中国抗癌协会神经内分泌肿瘤诊治指南（2025年版）

doi:10.19401/j.cnki.1007-3639.2025.01.010

摘要/Abstract

摘要：

神经内分泌肿瘤（neuroendocrine neoplasms，NENs）是一类起源于肽能神经元和神经内分泌细胞，具有神经内分泌分化特性并表达神经内分泌标志物的少见肿瘤，可发生于全身各处，以肺和胃肠胰最为常见。国内外研究均显示，NENs的发病率在不断上升。NENs的异质性较高，可起源于多个组织和器官，包括垂体、甲状腺、甲状旁腺、皮肤、支气管肺及胸腺、胃肠胰、肾上腺、生殖泌尿器官等，且同一组织或器官起源的NENs分类、分级不同时，亦有显著不同的生物学行为。NENs的高度异质性决定其诊断的困难和复杂性，除了临床症状，还需包括特殊的生物标志物、内镜、超声、计算机体层成像（computed tomography，CT）、磁共振成像（magnetic resonance imaging，MRI）等常规影像学检查以及各种功能影像学检查手段进行整合诊断。此外，NENs的治疗方式也涵盖了内镜治疗、外科治疗、介入治疗、药物治疗、放疗及肽受体放射性核素治疗（peptide receptor radionuclide therapy，PRRT）等多种手段。治疗策略的制定既要遵循指南规范，又要在多学科团队（multidisciplinary team，MDT）协作整合诊治的基础上进行个体化选择。2024年，中国抗癌协会神经内分泌肿瘤专业委员会再次组织本领域相关专家，在《中国抗癌协会神经内分泌肿瘤诊治指南（2022年版）》、其他相关国内外指南和共识、以及最新临床研究结果的基础上，制定了《中国抗癌协会神经内分泌肿瘤诊治指南（2025年版）》。本指南已在国际实践指南注册与透明化平台（Practice guideline REgistration for transPAREncy，PREPARE）上注册，注册编号为PREPARE-2024CN1158。2025年版指南对2022年版指南相应内容进行更新及修订，并进一步扩充了除胸部和胃肠胰以外的NENs，包括垂体神经内分泌瘤（pituitary neuroendocrine tumors，PitNETs）、甲状腺髓样癌（medullary thyroid carcinoma，MTC）、嗜铬细胞瘤/副神经节瘤（pheochromocytoma and paragangliomas，PPGLs）及Merkel细胞癌（Merkel cell carcinoma，MCC）的诊治推荐，以期为临床工作者提供参考。

关键词: 神经内分泌肿瘤, 诊断, 治疗, 指南

Abstract:

Neuroendocrine neoplasms (NENs) are a rare group of tumors that originated from peptidergic neurons and neuroendocrine cells, which has neuroendocrine differentiation characteristics and expresses neuroendocrine markers. NENs occur in all parts of the body, especially in lung, gastrointestinal tract and pancreas. Both domestic and foreign researches showed that the incidence of NENs is on the rise. NENs have high heterogeneity and can originate in multiple tissues and organs, including pituitary, thyroid, parathyroid, skin, bronchial lung and thymus, gastrointestinal tract and pancreas, adrenal glands, genitourinary organs, etc. At the same time, when the classification and grading of NENs originating from the same tissue or organ are different, they also have significantly different biological behaviors. The high heterogeneity of NENs determines the difficulty and complexity of its diagnosis. In addition to clinical symptoms, it also needs to include special biomarkers, endoscopy, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and various functional imaging methods for integrated diagnosis. In addition, the treatment of NENs also covers endoscopic therapy, surgical treatment, interventional therapy, drug therapy, radiotherapy and peptide receptor radionuclide therapy (PRRT). The development of treatment strategies requires not only following guidelines, but also making individual choices on the basis of multidisciplinary team (MDT) collaboration and integrated diagnosis and treatment. In 2024, the Society of Neuroendocrine Neoplasm of China Anti-Cancer Association once again organized experts in relevant fields to formulate the “China Anti-Cancer Association guideline for diagnosis and treatment of neuroendocrine neoplasms (2025 edition)” on the basis of the “China Anti-Cancer Association guideline for diagnosis and treatment of neuroendocrine neoplasm (2022 edition)”, domestic and international guidelines and consensus, as well as the latest clinical research results. The guideline had been registered on Practice guideline REgistration for transPAREncy (PREPARE) with the registration number PREPARE-2024CN1158. The 2025 edition updated and revised the relevant content from the 2022 edition and further expanded recommendations beyond thoracic, gastrointestinal tract and pancreas NENs, including pituitary neuroendocrine tumors (PitNETs), medullary thyroid carcinoma (MTC), pheochromocytoma/paragangliomas (PPGLs) and Merkel cell carcinoma (MCC), with the expectation of providing references for clinical practitioners.

Key words: Neuroendocrine neoplasms, Diagnosis, Treatment, Guideline

中图分类号:

R736
R739.4

中国抗癌协会神经内分泌肿瘤专业委员会. 中国抗癌协会神经内分泌肿瘤诊治指南（2025年版）[J]. 中国癌症杂志, 2025, 35(1): 85-142.

Society of Neuroendocrine Neoplasm of China Anti-Cancer Association. China Anti-Cancer Association guideline for diagnosis and treatment of neuroendocrine neoplasms (2025 edition)[J]. China Oncology, 2025, 35(1): 85-142.

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第9版AJCC GEP-NET TNM定义"

分期	TNM定义
Tx	原发肿瘤无法评估
T1	侵犯黏膜固有层或黏膜下层，且肿瘤直径≤1 cm（胃、十二指肠、空回肠）；局限于Oddi氏括约肌，且肿瘤直径≤1 cm（壶腹部）；肿瘤最大径≤2 cm（阑尾）；侵犯黏膜固有层或黏膜下层，且肿瘤直径≤2 cm（结直肠）：肿瘤直径≤1 cm为T1a期，1 cm<肿瘤直径≤2 cm为T1b期；局限于胰腺内，且肿瘤直径≤2 cm（胰腺）
T2	侵犯固有肌层，或肿瘤直径>1 cm（胃、十二指肠、空回肠）；侵犯十二指肠固有肌层或黏膜下层，或肿瘤直径>1 cm（壶腹部）； 2 cm<肿瘤直径≤4 cm（阑尾）；侵犯固有肌层，或侵犯黏膜固有层或黏膜下层，且肿瘤直径>2 cm（结直肠）；局限于胰腺内，且2 cm<肿瘤直径≤4 cm（胰腺）
T3	穿透固有肌层至浆膜下层，未突破浆膜层（胃、空回肠、结直肠）；侵犯胰腺或胰周脂肪组织（十二指肠、壶腹部）；肿瘤直径>4 cm，或侵犯浆膜下层，或侵犯阑尾系膜（阑尾）；局限于胰腺内，且肿瘤直径>4 cm；或侵犯十二指肠、壶腹部或胆管（胰腺）
T4	侵犯脏腹膜或其他器官或邻近组织（胃、十二指肠、壶腹部、空回肠、结直肠、阑尾）；侵犯邻近器官，如胃、脾、结肠、肾上腺，或大血管壁，如腹腔干、肠系膜上动脉/静脉、脾动脉/静脉、胃十二指肠动脉/静脉、门静脉（胰腺）
Nx	区域淋巴结无法评估
N0	无区域淋巴结转移（所有部位）
N1	区域淋巴结转移，数量不限（除空回肠外其他部位）；区域淋巴结转移数量<12颗（空回肠）
N2	直径>2 cm的肠系膜根部肿物和（或）广泛淋巴结转移（大于12枚），尤其是包绕肠系膜上血管的淋巴结（仅针对空回肠）
M0	无远处转移（所有部位）
M1	有远处转移（所有部位）
M1a	转移局限于肝脏
M1b	转移到至少1个肝外部位（如肺、卵巢、非区域淋巴结、腹膜、骨）
M1c	肝脏和肝外转移瘤

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第9版AJCC肺NENs TNM定义"

分期	TNM定义
Tx	原发肿瘤无法评估，或痰液或支气管灌洗液中存在恶性细胞，但支气管镜未观察到原发肿瘤
T0	没有原发肿瘤的证据
Tis	原位癌
T1	肿瘤最大径≤3 cm，周围被肺或脏层胸膜包绕，支气管镜未发现肿瘤侵犯超过叶支气管近端（即主支气管未见肿瘤侵犯）
T1a	肿瘤最大径≤1 cm
T1b	肿瘤最大径>1 cm，≤2 cm
T1c	肿瘤最大径>2 cm，≤3 cm
T2	3 cm<肿瘤最大直径≤5 cm或有以下任一特征： ① 累及主支气管，无论距离气管隆突多远，但不包括气管隆突； ② 侵犯脏层胸膜（PL1或PL2）； ③ 合并肺不张或阻塞性肺炎，延伸至肺门，累及部分或全肺
T2a	3 cm<肿瘤最大径≤4 cm
T2b	4 cm<肿瘤最大径≤5 cm
T3	5 cm<肿瘤最大径≤7 cm，或直接侵犯以下部位：壁层胸膜（PL3）、胸壁（包括肺上沟）、膈神经、心包壁层、或与原发灶同一叶内出现单个或多个分散的瘤结节
T4	肿瘤>7 cm，或任何大小的肿瘤侵犯下列任一结构：横膈膜、纵隔、心脏、大血管、气管、喉返神经、食管、椎体、气管隆突或与原发灶同侧但不同肺叶出现单个或多个分散的瘤结节
Nx	区域淋巴结无法评估
N0	无区域淋巴结转移
N1	转移至同侧支气管周围和（或）同侧肺门淋巴结，包括直接侵犯
N2	转移至同侧纵隔和（或）锁骨下淋巴结
N2a	转移至1站同侧纵隔和（或）锁骨下淋巴结
N2b	转移至同侧纵隔多站淋巴结，包括/不包括锁骨下淋巴结侵犯
N3	转移至对侧纵隔、对侧肺门、同侧或对侧斜角肌或锁骨上淋巴结
M0	无远处转移
M1	有远处转移
M1a	对侧肺叶出现散在的肿瘤结节；出现胸膜结节、心包结节、恶性胸腔或心包积液。大部分胸腔（心包）积液是肿瘤引起的。但在少数患者中，胸腔（心包）积液多次显微镜检查，肿瘤细胞均是阴性，且积液是非血性、非渗出液。综合考虑这些因素和临床判断确定积液与肿瘤无关时，积液应不作为分期参考因素
M1b	单个器官内单一胸外转移（包括单个非区域性结节的累及）
M1c	单个器官或多个器官发生多个胸外转移
M1c1	单个器官发生多个胸外转移
M1c2	多个器官发生多个胸外转移

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用于NET的常用TKIs的主要靶点、临床研究结果及应用推荐"

药物名	主要靶点	研究结果	临床使用推荐
舒尼替尼	VEGFR1-3 PDGFR、c-KIT、RET、FLT3、CSF-1R	⑴ pNET Ⅲ期临床试验^[227]：安慰剂对照，171例进展期pNET患者，舒尼替尼组和安慰剂组的中位PFS分别为11.4和5.5个月，ORR分别为9.3%和0.0%； ⑵ MTC Ⅱ期临床试验（THYSU）^[228]：单臂，71例晚期甲状腺癌患者，26例MTC中，ORR为38.5%，中位PFS为16.5个月，中位OS为29.4个月； ⑶ PPGLs Ⅱ期临床试验（FIRSTMAPPP）^[229]：安慰剂对照，78例晚期PPGLs患者，舒尼替尼组和安慰剂组的12个月PFS率分别为35.9%和18.9%，ORR分别为36.1%和8.3%	⑴ 进展期G1/G2级pNET； ⑵ 局部进展或晚期MTC； ⑶ 晚期；PPGLs
索凡替尼	VEGFR1-3、FGFR1、CSF1R	⑴ pNET Ⅲ期临床试验（SANET-p）^[16]：安慰剂对照，172例进展期G1/G2级pNET患者，索凡替尼组和安慰剂组的中位PFS分别为13.9和4.6个月，ORR分别为14%和2%； ⑵ 胰腺以外NET Ⅲ期临床试验（SANET-ep）^[17]：安慰剂对照，198例进展期胃肠道、肺、胸腺、肝、不明原发灶G1/G2级NET患者，索凡替尼组和安慰剂组的中位PFS分别为7.4和3.9个月，ORR分别为8%和0%； ⑶ MTC Ⅱ期临床试验^[230]：开放标签，局部进展或晚期甲状腺未分化癌或MTC，包括27例MTC，ORR为22.2%，中位PFS为11.1个月	⑴ 进展期G1/G2级胃肠胰、胸部、不明原发灶NET； ⑵ 局部进展或晚期MTC
仑伐替尼	VEGFR1-3、FGFR1-4、PDGFR、RET、c-KIT	⑴ GEP-NET Ⅱ期临床试验（TALENT）^[231]：单臂，55例G1/G2级pNET和56例G1/G2级GI-NET患者，总体的ORR为29.9%，pNET的ORR为44.2%，GI-NET的ORR为16.4%。中位PFS为15.7个月； ⑵ MTC Ⅱ期临床试验^[232]：单臂，59例进展期MTC患者，ORR为36%，中位PFS为9.0个月	局部进展或晚期MTC
Cabozantinib	VEGFR1-3、KIT、TRKB、FLT-3、AXL、RET、MET、TIE-2	⑴ NET Ⅲ期临床试验（CABINET）^[233]：安慰剂对照，298例前线治疗进展的NET患者（G1/G2/G3级，95例pNET，203例胰腺外NET），pNET cabozantinib组和安慰剂组的中位PFS分别为13.8和4.4个月；胰腺外NET cabozantinib组和安慰剂组的中位PFS分别为8.4和3.9个月； ⑵ MTC Ⅲ期临床试验^[234]：安慰剂对照，330例晚期MTC患者，cabozantinib组和安慰剂组的中位PFS分别为11.2和4.0个月，ORR分别为28%和0%	⑴ 进展期G1/G2级胃肠胰、胸部、不明原发灶NET^； ⑵ 局部进展或晚期MTC^
Vandetanib	RET、VEGFR、EGFR	MTC Ⅲ期临床试验^[235]：安慰剂对照，331例晚期MTC患者，vandetanib组和安慰剂组的中位PFS分别为未达到和19.3个月，6个月PFS率分别为83%和63%，ORR分别为45%和13%	局部进展或晚期MTC^*
安罗替尼	VEGFR2-3、FGFR1-4、PDGFR、RET、c-KIT	MTC Ⅱ期临床试验^[236]：安慰剂对照，91例局部晚期或转移性MTC患者，安罗替尼组和安慰剂组的中位PFS分别为20.7和11.1个月，ORR分别为48.4%和6.9%	局部进展或晚期MTC

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类型	发病率（n/100万人年）	分泌激素	常见部位	转移比例	主要症状
胰岛素瘤	1~4	胰岛素	胰腺	5%~10%	发作性低血糖症候群
胃泌素瘤	0.5~3	胃泌素	十二指肠、胰腺	<50%	卓-艾综合征
VIP瘤	0.05~0.20	VIP	胰腺	40%~80%	水样泻、低钾血症、胃酸缺乏、酸中毒
胰高血糖素瘤	0.01~0.10	胰高血糖素	胰腺	50%~80%	坏死游走性红斑、贫血、葡萄糖不耐受、体重下降
生长抑素瘤	罕见	生长抑素	胰腺、十二指肠、空肠	50%~60%	糖尿病、胆石症、腹泻、胃酸缺乏、低血糖
产生ACTH的NET	少见	ACTH	胰腺、胸腺垂体	>90%	库欣综合征
产生5-羟色胺的NET	少见	5-羟色胺	小肠、肺、胰腺	>60%	类癌综合征
产生甲状旁腺激素相关肽的NET	罕见	甲状旁腺激素相关肽	胰腺	>90%	高钙低磷血症
Ctn瘤	罕见	Ctn	胰腺	>90%	腹泻、潮红
产生生长激素释放激素的NET	罕见	生长激素释放激素	胰腺、肺	>60%	异位肢端肥大症
嗜铬细胞瘤	0.2~0.8	儿茶酚胺激素	肾上腺	15%~20%	高血压、心悸、头痛、出汗
生长激素瘤	0.2~1.1	生长激素	垂体	0.2%	肢端肥大症
泌乳素瘤	2.1~5.4	泌乳素	垂体	0.2%	闭经、异常泌乳、男性性功能障碍
促甲状腺素瘤	0.03~0.04	促甲状腺激素	垂体	0.2%	甲亢

遗传综合征	遗传方式	基因	主要临床表现
MEN1	常染色体显性遗传	MEN1	甲状旁腺腺瘤/增生、PitNETs、肺NET、胸腺NET、十二指肠NET、pNET、肾上腺皮质腺瘤
MEN2A	常染色体显性遗传	RET	MTC、嗜铬细胞瘤、甲状旁腺腺瘤/增生、CLA、HD
FMTC	常染色体显性遗传	RET	MTC
MEN2B	常染色体显性遗传	RET	MTC、嗜铬细胞瘤、特殊面容、马方综合征样体型、舌黏膜神经瘤、肠道神经节瘤等
MEN4	常染色体显性遗传	CDKN1A、CDKN1B、CDKN1C	甲状旁腺腺瘤/增生、PitNETs、pNET或十二指肠NET、肾上腺皮质腺瘤
MEN5	常染色体显性遗传	MAX	PPGLs、PitNETs、pNET等
VHL	常染色体显性遗传	VHL	PPGLs、pNET、胰腺多发囊肿、肾透明细胞癌、中枢/视网膜血管母细胞瘤
NF1	常染色体显性遗传	NF1	皮肤多发牛奶咖啡斑、皮肤多发神经纤维瘤、虹膜Lisch结节、胶质瘤、嗜铬细胞瘤、pNET
TSC	常染色体显性遗传	TSC1或TSC2	低黑色素斑疹、鲨鱼皮斑、肾血管平滑肌脂肪瘤、多发性和弥漫性错构瘤、精神发育迟滞、pNET
遗传性PPGLs综合征	常染色体显性遗传/ 父系遗传	MAX、SDHA、SDHAF2、SDHB、SDHC、SDHD、TMEM127	多发或早发PPGLs
MAFA相关性胰岛素瘤	常染色体显性遗传	MAFA p.Ser64Phe	家族性胰岛素瘤病或糖尿病

部位	类型	分级/亚型	诊断标准
胃肠胰和肝胆	NET	G1	<2个核分裂象/2 mm²和（或）Ki-67增殖指数<3%
		G2	2~20个核分裂象/2 mm²和（或）Ki-67增殖指数为3%~20%
		G3	>20个核分裂象/2 mm²和（或）Ki-67增殖指数>20%
	NEC	SCNEC	>20个核分裂象/2 mm²和（或）Ki-67增殖指数>20%（常>70%，具有SCNEC的形态特征）
		LCNEC	>20个核分裂象/2 mm²和（或）Ki-67增殖指数>20%（常>70%，具有LCNEC的形态特征）
上呼吸消化道和唾液腺	NET	G1	<2个核分裂象/2 mm²和没有坏死，以及Ki-67增殖指数<20%
		G2	2~10个核分裂象/2 mm²和（或）坏死，以及Ki-67增殖指数<20%
		G3	>10个核分裂象/2 mm²和（或）Ki-67增殖指数>20%
	NEC	SCNEC	>10个核分裂象/2 mm²和（或）Ki-67增殖指数>20%（常>70%，具有SCNEC的形态特征）
		LCNEC	>10个核分裂象/2 mm²和（或）Ki-67增殖指数>20%（常>55%，具有LCNEC的形态特征）
肺和胸腺	NET	TC/NET，G1	<2个核分裂象/2 mm²和没有坏死
		AC/NET，G2	2~10个核分裂象/2 mm²和（或）坏死（通常是点状坏死）
		伴核分裂象和（或）Ki-67增殖指数增高的类癌（相当于NET，G3）	具有AC形态，但>10个核分裂象/2 mm²和（或）Ki-67增殖指数>30%
	NEC	SCNEC	>10个核分裂象/2 mm²，常伴坏死和SCNEC的形态
		LCNEC	>10个核分裂象/2 mm²，几乎总伴坏死和具有LCNEC的形态
甲状腺	MTC	低级别MTC	<5个核分裂象/2 mm²和没有坏死，以及Ki-67增殖指数<5%
		高级别MTC	下列3个指标中至少有1个：① ≥5个核分裂象/2 mm²；② 出现坏死；③ Ki-67增殖指数≥5%

抗体名称	起源/分化
PIT-1/T-PIT/SF-1	PitNETs
CDX2、serotonin	小肠NET、十二指肠NET
Islet-1	pNET
TTF1	肺NET、胸腺NET、MTC、下丘脑NET；各部位NEC
SATB2	直肠NET
Claudin18.2	g-NET
PSAP	泌尿生殖系统NET
CK20	MCC
GATA3	PPGLs、甲状旁腺和垂体及乳腺等上皮型NET；各部位NEC

基因/蛋白	NENs类型	用途	治疗选择	检测方法
SSTR	NET>NEC	鉴别NET和NEC	是（SSAs和PRRT）	IHC
DAXX/ATRX	NET	鉴别NET G3和NEC；预后	是，按NET还是NEC方向治疗	IHC
RET	NET	预后	是（RET靶向TKIs）	测序
SDHB	PPGLs	预后	否	IHC/测序
Rb和P53	NEC	鉴别NET G3和NEC	是（含铂类药物化疗）	IHC
MGMT	NET	预后	是（TMZ）	测序/IHC