不同类型胃恶性神经内分泌肿瘤与胃腺癌的临床病理特征和生存情况比较

Comparison of clinicopathological characteristics and overall survival between different types of gastric malignant neuroendocrine neoplasms and gastric adenocarcinoma

背景胃恶性神经内分泌肿瘤包括胃神经内分泌癌和含有神经内分泌癌成分的混合性神经内分泌-非神经内分泌肿瘤,混合性神经内分泌-非神经内分泌肿瘤绝大多数为腺-神经内分泌癌,因其罕见性,目前缺乏系统性的研究提高对其临床病理特征及预后的认识。目的以胃腺癌为参照,探究胃恶性神经内分泌肿瘤的临床病理特征和生存情况。方法采用回顾性病例对照研究的方法,收集2008年1月-2018年12月在解放军总医院第一医学中心行手术治疗的非cM1期胃恶性神经内分泌肿瘤及胃腺癌患者资料,分析、比较其临床病理特征。1:3倾向性评分匹配(PSM)调整胃恶性神经内分泌肿瘤和胃腺癌队列之间的混杂因素。Kaplan-Meier法绘制生存曲线,log-rank检验分析组间总生存率的差异,Cox回归模型分析患者预后的独立关联因素。结果共纳入5443例(96.0%)胃腺癌与226例(4.0%)胃恶性神经内分泌肿瘤,后者包括148例神经内分泌癌和78例腺-神经内分泌癌。胃恶性神经内分泌肿瘤与胃腺癌首诊年龄、性别、肿瘤大小、肿瘤部位、手术方法、胃切除方式、T分期、N分期、TNM分期的差异有统计学意义(P<0.05)。2875例胃腺癌和215例胃恶性神经内分泌肿瘤有完整的生存信息,倾向性匹配后进行生存分析,发现胃腺癌患者的总生存率显著优于胃恶性神经内分泌肿瘤患者(3年、5年生存率:67.3%vs 58.9%,59.8%vs 48.3%,P=0.002),亚组分析显示,胃腺癌患者的总生存率优于神经内分泌癌和腺-神经内分泌癌患者(3年、5年生存率:67.3%vs 57.5%和61.1%,59.8%vs 50.5%和44.9%,P均<0.05),但神经内分泌癌患者与腺-神经内分泌癌患者的总生存率无统计学差异(P=0.993)。对胃恶性神经内分泌肿瘤的分析显示,神经内分泌癌与腺-神经内分泌癌在首诊年龄、性别、肿瘤大小、肿瘤部位、手术方法、胃切除方式、T分期、N分期、TNM分期、免疫标记物表达上无统计学差异(P<0.05)。生存分析结果表明年龄(HR=1.945,95%CI:1.249~3.030)、肿瘤大小(HR=2.199,95%CI:1.029~4.701)、TNM分期[Ⅱ期vsⅠ期(HR=1.669,95%CI:0.596~4.670),Ⅲ期vsⅠ期(HR=5.710,95%CI:2.197~14.837)]与胃恶性神经内分泌肿瘤患者生存独立关联。结论胃恶性神经内分泌肿瘤与胃腺癌有着截然不同的临床病理特征,胃恶性神经内分泌肿瘤浸润能力更强,侵袭性更高,总生存率显著劣于胃腺癌,神经内分泌癌和腺-神经内分泌癌有着相似的临床病理特征及总生存率;年龄≥60岁、肿瘤≥3 cm、Ⅲ期多提示胃恶性神经内分泌肿瘤患者较差的预后。

Background Gastric malignant neuroendocrine neoplasms(NEN)include neuroendocrine carcinoma(NEC)and mixed neuroendocrine&non-neuroendocrin(MiNEN)containing NEC components.The majority of MiNEN is mixed adenoendocrine carcinoma(MANEC).Because of its rarity,there is a lack of systematic research in improving the understanding of its clinicopathological characteristics and prognosis.Objective To explore the clinicopathological characteristics and the overall survival rate(OS)of gastric malignant NEN taking gastric adenocarcinoma as reference.Methods A retrospective case control study was performed in the clinical data about non cM1 gastric malignant NEN and gastric adenocarcinoma patients who underwent surgical treatment in the First Medical Center of Chinese PLA General Hospital from January 2008 to December 2018,and their clinicopathological characteristics were analyzed and compared.An 1:3 Tendency score matching(PSM)was used to adjust the confounding factors between gastric malignant NEN and gastric adenocarcinoma cohort.Kaplan-Meier method was used to draw survival curve.Log-rank test was used to analyze the difference of overall survival(OS)rate among groups.Cox regression model was used to analyze the independent risk factors affecting the prognosis of patients.Results The clinicopathological information of 5669 patients was included,including 5443(96.0%)cases of gastric adenocarcinoma and 226(4.0%)cases of gastric malignant NEN.Gastric malignant NEN included 148 cases of NEC and 78 cases of MANEC.There were statistically significant differences between gastric malignant NEN patients and gastric adenocarcinoma patients in age,sex,tumor size,tumor location,surgical approach,type of gastrectomy,T stage,N stage and TNM stage(all P<0.05).A total of 2875 patients with gastric adenocarcinoma and 215 patients with gastric malignant NEN had complete survival information.After PSM,the OS of patients with gastric adenocarcinoma was significantly better than that of patients with gastric malignant NEN(3-year,5-year OS:67.3%vs 58.9%,59.8%vs 48.3%,P=0.002).Subgroup analysis showed that the OS rate of gastric adenocarcinoma patients was significantly better than that of the NEC patients and the MANEC patients(3-year,5-year OS rate:67.3%vs 57.5%and 61.1%,59.8%vs 50.5%and 44.9%,P<0.05,respectively).There was no significant difference in OS rate between NEC patients and MANEC patients(P=0.993).NEC and MANEC had no significant difference in age,sex,tumor size,tumor location,surgical approach,type of gastrectomy,T stage,N stage,TNM stage and expression of immune markers.Multivariate analysis showed that age(HR=1.945,95%CI:1.249-3.030),tumor size(HR=2.199,95%CI:1.029-4.701)and TNM stage(Ⅱstage vsⅠstage[HR=1.669,95%CI:0.596-4.670],Ⅲstage vsⅠstage[HR=5.710,95%CI:2.197-14.837])were independent risk factors for survival of patients with gastric malignant NEN.Conclusion Gastric malignant NEN and gastric AC have distinctly different clinicopathological features.Gastric malignant NEN shows stronger infiltration ability and higher invasion,and the OS rate of gastric malignant NEN is significantly worse than that of gastric AC,while NEC and MANEC patients have similar clinicopathological features and OS rate.The patients with age≥60 years,tumor≥3 cm andⅢstage have poor prognosis.