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Volume 35, Issue 8 e13306
《神经内分泌学杂志》第 35 卷第 8 期 e13306
CLINICAL GUIDELINE  临床指南
Open Access  开放获取

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1–G3
欧洲神经内分泌肿瘤学会(ENETS)2023 年胃十二指肠神经内分泌肿瘤(NETs)G1-G3 诊疗指南

Francesco Panzuto

Corresponding Author

Francesco Panzuto

Department of Medical-Surgical Sciences and Translational Medicine, Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy

Correspondence

Francesco Panzuto, Department of Medical-Surgical Sciences and Translational Medicine, Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Sapienza University of Rome, via di Grottarossa 1035, 00189 Rome, Italy.

Email: francesco.panzuto@uniroma1.it

Contribution: Conceptualization, Methodology, Supervision, Writing - original draft, Writing - review & editing

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John Ramage

John Ramage

Department of Gastroenterology, Hampshire Hospitals and ENETS Center, Kings Health Partners London, London, United Kingdom

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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D. Mark Pritchard

D. Mark Pritchard

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Marie-Louise F. van Velthuysen

Marie-Louise F. van Velthuysen

Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Joerg Schrader

Joerg Schrader

Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Nehara Begum

Nehara Begum

Department for General-, Visceral-, Thoracic- and Endocrine Surgery, Johannes-Wesling-Klinikum Minden, University Hospital of the Ruhr-University Bochum, Bochum, Germany

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Anders Sundin

Anders Sundin

Department of Surgical Sciences, Radiology & Molecular Imaging, Uppsala University, Uppsala, Sweden

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Massimo Falconi

Massimo Falconi

Pancreas Translational and Clinical Research Center, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Contribution: Conceptualization, Writing - original draft, Writing - review & editing

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Dermot O'Toole

Dermot O'Toole

National Centre for Neuroendocrine Tumours, ENETS Centre of Excellence, St. Vincent's University Hospital, Dublin, Ireland

Contribution: Conceptualization, Methodology, Supervision, Writing - original draft, Writing - review & editing

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First published: 20 May 2023
首次发布时间:2023 年 5 月 20 日
Citations: 4  引用次数:4

Abstract  摘要

The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.
本指南文件旨在更新欧洲神经内分泌肿瘤学会(ENETS)先前关于高分化胃及十二指肠神经内分泌肿瘤(NETs)的指南,为专科医生提供胃十二指肠 NETs 诊断与管理的实用指导。II 型胃 NETs、神经内分泌癌(NECs)及功能性十二指肠 NETs 不在本文讨论范围内,将由其他 ENETS 指南文件另行阐述。

1 GASTRIC NEUROENDOCRINE TUMOURS
1 胃神经内分泌肿瘤

1.1 Introduction – general background
1.1 引言——总体背景

Gastric neuroendocrine neoplasms (gNENs) are rare tumours with an increasing annual incidence of ~0.4/100,000, and a prevalence of 3/100,000.1 The vast majority of gNENs are well-differentiated neuroendrocrine tumours (NETs), which are usually classified according to the background gastric pathology into three major categories: (i) type I when chronic atrophic gastritis (CAG) is present resulting in hypergastrinaemia (the most common type, accounting for 75%–80% of all gNENs); (ii) type II when the tumour  occurs due to hypergastrinaemia in the context of Zollinger–Ellison syndrome (ZES) and multiple endocrine neoplasia type I (MEN-I) syndrome (5% of gNENs); type III, which are sporadic lesions not associated with hypergastrinaemia (15%–25% of gNENs). Type I gNETs are indolent, with negligible risk of metastases (<5%) and excellent long-term survival (almost 100%); the prognosis of a patient with type II gNETs needs to be assessed in the context of MEN-I syndrome; however, the risk of metastases may vary between 10% and 30%. Type III tumours are usually more aggressive, owing to the high prevalence of metastatic disease (>50%) and the more unfavourable long-term survival (5-year survival rate 70%), although they present well-differentiated morphology in the majority of cases. Type III gNENs may also have higher grades. The key questions discussed in the present paper are summarised in Table 1. Data were identified by MEDLINE database searches and expert opinion/recommendations given according to the best available evidence and the authors’ experience. Each recommendation for treatment and diagnosis will have a level of evidence and grade of recommendation as per the GRADE system (Table S1). The major features of gNETs are summarised in Table 2.
胃神经内分泌肿瘤(gNENs)是一种罕见肿瘤,年发病率约为 0.4/10 万且呈上升趋势,患病率为 3/10 万。绝大多数 gNENs 为高分化神经内分泌肿瘤(NETs),通常根据背景胃病理学分为三大类:(i)I 型——伴随慢性萎缩性胃炎(CAG)导致的高胃泌素血症(最常见类型,占所有 gNENs 的 75%-80%);(ii)II 型——因卓-艾综合征(ZES)和多发性内分泌肿瘤 I 型(MEN-I)综合征引发的高胃泌素血症所致(占 gNENs 的 5%);(iii)III 型——与高胃泌素血症无关的散发病变(占 gNENs 的 15%-25%)。I 型 gNETs 呈惰性,转移风险极低(<5%),长期生存率极佳(近 100%);II 型 gNETs 患者的预后需结合 MEN-I 综合征评估,其转移风险可能在 10%-30%之间波动。 III 型肿瘤通常更具侵袭性,这归因于其较高的转移性疾病发生率(>50%)及相对不利的长期生存率(5 年生存率为 70%),尽管大多数病例呈现分化良好的形态学特征。III 型胃神经内分泌肿瘤(gNENs)也可能具有更高的分级。本文讨论的核心问题总结于表 1。数据通过 MEDLINE 数据库检索获取,专家意见/建议基于现有最佳证据及作者经验提出。每项诊疗建议均按照 GRADE 系统(表 S1)标注证据等级和推荐强度。胃神经内分泌肿瘤(gNETs)的主要特征总结于表 2。

TABLE 1. List of questions.
表 1. 问题列表。
GASTRIC NET  胃神经内分泌肿瘤
Q1 – What is the role of endoscopic resection for type I gNETs? Is additional treatment required in cases of R1 endoscopic resection?
问题 1——内镜切除术对 I 型胃神经内分泌肿瘤的作用是什么?R1 内镜切除术后是否需要追加治疗?
Q2 – When should somatostatin analogues be used to treat type I gNETs?
Q2 – 何时应使用生长抑素类似物治疗 I 型胃神经内分泌肿瘤?
Q3 – What is the recommended follow-up schedule in type I gNETs?
Q3 – I 型胃神经内分泌肿瘤的推荐随访计划是什么?
Q4 – When is surgery recommended for type I gNETs?
Q4 – 何时建议对 I 型胃神经内分泌肿瘤进行手术治疗?
Q5 – Can endoscopic treatments be proposed to treat type III gNETs?
Q5 – 内镜治疗能否用于 III 型胃神经内分泌肿瘤的治疗?
Q6 – When should limited or extended surgical treatments be proposed to treat type III gNETs?
Q6 – 何时应建议采用局限性或扩大性手术治疗 III 型胃神经内分泌肿瘤?
Q7 – What scheduled follow-up is recommended after endoscopic/surgical resection of type III gNETs?
Q7 – III 型胃神经内分泌肿瘤内镜/手术切除后推荐何种定期随访方案?
DUODENAL NET  十二指肠神经内分泌肿瘤
Q8 – When is endoscopic resection indicated?
Q8 – 何时适合进行内镜下切除术?
Q9 – Can a “watch and wait” strategy be proposed in dNETs?
Q9 – 对于 dNETs(十二指肠神经内分泌肿瘤),可以采取“观察等待”策略吗?
Q10 – When is surgery indicated?
Q10 – 何时需要手术干预?
TABLE 2. Diagnostic criteria and prognosis of gNET subtypes.
表 2. gNET(胃神经内分泌肿瘤)亚型的诊断标准及预后。
Type  类型 Gastric pH  胃酸 pH 值 Histology of surrounding mucosa
周围黏膜组织学检查
Gastrin levels  胃泌素水平 Grading  分级 Prognosis  预后
I High   Gastric body atrophy, ECL-cell hyperplasia
胃体萎缩,ECL 细胞增生
High   G1 (G2)  G1(G2) Excellent: Risk of metastases very low. In general, normal life expectancy
极佳:转移风险极低。通常预期寿命正常
II Low   ECL-cell hyperplasia  ECL 细胞增生 High   (G1) G2 Unclear due to lack of data: Overall survival likely to be defined by underlying MEN1 syndrome
因数据不足尚不明确:总生存期可能取决于潜在的 MEN1 综合征
III Normal  正常 Normal  正常 Normal  正常 G2/G3  G2/G3 级 Poor: Risk of metastases high. Overall survival compromised except for early stages.
预后不良:转移风险高。除早期阶段外,总体生存率受影响。
  • Abbreviation: ECL, enterochromaffin-like; gNET, gastric neuroendocrine tumour.
    缩写:ECL,肠嗜铬样细胞;gNET,胃神经内分泌肿瘤。

1.2 Assessment of gastric neuroendocrine tumours
1.2 胃神经内分泌肿瘤的评估

1.2.1 Pathology  1.2.1 病理学

Gastric neuroendocrine tumours (gNETs) are different from other gastrointestinal NETs as in the stomach a clear aetiology is emerging where gastric NETs are induced in the context of hyperplasia of enterochromaffin-like (ECL) cells. In 1993 an aetiological framework for gastric NETs was reported,2 where gastric NETs were either found in a setting of ECL cell hyperplasia associated with high gastrin levels due to autoimmune fundic atrophic gastritis (type I NETs), high gastrin levels due to gastrinoma (type II NETs) or without ECL hyperplasia (type III NETs). More recently, general atrophy in chronic H. pylori associated gastritis,3 functional failure of parietal cells due to mutations4 or proton pump inhibitor (PPI) use5 have also been reported to be associated with NETs, some with a background of ECL cell hyperplasia but in cases of proton pump inhibition also associated with parietal cell hyperplasia. These newly described gastric NETs are similar to the originally described type I gNETs as they are secondary to failed acid secretion. The secondary (type I and type II) gNETs have a more indolent course2, 5 and can be reversible if the cause can be impeded. It is therefore important to recognise the associated gastric mucosal changes.6
胃神经内分泌肿瘤(gNETs)与其他胃肠道 NETs 不同,因为在胃部已明确其发病机制——胃 NETs 是在肠嗜铬样(ECL)细胞增生的背景下诱发的。1993 年提出的胃 NETs 病因学框架将胃 NETs 分为三类:与自身免疫性胃底萎缩性胃炎导致高胃泌素血症相关的 ECL 细胞增生型(I 型 NETs)、胃泌素瘤导致高胃泌素血症型(II 型 NETs)以及无 ECL 细胞增生型(III 型 NETs)。最新研究发现,慢性幽门螺杆菌相关性胃炎的整体萎缩、壁细胞功能缺陷(由基因突变或质子泵抑制剂(PPI)使用引起)也与 NETs 相关,部分病例存在 ECL 细胞增生背景,而质子泵抑制剂使用相关病例还伴有壁细胞增生。这些新发现的胃 NETs 与经典 I 型 gNETs 相似,均继发于胃酸分泌障碍。继发性(I 型和 II 型)gNETs 病程更为惰性,若阻断病因可实现病情逆转。 因此,识别伴随的胃黏膜变化至关重要。 6

Adequate tumour sampling is essential for grading NETs as prescribed in the World Health Organization (WHO) classification of gastrointestinal tumours of 2019.7 As NETs are usually located deep in the mucosa (not at the surface) attention should be paid to this when taking biopsies.
根据 2019 年世界卫生组织(WHO)胃肠道肿瘤分类标准,充分的肿瘤取样对于神经内分泌肿瘤(NETs)的分级至关重要。 7 由于 NETs 通常位于黏膜深层(而非表面),活检时需特别注意这一点。

Gastric NETs are graded using the same criteria as for all gastrointestinal sites:8
胃神经内分泌肿瘤(Gastric NETs)的分级标准与所有胃肠道部位相同: 8

G1: mitotic count <2 in 2 mm2 and/or Ki-67 index <3% in hotspot of at least 500 cells.
G1 级:每 2 平方毫米有丝分裂计数<2 个 2 ,和/或热点区域至少 500 个细胞中 Ki-67 指数<3%。

G2: mitotic count between 2 and 20 in 2 mm2 and/or Ki-67 index between 3% and 20% in hotspot of at least 500 cells.
G2 级:每 2 平方毫米有丝分裂计数 2-20 个 2 ,和/或热点区域至少 500 个细胞中 Ki-67 指数 3%-20%。

G3: mitotic count >20 in 2 mm2 and/or Ki-67 index >20% in hotspot of at least 500 cells.
G3 级:每 2 平方毫米有丝分裂计数>20 个 2 ,和/或热点区域至少 500 个细胞中 Ki-67 指数>20%。

1.2.2 Endoscopy  1.2.2 内镜检查

The primary diagnostic tool for gNETs is oesophagogastroduodenoscopy (OGD). For the assessment of gastric NETs, not only representative biopsies of the tumour but also biopsies of the surrounding mucosa and other parts of the stomach (antrum and body-fundus) are essential as these give clues on the nature/aetiology and, with this, the prognosis and treatment of the NET. In addition, sampling of gastric juice for pH measurement is strongly encouraged. Furthermore, virtual chromoendoscopy (narrow-band imaging, blue light imaging, i-scan) may be useful to provide additional information to identify field changes or precancerous lesions in underlying atrophic mucosa.9 In addition to OGD, endoscopic ultrasound (EUS) should be performed in all lesions >1 cm regardless of type and in all lesions of type III regardless of size, unless large or metastatic lesions are found. Reporting should include size of the lesion infiltration depth and assessment of local lymph nodes.
胃神经内分泌肿瘤(gNETs)的主要诊断工具是食管胃十二指肠镜检查(OGD)。对于胃 NETs 的评估,不仅需要获取肿瘤的代表性活检标本,还必须对周围黏膜及胃的其他部位(如胃窦和胃体-胃底)进行活检,因为这些活检结果能提供关于肿瘤性质/病因的线索,进而影响其预后和治疗方案。此外,强烈建议采集胃液进行 pH 值测定。虚拟染色内镜技术(窄带成像、蓝光成像、i-scan)可能有助于提供额外信息,以识别潜在萎缩性黏膜中的区域改变或癌前病变。 9 除 OGD 外,所有直径>1 cm 的病灶(无论类型)以及所有 III 型病灶(无论大小)均应进行超声内镜(EUS)检查,除非发现病灶较大或存在转移。报告内容应包括病灶大小、浸润深度及局部淋巴结评估。

Recommendations  建议

Evaluation of gNETs should always include:
gNETs 的评估应始终包括:
  1. Biopsies to evaluate proliferative activity of the tumour (Ki67 and/or mitotic count) for grading (2b-A).
    活检以评估肿瘤的增殖活性(Ki67 和/或有丝分裂计数)用于分级(2b-A)。
  2. Evaluation of the type of gNET by assessing separate biopsies from the antral and fundic mucosa (2b-A).
    通过分别取胃窦和胃底黏膜活检评估 gNET 类型(2b-A 级证据)。
  3. EUS is recommended in tumours >1 cm (3b-B).
    对于直径>1 厘米的肿瘤,推荐进行超声内镜检查(3b-B 级证据)。

1.2.3 Imaging and laboratory examinations
1.2.3 影像学与实验室检查

Biomarker assessment should include fasting gastrin and chromogranin A (CgA). Whereas gastrin may be useful to differentiate between different types (elevated in type I and type II, normal in type III), CgA is only useful as a tumour marker in type III gNETs. In the presence of ongoing PPI therapy gastrin and CgA are not diagnostic and are difficult to interpret. In general, caution should be used when evaluating CgA values, considering the different diagnostic accuracy of available assays. Parietal cell and intrinsic factor antibodies, vitamin B12 and thyroid function parameters should be measured in suspected cases of autoimmune gastritis.
生物标志物检测应包括空腹胃泌素和嗜铬粒蛋白 A(CgA)。胃泌素有助于区分不同类型(I 型和 II 型升高,III 型正常),而 CgA 仅作为 III 型 gNET 的肿瘤标志物有效。在持续使用质子泵抑制剂治疗的情况下,胃泌素和 CgA 无诊断价值且难以解读。总体而言,评估 CgA 值时需谨慎,考虑不同检测方法的诊断准确性差异。疑似自身免疫性胃炎病例应检测壁细胞抗体、内因子抗体、维生素 B12 及甲状腺功能参数。

Whereas type I gNETs do not usually require additional cross-sectional imaging, type III gNETs should undergo cross-sectional imaging – liver contrast-enhanced magnetic resonance imaging (MRI) and/or contrast-enhanced thoracoabdominal computed tomography (CT), with previous ingestion of water immediately before examination, to fill stomach and duodenum and better depict small enhancing lesion in the arterial phase, and functional imaging, preferentially somatostatin receptor PET/CT (68Ga-SSA-PET-CT).
I 型胃神经内分泌肿瘤通常无需额外进行横断面成像检查,而 III 型胃神经内分泌肿瘤则应接受横断面成像——肝脏对比增强磁共振成像(MRI)和/或对比增强胸腹部计算机断层扫描(CT),检查前立即饮水以充盈胃和十二指肠,从而在动脉期更好地显示小强化病灶,同时进行功能成像,优先选择生长抑素受体 PET/CT( 68 镓-SSA-PET-CT)。

These should also be considered in cases of type I gNETs with metastases on EUS or high-risk features of metastases (G2, lymphatic or vascular invasion, size ≥1 cm). Recently, 68Ga-SSA-PET-CT has been suggested in selected cases with tumour diameter >1 cm, G2 tumours (perhaps Ki-67 > 10 but exact cutoff not determined), or R1 margins after endoscopic resection.10
对于 I 型胃神经内分泌肿瘤,若超声内镜(EUS)发现转移灶或存在转移高风险特征(G2 分级、淋巴或血管浸润、肿瘤大小≥1 厘米),也应考虑上述检查。近期有建议指出,对于肿瘤直径>1 厘米、G2 分级(可能 Ki-67>10 但具体临界值未定)或内镜切除后切缘阳性(R1)的特定病例,可采用 68 镓-SSA-PET-CT 检查。 10

Prognosis depends on type, size, grading, histological risk factors (e.g., lymphovascular invasion, perineural invasion), completeness of resection and initial tumour stage.
预后取决于肿瘤类型、大小、分级、组织学危险因素(如淋巴血管侵犯、神经周围侵犯)、切除完整性及初始肿瘤分期。

Recommendations  建议

  1. Gastrin assessment is useful to differentiate between different types of gNETs. CgA is useful as tumour marker only in type III gNETs (3b-A).
    胃泌素检测有助于区分不同类型胃神经内分泌肿瘤(gNETs)。嗜铬粒蛋白 A(CgA)仅作为 III 型 gNETs 的肿瘤标志物具有参考价值(3b-A 级证据)。
  2. Cross-sectional radiological imaging (CT/MRI) and 68Ga-SSA-PET-CT are not required in type I gNETs, unless metastases on EUS or in the presence of high-risk features (G2, vessel invasion, suspected T2 on EUS ) (3b–A).
    I 型 gNETs 通常无需进行横断面影像学检查(CT/MRI)和 68 镓标记生长抑素受体 PET-CT,除非超声内镜(EUS)发现转移灶或存在高危特征(G2 级、血管侵犯、EUS 疑似 T2 期)(3b–A 级证据)。

1.3 Management strategy for type I gNETs
1.3 I 型胃神经内分泌肿瘤的管理策略

1.3.1 Introduction  1.3.1 引言

Treatment options for type I gNETs include surveillance, endoscopic resection, somatostatin analogues (SSA) and eventually surgery. As prognosis is usually quite favourable and tumour growth slow and risk of metastases is below 1% in tumours <10 mm, all NET <1 cm can be observed without any need for intervention.11, 12 The ideal schedule for observational OGD is not defined and clinical practice ranges from every 6 months to every 2 years. Planning the first follow-up after 6 months and then every 12 months is the most widely used approach. A regular rebiopsy of lesions is not necessary unless atypical features (e.g., ulceration, erosion, pitting) appear, suggesting invasive progression of the lesion. The management of type I gNETs is summarised in Figure 1.
对于 I 型胃神经内分泌肿瘤(gNETs)的治疗选择包括监测、内镜下切除、生长抑素类似物(SSA)及必要时的手术治疗。由于此类肿瘤预后通常较好,生长缓慢且小于 10 毫米的肿瘤转移风险低于 1%,所有直径小于 1 厘米的 NET 均可采取观察策略而无需干预。 11, 12 理想的观察性胃镜检查间隔尚未明确,临床实践中从每 6 个月到每 2 年不等。首次随访安排在 6 个月后,之后每 12 个月复查一次是最普遍采用的方式。除非出现提示病变侵袭性进展的非典型特征(如溃疡、糜烂、凹陷),否则无需定期重复活检。I 型 gNETs 的管理流程总结见图 1。

Details are in the caption following the image
Management of type I gastric neuroendocrine tumours (gNETs).
I 型胃神经内分泌肿瘤(gNETs)的管理。

1.3.2 Q1 – What is the role of endoscopic resection for type I gNETs? Is additional treatment required in cases of R1 endoscopic resection?
1.3.2 问题 1 – 内镜切除术在 I 型 gNETs 中的作用是什么?对于 R1 内镜切除术后的病例,是否需要额外治疗?

Endoscopic resection should be considered for type I gNETs larger than 1 cm and for those lesions demonstrating increased Ki-67 as these features are associated with an increased risk of metastases and progression.11, 13 Many small type I gNETs are G1 or low G2 (Ki-67 < 10%);14 however, a Ki-67 cutoff has not been defined to determined when excision should be performed. Endoscopic ultrasonography to determine depth of local invasion and assessment of local lymph nodes should be performed in lesions >1 cm and in smaller tumours with “high” G2 grade (cutoff not established) before any resection. No other imaging modality is required at this stage. The resection technique of choice depends on size and position of the lesion, invasion depth and local experience. Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD) and full-thickness resection (FTR) are all associated with a low risk profile for both bleeding and perforation. It is not clear which is the best endoscopic technique to be used for achieving a complete R0 resection.15 However, resection by ESD or FTR achieve higher rates of R0 resection, but no randomised trials have compared all techniques head-to-head.16, 17 For R1 resection status a re-resection in a “step-up” approach could be recommended (e.g., ESD after EMR, FTR after ESD), although data showing risk of local recurrence after R1 resection are scarce,18 particularly for smaller tumours which may be managed by a non-interventional endoscopic surveillance after initial R1 resection.19
对于大于 1 厘米的 I 型胃神经内分泌肿瘤(gNETs)以及 Ki-67 升高的病灶,应考虑进行内镜下切除,因为这些特征与转移和进展风险增加相关。 11, 13 许多小型 I 型 gNETs 为 G1 或低级别 G2(Ki-67 < 10%); 14 然而,目前尚未确定 Ki-67 的临界值以决定何时应进行切除。对于大于 1 厘米的病灶以及“高级别”G2(临界值未确定)的较小肿瘤,在切除前应进行超声内镜检查以确定局部浸润深度并评估局部淋巴结情况。此阶段无需其他影像学检查。切除技术的选择取决于病灶的大小、位置、浸润深度及当地经验。内镜下黏膜切除术(EMR)、内镜黏膜下剥离术(ESD)和全层切除术(FTR)均具有较低的出血和穿孔风险。目前尚不清楚哪种内镜技术最适合实现完整的 R0 切除。 15 然而,内镜黏膜下剥离术(ESD)或全层切除术(FTR)可实现更高的 R0 切除率,但目前尚无随机试验直接比较所有技术。 16, 17 对于 R1 切除状态,可推荐采用“逐步升级”方法进行再切除(例如 EMR 后行 ESD,ESD 后行 FTR),尽管显示 R1 切除后局部复发风险的数据有限, 18 特别是对于较小的肿瘤,初次 R1 切除后可能通过非干预性内镜监测进行处理。 19

Conclusion/recommendations
结论/建议

  1. Endoscopic resection should be proposed in type I gNETs larger than 1 cm (2b-A).
    对于大于 1 厘米的 I 型胃神经内分泌肿瘤,应建议内镜下切除(2b-A)。
  2. ESD and FTR are more effective to achieve R0 resection compared to EMR (2b-B).
    与内镜下黏膜切除术(EMR)相比,内镜黏膜下剥离术(ESD)和全层切除术(FTR)能更有效地实现 R0 切除(2b-B)。
  3. In case of incomplete resection (R1) of a NET >1 cm a step-up approach (EMR > ESD > FTR > surgery) is recommended (4-C).
    对于大于 1 厘米的神经内分泌肿瘤不完全切除(R1)的情况,推荐采用阶梯式治疗策略(EMR>ESD>FTR>手术)(4-C)。

1.3.3 Q2 – When should somatostatin analogues be used to treat type I gNETs?
1.3.3 Q2 – 何时应使用生长抑素类似物治疗 I 型胃神经内分泌肿瘤?

Type I gNETs usually express somatostatin receptors. Thus, therapy with SSA can be initiated in metastasised patients or patients not amenable to endoscopic or surgical resection (e.g., difficult location, old age, comorbidities). SSA therapy is associated with a high complete response rate of 25%–100%, but relapse is frequently observed after discontinuation of therapy.20 Thus, continuous therapy would be the appropriate approach. Another reason for starting SSA therapy could be large tumour size or the requirement of repeated endoscopic resection for progressive lesions, although data evaluating this approach are lacking. Another therapeutic approach could be direct inhibition of gastrin signalling in tumour cells. Indeed, the gastrin receptor inhibitor netazepide has been evaluated in a proof-of-concept phase II trial with 16 patients showing a complete response rate in 30% of patients.21 Like SSA treatment, tumour relapse after discontinuation was observed in all patients. The clinical benefit of netazepide needs to be evaluated in larger randomised clinical trials before any recommendation for its use can be formulated.
I 型胃神经内分泌肿瘤通常表达生长抑素受体。因此,对于发生转移或无法进行内镜或手术切除(如位置困难、高龄、合并症)的患者,可启动生长抑素类似物(SSA)治疗。SSA 治疗与 25%-100%的高完全缓解率相关,但停药后常观察到复发。 20 因此,持续治疗可能是更合适的方法。启动 SSA 治疗的其他原因可能包括肿瘤体积较大或需要对进展性病变进行重复内镜切除,尽管目前缺乏评估这种方法的数据。另一种治疗方法可能是直接抑制肿瘤细胞中的胃泌素信号传导。事实上,胃泌素受体抑制剂 netazepide 已在一项概念验证性 II 期试验中进行了评估,16 名患者中有 30%显示完全缓解。 21 与 SSA 治疗类似,所有患者在停药后均观察到肿瘤复发。在提出任何使用建议之前,需要在更大规模的随机临床试验中评估 netazepide 的临床益处。

Recommendations  建议

  1. In type I gNET patients when tumour resection is indicated but endoscopic or surgical techniques are not possible, SSA therapy is appropriate (2b-A).
    对于 I 型胃神经内分泌肿瘤患者,当需要切除肿瘤但内镜或手术技术不可行时,生长抑素类似物(SSA)治疗是合适的(2b-A)。

1.3.4 Q3 – What is the recommended follow-up schedule in type I gNETs?
1.3.4 问题 3——I 型胃神经内分泌肿瘤的推荐随访方案是什么?

An endoscopic follow-up every 12 months is recommended after complete endoscopic resection of a type I gNET. Whether this interval can be increased after prolonged periods without evidence of relapse or whether the interval should be shortened in case of incomplete (R1) resection or risk factors associated with progression (grading G2, size >20 mm) should be carefully discussed with the patient. In general, no cross-sectional imaging is required for follow-up. In addition, repeated evaluation of biomarkers CgA and gastrin should not be performed as these markers are elevated due to the underlying CAG and are not an indicator of relapse or progression. Follow-up OGD is recommended in a type I gNET that does not require resection, although the optimal interval for planning endoscopy is not established (1–2 years can be considered, following first follow-up 6–12 months after initial diagnosis). Apart from risk of tumour progression or relapse after resection in NET lesions, patients with CAG carry a relevant risk of developing gastric adenocarcinoma. Although only one international guideline recommends a regular endoscopic follow-up for patients with CAG, the yearly rate of adenocarcinoma detection is up to 1% in patients with type I gNETs.14 Whether this reflects an increased risk of adenocarcinoma development in patients with a previous diagnosis of gNET is not clear. For CAG patients without a gNET, intestinal metaplasia and H. pylori infection have been linked to an increased risk of adenocarcinoma progression. Given the high risk of adenocarcinoma detection upon follow-up of gNETs, this supports the recommendation to perform an endoscopic follow-up every 12–24 months in patients with previously diagnosed gNETs (specific timing may be proposed according to tumour size and histological features), whereas a 3-year interval is recommended in CAG patients without gNETs.22
对于 I 型胃神经内分泌肿瘤(gNET)完全内镜切除后,建议每 12 个月进行一次内镜随访。若长期无复发证据,是否可延长随访间隔;或在不完全(R1)切除或存在进展风险因素(分级 G2、肿瘤大小>20 mm)时缩短间隔,应与患者充分讨论。通常随访无需进行横断面影像学检查。此外,不应重复检测生物标志物 CgA 和胃泌素,因这些指标会因基础慢性萎缩性胃炎(CAG)升高,不能提示复发或进展。对于无需切除的 I 型 gNET,建议进行随访性食管胃十二指肠镜检查(OGD),但最佳内镜间隔尚未确立(初次诊断后 6-12 个月首次随访,之后可考虑 1-2 年)。除 NET 病灶切除后的肿瘤进展或复发风险外,CAG 患者还面临发生胃腺癌的显著风险。 尽管仅有一项国际指南建议对慢性萎缩性胃炎(CAG)患者进行定期内镜随访,但在 I 型胃神经内分泌肿瘤(gNETs)患者中,每年腺癌检出率高达 1%。 14 这是否反映既往诊断为 gNET 的患者发生腺癌的风险增加尚不明确。对于未患 gNET 的 CAG 患者,肠上皮化生和幽门螺杆菌感染与腺癌进展风险增加相关。鉴于 gNETs 随访中发现腺癌的高风险,这支持对既往诊断为 gNETs 的患者每 12-24 个月进行一次内镜随访的建议(具体时间可根据肿瘤大小和组织学特征提出),而未患 gNETs 的 CAG 患者则建议每 3 年随访一次。 22

Recommendations  建议

  1. An endoscopic follow-up by OGD is recommended 12 months after complete endoscopic resection of type I gNET (2b-B).
    对于 I 型胃神经内分泌肿瘤(gNET)完全内镜切除后,建议 12 个月时进行上消化道内镜(OGD)随访(2b-B 级证据)。
  2. In those not requiring resection first follow-up should be 12 months and then consider annual to every 1–2 years (2b-B).
    对于无需手术切除的患者,首次随访应在 12 个月后进行,之后可考虑每年至每 1-2 年随访一次(2b-B 级证据)。
  3. In patients with type I gNET, endoscopic follow-up by OGD is recommended also given the risk of developing gastric adenocarcinoma related to CAG (2b-A).
    I 型胃神经内分泌肿瘤患者还需考虑慢性萎缩性胃炎(CAG)相关胃腺癌风险,建议定期进行上消化道内镜随访(2b-A 级证据)。

1.3.5 Q4 – When is surgery recommended for type I gNETs?
1.3.5 问题 4——何时建议对 I 型胃神经内分泌肿瘤进行手术治疗?

Although type I gNETs are usually treated by an endoscopic approach, upfront surgical resection is recommended in all tumours that are greater than 20 mm in size or with suspected muscolaris propria invasion (either on axial imaging or EUS). In addition, surgery could be considered in tumours showing high risk features on biopsy (e.g., high grade 2 NET [cutoff not established], lymphovascular invasion). A limited resection with sampling of local lymph nodes is the preferred approach. Total gastrectomy with D2 lymphadenectomy should be discussed in patients with known lymph node metastases or might be proposed as a completion procedure after final histology has proven lymphatic spread, although there are no solid data supporting this option.
尽管 I 型胃神经内分泌肿瘤通常采用内镜治疗,但对于所有直径大于 20 毫米或疑似固有肌层侵犯(通过轴向成像或超声内镜判断)的肿瘤,推荐首选手术切除。此外,对于活检显示高风险特征(如高级别 G2 NET[临界值未确定]、淋巴血管侵犯)的肿瘤,也可考虑手术。局限性切除联合局部淋巴结取样是首选方案。对于已知淋巴结转移的患者,应讨论全胃切除联合 D2 淋巴结清扫术,或在最终病理证实淋巴扩散后作为补充手术方案提出,但目前尚无确凿数据支持该选择。

Endoscopic resection should not be attempted in the presence of invasion into the muscularis propria, suspected lymph node metastases or high-risk features of metastatic spread (e.g., high Ki-67, vascular invasion, size >20 mm). These patients should receive full staging including cross-sectional imaging as described previously and 68Ga-SSA-PET-CT and upfront surgical management. The optimal cutoff value for Ki-67 is not determined, but Ki-67 values above 10% should trigger evaluation of surgical treatment. In the rare instance of a G3 type I gNET a primarily surgical approach is recommended due to high risk of metastases.23 Regarding tumour size, no clear cutoff for surgical management can be defined. Only limited data exist on tumour size and risk of metastases in the subgroup of type I gNETs. Data from the SEER database and from a large series from Taiwan showed that a cutoff of 20 mm was associated with an increased risk of lymph node metastases.13, 24
对于已侵犯固有肌层、疑似淋巴结转移或存在转移高风险特征(如 Ki-67 高表达、血管侵犯、肿瘤大小>20 mm)的患者,不应尝试内镜下切除。这些患者应接受包括前述横断面成像、 68 Ga-SSA-PET-CT 在内的全面分期检查,并优先考虑外科手术治疗。Ki-67 的最佳临界值尚未确定,但 Ki-67 值超过 10%时应评估手术治疗的必要性。对于罕见的 I 型 G3 级胃神经内分泌肿瘤(gNET),由于高转移风险,推荐首选外科手术方案。 23 关于肿瘤大小,目前无法明确界定外科治疗的绝对临界值。在 I 型 gNET 亚组中,关于肿瘤大小与转移风险的数据有限。来自 SEER 数据库和台湾地区大型病例系列的数据表明,20 mm 的临界值与淋巴结转移风险增加相关。 13, 24

In case of incomplete endoscopic resection (R1) or risk features in final pathology after endoscopic resection, a surgical approach should be discussed with the patient to achieve R0 resection and/or resection of local lymph nodes to exclude metastatic spread. In cases of lesions not amenable to an endoscopic approach (e.g., location close to cardia) a primary surgical resection might be necessary.
在内镜切除不完全(R1)或内镜切除后最终病理显示存在风险特征的情况下,应与患者讨论手术方案,以实现 R0 切除和/或局部淋巴结切除以排除转移扩散。对于不适合内镜处理的病灶(如靠近贲门的位置),可能需要进行初次手术切除。

SSA treatment to reduce gastrin production, thus diminishing the stimulus for further tumour growth and progression, could be proposed in patients who could not undergo resection or for multiple larger tumours or frequent relapse. Antrectomy should no longer be routinely offered but might be an option in patients not tolerating SSA or declining continuous application.
对于无法接受切除术、多发较大肿瘤或频繁复发的患者,可考虑采用 SSA(生长抑素类似物)治疗以降低胃泌素分泌,从而减少肿瘤进一步生长和进展的刺激。胃窦切除术不再作为常规推荐,但对于无法耐受 SSA 治疗或拒绝持续用药的患者,仍可作为备选方案。

Recommendations  建议

  1. Surgical approach is recommended in tumours >20 mm or with suspected muscolaris propria invasion (either on axial imaging or EUS). In addition, surgery could be considered  (in tumours showing high risk features on biopsies (high Ki-67, lymphovascular invasion) (2b-A).
    对于肿瘤直径>20 毫米或疑似侵犯固有肌层(通过横断面影像学或超声内镜评估)的病例,建议采用手术干预。此外,若活检显示高风险特征(如 Ki-67 指数高、存在淋巴血管浸润),也可考虑手术治疗(证据等级 2b-A)。
  2. Limited resection with local nodal sampling is the preferred surgical strategy (3b-A).
    局限性切除联合局部淋巴结取样是首选的手术策略(证据等级 3b-A)。
  3. Gastrectomy with D2 lymphadenectomy (specific kind of resection according with the tumour site) should be discussed in patients with known lymph node metastases or might be proposed as a completion procedure after final histology has proven lymphatic spread after full exploration with cross sectional imaging (3b-A).
    对于已知淋巴结转移的患者,应讨论是否实施胃切除术联合 D2 淋巴结清扫(根据肿瘤具体位置选择相应术式);或在完成横断面影像学全面评估后,若最终病理证实存在淋巴扩散,也可将该术式作为补充性治疗措施(证据等级 3b-A)。

1.4 Type II gNETs
1.4 II 型胃神经内分泌肿瘤

Type II gNETs are the rarest type of gNET (5% of cases). They arise in the context of hypergastrinaemia associated with ZES which may occur in patients with MEN-I. Treatment of patients with type II gNETs strictly depends on the management of the MEN-I syndrome.25
II 型胃神经内分泌肿瘤(gNETs)是最罕见的类型(占病例的 5%)。它们发生在与佐林格-埃利森综合征(ZES)相关的高胃泌素血症背景下,后者可能出现在多发性内分泌腺瘤病 I 型(MEN-I)患者中。II 型 gNETs 患者的治疗严格取决于 MEN-I 综合征的管理。 25

1.5 Management strategy for type III gNETS
1.5 III 型胃神经内分泌肿瘤的管理策略

1.5.1 Background  1.5.1 背景

Type III gNETs have been traditionally regarded as highly aggressive tumours requiring extended surgical resections (i.e., partial or total gastrectomy) with lymphadenectomy. However, with the widespread use of high-definition endoscopy, type III gNETs of smaller size and lower grade are increasingly being detected. A recent systematic review of 147 type III gNENs in which tumour management was reported found that ~45% were G1, 35% were G2 and 20% were G3.26 As a result, less invasive treatment options, ranging from endoscopic resection to surgical wedge resection, have been investigated in highly selected patients. The management of type III gNETs is summarised in Figure 2.
III 型胃神经内分泌肿瘤(gNETs)传统上被视为高度侵袭性肿瘤,需进行扩大手术切除(如部分或全胃切除术)联合淋巴结清扫。然而,随着高清内镜的广泛应用,体积较小、分级较低的 III 型 gNETs 检出率日益增高。一项针对 147 例 III 型胃神经内分泌肿瘤(gNENs)治疗策略的系统综述显示,约 45%为 G1 级,35%为 G2 级,20%为 G3 级。 26 因此,在严格筛选的患者中,研究者已探索了从内镜切除到外科楔形切除等创伤性更小的治疗方案。III 型 gNETs 的治疗策略总结见图 2。

Details are in the caption following the image
Management of type III gastric neuroendocrine tumours (gNETs).
Ⅲ型胃神经内分泌肿瘤(gNETs)的管理。

1.5.2 Q5 – Can endoscopic treatments be proposed to treat type III gNETs?
1.5.2 问题 5 – 内镜治疗能否用于治疗Ⅲ型 gNETs?

Type III gNETs should be carefully characterised using endoscopy, biopsy, cross sectional thoracoabdominal CT and liver MRI, and often functional imaging (68Ga-SSA-PET-CT or FDG/PET-CT depending on tumour grade) and in most cases EUS. Evidence from several retrospective case series suggests that carefully selected patients who have no evidence of lymph node involvement can be safely and successfully managed by endoscopic resection. Endoscopic resection appears to be most appropriate in patients who have localised G1 tumours ≤10 mm in diameter, because tumours greater than this size are more likely to have lymph node metastases (even though these may not be detected by imaging techniques).26, 27 However endoscopic resection can also be considered in patients with slightly larger tumours (<15 mm) and low G2 (Ki-67 3–10%) histology, particularly if the risks of surgical resection are considered to be high.26 Current evidence does not support the use of a particular endoscopic resection technique (EMR vs. ESD).26 Some very small (<5 mm) tumours have also been unintentionally removed by avulsion biopsy with no evidence of subsequent tumour recurrence, but this approach is not generally recommended.26 Patients with positive resection margins (R1) should be considered for additional endoscopic resection or surgical salvage if appropriate. Patients who have undergone endoscopic resection should have close follow up with endoscopy and imaging (thoracoabdominal CT and liver MRI) to detect local and distant tumour recurrence.
Ⅲ型 gNETs 需通过内镜、活检、胸腹部 CT 平扫及肝脏 MRI 仔细评估,常需功能性影像(根据肿瘤分级选择 68 镓标记生长抑素类似物 PET-CT 或 FDG/PET-CT),多数情况下还需超声内镜(EUS)。多项回顾性病例系列研究证据表明,经严格筛选且无淋巴结转移证据的患者可安全成功地接受内镜切除治疗。内镜切除最适用于直径≤10 毫米的局限性 G1 级肿瘤,因为更大尺寸肿瘤更可能伴淋巴结转移(即便影像技术未能检出)。 26, 27 但对于稍大肿瘤(<15 毫米)及低增殖活性 G2 级(Ki-67 3-10%)患者,若手术风险较高,亦可考虑内镜切除。 26 现有证据未支持特定内镜切除技术(EMR vs. ESD)的优选性。 26 部分极小的肿瘤(<5 毫米)也曾因活检撕脱被无意中切除,且未见后续肿瘤复发迹象,但此方法通常不予推荐。 26 对于切缘阳性(R1)的患者,应考虑追加内镜切除或酌情进行手术补救。接受内镜切除的患者需通过内镜和影像学检查(胸腹 CT 及肝脏 MRI)密切随访,以监测局部及远处肿瘤复发。

Recommendations  建议

  1. Endoscopic resection may be considered in patients who have localised type III G1 gNETs ≤10 mm, and occasionally larger tumours with Ki-67 <10% and <15 mm in diameter if the risks of surgical resection are high provided adequate staging is allowed (3a–C).
    对于局限型 III 类 G1 级胃神经内分泌肿瘤(≤10 毫米)患者,可考虑内镜切除;若手术风险较高且肿瘤 Ki-67<10%、直径<15 毫米时,经充分分期评估后(3a–C 级证据),偶尔也可对较大肿瘤实施该术式。

1.5.3 Q6 – When should limited or extended surgical treatments be proposed to treat type III gNETs?
1.5.3 问题 6——何时应对 III 型胃神经内分泌肿瘤提出局限性或扩大性手术治疗方案?

Several clinicopathological features should be carefully evaluated to identify the best surgical option (limited vs. extended resection) for patients with type III gNETs.
需综合评估多项临床病理特征,以确定 III 型胃神经内分泌肿瘤患者的最佳手术方案(局限性切除 vs.扩大切除)。

A limited gastric wedge resection without standard lymphadenectomy can be considered as treatment option in patients with localised, G1 type III gNETs with no evidence of lymph node involvement on preoperative imaging (including EUS).26 In patients fulfilling the above-mentioned criteria, tumour size, depth of infiltration and presence of lymphovascular invasion should be further assessed to define the extent of surgical resection. Therefore, a wedge resection can be safely proposed to patients with G1 type III gNETs <20 mm, limited to the submucosal layer and with no evidence of lymphovascular invasion.26, 28 The role of wedge resections in patients with G2 type III gNETs remains debated, as tumour grade represents a powerful predictor of disease aggressiveness. Similarly, the tumour size cutoff for proposing limited surgical resection is not clearly defined. Type III gNETs <10 mm are usually managed with endoscopic resection, whereas a limited surgical resection might be considered as initial treatment option for lesions measuring >10 mm and <20 mm.26 Recent experiences report favourable oncological outcomes after endoscopic resection/limited surgical resection, thus strengthening the notion that a conservative approach might be appropriate for highly selected patients with type III gNETs.27, 29 In the presence of positive margins (R1) after endoscopic resection, salvage surgical wedge resection represents a possible treatment strategy.
对于术前影像学检查(包括超声内镜)未发现淋巴结受累的局限性 G1 型 III 类胃神经内分泌肿瘤患者,可考虑采用不进行标准淋巴结清扫的局限性胃楔形切除术作为治疗选择。 26 对于符合上述标准的患者,应进一步评估肿瘤大小、浸润深度及是否存在淋巴血管侵犯以确定手术切除范围。因此,对于肿瘤直径<20 毫米、局限于黏膜下层且无淋巴血管侵犯证据的 G1 型 III 类胃神经内分泌肿瘤患者,可安全推荐楔形切除术。 26, 28 楔形切除术在 G2 型 III 类胃神经内分泌肿瘤患者中的应用仍存争议,因为肿瘤分级是疾病侵袭性的重要预测指标。同样,推荐局限性手术切除的肿瘤大小临界值尚未明确定义。直径<10 毫米的 III 类胃神经内分泌肿瘤通常采用内镜切除处理,而对于直径>10 毫米且<20 毫米的病灶,可考虑将局限性手术切除作为初始治疗选择。 26 近期经验报告显示,内镜切除/局限性手术切除后肿瘤学结果良好,从而强化了对于经过严格筛选的 III 型胃神经内分泌肿瘤患者,保守治疗可能是合适选择的观点。 27, 29 在内镜切除后切缘阳性(R1)的情况下,补救性手术楔形切除是一种可能的治疗策略。

Radical surgical resection, either total or subtotal gastrectomy, with lymphadenectomy represents the procedure of choice for all the patients diagnosed with type III gNETs showing at least one of the following features: (1) nodal or distant metastases on preoperative imaging, (2) Ki-67 proliferative index defining a G3 tumour (Ki-67 >20%), and (3) tumour size >20 mm. Radical surgery is recommended as second-line treatment when final histology reveals one or more of the following findings: presence of nodal metastases, higher tumour grade compared with original biopsy, lymphovascular invasion or lack of complete tumour clearance (R1), in patients initially managed with a limited wedge resection.26
对于诊断为 III 型胃神经内分泌肿瘤且至少符合以下任一特征的患者,根治性手术切除(全胃或次全胃切除术联合淋巴结清扫)是首选治疗方案:(1)术前影像学显示淋巴结或远处转移,(2)Ki-67 增殖指数界定为 G3 肿瘤(Ki-67 >20%),(3)肿瘤大小>20 mm。对于初始接受局限性楔形切除术的患者,若最终病理学检查发现以下一项或多项结果:存在淋巴结转移、肿瘤分级较原活检升高、淋巴血管侵犯或肿瘤未完全切除(R1),则推荐将根治性手术作为二线治疗。

Recommendations  建议

  1. A limited wedge resection with local nodal sampling (without standard lymphadenectomy) can be considered as a treatment option in patients with localised, G1–G2 type III gNETs, with no evidence of lymphadenopathy on full staging preoperative imaging (including EUS) (2b-B).
    对于局限型、G1-G2 级 III 型胃神经内分泌肿瘤患者,若术前全面分期影像学检查(包括超声内镜)未发现淋巴结肿大,可考虑采用局限性楔形切除联合局部淋巴结取样(不进行标准淋巴结清扫术)作为治疗方案(2b-B 级证据)。
  2. Radical surgical resection with lymphadenectomy is recommended in type III gNETs when nodal metastases are found/suspected on preoperative staging, if Ki67 >20% or tumour diameter >20 mm (2b-B).
    当 III 型胃神经内分泌肿瘤术前分期发现或怀疑存在淋巴结转移,或 Ki67 指数>20%、肿瘤直径>20 毫米时,推荐实施根治性手术切除联合淋巴结清扫术(2b-B 级证据)。

1.5.4 Q7 – What scheduled follow-up is recommended after endoscopic/surgical resection of type III gNETs?
1.5.4 问题 7——III 型胃神经内分泌肿瘤内镜/手术切除后建议采用何种规范化随访方案?

Follow-up of patients who underwent surgical resection of type III gNETs is based on contrast-enhanced cross-sectional imaging (thoracoabdominal CT/liver-MRI with sometimes OGD and/or EUS or functional imaging [68Ga-SSA-PET-CT and/or FDG-PET/CT depending on the tumour grade]). The timing of follow-up has never been clearly defined. When a total gastrectomy with lymphadenectomy is performed, the follow-up schedule adopted for gastric adenocarcinoma should be applied.26 On the other hand, patients managed conservatively (endoscopic or surgical local excision) should undergo OGD after about 3 months to check the resection site and if this shows no macroscopic residual tumour, they should have regular follow-up with cross-sectional imaging and endoscopy/EUS. The frequency and choice of test will be influenced by the final tumour size and grade as well as patient fitness and in most cases, it will be possible to reduce the frequency of follow up as time progresses after resection. 68Ga-SSA-PET-CT (or FDG-PET/CT depending on the tumour grade) and biopsies should be performed in the presence of a suspected disease relapse, but they are not routinely part of the follow-up programme.30
对接受手术切除的 III 型胃神经内分泌肿瘤(gNETs)患者的随访基于增强横断面成像(胸腹部 CT/肝脏 MRI,有时结合 OGD 和/或 EUS 或功能成像[根据肿瘤分级选用 68 Ga-SSA-PET-CT 和/或 FDG-PET/CT])。随访时间从未明确定义。若实施全胃切除加淋巴结清扫术,应采用胃癌的随访方案。 26 另一方面,保守治疗(内镜或手术局部切除)的患者应在约 3 个月后接受 OGD 检查切除部位,若无宏观残留肿瘤,则定期进行横断面成像和内镜/EUS 随访。检查频率和选择取决于最终肿瘤大小、分级及患者身体状况,多数情况下可随术后时间推移减少随访频次。 68 Ga-SSA-PET-CT(或根据肿瘤分级选用 FDG-PET/CT)和活检应在疑似复发时进行,但非常规随访项目。 30

Recommendations  建议

  1. Radiological follow-up by contrast-enhanced CT or MRI is recommended in patients treated by surgical resection for type III gNETs (5-A).
    对于接受手术切除治疗的 III 型胃神经内分泌肿瘤患者,推荐采用对比增强 CT 或 MRI 进行放射学随访(5-A 级证据)。

2 DUODENAL NEUROENDOCRINE TUMOURS
2 十二指肠神经内分泌肿瘤

2.1 Introduction – general background
2.1 引言——基本背景

Like gNETs, duodenal neuroendocrine tumours (dNETs) are rare tumours but also with an increasing incidence found mostly at OGD or axial imaging for other reasons (incidental discovery) but also can be found as primaries at workup for patients with stage 4 diseases or more rarely as part of inherited syndromes such as MEN-I and neurofibromatosis type 1 (NF1). Most dNETs are non-functional tumours, but duodenal tumours secreting gastrin are not infrequent (either sporadic or as part of MEN-I) and more rarely tumours secreting somatostatin (so called somatostatinomas) (see Guidance paper on functional pancreatic NETs).
与胃神经内分泌肿瘤(gNETs)类似,十二指肠神经内分泌肿瘤(dNETs)虽属罕见肿瘤,但其发病率亦呈上升趋势,多数病例是在进行上消化道内窥镜检查或轴向影像学检查时因其他原因偶然发现(偶发检出),也可作为 4 期疾病患者检查时的原发病灶被检出,极少数情况下作为多发性内分泌腺瘤病 1 型(MEN-I)或 1 型神经纤维瘤病(NF1)等遗传综合征的组成部分。大多数 dNETs 为非功能性肿瘤,但分泌胃泌素的十二指肠肿瘤并不少见(散发性或作为 MEN-I 的一部分),更为罕见的则是分泌生长抑素的肿瘤(即所谓生长抑素瘤)(参见功能性胰腺 NETs 指南文件)。

The overall incidence of dNETs is low accounting for only 2.8% of all NETs.31, 32 The annual age adjusted incidence for dNET has been reported to be 0.19 per 100,000.32 Traditionally, dNETs have been classified into non-functioning (approximately 90% of lesions) or functioning tumours (those secreting specific peptides of hormones eliciting a functional clinical consequence or syndrome)33 and can be summarised as:
dNETs 总体发病率较低,仅占所有 NETs 的 2.8%。 31, 32 据报道,dNET 的年龄调整年发病率为每 10 万人 0.19 例。 32 传统上,dNETs 被分为非功能性(约占病变的 90%)或功能性肿瘤(那些分泌特定肽类或激素并引发功能性临床症状或综合征的肿瘤) 33 ,可概括为:
  1. Non-functioning dNETs (they can secrete peptides and substances not resulting in a clinical condition or syndrome).
    非功能性 dNETs(它们可能分泌不会导致临床病症或综合征的肽类和其他物质)。
  2. Duodenal composite gangliocytoma/neuroma and neuroendocrine tumour (CogNET) (previously known as gangliocytic paraganglioma), occurs almost exclusively in the second part of the duodenum and periampullary region and is considered a composite tumour of epithelial NETs and ganglioneuroma.34
    十二指肠复合性神经节细胞瘤/神经瘤与神经内分泌肿瘤(CogNET)(旧称节细胞性副神经节瘤)几乎仅发生于十二指肠第二段及壶腹周围区域,被认为是由上皮性神经内分泌肿瘤与神经节细胞瘤组成的复合性肿瘤。 34
  3. Duodenal gastrinoma (gastrin secreting and either sporadic or part of MEN-I where duodenal localisation is very frequent) and somatostatinomas (not discussed in the present paper, see guidance paper on functioning pancreatic NETs).
    十二指肠胃泌素瘤(分泌胃泌素,可为散发性或 MEN-I 综合征的一部分,后者十二指肠部位极为常见)及生长抑素瘤(本文未讨论,参见功能性胰腺神经内分泌肿瘤指南文件)。
  4. Duodenal NEC (not discussed in the present paper, see guidance paper for digestive neuroendocrine carcinomas35).
    十二指肠神经内分泌癌(本文未讨论,参见消化系统神经内分泌癌指南文件 35 )。

2.2 Assessment of dNETs
2.2 十二指肠神经内分泌肿瘤的评估

2.2.1 Pathology  2.2.1 病理学

Pathological assessment and grading of dNETs is like that of NETs of all other sites. Adequate sampling is needed and the deep mucosal location of these lesions, usually suspected by the endoscopist due to the smooth surface as opposed to the more common adenomas and carcinomas of the duodenum, warrants an attempt to perform deep biopsies. Morphologically, the main differential diagnosis in the duodenum is the CoGNET, previously classified as a ganglioneuroma or paraganglioma, but now shown to be more similar to NETs.36, 37
十二指肠神经内分泌肿瘤(dNETs)的病理评估与分级与其他部位 NETs 相同。需进行充分取材,由于这类病变通常位于黏膜深层(内镜医师可通过其表面光滑特征与更常见的十二指肠腺瘤/癌进行鉴别),建议尝试深部活检。形态学上,十二指肠区主要需与节细胞性神经内分泌肿瘤(CoGNET)鉴别,该肿瘤曾归类为神经节瘤或副神经节瘤,现证实更接近 NETs。 36, 37

In cases with a high proliferation rate (i.e., mitotic count >20 in 2 mm2 and/or Ki-67 index >20%), NEC and adenocarcinoma with neuroendocrine features should be ruled out (see guidance paper for digestive neuroendocrine carcinomas35).
若增殖活性较高(即 2mm²内核分裂象>20 个 2 和/或 Ki-67 指数>20%),需排除神经内分泌癌(NEC)及伴神经内分泌特征的腺癌(参见消化系统神经内分泌癌指南 35 )。

2.2.2 Endoscopy  2.2.2 内镜检查

Most dNETs are in the first or second part of the duodenum.38 Symptoms range from mostly none at incidental discovery to symptoms attributed to gastric outlet obstruction (in rare cases of large lesions) or anaemia. Patients with dNETs close to the ampulla and CoGNET which occur in the periampullary region can present with gastrointestinal bleeding, abdominal pain, anaemia or jaundice.38, 39 Periampullary dNETs are not infrequent in patients with neurofibromatosis type 1 (NF1), also known as Von Recklinghausen's disease including somatostatinomas.40, 41
大多数十二指肠神经内分泌肿瘤(dNETs)位于十二指肠的第一或第二部分。 38 症状从偶然发现的无症状到罕见大病灶引起的胃出口梗阻症状或贫血不等。靠近壶腹及壶腹周围发生的 CoGNET 患者可表现为消化道出血、腹痛、贫血或黄疸。 38, 39 壶腹周围 dNETs 在 1 型神经纤维瘤病(NF1,又称 Von Recklinghausen 病)患者中并不罕见,包括生长抑素瘤。 40, 41

At OGD, dNETs have similar features to gNETs but are typically single small sessile, erythematous or pale lesions in the duodenal cap, bulb or D1 to D2.6 In recent years, increasingly smaller lesions have been detected, owing to the better mucosal visualisation with modern endoscopic tools. The reported mean size of dNETs varies between 7 mm and 1.5 cm.42 Up to 10% of dNETs can occur as multiple tumours, which should prompt a diagnosis of MEN-I. It has been reported that approximately a quarter to a third of patients with dNETs and ZES, have undiagnosed MEN-I.43, 44
胃镜检查中,dNETs 与胃神经内分泌肿瘤(gNETs)特征相似,但通常表现为十二指肠球部、球帽或 D1 至 D2 段的单发小型无蒂、红斑或苍白病灶。 6 近年来,随着现代内镜工具对黏膜可视化能力的提升,检测到的病灶越来越小。文献报道 dNETs 的平均大小在 7 毫米至 1.5 厘米之间。 42 多达 10%的 dNETs 可表现为多发性肿瘤,这种情况应提示多发性内分泌腺瘤病 I 型(MEN-I)的诊断。据报道,约四分之一至三分之一的 dNETs 合并胃泌素瘤(ZES)患者存在未确诊的 MEN-I。 43, 44

Endoscopic characterisation of dNETs has been described by Borbath and colleagues.6 Diagnosis is usually confirmed at endoscopic forceps biopsy (care as very small lesions may be almost completely excised at biopsy sampling and making future identification hard in case of R1 resection). Tumours of 1 cm or above should have accurate local staging by EUS as regional lymph node metastases occur in up to 40%–60% of cases, especially in duodenal gastrinomas.43, 45, 46
Borbath 及其同事描述了 dNETs 的内镜特征。 6 诊断通常通过内镜钳活检确认(需注意极小的病灶可能在活检取样时几乎被完全切除,导致 R1 切除后难以再次识别)。对于 1 厘米或更大的肿瘤,应通过超声内镜(EUS)进行精确的局部分期,因为区域淋巴结转移发生率高达 40%-60%,尤其是十二指肠胃泌素瘤。 43, 45, 46

Recommendations  建议

Evaluation of dNETs should always include:
对 dNETs 的评估必须包括:
  1. Biopsies to confirm the diagnosis and to evaluate proliferative activity of the tumour (Ki-67 and/or mitotic count) for grading (2b-A).
    通过活检确认诊断并评估肿瘤增殖活性(Ki-67 指数和/或有丝分裂计数)以进行分级(2b-A 级推荐)。
  2. Endoscopic assessment of dNETs should include tumour location to identify periampullary tumours (2b-A).
    dNETs 的内镜评估应包括肿瘤定位,以识别壶腹周围肿瘤(2b-A 级推荐)。
  3. EUS is recommended in tumours >1 cm (3b-B).
    对于直径>1 厘米的肿瘤,推荐进行超声内镜检查(3b-B 级证据)。

2.2.3 Imaging and laboratory examinations
2.2.3 影像学与实验室检查

Duodenal NETs are generally diagnosed by endoscopy and endoscopic ultrasound. Computed tomography after ingestion of water to fill stomach and duodenum, is recommended to help preoperative exploration. CT-enterography, MRI, 68Ga-SSA-PET-CT and 18F-DOPA-PET/CT are not sufficiently accurate for localisation of well-differentiated gastroduodenal primary tumours,47-49 but these examinations are used to help staging of regional and distant metastases.50
十二指肠神经内分泌肿瘤(NETs)通常通过内镜和超声内镜诊断。建议术前采用饮水充盈胃十二指肠后的计算机断层扫描(CT)辅助探查。CT 小肠造影、磁共振成像(MRI)、 68 镓标记生长抑素类似物 PET-CT 及 18 氟代多巴 PET/CT 对于高分化胃十二指肠原发肿瘤的定位准确性不足, 47-49 但这些检查可用于评估区域性和远处转移的分期。 50

Laboratory tests are required for patients newly diagnosed with dNET. It is especially important to recognise potential gastrinoma (serum gastrin, chromogranin and occasionally secretin testing). Other laboratory tests, if symptoms are suggestive, may include somatostatin, and very rarely growth hormone releasing factor and cortisol with urinary 5-hydoxyindoleacetic acid.38 If a diagnosis of genetic syndrome is suspected (e.g., MEN-I or NF1) specific laboratory tests and germline testing is advised38, 51 Distinguishing between dNET and neurofibromas may be difficult in some cases especially on axial imaging.
新确诊的十二指肠 NET 患者需进行实验室检测。尤其需识别潜在的胃泌素瘤(血清胃泌素、嗜铬粒蛋白及必要时胰泌素激发试验)。若存在相关症状,其他实验室检测可能包括生长抑素测定,极少数情况下需检测生长激素释放因子、皮质醇及尿 5-羟基吲哚乙酸。 38 若怀疑遗传综合征(如多发性内分泌腺瘤病 1 型或神经纤维瘤病 1 型),建议进行特异性实验室检测和胚系基因检测。 38, 51 在某些病例中,尤其是轴位影像学检查时,区分十二指肠 NET 与神经纤维瘤可能存在困难。

Recommendations  建议

  1. Locoregional and distant staging examiner actions for dNETs include contrast-enhanced CT (with water ingestion), liver -MRI and 68Ga-SSA-PET-CT (3b-B).
    十二指肠神经内分泌肿瘤(dNETs)的局部区域和远处分期检查手段包括:对比增强 CT(需饮水)、肝脏 MRI 以及 68Ga-SSA-PET-CT(3b-B 级证据)。
  2. Ruling out gastrinoma and screening for genetic syndromes when appropriate should be considered for dNETs (3b-B).
    对于 dNETs 患者,应考虑排除胃泌素瘤并在适当时进行遗传综合征筛查(3b-B 级证据)。

2.3 Management strategy for dNETs
2.3 十二指肠神经内分泌肿瘤(dNETs)的治疗策略

Factors that need to be considered prior to endoscopic resection of dNET are:
在内镜切除 dNET 前需评估以下因素:
  1. Size of tumour (commonly estimated at EUS and OGD).
    肿瘤大小(通常通过超声内镜和胃镜检查评估)。
  2. Depth of invasion in relation to the deep muscle layer (estimated at EUS).
    肿瘤浸润深度与深肌层的关系(通过超声内镜评估)。
  3. Any evidence of lymphadenopathy and/or metastatic spread on EUS, liver-MRI, thoracoabdominal CT and functional imaging, preferably 68Ga-SSA-PET-CT.
    内镜超声(EUS)、肝脏 MRI、胸腹部 CT 及功能成像(首选 68 Ga-SSA-PET-CT)显示淋巴结病变和/或转移扩散的任何证据。
  4. Grade and morphology of tumour (determined by endoscopy, EUS and endoscopic biopsy).
    肿瘤分级及形态学特征(通过内镜检查、超声内镜及内镜下活检确定)。
  5. Endoscopic appearance: central depression/ulceration implies invasion.
    内镜下表现:中央凹陷/溃疡提示浸润性生长。
  6. Suitability for endoscopic resection: size of lesion/endoscopic access/location of lesion/proximity to ampulla.
    内镜切除的适用性:病灶大小/内镜可及性/病灶位置/与壶腹的接近程度。
  7. Hormone secretion status.
    激素分泌状态
  8. Patient age and performance status.
    患者年龄与体能状态

Size of the lesion is not a definitive guide to the correct treatment. Treatment options are: endoscopic surveillance, endoscopic resection (by EMR/ESD/underwater EMR/over the scope clip), local duodenal resection (LR) or pancreatoduodenectomy (PD). The outcomes may be related to the factors of the tumour at presentation rather than the type of resection procedure.52 The management of dNETs is summarised in Figure 3.
病变大小并非决定正确治疗的绝对标准。治疗选项包括:内镜监测、内镜下切除(通过 EMR/ESD/水下 EMR/套扎器)、局部十二指肠切除术(LR)或胰十二指肠切除术(PD)。治疗结果可能与肿瘤呈现时的特征相关,而非切除手术的类型。 52 dNETs 的管理总结见图 3。

Details are in the caption following the image
Management of duodenal neuroendocrine tumours (dNETs).
十二指肠神经内分泌肿瘤(dNETs)的管理。

When defining surgical indications for dNET, several key points should be considered (see section 8.3).
在确定 dNET 手术适应症时,应考虑几个关键点(参见第 8.3 节)。

2.3.1 Q8 – When is endoscopic resection indicated?
2.3.1 Q8 – 何时需要内镜下切除?

Very small non-functioning lesions 5 mm or less in D1 are commonly removed after lifting injection and snare (or by diagnostic biopsy) before any histological diagnosis is made and these lesions do not usually recur or metastasise.
直径 5 毫米或更小的 D1 区非功能性微小病灶通常在未进行组织学诊断前,通过注射抬举后圈套切除(或诊断性活检)即可清除,这些病灶通常不会复发或转移。

For younger and fitter patients who have lesions of 5–10 mm (and up to 15 mm in some centres), an opinion should be sought from therapeutic endoscopy about resection and the associated risks. EUS should be performed as well as axial and functional imaging. Most of these lesions are grade 1 and not invading the muscle layer. In these circumstances an endoscopic resection using EMR/Cap EMR/ESD is reasonable, but risks of perforation are significant, especially in D2. If endoscopic therapy is high risk (published rates of perforation 15%–25%) or unlikely to be curative, LR (i.e., duodenotomy with tumour excision or enucleation) or pancreatoduodenectomy (PD) (if considered essential by the surgeon) should be considered. Endoscopic therapy combined with laparoscopy for rescue in the event of perforation has been performed which may represent a novel and valuable alternative to ESD, able to guarantee a high R0 rate and a low risk of intraoperative duodenal perforation.53
对于病灶大小为 5-10 毫米(部分医疗中心放宽至 15 毫米)且身体状况较好的年轻患者,应咨询治疗性内镜专家关于切除手术及相关风险的评估意见。需同时进行超声内镜(EUS)检查以及轴位和功能成像检查。此类病灶多为 1 级且未侵犯肌层。在此情况下,采用 EMR/帽式 EMR/ESD 进行内镜下切除是合理的,但穿孔风险较高(尤其在十二指肠第二段)。若内镜治疗存在高风险(文献报道穿孔率为 15%-25%)或难以达到根治效果,则应考虑局部切除(即十二指肠切开肿瘤切除术或剜除术)或胰十二指肠切除术(PD)(外科医生认为必要时)。已有研究采用内镜治疗联合腹腔镜穿孔补救方案,这可能成为 ESD 的新型替代方案,既能保证较高的 R0 切除率,又可降低术中十二指肠穿孔风险。 53

Duodenal NETs can be multiple, particularly if they are gastrinomas, and an association with MEN-I exists. Somatostatinomas can also occur in the duodenum, often close to the ampulla, but generally are without a clinical syndrome. There is an association with NF1 (functioning tumours are being addressed in a separate guidance paper on pancreatic functional NETs).
十二指肠 NETs 可为多发性,尤其当其为胃泌素瘤时,且与 MEN-I 存在关联。生长抑素瘤也可发生于十二指肠,通常靠近壶腹部,但通常不伴随临床综合征。该类肿瘤与 NF1 相关(功能性肿瘤的处理详见另一份关于胰腺功能性 NETs 的指南文件)。

Recommendations  建议

  1. Very small non-functioning tumours in D1 should be removed using EMR type techniques (3b-C).
    D1 部位的非常小的无功能肿瘤应使用 EMR 类技术切除(3b-C)。
  2. Lesions of 5–10 mm (and up to 15 mm in some centres) can be removed endoscopically after imaging work-up, but risks are relatively high (3b-C).
    5-10 毫米的病灶(在某些中心可达 15 毫米)在影像学检查后可通过内镜切除,但风险相对较高(3b-C)。

2.3.2 Q9 – Can a “watch and wait” strategy be proposed in dNETs?
2.3.2 Q9 – 对于 dNETs,是否可以采取“观察等待”策略?

A watch and wait policy could be considered for very small (<5 mm) dNETs that cannot easily be resected, are non-functional, G1 and not invading the muscularis propria. This policy has usually been applied in patients unfit for endoscopic resection or surgery, since a more definitive therapy would be recommended in most cases, although a watch and wait policy has more recently been recommended as a result from some small series with limited follow-up. It is not clear if watch and wait is a suitable option in a patient who is fit for resection.54, 55
对于无法轻易切除、无功能、分级为 G1 且未侵犯固有肌层的极小型(<5 毫米)十二指肠神经内分泌肿瘤(dNETs),可考虑采取观察等待策略。该策略通常适用于不适合内镜切除或手术的患者,因为在大多数情况下会推荐更明确的治疗方案,不过近期一些随访有限的小型研究也建议采用观察等待策略。目前尚不清楚观察等待是否适合适合切除的患者。 54, 55

Recommendations  建议

There is very limited evidence for a watch and wait policy and generally this is applied to those unfit for surgery or endoscopic resection (3b-C).
关于“观察等待”策略的证据非常有限,通常仅适用于不适合手术或内镜切除的患者(证据等级 3b-C)。

2.3.3 Q10 – When is surgery indicated?
2.3.3 Q10 – 何时需要手术干预?

Data on nodal risk in very small non-functioning dNETs are scarce. Some series report nodal metastases as a common finding in patients with dNET (40%–60%), with tumour size being the most relevant risk factor for nodal involvement.56 In cases with a tumour diameter >1 cm, nodal metastases were found in 13 out of 18 cases. Tumour location may be another important feature to be considered when defining surgical indication. Lesions arising in the ampullary/periampullary area differ from other dNETs due to a more aggressive biological behaviour in some studies57 but not in others.56 Functioning neoplasms harbour a higher metastatic potential.58 Tumour invasion beyond the submucosa, tumour grade G2–G3 and lymphovascular invasion are factors affecting the risk of nodal metastases.
关于极小型无功能性十二指肠神经内分泌肿瘤(dNETs)淋巴结转移风险的数据较少。部分研究系列报告显示,dNET 患者淋巴结转移较为常见(40%–60%),其中肿瘤大小是淋巴结受累的最主要风险因素。 56 在肿瘤直径>1 厘米的病例中,18 例中有 13 例发现淋巴结转移。肿瘤位置可能是决定手术适应症时需考虑的另一重要特征。起源于壶腹/壶腹周围区域的病变在某些研究中表现出更具侵袭性的生物学行为 57 ,但其他研究未得出相同结论 56 。功能性肿瘤具有更高的转移潜能 58 。肿瘤浸润超出黏膜下层、肿瘤分级 G2–G3 以及淋巴血管侵犯是影响淋巴结转移风险的因素。

Despite very low grade evidence surgical resection may be indicated in patients with dNETs showing any of the following features:
尽管证据等级非常低,但对于表现出以下任一特征的 dNET 患者,可能建议进行手术切除:
  1. Tumour size >10 mm; (some centres may advocate endoscopic removal in 10–15 mm).
    肿瘤大小超过 10 毫米(部分医疗中心可能建议对 10-15 毫米的肿瘤进行内镜下切除)。
  2. Tumour extending beyond the submucosa.
    肿瘤浸润至黏膜下层以外。
  3. Tumour grade G2–G3.  肿瘤分级为 G2-G3 级。
  4. Lymphovascular invasion.
    存在淋巴血管侵犯。
  5. Functioning neoplasms.  功能性肿瘤。

Regarding the extent of resection, PD (pancreatoduodenectomy) and LR (local resection) represent the two main alternatives:
关于切除范围,PD(胰十二指肠切除术)和 LR(局部切除术)是两种主要选择:

In general, pancreatoduodenectomy with lymphadenectomy is the procedure of choice for ampullary/periampullary neoplasms, due to their particular aggressiveness. When nodal metastases are pre- or intraoperatively identified, PD with nodal dissection is indicated in order to obtain a proper oncological clearance. However, for lesions <20 mm, less aggressive approaches (i.e., local excision with lymphadenectomy or pancreas-sparing total duodenectomy) may be considered options. At least eight lymph nodes should be harvested to stage patients accurately.59 However, radical surgery is associated with a high rate of short- and long-term complications. Therefore, when feasible from an oncological perspective, other surgical strategies should be considered.
一般而言,胰十二指肠切除术联合淋巴结清扫是壶腹部/壶腹周围肿瘤的首选术式,因其具有特殊的侵袭性。若术前或术中确认存在淋巴结转移,则需行胰十二指肠切除术联合淋巴结清扫以确保充分的肿瘤学切缘。但对于<20 毫米的病灶,可考虑创伤性较小的替代方案(如局部切除联合淋巴结清扫或保留胰腺的全十二指肠切除术)。为准确分期,至少应获取 8 枚淋巴结。 59 然而,根治性手术伴随较高的短期及长期并发症发生率。因此,在肿瘤学允许的情况下,应考虑其他手术策略。

Local duodenal resection (i.e., duodenotomy with tumour excision or enucleation) represents a valuable and safe option, especially for patients with non-ampullary, non-functioning, dNET and without suspected nodal involvement at staging,52 (where endoscopic resection is not possible). The role of nodal dissection in this setting is unclear as recent experience does not support the clearance of occult nodal metastases due to lack of association with survival advantages.60
局部十二指肠切除术(即十二指肠切开术联合肿瘤切除或剜除术)是一种有效且安全的选择,尤其适用于非壶腹、无功能、无淋巴结转移迹象的十二指肠神经内分泌肿瘤患者(当内镜下切除不可行时)。 52 在此情况下,淋巴结清扫的作用尚不明确,因为近期经验表明,由于缺乏生存获益关联,清除隐匿性淋巴结转移并无必要。 60

Recommendations  建议

  1. Surgery is recommended in cases of size >10–15 mm and/or tumour extending beyond the submucosa and/or grade G2-G3 and/or lymphovascular invasion (3-B).
    对于肿瘤大小超过 10-15 毫米和/或肿瘤超出黏膜下层和/或分级为 G2-G3 和/或存在淋巴血管侵犯的情况,建议进行手术(3-B)。

3 MANAGEMENT STRATEGY FOR GASTRIC AND DUODENAL G2–G3 METASTATIC NETS
3 胃和十二指肠 G2-G3 转移性神经内分泌肿瘤的管理策略

3.1 Treatment with curative intent
3.1 以治愈为目的的治疗

Due to the lack of effective systemic therapeutic options surgery should be evaluated even in the presence of metastatic condition depending on the tumour spread and tumour biology if a complete tumour resection seems to be possible (R0-resection).
由于缺乏有效的全身治疗选择,即使在转移情况下,如果肿瘤扩散和肿瘤生物学特性显示完全切除(R0 切除)可能实现,也应考虑手术评估。

Gastrectomy with D2-lymphadenectomy includes the removal of locoregional lymph nodes, so the presence of locoregional lymph node metastases should not preclude surgery as a treatment option. In dNET a transduodenal tumour excision with lymph node sampling or pancreatoduodenectomy are the treatments of choice.30 The complete resection of single or multiple liver metastases might be beneficial even for G3 tumours.61 Thus, surgical resection should be evaluated in G2 and in very selected cases of G3-NET depending on the general health condition of the patient. Single or multiple metastases in other locations should be evaluated for a complete resection.
胃切除术联合 D2 淋巴结清扫术包括切除局部淋巴结,因此局部淋巴结转移的存在不应排除手术作为治疗选择。对于十二指肠神经内分泌肿瘤(dNET),经十二指肠肿瘤切除联合淋巴结取样或胰十二指肠切除术是首选治疗方法。 30 即使是 G3 级肿瘤,完全切除单个或多个肝转移灶也可能有益。 61 因此,应根据患者的整体健康状况评估 G2 级及严格筛选的 G3 级神经内分泌肿瘤(NET)患者的手术切除可行性。其他部位的单个或多个转移灶也应评估是否适合完全切除。

3.2 Widespread metastatic disease
3.2 广泛转移性疾病

In the presence of metastases, a systemic therapeutic approach is similar to that recommended for advanced/unresectable NET from other primary sites, owing to the lack of available data in homogeneous series of gastric or duodenal NETs. Somatostatin analogues are indicated for NETs G1–G2 with low Ki67 (<10%), and positive somatostatin receptors but can be administered in tumours with higher Ki-67 if slow tumour growth or slow progression are seen. Peptide receptor radionuclide therapy (PRRT) is a valid option depending on the receptor status of the tumour. Molecular-targeted therapy with everolimus is a therapeutic option, but with limited evidence.62 In NET G3 chemotherapy should be administered.63
在存在转移的情况下,由于缺乏关于胃或十二指肠神经内分泌肿瘤(NETs)同质系列的数据,系统性治疗方法与其他原发部位晚期/不可切除 NETs 的推荐方案相似。生长抑素类似物适用于 Ki67 较低(<10%)且生长抑素受体阳性的 G1-G2 级 NETs,但如果观察到肿瘤生长或进展缓慢,也可用于 Ki-67 较高的肿瘤。肽受体放射性核素治疗(PRRT)根据肿瘤受体状态是一种有效选择。依维莫司的分子靶向治疗是一种治疗选择,但证据有限。 62 对于 G3 级 NETs,应进行化疗。 63

3.3 Palliative primary tumour resection
3.3 姑息性原发肿瘤切除术

In cases of unresectable distant metastases a palliative primary tumour resection can be considered rarely to avoid local complications. The kind and extent of surgery has to be evaluated depending on the location of the tumour and possibility of complications of surgery. A gastrectomy can be necessary in rare cases but a wedge resection, distal or subtotal gastric resection should be preferred to reduce perioperative morbidity. A gastric bypass without tumour resection should be favoured in case of bulky disease with infiltration of the visceral arteries or pancreas.
对于无法切除的远处转移病例,极少情况下可考虑姑息性原发肿瘤切除术以避免局部并发症。手术方式及范围需根据肿瘤位置和手术并发症可能性进行评估。胃切除术在极少数情况下是必要的,但为降低围手术期发病率,应优先选择楔形切除、远端胃切除或次全胃切除术。若存在大块病变且浸润内脏动脉或胰腺,则更倾向于不切除肿瘤的胃旁路手术。

3.4 Local recurrence  3.4 局部复发

In the presence of local recurrence without diffuse metastatic spread, operative resection should be favoured to avoid bleeding or intestinal obstruction and to maintain quality of life. Even in the presence of distant metastatic spread palliative surgery should be considered to ensure quality of life depending on the tumour biology and the general health status of the patient. Endoscopic procedures such as stent or jejunal catheterisation are alternatives for patients with a poor general health status.
若出现局部复发但无弥漫性转移扩散,应优先选择手术切除以避免出血或肠梗阻,并维持生活质量。即使存在远处转移,也应根据肿瘤生物学特性和患者整体健康状况考虑姑息性手术以保障生活质量。对于一般健康状况较差的患者,可选用支架置入或空肠导管置入等内镜手术作为替代方案。

3.5 Follow-up  3.5 随访

The interval for follow-up by contrast-enhanced thoracoabdominal CT and/or liver-MRI, 3–12 months, should be based on the malignant potential of the tumour.64 Follow-up by additional 68Ga-SSA-PET-CT is helpful when the patient's clinical status and the results of CT or MRI and biochemistry are discordant. The sensitivity of 68Ga-SSA-PET-CT is superior to contrast-enhanced thoracoabdominal CT for characterisation and detection of lymph node metastases and for visualisation of metastases to bone and liver,65 and therefore provides earlier detection of new lesions. FDG-PET/CT is instead used in G3 tumours and can also be helpful in high G2 NET when 68Ga-SSA-PET-CT is negative. Re-evaluation of untreated patients should be performed at 3–6 month intervals.
随访间隔应根据肿瘤的恶性潜能,通过对比增强胸腹 CT 和/或肝脏 MRI 进行,时间为 3-12 个月。 64 当患者的临床状态与 CT、MRI 及生化检查结果不一致时,额外的 68 Ga-SSA-PET-CT 随访有助于诊断。 68 Ga-SSA-PET-CT 在淋巴结转移的特征识别、检测以及骨和肝转移的可视化方面,其敏感性优于对比增强胸腹 CT, 65 因此能更早发现新病灶。对于 G3 肿瘤,则使用 FDG-PET/CT,且在 68 Ga-SSA-PET-CT 结果为阴性时,对高 G2 NET 也有帮助。未接受治疗的患者应每 3-6 个月重新评估一次。

Recommendations  建议

1. Surgery with curative intention of metastatic gastroduodenal NET G1/G2/G3 should be performed, if a complete tumour (including metastases) resection seems feasible (4-B).
1. 如果肿瘤(包括转移灶)完全切除可行,则应进行具有治愈意图的胃十二指肠神经内分泌肿瘤 G1/G2/G3 转移灶手术(4-B)。
  1. Palliative surgery (primary resection, bypass) may be indicated in metastatic disease to maintain quality of life (4-C).
    对于转移性疾病,为维持生活质量可考虑姑息性手术(原发灶切除、旁路手术)(4-C 级证据)。
  2. The choice of systemic therapy for metastatic gastroduodenal NET depends on tumour grading and includes biotherapy, everolimus, PRRT and chemotherapy (4-B).
    转移性胃十二指肠神经内分泌肿瘤的系统治疗方案选择需依据肿瘤分级,包括生物治疗、依维莫司、肽受体放射性核素治疗(PRRT)及化疗(4-B 级证据)。

4 CONCLUSIONS  4 结论

4.1 Gastric NETs  4.1 胃神经内分泌肿瘤

  1. Evaluation of the type of gNETs by assessing separate biopsies from the antral and fundic mucosa is needed.
    需要通过分别对胃窦和胃底黏膜进行活检来评估胃神经内分泌肿瘤(gNETs)的类型。
  2. Endoscopic resection should be proposed in type I gNETs larger than 1 cm, whereas a surgical approach should be proposed in tumours larger than 2 cm. Tumours between 1 cm and 2 cm in size are usually managed by endoscopic resection after EUS evaluation, although surgery might be indicated in selected cases with G2 tumours and high Ki-67 (cutoff not established), and in G3 tumours.
    对于大于 1 厘米的 I 型胃神经内分泌肿瘤,建议采用内镜下切除术;而大于 2 厘米的肿瘤则建议采用手术方法。对于 1 至 2 厘米大小的肿瘤,通常在超声内镜评估后采用内镜下切除术处理,但在某些特定情况下,如 G2 级肿瘤且 Ki-67 较高(具体临界值未确定)以及 G3 级肿瘤,可能需要考虑手术治疗。
  3. In type III gNETs, a surgical approach is recommended. However, in selected patients with small (<1 cm) G1 tumours, endoscopic resection may be appropriate.
    对于 III 型胃神经内分泌肿瘤,推荐采用手术治疗。然而,在特定患者中,如肿瘤较小(小于 1 厘米)且为 G1 级的病例,内镜下切除术可能是合适的选择。

4.2 Duodenal NETs  4.2 十二指肠神经内分泌肿瘤

  1. Endoscopic assessment should include tumour location to identify periampullary tumours. EUS is recommended in tumours >1 cm.
    内镜评估应包括肿瘤定位以识别壶腹周围肿瘤。对于大于 1 厘米的肿瘤,推荐进行超声内镜检查。
  2. Very small non-functioning tumours in D1 may be removed using EMR type techniques, whereas larger tumours (>1 cm) and/or tumour extending beyond the submucosa and/or grades G2–G3 and/or lymphovascular invasion and/or functioning neoplasms should be managed by a surgical approach after complete disease staging by dedicated CT, liver-MRI+/− 68Ga-SSA-PET-CT.
    位于十二指肠第一部(D1)的极小型无功能性肿瘤可采用内镜下黏膜切除术(EMR)类技术切除,而较大肿瘤(>1 厘米)和/或肿瘤浸润超过黏膜下层、和/或分级为 G2–G3、和/或存在淋巴血管侵犯、和/或功能性肿瘤,应在完成包括专用 CT、肝脏 MRI(必要时联合⁶⁸Ga-SSA-PET-CT)的全面疾病分期后,采用手术方法治疗。

4.3 Unmet needs  4.3 未满足的需求

  1. The prognostic role of Ki67 in type I gNETs is unclear.
    Ki67 在 I 型胃神经内分泌肿瘤中的预后作用尚不明确。
  2. Long-term outcomes of endoscopic resection for both selected gastric type 3 NETs, and also duodenal NETs, are lacking.
    对于特定胃 3 型神经内分泌肿瘤及十二指肠神经内分泌肿瘤,内镜切除术的长期疗效数据尚不充分。
  3. The risk of progression in low-grade gastroduodenal NETs after incomplete R1 endoscopic resection is unknown.
    低级别胃十二指肠神经内分泌肿瘤经内镜 R1 不完全切除后的进展风险尚未明确。
  4. The role of somatostatin analogue treatments in managing type I gNETs has not yet been established.
    生长抑素类似物在治疗 I 型胃神经内分泌肿瘤中的作用尚未确立。
  5. More data are required regarding natural history PPI-induced gNETs.
    关于质子泵抑制剂诱发的胃神经内分泌肿瘤自然病程仍需更多数据支持。

AUTHOR CONTRIBUTIONS  作者贡献

Francesco Panzuto: Conceptualization; methodology; supervision; writing – original draft; writing – review and editing. John Ramage: Conceptualization; writing – original draft; writing – review and editing. Mark Pritchard: Conceptualization; writing – original draft; writing – review and editing. Marie-Louise van Velthuysen: Conceptualization; writing – original draft; writing – review and editing. Jörg Schrader: Conceptualization; writing – original draft; writing – review and editing. Nehara Begum: Conceptualization; writing – original draft; writing – review and editing. Anders Sundin: Conceptualization; writing – original draft; writing – review and editing. Massimo Falconi: Conceptualization; writing – original draft; writing – review and editing. Dermot O'Toole: Conceptualization; methodology; supervision; writing – original draft; writing – review and editing.
弗朗切斯科·潘祖托:概念化;方法论;监督;撰写初稿;撰写及审阅编辑。约翰·拉梅奇:概念化;撰写初稿;撰写及审阅编辑。马克·普里查德:概念化;撰写初稿;撰写及审阅编辑。玛丽-路易斯·范·维尔图伊森:概念化;撰写初稿;撰写及审阅编辑。约尔格·施拉德:概念化;撰写初稿;撰写及审阅编辑。内哈拉·贝古姆:概念化;撰写初稿;撰写及审阅编辑。安德斯·桑丁:概念化;撰写初稿;撰写及审阅编辑。马西莫·法尔科尼:概念化;撰写初稿;撰写及审阅编辑。德莫特·奥图尔:概念化;方法论;监督;撰写初稿;撰写及审阅编辑。

ACKNOWLEDGEMENTS  致谢

Participants of the ENETS Guidance Paper Consensus Meeting – 13 October 2022. Bartsch, D. K. (Department of Visceral-, Thoracic- and Vascular Surgery Philipps-University Marburg, Marburg, Germany); Capdevila, J. (Medical Oncology Department, Gastrointestinal and Endocrine Unit, Vall d'Hebron University Hospital, Barcelona, Spain); Caplin, M. (Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital and University College London, London, UK); Castaño, J. P. (Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain); Couvelard, A. (Pathology Department, Bichat Hospital, AP-HP and Université Paris Cité, Paris, France); De Mestier L. (Beaujon Hospital, Université Paris-Cité, Pancreatology and Digestive Oncology, Paris, France); Denecke, T. (Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Leipzig, Leipzig, Germany); Fazio, N. (Division of Gastrointestinal Medical Oncology and neuroendocrine tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy); Garcia-Carbonero, R. (Department of Oncology, Hospital Universitario Doce de Octubre, Imas12, UCM, Madrid, Spain); Hofland, J. (Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands); Kaltsas, G. (1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece); Kjaer, A. (Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark); Knigge, U. (Departments of Surgery and Clinical Endocrinology, ENETS Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark); Koumarianou A. (National and Kapodistrian University of Athens, Haematology Oncology Unit, 4th Department of Internal Medicine, Athens, Greece); Pavel, M. (Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany); Rindi, G. (Section of Anatomic Pathology, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore/Unit of Head and Neck, Thoracic and Endocrine Pathology, Department of Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia/Roma European Neuroendocrine Tumour Society (ENETS) Center of Excellence, Rome, Italy); Santos A. P. (Endocrinology Department, Endocrine Tumours Clinic, Precancerous Lesions and Early Cancer Management Group, RISE@CI-IPO (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal); Srirajaskanthan R. (Neuroendocrine Tumour Unit, Kings College Hospital/Department of Gastroenterology, Hambleden Wing, Kings College Hospital, London, UK); Tiensuu Janson, E. (Department of Medical Sciences, Endocrine Oncology, Medical Faculty, Uppsala Universitet, Uppsala, Sweden); Toumpanakis, C. (Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital and University College London, London, UK); Walter, T. (Department of Medical Oncology, Hôpital Edouard Herriot, Lyon, France).
ENETS 指南共识会议参与者——2022 年 10 月 13 日。Bartsch, D. K.(德国马尔堡菲利普斯大学内脏、胸部和血管外科);Capdevila, J.(西班牙巴塞罗那 Vall d'Hebron 大学医院肿瘤内科,胃肠和内分泌科);Caplin, M.(英国伦敦皇家自由医院和伦敦大学学院神经内分泌肿瘤科,ENETS 卓越中心);Castaño, J. P.(西班牙科尔多瓦 Reina Sofia 大学医院,科尔多瓦大学 Maimonides 生物医学研究所);Couvelard, A.(法国巴黎 Bichat 医院病理科,AP-HP 和巴黎西岱大学);De Mestier L.(法国巴黎 Beaujon 医院,巴黎西岱大学,胰腺和消化肿瘤科);Denecke, T.(德国莱比锡大学医院诊断和介入放射科);Fazio, N.(意大利米兰欧洲肿瘤研究所(IEO),IRCCS,胃肠肿瘤和神经内分泌肿瘤科);Garcia-Carbonero, R. (西班牙马德里 Hospital Universitario Doce de Octubre 医院肿瘤科,Imas12,UCM);Hofland, J.(荷兰鹿特丹 Erasmus MC 内科);Kaltsas, G.(希腊雅典国立卡波季斯特里安大学第一内科预科系);Kjaer, A.(丹麦哥本哈根大学医院临床生理与核医学科及分子影像中心,哥本哈根大学医院 Rigshospitalet & 生物医学系);Knigge, U.(丹麦哥本哈根大学医院外科与临床内分泌科,ENETS 卓越中心,Rigshospitalet);Koumarianou A.(希腊雅典国立卡波季斯特里安大学血液肿瘤科,第四内科);Pavel, M.(德国埃尔兰根大学医院第一内科);Rindi, G. (解剖病理学科,生命科学与公共卫生系,圣心天主教大学/头颈、胸部和内分泌病理科,妇女与儿童健康科学及公共卫生系,A. Gemelli IRCCS 大学基金会综合医院,意大利罗马/罗马欧洲神经内分泌肿瘤学会(ENETS)卓越中心,意大利罗马);Santos A. P.(内分泌科,内分泌肿瘤诊所,癌前病变和早期癌症管理组,RISE@CI-IPO(健康研究网络),波尔图葡萄牙肿瘤研究所(IPO Porto)/波尔图综合癌症中心(Porto.CCC),葡萄牙波尔图);Srirajaskanthan R.(神经内分泌肿瘤科,国王学院医院/消化内科,Hambleden Wing,国王学院医院,英国伦敦);Tiensuu Janson, E.(医学科学系,内分泌肿瘤学,医学院,乌普萨拉大学,瑞典乌普萨拉);Toumpanakis, C.(神经内分泌肿瘤科,ENETS 卓越中心,皇家自由医院和伦敦大学学院,英国伦敦);Walter, T.(肿瘤内科,爱德华·赫里欧医院,法国里昂)。

    CONFLICT OF INTEREST STATEMENT
    利益冲突声明

    D. Mark Pritchard received funding for consultancy, lectures and conference attendance from Ipsen, Advanced Accelerator Applications and Mayoly Spindler laboratories and research funding to investigate the role of netazepide in type I gastric NETs from Trio Medicines Ltd. John Ramage received research funding from Novartis and Ipsen.
    D·马克·普里查德曾接受益普生、先进加速器应用及 Mayoly Spindler 实验室的咨询费、讲座及会议差旅资助,并获 Trio Medicines Ltd 资助研究 netazepide 在 I 型胃神经内分泌肿瘤中的作用。约翰·拉梅奇曾获诺华及益普生的研究经费支持。

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