Prognostic Significance Of Tumor Budding In Pancreatic Neuroendocrine Tumors

Background and object:Pancreatic neuroendocrine tumor(PNET)is a heterogeneous neoplasm with malignant potential,representing about 50% of the gastrointestinal neuroendocrine tumors.Metastatic dissemination of PNETs,predominantly to the liver,always occurred in different pathological grades and is considered as a pathological hallmark of this disease.Radical excision of primary and metastatic lesions whenever possible is recognized as the preferred treatment modality,with a 5‐year disease‐free survival(DFS)rates of approximately 53.6%.Given the poor prognosis of PNET and high rates of postoperative liver metastasis,valuable factors predictive of metastatic potential that may be applied to develop the rational management of PNET sensitively and specifically is desperately needed.Tumor budding is a histological phenomenon corresponds to a type of diffusely infiltrative growth pattern that is observed at the invasive tumor fronts,which is recognized as the morphological expression of epithelial–mesenchymal transition(EMT).In multiple gastrointestinal malignancies,accumulating evidence has demonstrated that tumor budding is involved in the process of tumorigenesis as well as invasion and metastasis.Nevertheless,studies correlated with relationships between tumor budding and postoperative metastasis after radical resection is quite limited.In the current research,complete clinicopathological data and follow-up information were retrospectively collected to research into the correlations between tumor budding and prognosis of PNET patients,hoping to shed lights on new prognostic biomarkers as well as novel therapeutic strategy.Methods:Complete clinicopathological data and follow-up information of 113 PNET patients underwent curative resection as the initial treatment at People’s Hospital of Zhengzhou University between January 2010 and December 2016 were included in the current research,including tumor diameter,number,location,differentiation,margin,vascular invasion,lymph node status,metastasis and Ki-67 index.Tumor budding is defined as isolated single cells or small cell clusters(up to five cells)surrounded by the stroma at the invasive edge of the tumor.All the hematoxylin-eosin and immunohistochemically stained slides of the cohort were retrieved from the Department of Pathology and tumor budding was counted under ×400 microscopic field.Receiver operating characteristic(ROC)analysis was carried out to screen the optimal cut‐off point for tumor budding,accordingly,budding was classified as low grade(≤10 buds/field)or high grade(>10 buds/field).Multivariate analysis was performed on predictors of the tumor.Results:1.Among the 113 cases,high-grade budding was observed in 37 cases and low-grade tumor budding in 76 cases.2.High-grade budding group are prone to develop tumors with advanced T stage,high risk of lymphatic metastasis,preoperative liver metastasis,vascular invasion and postoperative recurrence(respectively χ2=8.460,4.517,5.882,9.038,4.290,all P<0.05).3.With regard to the other quantitative clinical parameters including age,gender,location,diameter,differentiation,tumor grade,tumor function,no significant difference was revealed in the two groups(all P>0.05).4.Kaplan-Meier survival curves revealed that high-grade budding group has significantly worsened overall survival compared to the low-grade one(P=0.029).5.Univariate analysis showed that high-grade tumor budding,tumor grade,T-stage,preoperative liver metastasis,vascular invasion were inversely associated with overall survival of PNET patients(respectively χ2=6.015,12.965,4.192,10.142,4.792,17.011,27.535,all P<0.05)6.Multivariate COX regression analysis showed that tumor budding(P=0.019),tumor grade(P=0.037),vascular invasion(P=0.038)was independent risk factors of PNET patients.7.Cohen’s κ statistic indicated that immunohistochemical staining has better interobserver concordance(the interobserver κ coefficient for the Synaptophysin immunostaining was 0.887)Conclusion:Tumor budding is highly associated with aggressively clinicopathological parameters of pancreatic neuroendocrine tumor,which is also an important prognostic factor.