Comparison of clinicopathological characteristics and overall survival between different types of gastric malignant neuroendocrine neoplasms and gastric adenocarcinoma
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摘要:
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 vs Ⅰ期(HR=1.669，95% CI：0.596 ~ 4.670)，Ⅲ期 vs Ⅰ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。 Abstract: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 5 669 patients was included, including 5 443 (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 2 875 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 (Ⅱ stage vs Ⅰ stage [HR=1.669, 95% CI: 0.596-4.670], Ⅲ stage vs Ⅰ stage [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 and Ⅲ stage have poor prognosis. -
Key words:
- gastric /
- neuroendocrine carcinoma /
- adenocarcinoma /
- overall survival rate /
- propensity score matching
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图 1 PSM前后，胃腺癌与恶性NEN患者OS的比较
A：PSM前胃腺癌与恶性NEN患者OS的比较；B：PSM后胃腺癌与恶性NEN患者OS的比较
Figure 1. Comparison of OS between gastric AC and malignant NEN before and after PSM
A: Comparison of OS between gastric AC and malignant NEN before PSM; B: Comparison of OS between gastric AC and malignant NEN after PSM
图 2 NEC、MANEC、腺癌患者之间OS的比较
A：NEC、腺癌患者之间OS的比较；B：MANEC、腺癌患者之间OS的比较；C：NEC、MANEC患者之间OS的比较
Figure 2. Comparison of OS among NEC, MANEC and AC patients
A: Comparison of OS between NEC and AC patients; B: Comparison of OS between MANEC and AC patients; C: Comparison of OS between NEC and AC patients
图 3 NEC和MANEC免疫组化结果
A：NEC和MANEC中Syn、CgA和CD56表达的情况；B：CgA在NEC和MANEC中的表达情况；C：Syn在NEC和MANEC中的表达情况；D：CD56在NEC和MANEC中的表达情况
Figure 3. Illustrations of immunohistochemical staining patterns in NEC and MANEC
A: An overview of the expression of Syn, CgA, and CD56 in NEC and MANEC; B: CgA expression in NEC and MANEC; C: Syn expression NEC and MANEC; D: CD56 expression in NEC and MANEC
图 4 不同临床病理特征的恶性NEN患者OS的比较
A：不同性别患者OS的比较；B：不同年龄患者OS的比较；C：不同手术方式患者OS的比较；D：不同胃切除方式患者OS的比较；E：不同肿瘤部位患者OS的比较；F：不同肿瘤大小患者OS的比较；G：不同TNM分期患者OS的比较
Figure 4. Comparison of OS in malignant NEN patients with different clinicopathological features
A: Comparison of OS between male and female patients; B: Comparison of OS between different age groups; C: Comparison of OS between different operation approaches; D: Comparison of OS between different types of gastrectomy; E: Comparison of OS between different tumor locations; F: Comparison of OS between different tumor size groups; G: Comparison of OS between different tumor TNM stage
表 1 胃恶性NEN与胃腺癌患者一般及临床病理特征比较(例，%)
Table 1. Comparison of characteristics of patients with gastric malignant NEN and AC (n, %)
临床病理特征 胃腺癌(n=5443) 胃恶性NEN (n=226) P值 胃腺癌(n=645) 胃恶性NEN (n=215) P值 年龄 ＜0.001 0.653 ＜60岁 2564(47.1) 77(34.1) 239(37.1) 76(35.3) ≥60岁 2879(52.9) 149(65.9) 406(62.9) 139(64.7) 性别 0.010 0.731 男性 4119(75.7) 193(85.4) 558(86.5) 184(85.6) 女性 1324(24.3) 33(14.6) 87(13.5) 31(14.4) 肿瘤位置 ＜0.001 0.624 胃上部 1911(35.1) 134(59.3) 377(58.4) 129(60.0) 胃中部 891(16.4) 30(13.3) 84(13.0) 27(12.5) 胃下部 2514(46.2) 56(24.8) 174(27.0) 53(24.7) 弥漫型 127(2.3) 6(2.6) 10(1.6) 6(2.8) 肿瘤直径 ＜0.001 0.286 ＜3 cm 1654(30.4) 41(18.1) 100(15.5) 40(18.6) ≥3 cm 3789(69.6) 185(81.9) 545(84.5) 175(81.4) 胃切除方式 ＜0.001 0.323 近端胃切除 1470(27.0) 101(44.7) 292(45.3) 96(44.6) 远端胃切除 2578(47.4) 57(25.2) 191(29.6) 55(25.6) 全胃切除 1395(25.6) 68(30.1) 162(25.1) 64(29.8) 手术路径 0.010 0.033 开放手术 3092(56.8) 113(50.0) 359(55.7) 107(49.8) 腹腔镜手术 1941(35.7) 102(45.1) 232(36.0) 97(45.1) 机器人手术 410(7.5) 11(4.9) 54(8.3) 11(5.1) T分期 ＜0.001 0.699 T1 ~ T2 1985(36.5) 43(19.0) 137(21.2) 43(20.0) T3 ~ T4 3458(63.5) 183(81.0) 508(78.8) 172(80.0) N分期 0.013 0.637 N0 ~ N1 3149(57.9) 112(49.6) 321(49.8) 111(51.6) N2 ~ N3 2294(42.1) 114(50.4) 324(50.2) 104(48.4) M分期 - - M0 5443(100) 226(100.0) 645(100) 215(100) M1 0(0) 0(0) 0(0) 0(0) TNM分期 ＜0.001 0.822 Ⅰ期 1535(28.2) 30(13.3) 88(13.7) 30(14.0) Ⅱ期 1468(27.0) 65(28.8) 182(28.2) 65(30.2) Ⅲ期 2440(44.8) 131(57.9) 375(58.1) 120(55.8) 
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表 2 神经内分泌癌与腺-神经内分泌癌患者一般及临床病理特征比较(例，%)
Table 2. Comparison of characteristics of patients with NEC and MANEC (n, %)
临床病理特征 胃恶性NEN P值 NEC (n=148) MANEC (n=78) 年龄 0.191 ＜60岁 46(31.1) 31(39.7) ≥60岁 102(68.9) 47(60.3) 性别 0.582 男性 125(84.5) 68(87.2) 女性 23(15.5) 10(12.8) 肿瘤位置 0.986 胃上部 88(59.5) 46(59.0) 胃中部 19(12.8) 11(14.1) 胃下部 37(25.0) 19(24.4) 弥漫型 4(2.7) 2(2.5) 肿瘤直径 0.502 ＜3 cm 25(16.9) 16(20.5) ≥3 cm 123(83.1) 62(79.5) 胃切除方式 0.890 近端胃切除 66(44.6) 35(44.9) 远端胃切除 36(24.3) 21(26.9) 全胃切除 46(31.1) 22(28.2) 手术路径 0.089 开放手术 81(54.7) 32(41.0) 腹腔镜手术 62(41.9) 40(51.3) 机器人手术 5(3.4) 6(7.7) T分期 0.066 T1 ~ T2 23(15.5) 20(25.6) T3 ~ T4 125(84.5) 58(74.4) N分期 0.855 N0 ~ N1 74(50.0) 38(48.7) N2 ~ N3 74(50.0) 40(51.3) M分期 - M0 148(100) 78(100) M1 0(0) 0(0) TNM分期 0.068 Ⅰ期 14(9.5) 16(20.5) Ⅱ期 44(29.7) 21(26.9) Ⅲ期 90(60.8) 41(52.6)
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表 3 胃恶性NEN患者生存情况的单因素及多因素Cox回归分析
Table 3. Univariate and multivariate Cox regression analysis of overall survival in patients with gastric malignant NEN
临床病理特征 单因素分析 多因素分析 HR 95% CI P值 HR 95% CI P值 年龄 0.020 0.003 ≥60岁 vs ＜60岁 1.607 1.079 ~ 2.393 1.945 1.249 ~ 3.030 性别 0.255 女性 vs 男性 0.727 0.420 ~ 1.258 病理分型 0.993 MANEC vs NEC 1.002 0.668 ~ 1.503 肿瘤位置 0.003 0.099 胃中部 vs 胃上部 0.939 0.518 ~ 1.703 0.836 1.221 0.658 ~ 2.263 0.527 胃下部 vs 胃上部 0.530 0.311 ~ 0.904 0.020 0.581 0.336 ~ 1.005 0.052 弥漫型 vs 胃上部 3.570 1.415 ~ 9.012 0.007 1.654 0.623 ~ 4.391 0.312 肿瘤直径 ＜0.001 0.042 ≥3 cm vs ＜3 cm 2.403 1.516 ~ 3.809 2.199 1.029 ~ 4.701 胃切除方式 0.009 0.194 远端胃切除 vs 近端胃切除 0.458 0.260 ~ 0.805 0.007 0.680 0.447 ~ 1.032 0.070 全胃切除 vs 近端胃切除 1.120 0.727 ~ 1.726 0.607 0.836 0.318 ~ 2.199 0.716 手术路径 0.080 腹腔镜手术 vs 开放手术 0.627 0.417 ~ 0.942 0.025 机器人手术 vs 开放手术 0.835 0.334 ~ 2.084 0.699 TNM 分期 ＜0.001 ＜0.001 Ⅱ期 vs Ⅰ期 2.106 0.785 ~ 5.648 0.139 1.669 0.596 ~ 4.670 0.329 Ⅲ期 vs Ⅰ期 7.610 3.064 ~ 18.900 ＜0.001 5.710 2.197 ~ 14.837 ＜0.001
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