ductal adenocarcinoma tissues specimens, including intratumoral and peritumoral tissues, extrapancreatic tissues consisting of the plexus pancreaticus capitalis, celiac plexus, superior mesenteric plexus, splenic plexus, common hepatic plexus, plexus in the hepatoduodenal ligament and lymph nodes. They were subjected to conventional hematoxylin/eosin staining. Double immunohistochemical staining using CK19 and D2-40 was performed to display tumor cells and lymphatic vessel. Tumor tissues was observed by immunohistochemical staining using VEGF-C, too. Survival data for all of these patients were obtained. Statistical analyses were performed to assess for associations.Results:D2-40/CK19 dual immunohistochemistry(DIHC) showed unequivocal lymph vessels and. Intratumoral LVD was significantly lower than periturmoral LVD (P<0.001). Extrapancreatic neural plexus invasion seem not significantly associated with gender, lymph node metastasis, tumor size and the tumor's location (P>0.05), but were obviously associated with lymphatic vessel invasion(LVI) in peritumoral tissues, peritumoral lymphatic vessel density(LVD) and VEGF-C expression in pancratic cancer cells. Lymphatic vessels were found to adhere extrapancreatic nerve fascicles or enter into the nerves in 15 cases (21.4%).There may be correlation between ranking of LVD and that of incidence of neural plexus invasion in all extrapancreatic neural plexuses tissues. The plexus pancreaticus capitalis and celiac plexus were respectively confirmed to be the spot with the highest LVD and the maximal incidence of neural plexus invasion simultaneously according to concrete location of tumor lesion of pancreas. To date, follow-up is complete for 81.4% (57 of 70 patients). The presence of peritumoral LVI, PV-SMV involvement, poor differentiation, LNM and extra-pancreatic neural plexus invasion were associated with poor overall survival in univariate analysis, but the presence of peritumoral LVI, PV-SMV involvement, LNM and extra-pancreatic neural plexus invasion involvement were identified as independent prognostic factors in multivariate analysis.Conclusions:Because of the high incidence of extrapancreatic neural plexus invasion, particular attention should be paid to the possible mechanism of this phenomenon. Our study suggested the possibility of the cancer spreading by route of peritumoral lymphangiogenesis, induced by VEGF-C, a lymphangiogenic growth factor, into the extrapancreatic neural plexuses. There may be correlation between ranking of LVD and that of incidence of neural plexus invasion in all extrapancreatic neural plexuses tissues. Pancreatectomy with appropriate dissection of retroperitoneal tissue including regional lymph nodes and extrapancreatic neural plexuses or intraoperative radiation should be considered as a basic procedure in the treatment of pancreatic carcinoma. Our data indicated the lymphatic vessels distribution in pancreatic adenocarcinoma samples and peritumoral lymphangiogenesis may promote the malignant progression of invading pancreatic peripheral nerves. Regulation of lymphangiogenesis in vivo by VEGF-C may be an important method for inhibition of lymphatic metastasis to extrapancreatic neural plexus. More particular attention should be paid to the lymphatic system because it is a more important pathway of outward invasion for pancreatic cancer than other malignant solid tumors and worthy further research.