Clinical And Pathological Analysis Of Gastric Neuroendocrine Neoplasms And The Research On Gene Mutations

According to the 2010 World Health Organization(WHO)classification of digestive system tumors,Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)covers a series of tumor ranging from inert to highly invasive one including Neuroendocrine tumors(NETs),Neuroendocrine carcinomas(NECs)and Mixed adenoneuroendocrine carcinomas(MANECs).What about the clinicopathological features of them and how about the prognosis of the patients?These tumors are similar to Adenocarcinomas(ACs)sometimes in morphology and then how do they relate to ACs?Are the two components of MANECs the same origin or different?Do MANECs/NECs derive from NETs or is there any other way?We performed a series of experiment and data analysis to explore these issues.Objective:1.To investigate the clinicopathological features,diagnosis,prognosis and treatment of gastric neuroendocrine neoplasms(NENs)and to analyze the relationship between clinicopathologic parameters and prognosis.Compare the differences of constitution ratio of clinicopathologic parameters among MANECs/NECs,NETs,well differentiated/Moderately differentiated adenocarcinomas(WD/MD-ACs)and poorly differentiated adenocarcinomas(PD-ACs)and analyze the correlations to prognosis.2.To observe the expression of CDH17 and CDX2 in different parameters of gastric NENs and evaluate the relationship between their expression and prognosis of NENs and the value of estimating patients' outcome.3.Molecular examination were performed for the purpose of exploring the origin of MANECs/NECs.Methods:1.A retrospective study was made on 40 gastric MANEC,12 gastric NEC and 98 gastric AC samples by surgical radical resection,and 20 cases of gastric NET specimens obtained by endoscopic biopsy or excision.The clinicopathological data of all patients were reviewed and all the patients were followed up.The differences of constitution ratio of clinicopathological parameters of gastric NENs were statistically analyzed and the relationship between these parameters and prognosis were analyzed as well and then compared with ACs.2.Immunohistochemistry(IHC)staining was performed to detect the expression of Syn,CgA,CD56,CKpan,CK7,CK8/18,carcinoembryonic antigen(CEA),CK5/6,P40 and Ki-67 in MANECs.CDH17 and CDX2 expression were detected and compared in groups of patameters and the correlation of their expression to prognosis were statistically analyzed.3.The Next-generation sequencing(NGS)was used to detect the changes of 416 genes in MANECs and ACs.Results:1.The distribution of clinicopathologic parameters and prognosis of gastric MANECs/NECs were significantly different from gastric NETs but were more similar to gastric PD-ACs.The prognosis of gastric NENs were significantly correlated to patient's age,tumor size,location,grades,pTNM stage,lymphoma metastasis,recurrence and distant metastasis(P<0.05).Distant metastasis was an independent prognostic factor.2.The expressions of CDH17 and CDX2 in gastric NENs were significantly correlated to patient's gender,location,tumor size,grades,pTNM stage,lymphoma metastasis and distant metastasis(P<0.05).Expression of them were positively correlate and both were negatively correlated with prognosis.3.The same gene mutations and the same gene CNVs were found in both components of MANECs.Many of the genes with mutation and gene CNVs checked out in MANECs/NECs were similar but more complex than those of ACs.Conclusions:1.Although both of gastric MANECs/NECs and NETs belong to NENs,the discrepancy of the clinicopathological parameters and prognosis were significant,thus the pathogenesis may different and the features of the former were similar to gastric PD-ACs.2.CDH17 and CDX2 may play an important role in the development of gastric MANECs/NECs and combined detection may help suggest pTNM stage,the risk of metastasis and predict the patient's prognosis.3.Gene detection supported the monoclonal origin of both components of MANEC.MANECs/NECs may originate from the same multipotent stem cells and develop into different direction.Some of them may evolve into ACs first,then dedifferentiate to MANECs or NECs.