| Objective: Microsatellite instability,PD-1 and PD-L1 expression in pancreatic neuroendocrine neoplasm were studied to study their relationship with clinicopathological characteristics and evaluate the impact on prognosis.Methods: The clinical data of 105 pnen patients admitted to the fourth hospital of Hebei Medical University from January 2007 to October 2019 were analyzed retrospectively.The MLH1,PMS2,MSH2,MSH6,BRAF,PD-1 and PD-L1 were measured in 23 patients.After that,5 indexes of MLH1,PMS2,MSH2,MSH6 and BRAF were added.We selected 8clinicopathological features: sex,age,grade,functional pancreatic neuroendocrine tumor(f-pnen)and non functional pancreatic neuroendocrine tumor(NF pnen),infiltration depth T stage,metastasis,nerve / vascular invasion,BRAF.The expression of microsatellite instability(MSI),programmed death receptor 1(PD-1),programmed death ligand 1(PD-L1)in pnen and their relationship with clinicopathological features and prognosis were analyzed.Results:1.A total of 105 p NENs were counted in this study,including 41 males and 64 females,with a male to female ratio of 0.64: 1.Aged between 20 and82,with a median age of 55.2.The main symptoms were abdominal pain,a total of 36 cases,followed by a pancreatic tumor found on physical examination,a total of 33 cases,abdominal distension,a total of 16 cases,jaundice,a total of 8 cases,abdominal discomfort,a total of 5 cases,diarrhea,a total of 4 cases,and anorexia A total of 4 cases,hypoglycemia,a total of 3 cases,syncope,a total of 3 cases,vomiting,a total of 3 cases,black stools,a total of 1 cases, unconsciousness,a total of 1 cases,yellow urine,a total of 17 cases.According to whether tumors cause clinical symptoms,p NEN could be divided into functional pancreatic neuroendocrine tumors(F-p NEN)and non-functional pancreatic neuroendocrine tumors(NF-p NEN).There were 18 cases of F-p NEN and 87 cases of NF-p NEN.3.The loss rate of mismatch repair protein(MMRP)expression in the tissues of 80 p NEN patients was 48.75%,among which the loss rates of MSH2,MSH6,MLH1 and PMS2 were 23.75%,13.75%,16.25%,32.50%Among them,the co-expression deletion rate of MLHI and PMS2 was 11.25%,and the co-expression deletion rate of MSH2 and MSH6 was 11.25%.4.Loss of expression of MLHI and gender(P = 0.226),age(P = 0.291),grade(P = 0.307),F-p NEN / NF-p NEN(P = 0.750),nerve / vascular invasion(P = 0.729)),BRAF(P = 0.051)was not statistically related(P> 0.05);it was only statistically related to the depth of tumor invasion(T stage)(P = 0.020)and distant metastasis(P = 0.008)(P <0.05).0.05).Loss of expression of PMS2 and age(P = 0.551),grade(P = 0.330),F-p NEN / NF-p NEN(P =0.616),nerve / vascular invasion(P = 0.939),BRAF(P = 0.207)None There was statistical correlation(P> 0.05);while it was related to gender(P = 0.024),depth of tumor invasion(T stage)(P = 0.003),and distant metastasis(P =0.008)(P <0.05).MSH2 expression loss and gender(P = 0.421),age(P =0.526),? ? grade(P = 0.471),F-p NEN / NF-p NEN(P = 0.676),depth of tumor invasion(T stage)(P = 0.490),distant metastasis(P = 0.151),nerve /vasculature invasion(P = 0.101)were not statistically related(P> 0.05);the loss of MSH2 expression was only related to BRAF(P = 0.016)expression.MSH6 expression loss rate and gender(P = 0.158),age(P = 0.206),grade(P= 0.113),F-p NEN / NF-p NEN(P = 0.057),nerve / vascular invasion(P =0.716)None Statistical correlation(P> 0.05);MSH6 expression loss rate was statistically related to tumor invasion depth(T stage)(P = 0.000)and distant metastasis(P = 0.001).5.There was no deletion of 4 mismatch repair proteins or only one deletion is normal mismatch repair(p MMR),and at least two or more mismatch repair protein deletions were mismatch repair defects(deficientd mismatch)repair,MMR).According to the lack of mismatch repair protein,80 patients with p NEN were divided into 2 groups: 18 in the d MMR group and62 in the p MMR group.Comparison of the two groups in this study showed that p NEN patients in the d MMR group were different from p NEN patients in the p MMR group in certain clinicopathological characteristics(P <0.05).d MMR expression was different at different ages(P = 0.188),NET grade(P =0.307),F-p NEN / NF-p NEN(P = 0.957),nerve / vascular invasion(P =0.265),BRAF(P = 0.106),etc.There was no significant difference between the factors(P> 0.05).d MMR is related to gender(P = 0.042),tumor invasion depth(T stage)(P = 0.001),distant metastasis(P = 0.001),and so on.The expression of d MMR was higher in women than in men,and higher in T3 / T4 than T1 / T2,indicating that the later the tumor stage was,the higher the expression of d MMR was,and higher in patients with metastasis.6.The expression of PD-1 and PD-L1 was detected by ICH in 23 patients with p NEN.The positive rate of PD-1 expression was 73.91%.The positive rate of PD-1 expression was 30.43%.The positive rates of PD-1 and PD-L1 expression were compared in terms of gender,age,grade,F-p NEN /NF-p NEN,depth of tumor invasion(T stage),presence or absence of metastasis,vascular / nerve invasion,BRAF,etc.The difference was not statistically significant(P> 0.05).7.105 cases of pnen were followed up,84 cases were followed up,21 cases were lost,the follow-up rate was 80%.Of the 84 patients followed up,14 died.The clinicopathological characteristics of PD-L1(P = 0.054),PD-1(P = 0.085),dmmr(P = 0.568),gender(P = 0.464),age(P = 0.399),f-pnen /NF pnen(P = 0.078),vessel / nerve invasion(P = 0.131),BRAF(P = 0.871)were not significantly related to the survival of patients(P < 0.05).Grade(P =0.000),tumor invasion depth(T stage)(P = 0.005),and metastasis(P = 0.004)were related to the prognosis of patients,that was,the prognosis of NEC G3 was worse than that of net G1 / G2 / G3,the prognosis of patients without metastasis was better than that of patients with metastasis;the prognosis of patients with early T stage(T1 and T2)was better than that of patients with late T stage(T3 and T4).Among the pnen patients with NEC G3,the survival time of PD-1 positive patients was significantly longer(P = 0.012).This suggests that PD-1 inhibitors in pnen with high value-added activity might have significant efficacy in patients with NEC G3.However,we also found that the survival period of PD-L1 positive patients in pnen was significantly prolonged,although there was a significant trend,but the overall survival difference did not reach statistical significance.Cox regression method was used to analyze the factors that may affect the prognosis of pnen patients.It could be seen that tumor grade(P = 0.012)and PD-1(P = 0.023)were independent factors affecting the prognosis of patients(P < 0.05)..Conclusion:1.The four types of MMRP were mainly related to T stage of invasion depth and distant metastasis,but the expression of the four types of MMRP and the clinicopathological characteristics of p NEN had their own characteristics,and the two pairs of MLH1 and PMS2,MSH2 and MSH6 showed the expression of synergistic expression or absence.2.d MMR was related to gender,depth of tumor invasion(T stage),and distant metastasis.The 5-year survival rate of patients with p MMR and d MMR was significantly different,and the 5-year survival rate of p NEN of p MMR had obvious advantages.3.Among the p NEN patients with NEC G3,the survival of PD-1 positive patients was significantly prolonged(P = 0.012).The survival time of PD-L1 positive patients was obviously prolonged,but the difference in overall survival time(P> 0.05)did not reach statistical significance.4.In Cox multivariate regression analysis,grading and PD-1 could be used as independent factors to affect the survival of pnen patients.Immunotherapy with anti-PD-1 antibody might be a reasonable choice for G3 patients with poor prognosis. |
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