修回日期: 2016-02-04
接受日期: 2016-02-18
在线出版日期: 2016-06-18
神经内分泌肿瘤(neuroendocrine neoplasm, NEN)是一组起源于肽能神经元和神经内分泌细胞、生物学行为呈多样性表现的少见异质性肿瘤. 近年来, NEN的发病率呈上升趋势, 其主要来源于胰腺和胃肠道. 嗜铬粒素A(chromogranin A, CgA)已作为NEN重要的肿瘤标志物. CgA的组织病理学阳性结果以及胃泌素、胰岛素原、血管活性肠肽(vasoactive intestinal peptide, VIP)、胰高糖素等特异性激素检测可作为NEN的病理和定性诊断依据. 此外, 计算机断层扫描(computed tomography, CT)、正电子发射计算机断层扫描(positron emission tomography/computed tomography, PET/CT)、磁共振成像(magnetic resonance imaging, MRI)、超声(ultrasound, US)、超声内镜(endoscopic ultrasound, EUS)、生长抑素受体闪烁成像(somatostatin receptor scintigraphy, SRS)等技术也用于NEN的定位诊断. 外科手术仍是NEN的首选治疗. 本文结合2010年第4版《世界卫生组织(WHO)消化系统肿瘤分类》对NEN的命名、分类和分级修订标准以及2013年中国临床肿瘤学会(Chinese Society of Clinical Oncology, CSCO)对胃肠胰NEN(gastroenteropancreatic neuroendocrine neoplasm, GEP-NEN)的诊治共识意见, 对近年来消化系统NEN的诊断和治疗进展, 包括原发性食管NEN、胃NEN、十二指肠NEN、小肠NEN、阑尾NEN、结肠NEN、直肠NEN、肝脏NEN、胆囊NEN、肝外胆管NEN、胰腺NEN进行了详尽阐述.
核心提示: 神经内分泌肿瘤(neuroendocrine neoplasm, NEN)是起源于弥散性神经内分泌细胞的一组少见异质性肿瘤, 本文结合2010年世界卫生组织关于NEN新的分类标准以及2013年中国临床肿瘤学会对胃肠胰NEN的诊治共识, 重点阐述了原发于胃肠道、胰腺、肝脏、胆囊以及肝外胆管NEN的诊断和治疗现状.
引文著录: 黄颖秋. 消化系统神经内分泌肿瘤的诊断和治疗现状. 世界华人消化杂志 2016; 24(17): 2625-2636
Revised: February 4, 2016
Accepted: February 18, 2016
Published online: June 18, 2016
Neuroendocrine neoplasms (NENs) are a group of heterogeneous, biologically diverse, rare malignancies originated from the peptidergic neurons and neuroendocrine cells. In recent years, the incidence of NENs has been increasing gradually. They typically arise in the pancreas and gastrointestinal tract. Chromogranin A (CgA) has long been used as an important broad-spectrum marker for the identification of NENs. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, vasoactive intestinal peptide (VIP) and glucagon. In addition, radiological modalities including computed tomography (CT), positron emission tomography and computed tomography (PET/CT), magnetic resonance imaging (MRI), ultrasound (US), endoscopic ultrasound (EUS), and somatostatin receptor scintigraphy (SRS) can help establish a diagnosis. Surgery is still one of the cornerstones in the management of NENs. This article reviews the current progress in the diagnosis and therapy of NENs of the digestive system, including the pathological features and clinical diagnostic modalities for primary esophageal, gastric, duodenal, small intestinal, appendiceal, colonic, rectal, hepatic, gallbladder, extrahepatic bile duct, and pancreatic NENs, according to a revised system of classification, nomenclature and grading of NENs proposed by the fourth edition of "World Health Organization (WHO) classification of tumours of the digestive system" in 2010, and consensus of diagnosis and treatment of gastroenteropancreatic NENs (GEP-NENs) proposed by the Chinese Society of Clinical Oncology (CSCO) in 2013.
- Citation: Huang YQ. Current progress in diagnosis and therapy of neuroendocrine neoplasms of the digestive system. Shijie Huaren Xiaohua Zazhi 2016; 24(17): 2625-2636
- URL: https://www.wjgnet.com/1009-3079/full/v24/i17/2625.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i17.2625
神经内分泌肿瘤(neuroendocrine neoplasm, NEN)起源于弥散性神经内分泌系统(diffuse neuroendocrine system, DNS)具有胺前体摄取和脱羧基功能(amine precursor uptake and decarboxylation, APUD)的神经内分泌细胞, 即APUD细胞, 是一组异质性显著的肿瘤, 具有从缓慢生长、惰性、低度恶性、显著恶性、高侵袭性和转移性的一系列生物学行为[1,2]. 部分NEN具有家族遗传性倾向, 诸如多发性内分泌瘤1型(multiple endocrine neoplasia type 1, MEN-1)、MEN-2、家族性副神经节瘤(paraganglioma, PGL)综合征、希佩尔-林道综合征(von Hippel-Lindau syndrome)、Carney-Stratakis综合征等, 他们可能与基因突变有关[3]. 根据有无临床症状及激素分泌水平, NEN又被分为功能性和无功能性两大类[1]. NEN以往相对少见, 过去15年间, NEN的年发病率从2.48/100000上升至5.86/100000, 呈逐年增加趋势, 这可能与诊断技术进步, 确诊率增加有关[4]. NEN可发生于人体多个器官和组织, 包括胃肠道、胰腺、肝脏、胆囊、胆管、支气管、肺、甲状腺、甲状旁腺、肾上腺髓质、副神经节以及其他部位的神经内分泌细胞, 其中胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasm, GEP-NEN)最为常见, 约占所有NEN的55%-70%[2,5]. 肝脏为GEP-NEN最常见的转移部位, 应根据原发灶部位、分期和分级标准采取相应的治疗方式或联合治疗手段. 本文结合2010年第4版世界卫生组织(World Health Organization, WHO)消化系统神经内分泌肿瘤命名和分类方法[6]以及2013年中国临床肿瘤学会(Chinese Society of Clinical Oncology, CSCO)的GEP-NEN专家诊治共识[7], 就近年来消化系统NEN的诊断和治疗现状概述如下.
2010年第4版《WHO消化系统肿瘤分类》[6]采用"neuroendocrine neoplasm, NEN"泛指所有源自神经内分泌细胞的肿瘤, 中文译名为"神经内分泌肿瘤". 根据其分化程度不同, 将高分化NEN命名为"neuroendocrine tumor, NET", 中文译名为"神经内分泌瘤", 将低分化NEN命名为"neuroendocrine carcinoma, NEC", 中文译名为"神经内分泌癌".
2010年第4版《WHO消化系统肿瘤分类》[6]采纳了欧洲神经内分泌肿瘤学会(European Neuroendocrine Tumor Society, ENETS)的补充分类方法, 将病理分级和临床分期分开, 而特殊部位神经内分泌肿瘤有其不同的分期系统(表1). 胃肠胰神经内分泌肿瘤按组织学和肿瘤细胞的增殖活性分级, 采用核分裂象和/或Ki-67指数两项指标(表2).
| 项目 | 种类 |
| NET | NET 1级(NET G1) |
| NET 2级(NET G2) | |
| NEC | NEC 3级(NEC G3) |
| 小细胞NEC(small cell NEC) | |
| 大细胞NEC(large cell NEC) | |
| 混合性腺神经内分泌癌(mixed adenoneuroendocrine carcinoma, MANEC) | |
| 部位特异性和功能性NET | EC细胞, 分泌5-羟色胺NET(EC cells, 5-HT-secreting NET) |
| 分泌胃泌素NET(gastrin-secreting NET) | |
| 节细胞副神经节瘤(ganglion cell paraganglionma) | |
| L细胞, 分泌高血糖素样肽和PP/PYY NET(L cell, secreting glucagon-like peptide and PP/PYY NET) | |
| 分泌生长抑素NET(somatostatin-secreting NET) | |
| 杯状细胞类癌(goblet-cell carcinoid) | |
| 小管状类癌(tubular carcinoid) | |
| 胃泌素瘤(gastrinoma) | |
| 高血糖素瘤(glucagonoma) | |
| 胰岛素瘤(insulinoma) | |
| 生长抑素瘤(somatostatinoma) | |
| 血管活性肠肽瘤(vasoactive intestinal peptide tumor, VIPoma) |
2013年, CSCO结合WHO 2010年版消化系统肿瘤病理分类、ENETS共识、北美神经内分泌肿瘤学会(North American Neuroendocrine Tumor Society, NANETS)共识、美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN)指南以及中国版胃肠胰神经内分泌肿瘤病理学诊断共识, 出台了中国GEP-NEN诊治共识[7]. 本共识中的NEN是指所有高、中、低分化的神经内分泌瘤; NET(neuroendocrine tumor)是指高、中分化的神经内分泌瘤; NEC(neuroendocrine carcinoma)是指低分化的神经内分泌癌. 本共识将GEP-NEN分为胰腺神经内分泌肿瘤(pancreatic neuroendocrine neoplasm, P-NEN)和胃肠道神经内分泌肿瘤(gastrointestinal neuroendocrine neoplasm, GI-NEN)两大部分[7].
多数GEP-NEN分泌突触素(synaptophysin, Syn)、嗜铬粒素A(chromogranin A, CgA)、神经元特异性烯醇化酶(neuron specific enolase, NSE)等神经内分泌标志物, Syn、CgA、NSE的联合血清学检测及免疫组织化学分析常作为NEN的必检项目, 而Ki-67指数的免疫组织化学染色则是NEN不可或缺的诊断步骤[8]. 其中, CgA是目前公认最有价值的GEP-NEN通用肿瘤标志物, 血浆CgA诊断GEP-NEN的敏感性在51.2%-53.6%之间[9,10], 特异性在78.6%-87.5%之间[9,10]. 此外, CgA还可用于GEP-NEN的疗效监测及预后评估[9,11]. 血浆CgA联合胰多肽(pancreatic polypeptide, PP)检测可以使P-NEN诊断的敏感性从74%提高至90%[7]. 然而, 最近Modlin等[12]研究发现, 采用一种基于血液的新型多基因转录组分析对GEP-NEN诊断的敏感性及特异性均显著优于血浆CgA检测(分别P<0.0001). 对于功能性P-NEN, 血清相关特异性激素, 如胃泌素、血管活性肠肽、胰高糖素、生长抑素、胰多肽等可作为相应P-NEN的特异性肿瘤标志物[13]. GI-NEN通常不被分成功能性及非功能性NEN, 但部分GI-NEN可分泌胃泌素及5-羟色胺, 可以有卓-艾氏综合征(Zollinger-Ellison syndrome)及类癌综合征的临床表现, 对此类患者应进行相应的激素检测[7].
消化系统NEN的定位诊断有赖于内镜及影像学检查, 包括内镜、超声内镜(endoscopic ultrasound, EUS)、超声内镜引导下细针穿刺吸取术(endoscopic ultrasonography guided fine needle aspiration, EUS-FNA)、超声(ultrasound, US)、腹腔镜超声(laparoscopic ultrasound, LUS)、术中超声(intraoperative ultrasonography, IOUS)、数字减影血管造影(digital subtraction angiography, DSA)、钙剂动脉激发试验(arterial calcium stimulation with hepatic venous sampling, ASVS)、计算机断层扫描(computed tomography, CT)、磁共振成像(magnetic resonance imaging, MRI)、正电子发射计算机断层扫描(positron emission tomography/computed tomography, PET/CT)、生长抑素受体闪烁成像(somatostatin receptor scintigraphy, SRS)等[13-15]. 微泡造影剂的应用, 使US对NEN肝转移的敏感性从68%提升至99%[14]. CT对于原发性NEN的敏感性为73%[14]. MRI、CT、SRS对于NEN肝转移的敏感性分别为95.2%、78.5%、49.3%[14]. 18F-FDG PET/CT对于高级别NEN更具诊断价值[14]. 将常规铟111(111InDT-PA-Octreotide)标记的奥曲肽受体闪烁成像(omatostatin receptor scintigraphy, SRS)与单光子发射计算机断层扫描(single photon emission computed tomography, SPECT/CT)融合可显著提高NEN的确诊率[14]. 最新的SRS模式采用正电子发射体68Ga标记各种生长抑素类似物, 包括68Ga-DOTATOC、68Ga-DOTANOC、68Ga-DOTATATE, 这些68Ga-PET/CT对NEN的敏感性和特异性更高, 有助于发现较为隐匿的病灶[14]. 最近, Pfeifer等[16]在一项前瞻性研究中发现, 64Cu-DOTATATE PET/CT对NEN的敏感性和准确率均为97%, 而传统的111InDT-PA-Octreotide SPECT/CT则分别为87%和88%, 因此, 64Cu-DOTATATE有望成为新一代的PET/CT示踪剂[16]. EUS及EUS-FNA对P-NEN均有确切的诊断价值[17,18]. Krishna等[18]研究显示, EUS-FNA对P-NEN的敏感性、特异性、准确性分别为98.9%、100.0%、99.9%. 近年来, 随着影像技术的不断进步, 越来越多的无功能NEN得以早期发现, 治愈率及生存期均显著提高.
食管神经内分泌肿瘤(esophageal neuroendocrine neoplasm, E-NEN)主要包括典型类癌(typical carcinoid, TC)[19]、非典型类癌(atypical carcinoid, AC)[20]、小细胞神经内分泌癌(small cell neuroendocrine carcinoma, SCNEC)[21,22]、大细胞神经内分泌癌(large cell neuroendocrine carcinoma, LCNEC)[23]等. Yagi等[19]报道1例罕见的食管TC病例, 内镜示食管黏膜下肿瘤, 直径约3 mm, 表面光泽红润, 无溃疡或糜烂, 放大窄带成像内镜(magnifying endoscopy with narrow-band imaging, ME-NBI)示黏膜下微血管呈网状结构, EUS示固有肌层内低回声肿瘤, CT未见肿瘤以及其他器官转移征象, 采用内镜黏膜下剥离术(endoscopic submucosal dissection, ESD)切除肿瘤, 放大内镜显示, 切除瘤体网状血管丰富, 免疫病理学示食管TC(NET, 1级), 无淋巴、血管浸润. Shah等[20]报道1例罕见的食管中段AC病例, 临床特征为进行性吞咽障碍、体质量减轻, 无类癌综合征表现, CT扫描示食管中段侧壁软组织密度肿物致管腔狭窄, 行食管内翻拔脱术(transhiatal esophagectomy)治疗, 组织病理学显示, 瘤细胞呈多形性, 排列成富含血管基质的巢状和梁状, 核分裂象数5-6/10 HPF, 病理诊断为食管AC(NET, 2级). 食管SCNEC十分罕见, 约占全部胃肠道NEN的0.04%-4.60%及食管癌的1.0%-2.8%[21], 发生转移者预后不佳[22]. Nayal等[22]研究发现, SCNEC的常见症状为吞咽困难和体质量减轻, 形态学示小细胞癌特征, 免疫组织化学染色示NEN标志物阳性, 多数患者发生远隔器官转移, 肝脏为最常见部位, 化疗和放疗为主要措施. 最近, Kuriry等[23]报道1例罕见的食管LCNEC病例, 主要症状为吞咽困难和体质量减轻, 胃镜距门齿23-27 cm处食管见一约4 cm溃疡性肿物, EUS示黏膜下层低回声团, 无淋巴结及血管浸润, CT扫描示食管下段3.2 cm×2.0 cm异常密度肿块, PET/CT显示食管高代谢肿瘤病灶, 左颈部淋巴结、骶骨中部及右髋骨转移, 组织病理学示大细胞癌特征, 瘤细胞呈大多边形, 不规则梁状排列, 免疫组织化学染色示Syn、CgA阳性, Ki-67指数75%, 病理诊断为食管LCNEC(NEC, 3级).
胃神经内分泌肿瘤(gastric neuroendocrine neoplasm, G-NEN)是一组具有不同临床病理特征和生物学行为的异质性肿瘤[24]. G-NEN的主要临床表现为胃息肉、胃溃疡, 也可表现为萎缩性胃炎或卓-艾氏综合征[7]. G-NEN的内镜检出率近年来逐渐增加, 其发生率约占所有胃息肉的0.6%-2.0%, 占全部NEN的6%[25]. 根据血浆胃泌素水平及胃pH值, G-NEN主要被分为3种类型, 1型、2型与高胃泌素血症有关, 3型与胃泌素无关[25]. 1型约占70%-80%, 常伴发慢性萎缩性胃炎、恶性贫血, 肿瘤多发, 瘤体<1 cm, 转移率<5%, Ki-67指数≤2, 核分裂象数<2, 血管受侵罕见, 血浆胃泌素显著升高, 胃pH显著升高, 血浆CgA升高, 预后佳[25]. 2型约占5%-10%, 常伴发MEN-1和卓-艾氏综合征, 肿瘤多发, 瘤体<1 cm, 转移率<10%, Ki-67指数≤2, 核分裂象数<2, 血管受侵<10%, 血浆胃泌素显著升高, 胃pH显著下降, 血浆CgA升高, 预后良[25]. 3型<20%, 肿瘤孤立, 瘤体2-5 cm, 转移率>50%, Ki-67指数>2%, 核分裂象数>2, 血管受侵>50%, 血浆胃泌素正常, 胃pH正常, 血浆CgA正常, 预后差[25]. 此外, G-NEN还有低分化胃神经内分泌癌[24]、混合性腺神经内分泌癌(mixed adenoneuroendocrine carcinoma, MANEC)[24]、恶性胃饥饿素瘤(malignant gastric ghrelinoma)[26]、胃神经内分泌癌/鳞状上皮癌碰撞癌[27]、胃神经内分泌癌/腺癌碰撞癌[28]、胃大细胞神经内分泌癌/腺癌碰撞癌[29]等罕见类型. G-NEN组织学形态呈显著多样性, 其组织学分类可能并无直接临床意义[30]. 1型、2型局部缓慢生长的小病灶(<15-20 mm, Ki-67<2%)通常采用内镜监测[31], 2型伴有潜在胃泌素瘤者应手术切除以减轻高胃泌素血症, 特异性胃泌素受体拮抗剂YF476或胃泌素抗体也用于1型和2型的治疗[31], 3型或肿瘤浸润并发转移者应行手术切除, 并联合生长抑素类似物[31]、细胞毒类抗肿瘤药物[31]、肽受体放射性核素治疗(peptide receptor radionuclide therapy, PRRT)[31,32]. 总之, 内镜监测、内镜切除、生长抑素类似物治疗是1型G-NEN(0-2A期)患者的有效选择[33], 内镜切除不仅安全有效, 且复发率较低[34], 对于3型G-NEN无淋巴结浸润, 直径<2 cm的黏膜下肿物, 内镜切除可作为初始治疗[35].
十二指肠神经内分泌肿瘤(duodenal neuroendocrine neoplasm, D-NEN)的年发病率已从1983年的0.27/100000上升至2010年的1.1/100000(P<0.001), 术前诊断十分困难, 难与其他十二指肠肿瘤区别, 确诊有赖于组织病理学检查[36]. D-NEN包括十二指肠类癌瘤(duodenal carcinoid tumors, DCT)[37,38]、十二指肠神经内分泌癌(duodenal neuroendocrine carcinoma, D-NEC)[39-41]、十二指肠副神经节瘤(duodenal gangliocytic paraganglioma, DGP)[42]、分泌生长抑素的十二指肠内分泌肿瘤(somatostatin immunoreactive duodenal neuroendocrine neoplasm, dSOMs)[43]、分泌胃泌素的十二指肠内分泌肿瘤[44]、壶腹部类癌瘤(ampullary carcinoid tumors, ACT)[45]、壶腹部神经内分泌癌(ampullary neuroendocrine carcinoma, ANEC)[45]、壶腹混合性腺神经内分泌癌(ampullary mixed adenoneuroendocrine carcinoma, AMANEC)[46]等类型. 对于直径<20 mm无转移的黏膜下D-NEN, 可行内镜下黏膜切除术(endoscopic mucosal resection, EMR)治疗[47], 而对直径≤10 mm的D-NEN, 可采用套扎器法内镜下黏膜切除术(endoscopic submucosal resection with a ligation device, ESMRL)治疗[48]. 动脉期或静脉期的DCT病灶均可强化, 若增强CT扫描未见十二指肠原发病灶, 临近淋巴结的增强扫描有助于提供DCT的线索[38], 对于直径≤10 mm的表浅DCT, 可在EUS引导下行内镜下尼龙绳结扎法治疗[49], 而对于生长缓慢, 无血管浸润, 直径<10 mm的黏膜下DCT可采用EMR或ESD治疗, 其5年生存率可达98.9%-100.0%[37]. 低分化D-NEC恶性度高, 常发生肺转移, 少数以肝脏多发转移及骨转移为首发症状[39], 对于发生远隔器官转移的D-NEC患者, 氨柔比星可作为补救性化疗的有效选择[40]. 手术仍是治疗D-NEC的首选方法, 也是唯一可治愈的治疗方式, 行胰十二指肠切除术的D-NEC患者均长期存活,而姑息性治疗者均已死亡[41]. DGP罕见, 最常发生于十二指肠降段, 其典型组织学特征由3种细胞构成: 上皮样神经内分泌细胞、梭形的许旺细胞、神经节细胞, 多数DGP为良性, 可行ESD局灶切除, 少数发生淋巴结和肝脏转移者, 应行化疗[42]. dSOMs罕见, 多数无生长抑素瘤综合征, 预后与肿瘤分级、浸润程度、Ki-67>5%相关[43]. ACT相对罕见, 瘤体较小, 淋巴结转移率为28.5%, 5年和10年生存率分别为82%、71%[45]. 高级别ANEC罕见, 瘤体较大, 淋巴结转移率为62%, 5年生存率为15.7%[45]. 小细胞、大细胞ANEC十分罕见, 分别占57例高分化ANEC中的9例和6例[45]. AMANEC非常罕见, 其形态学呈腺癌和神经内分泌癌表型[46]. 14例AMANEC中, 腺癌类型依次为肠型腺癌(6/14)、杯状细胞型类癌(3/14)、印戒细胞癌(2/14)、胰胆管型腺癌(2/14)、胰腺腺泡细胞癌(1/14)[46], 肠型、杯状细胞型AMANEC无远隔转移及死亡, 而印戒细胞型、胰胆管型、胰腺腺泡型AMANEC的远隔转移率及病死率均为80%[46]. 总之, 壶腹部NEN的生存率低于十二指肠NEN, 但对于局部切除的NEN, 二者的生存率相似[50].
小肠神经内分泌肿瘤(small intestine neuroendocrine neoplasm, SI-NEN)的发病率近几十年来显著增加[51,52], 每年的新发病率为0.86/100000[52]. SI-NEN可能有遗传或家族性特征[53], 常发生淋巴结或远隔器官转移[51], 进展期不可切除的肿瘤生存期很短[52]. 绝大多数的SI-NEN为低级别肿瘤(Ki-67<2%), 88.1%的患者有淋巴结转移, 57.1%有肝转移, 2.4%有腹膜转移, 1.2 %有骨转移[51]. SI-NEN最易出现类癌综合征的症状[7]. 研究[52]显示, 血液Ñ环肿瘤细胞(circulating tumor cells)和肿瘤源性RNA(tumor-derived RNA)有望成为SI-NEN新的标志物. Salaria等[54]发现, 95%的回肠NEN患者CD24(干细胞标志物)表达阳性, 而十二指肠NEN、胰腺NEN的CD24表达仅为15%和5%(分别P<0.01), 此外, 回肠NEN的转移灶也呈CD24阳性表达, 提示CD24表达对回肠NEN可能有诊断和治疗价值[54]. 尽管US、CT、胶囊内镜等检查有助于发现SI-NEN病灶, 但术前的影像诊断率仅为70%, 细致的术中探查优于任何影像检查技术[51]. SI-NEN对细胞毒化疗药物耐药[52], 多种治疗模式联合应用有助于延长生存期[51]. 家族性SI-NEN通常无症状, 可通过积极筛查确诊, 早期发现可增加手术切除机会, 改变其自然史, 甚至可以治愈[53]. TNM分期和分级有助于SI-NEN的预后评估, 空回肠NEN在瘤体很小时即发生淋巴结、腹腔及肝脏的多发转移, 生存期约为2年[55]. 术前的肠系膜淋巴结转移分级可能有助于SI-NEN的标准化规范手术治疗[56]. Ⅱ期临床试验证实了长效生长抑素类似物兰瑞肽(lanreotide)对进展期SI-NEN的抗肿瘤活性, 哺乳动物雷帕霉素靶标(mammalian target of rapamycin, mTOR)抑制剂依维莫司(everolimus, RAD001)是治疗SI-NEN的另一种选择, 但RAD001的确切疗效仍在验证中[52]. 全基因组外显子测序发现了在SI-NEN发生表观遗传学改变的一系列重要驱动基因, 如SRC、SMAD基因、极光激酶、表皮生长因子受体、热休克蛋白90、血小板衍生生长因子受体、RACα丝氨酸/苏氨酸蛋白激酶(AKT1或AKT2)相互排斥放大以及其他mTOR/PI3K/Akt信号基因, 从药物研发的角度选择影响上述基因的突变, 有望为SI-NEN提供新的靶向基因治疗[52]. 通过小部分基因插入或删除可致8%的SI-NEN患者CDKN1B基因失活, 提示细胞周期抑制剂可作为SI-NEN新的候选药物[52]. 此外, Sabet等[57]研究显示, 177Lu标记的生长抑素类似物肽受体放射性核素(PRRT)治疗对进展期SI-NEN耐受性良好, 且效果显著.
阑尾神经内分泌肿瘤(appendiceal neuroendocrine neoplasm, A-NEN)的术前诊断仍面临挑战, 除非患者有典型的类癌综合征表现或肿瘤转移征象[58]. 大多数病例是在术后对阑尾切除标本的组织病理学检查时被偶然发现, 因此对阑尾切除标本的常规精确检查至关重要[58]. A-NEN的年发病率约为0.15/100000, 约占阑尾切除病例的(3-5)/1000, 5年生存率依次为局限性病变者95%-100%, 局部病变者85%-100%, 远隔器官转移者约25%[59]. CgA可作为替代指标, 但尚未确定其对A-NEN有特定的诊断和随访价值[59]. 单独行腹部CT或MRI检查有助于排除淋巴结或远隔转移, 对直径>2 cm伴阑尾系膜深部或血管浸润的肿瘤, 腹部CT、MRI、SRS与SPECT/CT联合或生长抑素受体PET/CT与三相增强CT联合可能有助于确定或排除潜在的远隔浸润病灶[59]. 对于边缘清晰直径≤1 cm伴浆膜或阑尾系膜浸润3 mm的A-NEN, 阑尾切除术后一般无再发风险[59]. 对于直径<1 cm且边界清晰的原发性肿瘤, 单独的阑尾切除术已足够, 而对于更大的肿瘤建议行右半结肠切除术治疗[58]. 但Nussbaum等[60]对916例A-NEN研究发现, 对于直径1-2 cm的肿瘤, 正规的右半结肠切除术即便对高级别的肿瘤似乎也并未改善生存期, 提示单独的阑尾切除术可用于全部<2 cm的肿瘤. 此外, 生长抑素类似物是目前唯一证实对A-NEN有效的药物[7].
结肠神经内分泌肿瘤(colon neuroendocrine neoplasm, C-NEN)发病率非常低, 约占全部消化道NEN的4%-8%[61]. C-NEN的临床表现多无特异性, 其原发灶的症状与结肠癌类似[7]. Shafqat等[62]对1367例C-NEN(小细胞型和非小细胞型)研究发现, 全部C-NEN的5年生存率为16.3%, 而Ⅰ期、Ⅱ期、Ⅲ期、Ⅳ期C-NEN则分别为57.4%、56.4%、26.3%、3.0%, 小细胞型C-NEN的生存率低于非小细胞型(10% vs 19%). 高级别C-NEN(低分化NEN)罕见, 发病率不足结肠恶性肿瘤的1%, 预后很差[63]. Smith等[63]研究显示, 高级别C-NEN的平均生存期为13.2 mo, 67%发生转移, 转移和非转移性病例的3年总生存期(overall survival, OS)分别为5%和18%, 对化疗应答是转移性病例与生存期相关的唯一因素, 而非转移性病例与生存期相关的唯一因素是肿瘤中的腺癌成分, 肿瘤切除与转移和非转移性病例的生存期均不相关. 此研究[63]表明, 高级别C-NEN是预后极差的恶性肿瘤.
直肠神经内分泌肿瘤(rectal neuroendocrine neoplasm, R-NEN)在GEP-NEN中的发病率最高, 约占全部NEN的17.7%和GEP-NEN的29.0%[64]. R-NEN原发灶的症状与直肠癌相似[7]. Weinstock等[64]采用ENETS和NANETS的肿瘤分期、分级系统对141例R-NEN患者回顾性研究发现, 肿瘤平均直径为0.88 cm, 直径<1 cm的肿瘤占75.6%, Ⅰ期、Ⅱ期、Ⅲ期、Ⅳ期肿瘤分别为79.4%、2.8%、5.0%、12.8%, 而G1、G2、G3肿瘤分别为88.1%、3.6%、8.3%, G1肿瘤中, 94.6%为Ⅰ期, 5.4%为Ⅳ期, 所有141例患者的中位生存期为6.8年(0.8-34.7年), G1、G2、G3肿瘤患者的5年生存率分别为87.7%、47.6%、33.3%. Li等[65]对156例R-NEN的回顾性分析显示, 全部患者的总体5年生存率为95.7%, 浸润深度是独立的预后因素(P<0.001), 淋巴结转移率为7.7%, 淋巴结转移与浸润深度和肿瘤大小密切相关(分别P = 0.003, P = 0.006), 提示R-NEN的手术方法应根据肿瘤大小、浸润深度及淋巴结转移等因素综合考虑[65]. 对于直径<15 mm局限于黏膜下层且无转移的R-NEN, 采用EMR、ESD等内镜治疗技术可取得非常满意的疗效[66]. 除此之外, 对R-NEN还可应用生长抑素类似物治疗[7].
原发性肝脏神经内分泌肿瘤(primary hepatic neuroendocrine neoplasm, PH-NEN)远比GI-NEN罕见, 临床上见到的肝脏NEN大多为GEP-NEN转移所致, 因此确诊PH-NEN十分困难, 治疗也面临诸多挑战[67]. Wang等[68]对29例PH-NEN的CT、MRI特征与病理分级对比发现, G1肿瘤在增强CT、MRI扫描的动脉期呈孤立性强化结节, 动态增强曲线示动脉期迅速强化, G2肿瘤呈单一或多个分布, 结节或边缘环形强化, G3肿瘤呈多个病灶, 瘤内坏死、出血, 提示CT和MRI能反映PH-NEN的肿瘤分级和病理特征, 有助于PH-NEN的确定诊断[68]. Wang等[67]对10例PH-NEN的回顾性研究发现, 7例患者的US、CT和/或MRI显示肝脏有囊实性肿块, 1、2、3、6年的无病生存期分别为80.0%、46.2%、46.2%、0.0%, 总体生存率分别为100.0%、67.1%、67.1%、33.6%, 早期(Ⅰ期、Ⅱ期)患者的无病生存期和总体生存率与进展期(Ⅲ期、Ⅳ期)患者相似, 单一治疗的无病生存期和总体生存率显著低于联合治疗者. 此研究表明, PH-NEN的发生发展过程有其独特性, 原发性肝癌的分期标准可能不适合PH-NEN, 更方便有效的影像学特征及实验室检查仍有待确定, 积极联合采取手术切除、肝动脉化疗栓塞、化疗和射频消融术等治疗措施, 有助于PH-NEN或复发者取得更好疗效, 并有望延长无病生存期和总体生存率[67].
原发性胆囊神经内分泌肿瘤(gallbladder neuroendocrine neoplasm, GB-NEN)十分罕见, 约占全部NEN的0.5%, 对其生物学行为知之甚少, 其临床症状及影像学特征均无明显特异性, 个别病例有类癌综合征, 其诊断主要依赖于病理学检查, 普遍恶性程度较高, 预后差, 目前尚无确切的治疗方案[69]. GB-NEN包括NET(G1、G2)、小细胞型NEC(SCNEC)、大细胞型NEC(LCNEC)、混合性腺NEC(MANEC)[70]. Eltawil等[69]研究显示, 278例GB-NEN的平均生存期为9.8 mo, NET、SCNEC的5年生存率分别为 36.9%、0.0%. Kamboj等[70]对19例GB-NEC研究发现, SCNEC 16例, LCNEC 2例, MANEC1例, 肿瘤分期均为Ⅲ期或Ⅳ期并远隔转移, 5例Ki-67指数介于20%-50%之间, 8例>50%, 14例患者平均生存期为3 mo, 5例患者失访. 根治性切除术后的积极辅助放化疗可能有助于缓解症状, 延长生存期[70].
原发性肝外胆管神经内分泌肿瘤(neuroendocrine neoplasm of the extrahepatic bile duct, EB-NEN)非常罕见, 无特殊临床表现, 很少伴有类癌综合征, 术前诊断十分困难[71]. Michalopoulos等[71]的一项回顾性研究发现, 60.3%的患者有黄疸, 9.2%有瘙痒, 19.2%合并胆管结石, 9.0%有血管活性肠肽相关症状, 19.2%位于肝总管和近端胆总管, 手术是治疗EB-NEN的主要手段. Hong等[72]对11例EB-NEN回顾性分析显示, 7例为NEC(64%), 3例为MANEC(27%), 1例为NET(9%). CT扫描显示, 7例位于胆总管(64%), 2例位于肝总管(18%), 2例位于胆囊管(18%), 5例肿瘤为结节型(45%), 5例为胆管腔内生长型(45%), 1例为胆管周围浸润型(9%)[72]. PET/CT扫描显示, 8例NEC的FDG活性增加[72]. 提示, EB-NEN的最常见部位为胆总管, 绝大多数肿瘤为结节型和胆管腔内生长型[72].
胰腺神经内分泌肿瘤(pancreatic neuroendocrine neoplasm, P-NEN)较罕见, 年发病率约为0.43/100000, 约占全部胰腺肿瘤的1%-2%, 占全部NEN的7%, 仅次于GI-NEN[73]. 大多数的P-NEN零星发病, 但大约10%的P-NEN与潜在的遗传综合征, 如MEN-1、MEN-4、希佩尔-林道综合征、神经纤维瘤病Ⅰ型(neurofibromatosis type Ⅰ, NF-1)、结节性硬化症(tuberous sclerosis complex, TSC)等疾病相关[3,73]. P-NEN分功能性和非功能性2种, 国外资料显示, 大约90%P-NEN为非功能性[73]. 但国内资料却大相径庭, 功能性P-NEN占89.6%[7]. 非功能性P-NEN可能没有任何症状, 多为体检发现, 或因肿块压迫引起黄疸、疼痛、消化道梗阻等症状[7]. 最常见的功能性P-NEN为胰岛素瘤、胃泌素瘤、胰高血糖素瘤、VIP瘤、生长抑素瘤[13,73]. 胰岛素瘤约占功能性P-NEN的35%-40%, 胃泌素瘤约占16%-30%, 胰高血糖素瘤和VIP瘤则均不足10%, 生长抑素瘤则不足5%[73]. CgA对P-NEN的敏感性和特异性分别为72%-100%和50%-80%, 并用于治疗监测和预后评估, 而NSE的敏感性和特异性则分别为30%-40%和100%, CgA和NSE的联合检测可改善单独检测的敏感性[73]. CT、MRI、SRS、PET/CT、EUS等有助于P-NEN的定位诊断[73]. EUS-FNA的敏感性、特异性、准确性分别为84.5%、99.4%、97.3%[74]. EUS引导下射频消融术(EUS-radiofrequency ablation, EUS-RA)对P-NEN的治疗也安全有效[75]. 手术切除仍是P-NEN的唯一有效治疗方法[13,76]. 对于局部浸润或转移者, 应行扩大根治术, 有时甚至需要切除多个器官, 对于肝转移者, 若技术可行, >90%的瘤体可行减瘤术, 有望延长总体生存期[76]. Gratian等[77]对1854例非功能性P-NEN的回顾性研究发现, 直径≤0.5 cm的肿瘤中, 33%区域淋巴结转移, 11%远隔转移, 5年总体生存期未手术者为27.6%, 而与之比较, 部分胰腺切除术者为83.0%, 胰十二指肠切除术者为 72.3%, 全胰腺切除术者为86.0%(P<0.01). 此研究表明, 术式与总体生存期无关[77]. 对于不可切除的P-NEN, 应首选化疗, 舒尼替尼的适应症也仅限于P-NEN[7]. 此外, 生长抑素类似物、细胞毒性化疗药物、靶向或生物制剂等也用于P-NEN的治疗, 依维莫司单独或联合长效帕瑞肽(signifor)治疗进展期P-NEN的Ⅱ期临床试验效果仍有待于进一步验证[78].
NEN是一组异质性非常显著的肿瘤, 消化系统NEN在其组织形态学、免疫表型以及生物学行为等方面均有各自特征, 临床罕见, 表现复杂, 诊断困难. 2010年第4版《WHO消化系统肿瘤》分类标准的颁布实施以及2013年CSCO中国GEP-NEN专家诊治共识的出台, 对于规范NEN的诊治流程有重要意义. 随着基础与转化医学研究的日渐深入和备受重视, NEN的分子生物学研究已取得一些进展, 寻找NEN诊治的新靶点和新方法已成为当今的研究热点和未来的努力方向. 目前我国尚无消化系统NEN的相关数据库, 也缺乏多中心的合作研究, 期望在不久的将来能得以实现.
神经内分泌肿瘤(neuroendocrine neoplasm, NEN)是一类来源于弥散神经内分泌系统的罕见肿瘤,占所有恶性肿瘤的1%-2%. 近30年内NEN的发病率增长了5倍, 2004年美国NEN的发病率约为5.25/100000, 其中来源于消化系统的NEN约占70%. 长期以来, NEN在命名和分类上存在不少混乱, 早期诊断十分困难, 进展期NEN的死亡率一直居高不下, 2010年第4版世界卫生组织(World Health Organization, WHO)消化系统肿瘤分类系统对NEN的命名和分类作了修订, 为消化系统NEN的规范化诊治提供了依据.
时永全, 教授, 主任医师, 第四军医大学西京医院消化内科
寻找在NEN中发生表观遗传学改变的重要驱动基因是当前的研究难点, 这些驱动基因有望成为NEN药物研发的新靶点基因, 为NEN的精准治疗提供思路.
阻断程序性死亡蛋白1(PD-1)与其配体(PD-L1)结合可以打破肿瘤细胞对T细胞的免疫逃逸, Grabowski等研究发现,低分化NEN、高分化NEN的PD-L1表达率分别为100%、50%, 提示抗PD-L1免疫治疗有可能为NEN开辟新的治疗途径.
本文结合2010年第4版《WHO消化系统NEN肿瘤分类标准》以及2013年CSCO关于GEP-NEN的诊治共识, 对原发性胃肠道NEN、肝脏NEN、胆囊NEN、胆管NEN、胰腺NEN的临床特征及治疗现状进行了阐述, 提供了大量有价值的信息.
本文结合大量最新文献资料, 对原发性食管NEN、胃NEN、十二指肠NEN、小肠NEN、阑尾NEN、结肠NEN、直肠NEN、肝脏NEN、胆囊NEN、胆管NEN、胰腺NEN的临床病理特征及治疗现状进行了阐述, 内容详实丰富, 对临床工作有指导意义.
多发性内分泌肿瘤1型: 是一种以累及甲状旁腺、胰岛细胞和垂体前叶的家族性常染色体显性遗传性肿瘤疾病, 临床表现复杂, 两个或两个以上的内分泌腺体发生功能性NEN, 而引起相应激素过剩的临床症候群.
本文系统地回顾分析了消化系统神经内分泌肿瘤的诊治情况, 对于临床工作有重要的指导意义.
编辑:郭鹏 电编:都珍珍
| 1. | Vinik AI, Chaya C. Clinical Presentation and Diagnosis of Neuroendocrine Tumors. Hematol Oncol Clin North Am. 2016;30:21-48. [PubMed] [DOI] |
| 2. | Fraenkel M, Faggiano A, Valk GD. Epidemiology of neuroendocrine tumors. Front Horm Res. 2015;44:1-23. [PubMed] [DOI] |
| 3. | PDQ Cancer Genetics Editorial Board. Genetics of endocrine and neuroendocrine neoplasias (PDQ®): Health Professional Version. PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); Nov 12. [PubMed] |
| 4. | Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015;121:589-597. [PubMed] [DOI] |
| 5. | Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072. [PubMed] [DOI] |
| 6. | Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. Lyon: IARC Press 2010; . |
| 8. | Guadagno E, Caro Mdel B, Insabato L. An update on the pathology of neuroendocrine tumors. Front Biosci (Schol Ed). 2016;8:1-12. [PubMed] |
| 9. | Wang YH, Yang QC, Lin Y, Xue L, Chen MH, Chen J. Chromogranin A as a marker for diagnosis, treatment, and survival in patients with gastroenteropancreatic neuroendocrine neoplasm. Medicine (Baltimore). 2014;93:e247. [PubMed] [DOI] |
| 10. | Hijioka M, Ito T, Igarashi H, Fujimori N, Lee L, Nakamura T, Jensen RT, Takayanagi R. Serum chromogranin A is a useful marker for Japanese patients with pancreatic neuroendocrine tumors. Cancer Sci. 2014;105:1464-1471. [PubMed] [DOI] |
| 11. | Massironi S, Rossi RE, Casazza G, Conte D, Ciafardini C, Galeazzi M, Peracchi M. Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution. Neuroendocrinology. 2014;100:240-249. [PubMed] [DOI] |
| 12. | Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H. The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol. 2015;110:1223-1232. [PubMed] [DOI] |
| 14. | Maxwell JE, Howe JR. Imaging in neuroendocrine tumors: an update for the clinician. Int J Endocr Oncol. 2015;2:159-168. [PubMed] [DOI] |
| 15. | Brabander T, Kwekkeboom DJ, Feelders RA, Brouwers AH, Teunissen JJ. Nuclear Medicine Imaging of Neuroendocrine Tumors. Front Horm Res. 2015;44:73-87. [PubMed] [DOI] |
| 16. | Pfeifer A, Knigge U, Binderup T, Mortensen J, Oturai P, Loft A, Berthelsen AK, Langer SW, Rasmussen P, Elema D. 64Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111In-DTPA-Octreotide in 112 Patients. J Nucl Med. 2015;56:847-854. [PubMed] [DOI] |
| 17. | Unno J, Kanno A, Masamune A, Kasajima A, Fujishima F, Ishida K, Hamada S, Kume K, Kikuta K, Hirota M. The usefulness of endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic neuroendocrine tumors based on the World Health Organization classification. Scand J Gastroenterol. 2014;49:1367-1374. [PubMed] [DOI] |
| 18. | Krishna SG, Bhattacharya A, Li F, Ross WA, Ladha H, Porter K, Atiq M, Bhutani MS, Lee JH. Diagnostic Differentiation of Pancreatic Neuroendocrine Tumor From Other Neoplastic Solid Pancreatic Lesions During Endoscopic Ultrasound-Guided Fine-Needle Aspiration. Pancreas. 2016;45:394-400. [PubMed] [DOI] |
| 19. | Yagi M, Abe Y, Sasaki Y, Nomura E, Sato T, Iwano D, Yoshizawa K, Sakuta K, Kanno N, Nishise S. Esophageal carcinoid tumor treated by endoscopic resection. Dig Endosc. 2015;27:527-530. [PubMed] [DOI] |
| 20. | Shah MJ, Birwa SB, Samanta ST, Patel MA. Atypical carcinoid of the esophagus. Indian J Pathol Microbiol. 2015;58:223-225. [PubMed] [DOI] |
| 21. | Huang YL, Chou SH, Chai CY, Hsu JS. Small cell neuroendocrine carcinoma of the esophagus. Kaohsiung J Med Sci. 2015;31:108-109. [PubMed] [DOI] |
| 22. | Nayal B, Vasudevan G, Rao AC, Kudva R, Valliathan M, Mathew M, Rao L. Primary small cell carcinoma of the esophagus - An eight year retrospective study. J Clin Diagn Res. 2015;9:EC04-EC06. [PubMed] [DOI] |
| 23. | Kuriry H, Swied AM. Large-Cell Neuroendocrine Carcinoma of the Esophagus: A Case from Saudi Arabia. Case Rep Gastroenterol. 2015;9:327-334. [PubMed] [DOI] |
| 24. | La Rosa S, Vanoli A. Republished: gastric neuroendocrine neoplasms and related precursor lesions. Postgrad Med J. 2015;91:163-173. [PubMed] [DOI] |
| 25. | Basuroy R, Srirajaskanthan R, Prachalias A, Quaglia A, Ramage JK. Review article: the investigation and management of gastric neuroendocrine tumours. Aliment Pharmacol Ther. 2014;39:1071-1084. [PubMed] [DOI] |
| 26. | Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L, Sundin A, Eriksson BK, Oberg KE, Janson ET. Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab. 2004;89:3739-3744. [PubMed] [DOI] |
| 27. | Erkol B, Tilki M, Comunoğlu N, Öven Ustaalıoğlu BB, Aker F, Sürmelioğlu A, Telli F, Gemici C, Kılıçoğlu ZG, Yeşil A. Neuroendocrine/squamous gastric collision tumor: A rare entity. Turk J Gastroenterol. 2014;25 Suppl 1:282-283. [PubMed] [DOI] |
| 28. | Kadowaki Y, Nishimura T, Komoto S, Yuasa T, Tamura R, Okamoto T, Ishido N. Gastroduodenal intussusception caused by a gastric collision tumor consisting of adenocarcinoma and neuroendocrine carcinoma. Case Rep Gastroenterol. 2014;8:89-94. [PubMed] [DOI] |
| 29. | Jang KY, Moon WS, Lee H, Kim CY, Park HS. Gastric collision tumor of large cell neuroendocrine carcinoma and adenocarcinoma--a case report. Pathol Res Pract. 2010;206:387-390. [PubMed] [DOI] |
| 30. | Ishida M, Sekine S, Fukagawa T, Ohashi M, Morita S, Taniguchi H, Katai H, Tsuda H, Kushima R. Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis. Am J Surg Pathol. 2013;37:949-959. [PubMed] [DOI] |
| 31. | Kidd M, Gustafsson BI. Management of gastric carcinoids (neuroendocrine neoplasms). Curr Gastroenterol Rep. 2012;14:467-472. [PubMed] [DOI] |
| 32. | van der Zwan WA, Bodei L, Mueller-Brand J, de Herder WW, Kvols LK, Kwekkeboom DJ. GEPNETs update: Radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol. 2015;172:R1-R8. [PubMed] [DOI] |
| 33. | Campana D, Ravizza D, Ferolla P, Faggiano A, Grimaldi F, Albertelli M, Berretti D, Castellani D, Cacciari G, Fazio N. Clinical management of patients with gastric neuroendocrine neoplasms associated with chronic atrophic gastritis: a retrospective, multicentre study. Endocrine. 2016;51:131-139. [PubMed] [DOI] |
| 34. | Uygun A, Kadayifci A, Polat Z, Yilmaz K, Gunal A, Demir H, Bagci S. Long-term results of endoscopic resection for type I gastric neuroendocrine tumors. J Surg Oncol. 2014;109:71-74. [PubMed] [DOI] |
| 35. | Kwon YH, Jeon SW, Kim GH, Kim JI, Chung IK, Jee SR, Kim HU, Seo GS, Baik GH, Choi KD. Long-term follow up of endoscopic resection for type 3 gastric NET. World J Gastroenterol. 2013;19:8703-8708. [PubMed] [DOI] |
| 36. | Fitzgerald TL, Dennis SO, Kachare SD, Vohra NA, Zervos EE. Increasing incidence of duodenal neuroendocrine tumors: Incidental discovery of indolent disease? Surgery. 2015;158:466-471. [PubMed] [DOI] |
| 37. | Harada H, Suehiro S, Shimizu T, Katsuyama Y, Hayasaka K, Ito H. Ligation-assisted endoscopic submucosal resection with circumferential mucosal incision for duodenal carcinoid tumor. World J Gastroenterol. 2015;21:10041-10044. [PubMed] [DOI] |
| 38. | Tsai SD, Kawamoto S, Wolfgang CL, Hruban RH, Fishman EK. Duodenal neuroendocrine tumors: retrospective evaluation of CT imaging features and pattern of metastatic disease on dual-phase MDCT with pathologic correlation. Abdom Imaging. 2015;40:1121-1130. [PubMed] [DOI] |
| 39. | Guo T, Ng KK, Chiang HW, Ma MF, Lin Y, Qian JM. Duodenal Neuroendocrine Carcinoma Presenting with Disseminated Liver and Bone Metastases as the Primary Manifestation: Case Report and Literature Review. Cell Biochem Biophys. 2015;72:305-309. [PubMed] [DOI] |
| 40. | Inoue T, Sano H, Mizushima T, Nishie H, Iwasaki H, Okumura F. A Case of Duodenal Neuroendocrine Carcinoma Treated with Amrubicin as Second-line Chemotherapy. J Gastrointestin Liver Dis. 2015;24:379-382. [PubMed] [DOI] |
| 42. | Park HK, Han HS. Duodenal Gangliocytic Paraganglioma With Lymph Node Metastasis. Arch Pathol Lab Med. 2016;140:94-98. [PubMed] [DOI] |
| 43. | Engelund Luna I, Monrad N, Binderup T, Boisen Thoegersen C, Hilsted L, Jensen C, Federspiel B, Knigge U. Somatostatin Immunoreactive Pancreatico-Duodenal Neuroendocrine Neoplasms Twenty-three cases evaluated according to the WHO 2010 Classification. Neuroendocrinology. 2015; Oct 28. [Epub ahead of print]. [PubMed] [DOI] |
| 44. | Rosentraeger MJ, Garbrecht N, Anlauf M, Raffel A, Knoefel WT, Wiedenmann B, Klöppel G. Syndromic versus non-syndromic sporadic gastrin-producing neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior. Virchows Arch. 2016;468:277-287. [PubMed] [DOI] |
| 45. | Albores-Saavedra J, Hart A, Chablé-Montero F, Henson DE. Carcinoids and high-grade neuroendocrine carcinomas of the ampulla of vater: a comparative analysis of 139 cases from the surveillance, epidemiology, and end results program-a population based study. Arch Pathol Lab Med. 2010;134:1692-1696. [PubMed] [DOI] |
| 46. | Zhang L, DeMay RM. Cytological features of mixed adenoneuroendocrine carcinoma of the ampulla: two case reports with review of literature. Diagn Cytopathol. 2014;42:1075-1084. [PubMed] [DOI] |
| 47. | Shroff SR, Kushnir VM, Wani SB, Gupta N, Jonnalagadda SS, Murad F, Early DS, Mullady DK, Edmundowicz SA, Azar RR. Efficacy of Endoscopic Mucosal Resection for Management of Small Duodenal Neuroendocrine Tumors. Surg Laparosc Endosc Percutan Tech. 2015;25:e134-e139. [PubMed] [DOI] |
| 48. | Osera S, Oono Y, Ikematsu H, Yano T, Kaneko K. Endoscopic submucosal resection with a ligation device for the treatment of duodenal neuroendocrine tumors. Surg Endosc. 2015; Dec 16. [Epub ahead of print]. [PubMed] [DOI] |
| 49. | Scherer JR, Holinga J, Sanders M, Chennat J, Khalid A, Fasanella K, Singhi AD, McGrath K. Small duodenal carcinoids: a case series comparing endoscopic resection and autoamputation with band ligation. J Clin Gastroenterol. 2015;49:289-292. [PubMed] [DOI] |
| 50. | Randle RW, Ahmed S, Newman NA, Clark CJ. Clinical outcomes for neuroendocrine tumors of the duodenum and ampulla of Vater: a population-based study. J Gastrointest Surg. 2014;18:354-362. [PubMed] [DOI] |
| 51. | Clift AK, Faiz O, Al-Nahhas A, Bockisch A, Liedke MO, Schloericke E, Wasan H, Martin J, Ziprin P, Moorthy K. Role of staging in patients with small intestinal neuroendocrine tumours. J Gastrointest Surg. 2016;20:180-188; discussion 188. [PubMed] [DOI] |
| 52. | Banck MS, Beutler AS. Advances in small bowel neuroendocrine neoplasia. Curr Opin Gastroenterol. 2014;30:163-167. [PubMed] [DOI] |
| 53. | Hughes MS, Azoury SC, Assadipour Y, Straughan DM, Trivedi AN, Lim RM, Joy G, Voellinger MT, Tang DM, Venkatesan AM. Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs). Surgery. 2016;159:350-356. [PubMed] [DOI] |
| 54. | Salaria S, Means A, Revetta F, Idrees K, Liu E, Shi C. Expression of CD24, a Stem Cell Marker, in Pancreatic and Small Intestinal Neuroendocrine Tumors. Am J Clin Pathol. 2015;144:642-648. [PubMed] [DOI] |
| 55. | Srirajaskanthan R, Ahmed A, Prachialias A, Srinivasan P, Heaton N, Jervis N, Quaglia A, Vivian G, Ramage JK. ENETS TNM staging predicts prognosis in small bowel neuroendocrine tumours. ISRN Oncol. 2013;2013:420795. [PubMed] [DOI] |
| 56. | Lardière-Deguelte S, de Mestier L, Appéré F, Vullierme MP, Zappa M, Hoeffel C, Noaves M, Brixi H, Hentic O, Ruszniewski P. Toward Preoperative Classification of Lymph-Node Metastases in Patients with Small Intestine Neuroendocrine Tumours in the Era of Intestinal-Sparing Surgery. Neuroendocrinology. 2015; Oct 8. [Epub ahead of print]. [PubMed] [DOI] |
| 57. | Sabet A, Dautzenberg K, Haslerud T, Aouf A, Sabet A, Simon B, Mayer K, Biersack HJ, Ezziddin S. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging. 2015;42:1238-1246. [PubMed] [DOI] |
| 58. | Amr B, Froghi F, Edmond M, Haq K, Thengungal Kochupapy R. Management and outcomes of appendicular neuroendocrine tumours: Retrospective review with 5-year follow-up. Eur J Surg Oncol. 2015;41:1243-1246. [PubMed] [DOI] |
| 59. | Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, Arnold R, Denecke T, Plöckinger U, Salazar R. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology. 2012;95:135-156. [PubMed] [DOI] |
| 60. | Nussbaum DP, Speicher PJ, Gulack BC, Keenan JE, Ganapathi AM, Englum BR, Tyler DS, Blazer DG. Management of 1- to 2-cm carcinoid tumors of the appendix: Using the national cancer data base to address controversies in general surgery. J Am Coll Surg. 2015;220:894-903. [PubMed] [DOI] |
| 61. | Lin HH, Lin JK, Jiang JK, Lin CC, Lan YT, Yang SH, Wang HS, Chen WS, Lin TC, Liang WY. Clinicopathological analysis of colorectal carcinoid tumors and patient outcomes. World J Surg Oncol. 2014;12:366. [PubMed] [DOI] |
| 62. | Shafqat H, Ali S, Salhab M, Olszewski AJ. Survival of patients with neuroendocrine carcinoma of the colon and rectum: a population-based analysis. Dis Colon Rectum. 2015;58:294-303. [PubMed] [DOI] |
| 63. | Smith JD, Reidy DL, Goodman KA, Shia J, Nash GM. A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. Ann Surg Oncol. 2014;21:2956-2962. [PubMed] [DOI] |
| 64. | Weinstock B, Ward SC, Harpaz N, Warner RR, Itzkowitz S, Kim MK. Clinical and prognostic features of rectal neuroendocrine tumors. Neuroendocrinology. 2013;98:180-187. [PubMed] [DOI] |
| 65. | Li P, Wu F, Zhao H, Dou L, Wang Y, Guo C, Wang G, Zhao D. Analysis of the factors affecting lymph node metastasis and the prognosis of rectal neuroendocrine tumors. Int J Clin Exp Pathol. 2015;8:13331-13338. [PubMed] |
| 66. | Sung HY, Kim SW, Kang WK, Kim SY, Jung CK, Cho YK, Park JM, Lee IS, Choi MG, Chung IS. Long-term prognosis of an endoscopically treated rectal neuroendocrine tumor: 10-year experience in a single institution. Eur J Gastroenterol Hepatol. 2012;24:978-983. [PubMed] [DOI] |
| 67. | Wang LM, An SL, Wu JX. Diagnosis and therapy of primary hepatic neuroendocrine carcinoma: clinical analysis of 10 cases. Asian Pac J Cancer Prev. 2014;15:2541-2546. [PubMed] |
| 68. | Wang LX, Liu K, Lin GW, Jiang T. Primary hepatic neuroendocrine tumors: comparing CT and MRI features with pathology. Cancer Imaging. 2015;15:13. [PubMed] [DOI] |
| 69. | Eltawil KM, Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors of the gallbladder: an evaluation and reassessment of management strategy. J Clin Gastroenterol. 2010;44:687-695. [PubMed] [DOI] |
| 70. | Kamboj M, Gandhi JS, Gupta G, Sharma A, Pasricha S, Mehta A, Chandragouda D, Sinha R. Neuroendocrine carcinoma of gall bladder: A series of 19 cases with review of literature. J Gastrointest Cancer. 2015;46:356-364. [PubMed] [DOI] |
| 71. | Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20:765-775. [PubMed] [DOI] |
| 72. | Hong N, Kim HJ, Byun JH, Kim SY, Kim KW, Kim JH, Hong SM. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40:181-191. [PubMed] [DOI] |
| 73. | McKenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg. 2014;3:258-275. [PubMed] [DOI] |
| 74. | Hijioka S, Hara K, Mizuno N, Imaoka H, Bhatia V, Mekky MA, Yoshimura K, Yoshida T, Okuno N, Hieda N. Diagnostic performance and factors influencing the accuracy of EUS-FNA of pancreatic neuroendocrine neoplasms. J Gastroenterol. 2016; Jan 14. [Epub ahead of print]. [PubMed] [DOI] |
| 75. | Pai M, Habib N, Senturk H, Lakhtakia S, Reddy N, Cicinnati VR, Kaba I, Beckebaum S, Drymousis P, Kahaleh M. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. World J Gastrointest Surg. 2015;7:52-59. [PubMed] [DOI] |
| 76. | D'Haese JG, Tosolini C, Ceyhan GO, Kong B, Esposito I, Michalski CW, Kleeff J. Update on surgical treatment of pancreatic neuroendocrine neoplasms. World J Gastroenterol. 2014;20:13893-13898. [PubMed] [DOI] |
| 77. | Gratian L, Pura J, Dinan M, Roman S, Reed S, Sosa JA. Impact of extent of surgery on survival in patients with small nonfunctional pancreatic neuroendocrine tumors in the United States. Ann Surg Oncol. 2014;21:3515-3521. [PubMed] [DOI] |
| 78. | Raj N, Reidy-Lagunes D. Systemic therapies for advanced pancreatic neuroendocrine tumors. Hematol Oncol Clin North Am. 2016;30:119-133. [PubMed] [DOI] |