Clinicopathological Significance Of Differential Diagnosis Between Neuroendocrine Tumor G3 And Neuroendocrine Carcinoma In Digestive System

Objective: To explore the clinicopathological significance of differentiating neuroendocrine carcinoma(NEC)and neuroendocrine tumor G3(NET G3)of the digestive system,and to provide a certain scientific basis for the prognosis evaluation and precise treatment of patients.Methods: 97 cases surgical specimens,including NEC(93 cases)and "high proliferative activity" neuroendocrine tumors(4 cases),and 12 cases corresponding biopsy specimens of digestive system diagnosed by pathology in the affiliated Hospital of Qingdao University during August 2010 to August 2020 were collected.They were rechecked by adding to do the corresponding immunohistochemical(IHC)indexes(p53,Rb,ATRX),according to the “World Health Organization(WHO)the classification and diagnosis criteria of digestive system tumors”(version 2019)and the “Chinese consensus on pathological diagnosis of gastrointestinal and pancreatic neuroendocrine tumors”(version 2020).All cases above were reclassified to NET G3 and NEC,and the histopathological characteristics of the two types were compared,and also the survival analysis was carried out by Kaplan-Meier method to explore the similarities and differences of both prognosis.Chi-square test and Fisher exact probability method were used to explore the relationship between the expression of p53,Rb and the clinicopathological features of NEC patients.Univariate and multivariate Cox regression analysis was used to explore the relationship between clinicopathological features,IHC indexes and the prognosis of NEC patients.SPSS 23.0 software was used.Results: Rechecked with histopathological observation combined p53,Rb and ATRX detection by IHC,we finally confirmed the diagnosis of 91 cases NEC,6 cases NET G3 from surgical specimens and 12 cases NEC biopsy from corresponding surgical specimens.Of 93 cases originally diagnosed as NEC reexamined,5 cases were eventually reclassified as NET G3.Of 4 cases originally diagnosed as "highly proliferative" neuroendocrine tumors reexamined,3 cases were eventually reclassified as NEC and 1case as NET G3.In terms of histopathology,it was found that there were well-differentiated tumor area in NET G3,and the expression range of Ki-67 positive index was 20%-60%.In contrast,tumors in NEC were poorly differentiated,and their Ki-67 positive index expression ranged from 40%-90%.The histopathological manifestations and IHC expression of the 12 biopsy specimens and the corresponding surgical specimens were roughly the same,and the biopsy specimens had certain limitations in the scope of histopathological observation.There was no significant difference in the abnormal expression rates of P53 and Rb proteins between biopsy specimens and corresponding surgical specimens(P>0.05).The results of IHC testing of surgical specimens showed that,The abnormal expression rate of p53 and(or)Rb was 89.0% in 91 cases NEC,and it of ATRX was 0.Of the 6 cases NET G3,3 cases had abnormal expression of ATRX,and all 6 cases had no abnormal expression of P53 and Rb.Abnormal p53 expression was higher in 91 NEC patients with small cell histological type(P=0.016),tumor diameter>2cm(P=0.048),and Ki-67 index>55%(P=0.019).Patients with Ki-67 index>55%(P=0.023)also had higher rate of abnormal Rb expression.Abnormal expression of p53 was not related to gender,age,vascular tumor plug,lymph node metastasis and nerve invasion(P>0.05,respectively).The abnormal expression of Rb was also not related to gender,age,histological type,tumor diameter,vascular tumor plug,lymph node metastasis and nerve invasion(P>0.05,respectively).Univariate analysis showed that the histological type,vascular tumor plug,lymph node metastasis,Ki-67 index,p53 abnormal expression,both p53 and Rb abnormal expression were significantly related to overall survival(OS)and disease-free survival(DFS)(P<0.05,respectively).Multivariate Cox regression analysis showed that small cell type,lymph node metastasis,Ki-67 index>55%,p53 abnormal expression,both p53 and Rb abnormal expression were independent risk factors for postoperative OS and DFS in NEC patients(P<0.05,respectively).The median postoperative OS and DFS of NEC patients were 25.0 and 19.0 months,respectively.All 6 NET G3 patients survived,and 1 patient relapsed.NET G3 patients had longer postoperative OS than NEC patients(P=0.019).Conclusion: The detection of P53,Rb and ATRX with IHC plays an important auxiliary role in the identification of NET G3 and NEC,and is more necessary for biopsy specimens;our results suggested that NEC patients with small cell type,tumor diameter>2cm and Ki-67 index>55% should be tested accordingly;the results showed that there were more indicators which were independent risk factors for the prognosis of NEC patients,may suggest that they can be used in the evaluation of patient prognosis;the prognosis of NEC patients was worse than that of NET G3 patients,may suggest that the correct identification of the two has important clinical significance.