胃肠胰神经内分泌肿瘤诊疗进展

神经内分泌肿瘤（neuroendocrine neoplasm,NEN）的发病率和患病率近年来迅速增长,其中以原发于胃肠道和胰腺的NEN最常见。2022年,美国国家综合癌症网络（National Comprehensive Cancer Network,NCCN）NEN指南及中国胃肠胰NEN专家共识进行了更新。本文主要参照比对2022年NCCN指南及2022版中国胃肠胰NEN专家共识对NEN的诊疗新进展进行评述。     

中药联合生长抑素类似物治疗晚期胃肠胰腺神经内分泌肿瘤的疗效分析

目的 探讨中药汤剂辨证施治联合生长抑素类似物（SSA）治疗晚期胃肠胰腺神经内分泌肿瘤（GEP NET）的疗效及安全性。方法 收集2011年9月至2015年8月于中日友好医院中西医结合肿瘤内科就诊的晚期GEP-NET患者39例,原发部位分别为胰腺19例、直肠8例、小肠8例、胃1例和原发灶不明的肝转移性神经内分泌肿瘤3例,均给予中药汤剂联合SSA治疗,具体治疗方案：注射用醋酸奥曲肽微球（善龙）20 mg,肌肉注射,3～4周1次或注射用醋酸兰瑞肽（索马杜林）40 mg,肌肉注射,10～14天1次;同时根据患者情况予中药辩证施治,每日1剂,早晚分服。每3个月采用RECIST 1.1标准评估疗效,采用NCI-CTC 3.0标准观察和判定不良反应。根据随访资料记录疾病进展时间（TTP）并动态监测血清嗜铬粒蛋白A（CgA）的变化。结果全组39例患者均可评价疗效,其中20例获疾病进展,19例获稳定,有效率为0,疾病控制率为48.7％,中位TTP为22.9个月。主要不良反应包括胆结石和1～2级腹泻。结论中药汤剂辨证施治联合SSA治疗可能延长晚期GEP-NET患者的TTP,不良反应轻,值得在临床上观察使用。     

血清SCML2在胃肠胰神经内分泌肿瘤中的表达及临床意义

目的探讨血清SCML2蛋白在胃肠胰神经内分泌肿瘤(GEP-NENs)中的表达及临床意义。方法收集南通大学附属医院2009年1月至2014年1月GEP-NENs组织和血清标本64例,另外收集同时期胃、肠、胰腺癌(均为腺癌)和胃肠息肉手术患者各30例组织和血清标本。采用TRFIA法检测血清SCML2水平,采用免疫组化法检测组织中SCML2蛋白表达。分析血清SCML2表达与GEP-NENs临床病理特征及预后的关系。结果GEP-NENs患者血清SCML2蛋白表达量[(62.50±34.0)ng/ml]明显高于腺癌患者[(24.89±15.32)ng/ml]、胃肠息肉患者[(21.83±16.49)ng/ml],差异具有统计学意义(P<0.05);且血清SCML2蛋白表达与病理类型、病理分级、浸润深度、TNM分期有关(P<0.05)。GEP-NENs患者血清SCML2水平与血清CgA水平(r=0.649,P<0.05)、组织SCML2蛋白表达(r=0.814,P<0.05)呈正相关。ROC曲线分析,血清SCML2诊断GEP-NENs的效能高于血清CgA[0.871(95%CI:0.812~0.930)vs.0.714(95%CI:0.624~0.804)]。GEP-NENs患者随访时间为2~125个月,中位生存时间(OS)为48.0个月(37.6~58.4个月),其中血清SCML2低表达患者中位OS为89.0个月(29.2~148.8个月),高于血清SCML2高表达患者中位OS为42.0个月(28.2~55.9个月),差异有统计学差异(χ^2=9.442,P=0.002)。结论血清SCML2在GEP-NENs患者中的表达量明显升高,与病理类型、病理分级、浸润深度、TNM分期、预后不良有关。     

中国胃肠胰神经内分泌肿瘤专家共识

1907年德国病理学家Obemdorfer首次提出了“类癌（carcinoid）”或“类癌瘤（carcinoidtumor）”这一术语,指的是一组发生于胃肠道和其他器官嗜银细胞的新生物,临床、组织化学和生化特征可因其发生部位不同而异。由于类癌是起源于神经内分泌细胞的肿瘤,能够合成、贮存和分泌生物活性胺、小分子多肽类或肽类激素,故又称为小分子多肽或肽类结构瘤（amineprecursoruptakeanddecarboxyla—tiontumor,APUDtumor,APUDOMA）。     

血清嗜铬粒蛋白A在神经内分泌肿瘤诊治中的应用

目的探讨血清嗜铬粒蛋白A(CgA)对神经内分泌肿瘤(NET)的诊断意义,及其对晚期NET患者的病情监测、疗效评估和判断预后的价值。方法采用免疫放射分析法(IRMA)检测125例NET患者血清CgA水平,并对其中45例患者进行定期随访。结果 NET带瘤患者组的血清CgA水平及阳性率明显高于健康对照组及非NET肿瘤组。血清CgA对胃NET的敏感性较好,小肠和胰腺NET敏感性中等,对直肠NET敏感性差。45例患者随访显示,肿瘤进展者血清CgA水平逐渐上升,治疗有效者血清CgA水平呈下降趋势,病情稳定者血清CgA水平无明显波动,术后无复发患者血清CgA水平均在正常范围。结论血清CgA对NET诊断的特异性高,敏感性因原发部位而异;血清CgA对晚期患者的病情监测、疗效评估及判断预后有临床意义。     

胃肠胰神经内分泌肿瘤患者预后的多因素分析

目的:分析胃肠胰神经内分泌肿瘤患者预后的危险因素,并探讨对应的干预对策,以期为临床提供借鉴。方法:回顾自2002年6月至2013年12月入院治疗的胃肠胰神经内分泌肿瘤患者的资料,对患者的一般情况如性别、年龄、肿瘤大小、肿瘤部位、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移、总生存期等数据进行分析,总结胃肠胰神经内分泌肿瘤患者预后的危险因素。结果:123患者平均发病年龄56.9岁,男性平均发病年龄59.5岁,女性平均发病年龄52岁。＜60岁患者68例,≥60岁55例,从发病到明确诊断时平均时间为9.8月,中位生存时间为46.1个月,1年生存率为69%,3年生存率为37.4%, 5年生存率为29.6%。通过单因素分析,年龄、肿瘤大小、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移与胃肠胰神经内分泌肿瘤患者预后显著相关,P＜0.05;性别、肿瘤部位与胃肠胰神经内分泌肿瘤患者预后无明显相关,P分别为0.784、0.988。通过多因素COX回归分析,年龄(HR=1.93,95%CI:1.06~3.50)及远处转移(HR=1.83,95%CI:1.24~2.72)为胃肠胰神经内分泌肿瘤患者预后的独立危险因素。结论:年龄、肿瘤大小、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移等是胃肠胰神经内分泌肿瘤患者生存预后的危险因素,年龄大、远处转移患者生存预后最差。     

胃肠胰高级别神经内分泌肿瘤病理诊断现状及研究进展

Abstract： Gastroenteropancreatic neuroendocrine neoplasm(GEP-NEN) are classified into low-grade and high-grade tumors according to the WHO classification criteria for digestive system tumors. The high-grade NEN include well differentiated neuroendocrine tumor G3 and poorly differentiated neuroendocrine cancer. The clinical pathological characteristics and treatment options of the two are significantly different, however, it is difficult in differential diagnosis pathologically. This paper summarizes the current pathological diagnostic criteria and research progress on immunohistochemical and molecular marker of these two types of tumors, to provide reference for the development of appropriate treatment plans.     

Akt/mTOR通路在胃肠胰神经内分泌肿瘤中的表达及其意义

目的探讨胃肠胰神经内分泌肿瘤中Akt/mTOR信号通路的作用及意义。方法选取60例胃肠胰神经内分泌肿瘤作为实验研究对象,同时纳入胃肠胰腺炎症患者30例作为对照组,ELISA法检测入组患者血液中Akt、mTOR水平,免疫组织化学法检测组织中Akt、mTOR的表达,分析AKt、mTOR表达水平与胃肠胰神经内分泌肿瘤临床病理特征的关系。结果实验组血清AKt、mTOR水平较对照组升高,差异有统计学意义(P<0.05);实验组瘤组织中AKt、mTOR阳性率均较瘤旁组织、对照组升高,差异有统计学意义(P<0.05);AKt、mTOR表达水平与胃肠胰神经内分泌肿瘤的分化程度、肿瘤大小、肿瘤数目、远处转移、患者生存时间有关(P<0.05)。结论在胃肠胰神经内分泌肿瘤患者的血清及组织中均存在AKt、mTOR的高度表达,表达水平与胃肠胰神经内分泌肿瘤的分化程度、肿瘤大小、肿瘤数目、远处转移、患者生存时间有关。     

胃肠胰神经内分泌肿瘤的免疫治疗研究进展

晚期胃肠胰神经内分泌肿瘤(Gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)的治疗药物有限,且疗效不佳。免疫治疗作为一种有前景的治疗方式,近年来在GEP-NENs中进行了初步应用探索。目前已有研究结果显示免疫检查点抑制剂在GEP-NENs中有良好的抗肿瘤活性和安全性。程序性死亡配体(PD-L1)在不同GEP-NENs的原发部位中表达有所差异,且与肿瘤分化程度呈负相关。PD-L1表达程度及免疫细胞浸润对GEP-NENs患者预后的影响仍有争议。能够预测免疫治疗获益的生物标志物尚未确定。本文就GEP-NENs的免疫治疗研究进展做一综述。     

胃肠胰-神经内分泌肿瘤的研究进展

胃肠胰-神经内分泌肿瘤(GEP-NENs)起源于胃肠胰的神经内分泌细胞系统,发病率低,临床表现多样,缺乏特异性.CgA、Syn是“通用”的肿瘤标记物,影像学检查是重要的定位诊断手段,但最终诊断依靠病理.按照“2013年国内共识”,将神经内分泌癌中肿瘤组织形态学分化良好,但Ki-67指数达到G3级(＞20％,＜60％),命名为“高增殖活性NET”.GEP-NENs的治疗需要以患者的基础健康状况、临床症状和肿瘤分期、分级等信息为根据,以循证医学为基础,应用多学科及多种手段,成立GEP-NENs的多学科专家团队,对患者进行个体化、多学科综合治疗.使患者达到控制功能性神经内分泌肿瘤激素过量分泌导致的相关症状或者综合征,并且控制肿瘤生长.生物治疗和分子靶向治疗在晚期GEP-NENs治疗中显示了较好的前景.     

mTORC1相关蛋白在胃肠胰神经内分泌肿瘤中的表达及其与预后的相关性

目的 探讨mTORC1相关蛋白在胃肠胰神经内分泌肿瘤中的表达与预后之间的相关性.方法 纳入75例胃肠胰神经内分泌肿瘤的患者,采用免疫组织化学方法检测mTORC1相关蛋白的表达水平,通过病理学分级、临床分期分析mTORC1相关蛋白在不同分层患者中的表达情况,采用Cox回归分析及log-rank检验分析预后与mTORC1相关蛋白表达的相关性.结果 mTOR1相关蛋白在胃肠胰神经内分泌肿瘤中阴性表达率远高于阳性率;病理学分级恶性程度高的标本mTOR1、Bcl-2、TSC2、PS6、SSR2、β-catenin的阴性率高,临床分期进展程度高的标本中,mTOR1、Bcl-2、TSC2、PS6、SSR2、β-catenin的阴性率高.Cox回归分析及log-rank检验分析mTORC1相关蛋白表达阴性是预后不良的独立影响因素.结论 mTORC1相关蛋白在胃肠胰神经内分泌肿瘤中的低表达与病理学分级、临床分期差、预后不良具有一定的相关性.     

Survival and Incidence Patterns of Pancreatic Neuroendocrine Tumors Over the Last 2 Decades: A SEER Database Analysis

BackgroundPancreatic neuroendocrine tumors (pNETs) are rare cancers with outcomes determined by multiple factors including grade, stage, and clinical presentation. In this study, we aimed to determine the prognosis of patients with pNETs using a large population-based database.Materials and MethodsIn this population-based study, we identified patients with pNETs from the SEER 18 registry (2000-2016) using a combination of ICD-O-3 and histology codes. We calculated age-adjusted incidence rates using SEER*Stat 8.3.5. In addition, we analyzed overall survival (OS) using the Kaplan-Meier method, and investigated prognostic factors using a multivariable Cox proportional hazards model.ResultsA total of 8944 pNETs patients were identified. Annual incidence rates increased from 0.27 to 1.00 per 100 000. This was largely explained by an increase in number of patients diagnosed with localized disease in more recent years (2012-2016). Median OS was 68 months (95% CI [64, 73]) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for patients diagnosed between 2009 and 2016 (median OS 85 months) compared with those diagnosed between 2000 and 2008 (median OS 46 months) (HR 0.66; 95% CI [0.62, 0.70]). This improvement in OS was consistent across all stages.Conclusions and RelevanceThis study shows a steady increase pNETs incidence with notable stage migration to earlier stages in recent years. This increase in incidence is accompanied by a significant improvement in survival across different disease stages.     

Serum chromogranin A is a useful marker for Japanese patients with pancreatic neuroendocrine tumors

Although chromogranin A (CGA) is a useful marker for pancreatic neuroendocrine tumors (pNET) in the West, its usefulness in Japanese populations is unclear. To assess this, we evaluated the serum CGA levels in 189 patients with various pancreatic diseases, including proven pNET (n = 69), pancreatic cancer (PC) (n = 50), chronic pancreatitis (CP) (n = 50) and autoimmune pancreatitis (AIP) (n = 20), and 112 normal controls (controls) using an ELISA kit. The mean CGA level of patients with pNET was significantly higher than any of the other groups (407.8 ± 984.6 ng/mL [pNET] vs 91.8 ± 101.8 ng/mL [PC], 93.6 ± 57.5 ng/mL [CP], 69.9 ± 52.4 ng/mL [AIP] and 62.5 ± 48.3 ng/mL [controls]). Limiting the analysis to patients not using proton pump inhibitors (PPI), the CGA level of patients with PC or CP was not significantly different compared with the controls. Discriminant analysis revealed that the best cut‐off value of CGA to distinguish patients with pNET from the controls was 78.7 ng/mL, with a sensitivity and specificity of 53.6% and 78.6%, respectively. In patients with pNET, significant factors associating with elevated CGA levels were tumor classification, tumor size, and the presence of liver metastases in univariate analysis as well as PPI use and the presence of liver metastases in multivariate analysis. We show that CGA is a useful marker for diagnosing pNET in Japanese populations and for distinguishing patients with pNET from patients with other pancreatic diseases. The increased use of CGA in Japan will likely be a helpful tool in managing these patients, as found in the West.     

胃神经内分泌肿瘤的临床病理组织学特点及预后分析

目的 分析胃神经内分泌肿瘤患者的病理组织学特点,为临床上其诊治提供参考.方法 对经胃镜取病理组织学检查或术后行病理检查确诊为胃神经内分泌肿瘤的136例患者的临床资料进行回顾性分析.结果 胃神经内分泌肿瘤的临床表现以上腹部不适或疼痛为多(66.9％),肿瘤均为单发性,其部位分布为:贲门部48例、胃体部47例、胃窦部21例、胃底8例、胃角部12例.肿瘤大体形态有溃疡型118例、息肉型18例.胃神经内分泌瘤17例,其中G1级9例,G2级8例;胃神经内分泌癌119例,全部为G3级.随访患者l、3、5年生存率分别为84.8％、50.2％、40.8％.结论 胃神经内分泌肿瘤患者的预后与肿瘤病理类型、有无淋巴结或远处转移密切相关.     

胃肠胰腺神经内分泌肿瘤中血管表皮生长因子的表达与淋巴结转移的关系及意义

目的通过检测胃肠胰腺神经内分泌肿瘤中血管表皮生长因子(VEGF)、淋巴管密度(LVD)水平的变化,分析其与淋巴结转移的关系。方法选取胃肠胰神经内分泌肿瘤(GEP-NEN)患者,采用免疫组织化学法检测组织中VEGF、LVD的表达,分析其与淋巴结转移的关系。结果淋巴结转移组VEGF阳性率为55.26%(21/38),淋巴结未转移组VEGF阳性率为13.64%(3/22),差异有统计学意义(P<0.05)。淋巴结转移组的LVD均值达(0.83±0.14),较淋巴结未转移组患者明显升高(P<0.05);VEGF阳性表达的患者,其LVD较VEGF阴性表达者升高(P<0.05);VEGF与LVD呈正相关(P<0.05)。结论出现淋巴结转移的胃肠胰腺神经内分泌肿瘤患者,其VEGF表达阳性率升高,LVD值明显升高,VEGF的表达与LVD呈正相关。     

Neuroendocrine Pancreatic Tumors Clinical Findings in a prospective study of 84 patients

Endocrine pancreatic tumors are slowly growing neuroendocrine neoplasms with a malignant potential which may cause symptoms such as hypoglycemia, multiple ulcers, diarrhea, flush, hyperglycemia and skin rash. A prospective study was performed on 84 patients with endocrine pancreatic tumors. In 59 patients (70%) the tumors were malignant. Of the 84 patients, 23 had insulinomas, 25 gastrinomas, 20 nonfunctioning tumors, 14 the WDHA syndrome, I somatostatinoma and 1 glucagonoma. The median age at diagnosis was 53 years and the median delay from first symptom to diagnosis was 2 years. The most common site of the pancreatic primary tumor was the tail (41 %), and metastases were most frequently located in the liver (60%) and lymph nodes (44%). Plasma chromogranin A + B was elevated in 94%, serum pancreatic polypeptide (PP) in 74%, plasma neurotensin in 67% and serum gastrin in 62%. Serum HCG-aL and -bT subunits were elevated in 41 and 30% respectively, all except 3 having a verified malignant tumor. The median survival from first symptom and diagnosis was 14.2 and 8.7 years respectively. Patients with MEN-1 had a significantly better survival from diagnosis than sporadic cases (median 15.1 versus 5.8 years). Patients who received interferon after failing chemotherapy had a significantly better survival than those given chemotherapy alone (5-year survival 65 and 50% respectively).