China Anti-Cancer Association guideline for diagnosis and treatment of neuroendocrine neoplasm (2022 edition)

doi:10.19401/j.cnki.1007-3639.2022.06.010

Abstract

Abstract:

Neuroendocrine neoplasm (NEN) is a kind of rare tumor that originated from peptidergic neurons and neuroendocrine cells, which has neuroendocrine differentiation and expresses neuroendocrine markers. NEN occurs in all parts of the body, especially in lung, stomach, intestine and pancreas. Domestic and international research data suggested that the incidences of NEN were rising. The results of epidemiological investigation showed that compared with other types of tumors, the incidences of NEN increased more significantly. On the basis of existing evidence, combined with domestic and international guidelines and consensus, the Society of Neuroendocrine Neoplasm of China Anti-Cancer Association has formulated its first guideline for diagnosis and treatment of NEN as reference for clinical physicians.

Key words: Neuroendocrine neoplasm, Diagnosis, Treatment, Guideline

CLC Number:

Society of Neuroendocrine Neoplasm of China Anti-Cancer Association. China Anti-Cancer Association guideline for diagnosis and treatment of neuroendocrine neoplasm (2022 edition)[J]. China Oncology, 2022, 32(6): 545-579.

Figures/Tables 15

分期	TNM 定义
T_x	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
T_is	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）
T_1a	肿瘤最大径≤1 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）
T_1b	肿瘤最大径>1 cm,≤2 cm
T_1c	肿瘤最大径>2 cm,≤3 cm
T₂	肿瘤最大直径>3 cm,≤5 cm或有以下任一特征：
	累及主支气管,无论距离气管隆嵴多远,但不包括气管隆嵴侵犯脏层胸膜（PL1或PL2）合并肺不张或阻塞性肺炎,延伸至肺门,累及部分或全肺。具有以上特征的T₂肿瘤,若直径≤4 cm或直径无法测量,归类于T_2a;直径>4 cm,≤5 cm,则归类于T_2b
T_2a	肿瘤最大径>3 cm,≤4 cm
T_2b	肿瘤最大径>4 cm,≤5 cm
T₃	肿瘤最大径>5 cm,≤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的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,气管隆嵴,或与原发灶同侧但不同肺叶的单个或多个分散的瘤结节
N_x	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
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
M_1a	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
M_1b	单个器官内单一胸外转移（包括单个非区域性结节的累及）
M_1c	单个器官或多个器官发生多个胸外转移

References 202

[1]	DASARI A,, SHEN C,, HALPERIN D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States[J]. JAMA Oncol, 2017, 3(10): 1335-1342. doi: 10.1001/jamaoncol.2017.0589
[2]	FANG C,, WANG W,, ZHANG Y, et al. Clinicopathologic characteristics and prognosis of gastroenteropancreatic neuroendocrine neoplasms: a multicenter study in South China[J]. Chin J Cancer, 2017, 36(1): 51. doi: 10.1186/s40880-017-0218-3
[3]	FAN J H,, ZHANG Y Q,, SHI S S, et al. A nation-wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in China[J]. Oncotarget, 2017, 8(42): 71699-71708. doi: 10.18632/oncotarget.17599
[4]	MINNETTI M,, GROSSMAN A. Somatic and germline mutations in NETs: implications for their diagnosis and management[J]. Best Pract Res Clin Endocrinol Metab, 2016, 30(1): 115-127. doi: 10.1016/j.beem.2015.09.007
[5]	FALCONI M,, ERIKSSON B,, KALTSAS G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors[J]. Neuroendocrinology, 2016, 103(2): 153-171. doi: 10.1159/000443171
[6]	FAVE G D,, O'TOOLE D,, SUNDIN A, et al. ENETS consensus guidelines update for gastroduodenal neuroendocrine neoplasms[J]. Neuroendocrinology, 2016, 103(2): 119-124. doi: 10.1159/000443168
[7]	XU J M,, SHEN L,, ZHOU Z W, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21(11): 1500-1512. doi: 10.1016/S1470-2045(20)30496-4
[8]	XU J M,, SHEN L,, BAI C M, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21(11): 1489-1499. doi: 10.1016/S1470-2045(20)30493-9
[9]	STROSBERG J,, EL-HADDAD G,, WOLIN E, et al. Phase 3 trial of ¹⁷⁷Lu-dotatate for midgut neuroendocrine tumors[J]. N Engl J Med, 2017, 376(2): 125-135. doi: 10.1056/NEJMoa1607427
[10]	CAPLIN M E,, PAVEL M,, ĆWIKŁA J B, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors[J]. N Engl J Med, 2014, 371(3): 224-233. doi: 10.1056/NEJMoa1316158
[11]	YAO J C,, SHAH M H,, ITO T, et al. Everolimus for advanced pancreatic neuroendocrine tumors[J]. N Engl J Med, 2011, 364(6): 514-523. doi: 10.1056/NEJMoa1009290
[12]	RAYMOND E,, DAHAN L,, RAOUL J L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors[J]. N Engl J Med, 2011, 364(6): 501-513. doi: 10.1056/NEJMoa1003825
[13]	FIORE F,, DEL PRETE M,, FRANCO R, et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors[J]. Endocrine, 2014, 47(1): 177-182. doi: 10.1007/s12020-013-0130-9
[14]	LIU Y M,, CHEN W C,, CUI W, et al. Quantitative pretreatment CT parameters as predictors of tumor response of NET liver metastasis to TAE[J]. Neuroendocrinology, 2020, 110(7-8): 697-704. doi: 10.1159/000504257
[15]	樊代明,总主编,. 李强,, 刘巍,, 刘红,主编. 整合肿瘤学-临床卷, 头胸部肿瘤分册[M]. 北京: 科学出版社, 2021: 289.
	FAN D M,editor in chief,. LI Q,, LIU W,, LIU LIU H chief editor. Integrated oncology clinical volume, head and chest tumor volume: clinical volume[M]. Beijing: Science Press, 2021: 289.
[16]	The current surgical treatment of pancreatic neuroendocrine neoplasms in China: a national wide cross-sectional study[J]. J Pancreatol, 2019, 2: 35-42. doi: 10.1097/JP9.0000000000000019
[17]	WU W M,, CHEN J,, BAI C M, et al. The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)[J]. Chin J Surg, 2021, 59(6): 401-421.
[18]	HALPERIN D M,, SHEN C,, DASARI A, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study[J]. Lancet Oncol, 2017, 18(4): 525-534. doi: 10.1016/S1470-2045(17)30110-9
[19]	FILOSSO P L,, YAO X P,, AHMAD U, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases[J]. J Thorac Cardiovasc Surg, 2015, 149(1): 103-109.e2.
[20]	MAROTTA V,, ZATELLI M C,, SCIAMMARELLA C, et al. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame[J]. Endocr Relat Cancer, 2018, 25(1): R11-R29.
[21]	HOFLAND J,, ZANDEE W T,, DE HERDER W W. Role of biomarker tests for diagnosis of neuroendocrine tumours[J]. Nat Rev Endocrinol, 2018, 14(11): 656-669. doi: 10.1038/s41574-018-0082-5
[22]	NOBELS F R,, KWEKKEBOOM D J,, COOPMANS W, et al. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones[J]. J Clin Endocrinol Metab, 1997, 82(8): 2622-2628.
[23]	BAUDIN E,, GIGLIOTTI A,, DUCREUX M, et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours[J]. Br J Cancer, 1998, 78(8): 1102-1107. doi: 10.1038/bjc.1998.635
[24]	MEIJER W G,, KEMA I P,, VOLMER M, et al. Discriminating capacity of indole markers in the diagnosis of carcinoid tumors[J]. Clin Chem, 2000, 46(10): 1588-1596. doi: 10.1093/clinchem/46.10.1588
[25]	MODLIN I M,, DROZDOV I,, KIDD M. The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood[J]. PLoS One, 2013, 8(5): e63364.
[26]	MODLIN I M,, DROZDOV I,, ALAIMO D, et al. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection[J]. Endocr Relat Cancer, 2014, 21(4): 615-628. doi: 10.1530/ERC-14-0190
[27]	LEWIS M A. Hereditary syndromes in neuroendocrine tumors[J]. Curr Treat Options Oncol, 2020, 21(6): 1-8. doi: 10.1007/s11864-019-0692-8
[28]	EISENHAUER E A,, THERASSE P,, BOGAERTS J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[J]. Eur J Cancer, 2009, 45(2): 228-247. doi: 10.1016/j.ejca.2008.10.026
[29]	YU R,, WACHSMAN A. Imaging of neuroendocrine tumors: indications, interpretations, limits, and pitfalls[J]. Endocrinol Metab Clin North Am, 2017, 46(3): 795-814. doi: 10.1016/j.ecl.2017.04.008
[30]	PAVEL M,, ÖBERG K,, FALCONI M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2020, 31(7): 844-860. doi: 10.1016/j.annonc.2020.03.304
[31]	SUNDIN A,, ARNOLD R,, BAUDIN E, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine & hybrid imaging[J]. Neuroendocrinology, 2017, 105(3): 212-244. doi: 10.1159/000471879
[32]	DAVAR J,, CONNOLLY H M,, CAPLIN M E, et al. Diagnosing and managing carcinoid heart disease in patients with neuroendocrine tumors: an expert statement[J]. J Am Coll Cardiol, 2017, 69(10): 1288-1304.
[33]	BEIDERWELLEN K,, SABET A,, LAUENSTEIN T C, et al. Neuroendokrine neoplasien des pankreas[J]. Der Radiol, 2016, 56(4): 348-354.
[34]	BINDERUP T,, KNIGGE U,, LOFT A, et al. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, ¹²³I-MIBG scintigraphy, and ¹⁸F-FDG PET[J]. J Nucl Med, 2010, 51(5): 704-712. doi: 10.2967/jnumed.109.069765
[35]	RINZIVILLO M,, PARTELLI S,, PROSPERI D, et al. Clinical usefulness of ¹⁸F-fluorodeoxyglucose positron emission tomography in the diagnostic algorithm of advanced entero-pancreatic neuroendocrine neoplasms[J]. Oncol, 2018, 23(2): 186-192. doi: 10.1634/theoncologist.2017-0278
[36]	KUIK W J,, KEMA I P,, BROUWERS A H, et al. In vivo biodistribution of no-carrier-added 6-¹⁸F-fluoro-3, 4-dihydroxy-L-phenylalanine (¹⁸F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added ¹⁸F-DOPA, prepared by conventional electrophilic substitution[J]. J Nucl Med, 2015, 56(1): 106-112. doi: 10.2967/jnumed.114.145730
[37]	PICCARDO A,, LOPCI E,, CONTE M, et al. Comparison of ¹⁸F-dopa PET/CT and ¹²³I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: a pilot study[J]. Eur J Nucl Med Mol Imaging, 2012, 39(1): 57-71. doi: 10.1007/s00259-011-1938-2
[38]	CARIDEO L,, PROSPERI D,, PANZUTO F, et al. Role of combined[⁶⁸Ga]Ga-DOTA-SST analogues and[¹⁸F]FDG PET/CT in the management of GEP-NENs: a systematic review[J]. J Clin Med, 2019, 8(7): 1032. doi: 10.3390/jcm8071032
[39]	MARZOLA M C,, CHONDROGIANNIS S,, GRASSETTO G, et al. ¹⁸F-DOPA PET/CT in the evaluation of hereditary SDH-deficiency paraganglioma-pheochromocytoma syndromes[J]. Clin Nucl Med, 2014, 39(1): e53-e58.
[40]	PAUWELS E,, CLEEREN F,, BORMANS G, et al. Somatostatin receptor PET ligands-the next generation for clinical practice[J]. Am J Nucl Med Mol Imaging, 2018, 8(5): 311-331.
[41]	PUTZER D,, GABRIEL M,, KENDLER D, et al. Comparison of ⁶⁸Ga-DOTA-Tyr(3)-octreo-tide and ¹⁸F-fluoro-L-dihydroxyphenylalanine positron emission tomography in neuroendocrine tumor patients[J]. Q J Nucl Med Mol Imaging, 2010, 54 (1): 68-75.
[42]	GAINS J E,, ALDRIDGE M D,, MATTOLI M V, et al. ⁶⁸Ga-DOTATATE and ¹²³I-mIBG as imaging biomarkers of disease localisation in metastatic neuroblastoma: implications for molecular radiotherapy[J]. Nucl Med Commun, 2020, 41(11): 1169-1177. doi: 10.1097/MNM.0000000000001265
[43]	TELLI T,, LAY ERGÜN E,, VOLKAN SALANCI B, et al. The complementary role of ⁶⁸Ga-DOTATATE PET/CT in neuroblastoma[J]. Clin Nucl Med, 2020, 45(4): 326-329. doi: 10.1097/RLU.0000000000002961
[44]	TORUN N. ⁶⁸Ga-DOTA-TATE in neuroblastoma with marrow involvement[J]. Clin Nucl Med, 2019, 44(6): 467-468. doi: 10.1097/RLU.0000000000002539
[45]	KIM Y I,, YOO C,, OH S J, et al. Tumour-to-liver ratio determined by[⁶⁸Ga]Ga-DOTA-TOC PET/CT as a prognostic factor of lanreotide efficacy for patients with well-differentiated gastroenteropancreatic-neuroendocrine tumours[J]. EJNMMI Res, 2020, 10(1): 63. doi: 10.1186/s13550-020-00651-z
[46]	LIU B N,, ZHANG Z Z,, WANG H, et al. Preclinical evaluation of a dual sstr2 and integrin α_vβ₃-targeted heterodimer[⁶⁸Ga]-NOTA-3PEG4-TATE-RGD[J]. Bioorg Med Chem, 2019, 27(21): 115094. doi: 10.1016/j.bmc.2019.115094
[47]	LUO Y P,, PAN Q Q,, YAO S B, et al. Glucagon-like peptide-1 receptor PET/CT with ⁶⁸Ga-NOTA-exendin-4 for detecting localized insulinoma: a prospective cohort study[J]. J Nucl Med, 2016, 57(5): 715-720. doi: 10.2967/jnumed.115.167445
[48]	HÖRSCH D,, SCHMID K W,, ANLAUF M, et al. Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): current strategies in diagnosis and treatment. Conclusions of an expert meeting February 2011 in Weimar, Germany[J]. Oncol Res Treat, 2014, 37(5): 266-276. doi: 10.1159/000362430
[49]	CAPLIN M E,, BAUDIN E,, FEROLLA P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids[J]. Ann Oncol, 2015, 26(8): 1604-1620. doi: 10.1093/annonc/mdv041
[50]	O''TOOLE D,, PALAZZO L. Endoscopy and endoscopic ultrasound in assessing and managing neuroendocrine neoplasms[M]// Neuroendocrine tumors: a multidisciplinary approach. S. KargerAG:88-103.
[51]	CHEN L H,, GUO Y,, ZHANG Y X, et al. Development of a novel scoring system based on endoscopic appearance for management of rectal neuroendocrine tumors[J]. Endoscopy, 2021, 53(7): 702-709. doi: 10.1055/a-1274-0161
[52]	RAMAGE J K,, DE HERDER W W,, DELLE FAVE G, et al. ENETS consensus guidelines update for colorectal neuroendocrine neoplasms[J]. Neuroendocrinology, 2016, 103(2): 139-143. doi: 10.1159/000443166
[53]	KHASHAB M A,, YONG E,, LENNON A M, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors[J]. Gastrointest Endosc, 2011, 73(4): 691-696. doi: 10.1016/j.gie.2010.08.030
[54]	DI LEO M,, POLIANI L,, RAHAL D, et al. Pancreatic neuroendocrine tumours: the role of endoscopic ultrasound biopsy in diagnosis and grading based on the WHO 2017 classification[J]. Dig Dis, 2019, 37(4): 325-333. doi: 10.1159/000499172
[55]	COSTA R D D,, KEMP R,, SANTOS J S D, et al. The role of conventional echoendoscopy (EUS) in therapeutic decisions in patients with neuroendocrine gastro-intestinal tumors[J]. Brazilian Archiv Digest Surg, 2020, 33 (2): e1512.
[56]	PELLICANO R,, FAGOONEE S,, ALTRUDA F, et al. Endoscopic imaging in the management of gastroenteropancreatic neuroendocrine tumors[J]. Minerva Endocrinologica, 2016, 41 (4): 490-8.
[57]	PATEL K K,, KIM M K. Neuroendocrine tumors of the pancreas: endoscopic diagnosis[J]. Curr Opin Gastroenterol, 2008, 24(5): 638-642. doi: 10.1097/MOG.0b013e32830bf7fb
[58]	RUSTAGI T,, FARRELL J J. Endoscopic diagnosis and treatment of pancreatic neuroendocrine tumors[J]. J Clin Gastroenterol, 2014, 48(10): 837-844. doi: 10.1097/MCG.0000000000000152
[59]	PULI S R,, KALVA N,, BECHTOLD M L, et al. Diagnostic accuracy of endoscopic ultrasound in pancreatic neuroendocrine tumors: a systematic review and meta analysis[J]. World J Gastroenterol, 2013, 19(23): 3678-3684. doi: 10.3748/wjg.v19.i23.3678
[60]	KOS-KUDŁA B,, BOLANOWSKI M,, HANDKIEWICZ-JUNAK D, et al. Diagnostic and therapeutic guidelines for gastrointestinal neuroendocrine tumors (recommended by the Polish Network of Neuroendocrine Tumors)[J]. Endokrynol Pol, 2008, 59(1): 41-56.
[61]	KIM M K. Endoscopic ultrasound in gastroenteropancreatic neuroendocrine tumors[J]. Gut Liver, 2012, 6(4): 405-410. doi: 10.5009/gnl.2012.6.4.405
[62]	VAN ASSELT S J,, BROUWERS A H, et al.VAN DULLEMEN H M, EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1[J]. Gastrointest Endosc, 2015, 81(1): 159-167.e2.
[63]	WHO CLASSIFICATION OF TUMOURS EDITORIAL BOARD. WHO classification of tumours of digestive system[M]. Lyon: IARC Press, 2019.
[64]	滕晓东,, 李君,, 来茂德. 肿瘤病理诊断规范(胃肠胰神经内分泌肿瘤)[J]. 中华病理学杂志, 2017, 46(2): 76-78.
	TENG X D,, LI J,, LAI M D. Criteria for pathological diagnosis of tumors (gastrointestinal pancreatic neuroendocrine tumors)[J]. Chin J Pathol, 2017, 46(2): 76-78.
[65]	中国胃肠胰神经内分泌肿瘤病理诊断共识专家组. 中国胃肠胰神经内分泌肿瘤病理诊断共识(2013版)[J]. 中华病理学杂志, 2013, 42(10): 691-694.
	Consensus Expert Group on Pathological Diagnosis of Gastrointestinal and Pancreatic Neuroendocrine Tumors in China. Consensus on pathological diagnosis of gastrointestinal and pancreatic neuroendocrine tumors in China 2013 edition[J]. Chin J Pathol, 2013, 42(10): 691-694.
[66]	中华医学会病理学分会消化疾病学组, 年中国胃肠胰神经内分泌肿瘤病理诊断共识专家组. 中国胃肠胰神经内分泌肿瘤病理诊断共识(2020版)[J]. 中华病理学杂志, 2021, 50(1): 14-20.
	Digestive diseases group, pathological branch, Chinese Medical Association, consensus expert group on pathological diagnosis of gastrointestinal and pancreatic neuroendocrine tumors in China. Chinese consensus on the pathological diagnosis of gastrointestinal and pancreatic neuroendocrine neoplasms(2020 edition)[J]. Chin J Pathol, 2021, 50(1): 14-20.
[67]	中华医学会消化病学分会胃肠激素与神经内分泌肿瘤学组. 胃肠胰神经内分泌肿瘤诊治专家共识(2020•广州)[J]. 中华消化杂志, 2021, 41(2): 76-87.
	Gastrointestinal Hormones and Neuroendocrine Oncology Group, Digestive Branch, Chinese Medical Association. Expert consensus on diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasm (2020, Guangzhou)[J]. Chin J Dig, 2021, 41(2): 76-87.
[68]	WHO CLASSIFICATION OF TUMOURS EDITORIAL BOARD. WHO classification of tumours of thoracic tumours[M]. Lyon: IARC Press, 2021. (WHO classification of tumours series, 5th ed.
[69]	RINDI G,, KLIMSTRA D S,, ABEDI-ARDEKANI B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal[J]. Mod Pathol, 2018, 31(12): 1770-1786. doi: 10.1038/s41379-018-0110-y
[70]	TRAVIS W D,, BRAMBILLA E,, BURKE A P, et al. WHO classification of tumours of the lung, pleura, thymus and heart[M]. Lyon (France): International Agency for Research on Cancer, 2015.WHO classification of tumours series, 4th ed, vol.7.
[71]	TRAVIS W D,, BRAMBILLA E,, MÜLLER-HERMELINK H K, et al. editors. Pathology and genetics of tumours of the lung, pleura, thymus and heart[M]. Lyon (France): International Agency for Research on Cancer, 2004. WHO classification of tumours series, 3rd ed, vol.10.
[72]	AJCC Cancer Staging Manual. 8th edition,, New York, NY, Springer.
[73]	陈洛海,, 周志伟,, 陈洁. 美国癌症联合委员会(AJCC)第8版胃肠胰神经内分泌肿瘤分期解读及评价[J]. 中华胃肠外科杂志, 2017, 20(9): 972-976.
	CHEN L H,, ZHOU Z W,, CHEN J. American Joint Committee on cancer (AJCC), 8th Edition, interpretation and evaluation of staging of gastrointestinal and pancreatic neuroendocrine tumors[J]. Chin J Gastrointestinal Surg, 2017, 20(9): 972-976.
[74]	BASUROY R,, SRIRAJASKANTHAN R,, PRACHALIAS A, et al. Review article: the investigation and management of gastric neuroendocrine tumours[J]. Aliment Pharmacol Ther, 2014, 39(10): 1071-1084. doi: 10.1111/apt.12698
[75]	MAIONE F,, CHINI A,, MILONE M, et al. Diagnosis and management of rectal neuroendocrine tumors (NETs)[J]. Diagnostics, 2021, 11(5): 771. doi: 10.3390/diagnostics11050771
[76]	CROSBY D A,, DONOHOE C L,, FITZGERALD L, et al. Gastric neuroendocrinetumours[J]. Dig Surg, 2012, 29(4): 331-348. doi: 10.1159/000342988
[77]	THOMAS D,, TSOLAKIS A V,, GROZINSKY-GLASBERG S, et al. Long-term follow-up of a large series of patients with type 1 gastric carcinoid tumors: data from a multicenter study[J]. Eur J Endocrinol, 2013, 168(2): 185-193. doi: 10.1530/EJE-12-0836
[78]	SHAH M H,, GOLDNER W S,, BENSON A B, et al. Neuroendocrine and adrenal tumors, version 2.2021, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021, 19(7): 839-868. doi: 10.6004/jnccn.2021.0032
[79]	GROZINSKY-GLASBERG S,, ALEXANDRAKI K I,, ANGELOUSI A, et al. Gastric carcinoids[J]. Endocrinol Metab Clin North Am, 2018, 47(3): 645-660. doi: 10.1016/j.ecl.2018.04.013
[80]	KIM G H,, KIM J I,, JEON S W, et al. Endoscopic resection for duodenal carcinoid tumors: a multicenter, retrospective study[J]. J Gastroenterol Hepatol, 2014, 29(2): 318-324. doi: 10.1111/jgh.12390
[81]	MATSUMOTO S,, MIYATANI H,, YOSHIDA Y. Future directions of duodenal endoscopic submucosal dissection[J]. World J Gastrointest Endosc, 2015, 7(4): 389-395. doi: 10.4253/wjge.v7.i4.389
[82]	HOTEYA S,, KAISE M,, IIZUKA T, et al. Delayed bleeding after endoscopic submucosal dissection for non-ampullary superficial duodenal neoplasias might be prevented by prophylactic endoscopic closure: analysis of risk factors[J]. Dig Endosc, 2015, 27(3): 323-330. doi: 10.1111/den.12377
[83]	MATSUMOTO S,, MIYATANI H,, YOSHIDA Y, et al. Duodenal carcinoid tumors: 5 cases treated by endoscopic submucosal dissection[J]. Gastrointest Endosc, 2011, 74(5): 1152-1156. doi: 10.1016/j.gie.2011.07.029
[84]	MORI H,, SHINTARO F,, KOBARA H, et al. Successful closing of duodenal ulcer after endoscopic submucosal dissection with over-the-scope clip to prevent delayed perforation[J]. Dig Endosc, 2013, 25(4): 459-461. doi: 10.1111/j.1443-1661.2012.01363.x
[85]	TAKIMOTO K,, IMAI Y,, MATSUYAMA K. Endoscopic tissue shielding method with polyglycolic acid sheets and fibrin glue to prevent delayed perforation after duodenal endoscopic submucosal dissection[J]. Dig Endosc, 2014, 26(Suppl 2): 46-49. doi: 10.1111/den.12280
[86]	MAKHLOUF H R,, BURKE A P,, SOBIN L H. Carcinoid tumors of the ampulla of Vater: a comparison with duodenal carcinoid tumors[J]. Cancer, 1999, 85(6): 1241-1249. doi: 10.1002/(SICI)1097-0142(19990315)85:6 < 1241::AID-CNCR5 > 3.0.CO;2-4
[87]	陈洛海,, 陈洁,, 周志伟. 胃肠道神经内分泌肿瘤治疗最新指南解读[J]. 中华胃肠外科杂志, 2016, 19(11): 1201-1204.
	CHEN L H,, CHEN J,, ZHOU Z W. Interpretation of the latest guidelines in the treatment of gastrointestinal neuroendocrine neoplasms[J]. Chin J Gastrointest Surg, 2016(11):1201-1204.
[88]	CHEUNG D Y,, CHOI S K,, KIM H K, et al. Circumferential submucosal incision prior to endoscopic mucosal resection provides comparable clinical outcomes to submucosal dissection for well-differentiated neuroendocrine tumors of the rectum[J]. Surg Endosc, 2015, 29(6): 1500-1505. doi: 10.1007/s00464-014-3831-0
[89]	ZHONG D D,, SHAO L M,, CAI J T. Endoscopic mucosal resection vs endoscopic submucosal dissection for rectal carcinoid tumours: a systematic review and meta-analysis[J]. Colorectal Dis, 2013, 15(3): 283-291. doi: 10.1111/codi.12069
[90]	CHOI C W,, KANG D H,, KIM H W, et al. Comparison of endoscopic resection therapies for rectal carcinoid tumor: endoscopic submucosal dissection versus endoscopic mucosal resection using band ligation[J]. J Clin Gastroenterol, 2013, 47(5): 432-436. doi: 10.1097/MCG.0b013e31826faf2b
[91]	刘雪梅,, 庹必光. 胃肠神经内分泌肿瘤的内镜诊断与治疗[J]. 中华胃肠外科杂志, 2021, 24(10): 854-860.
	LIU X M,, TUO B G. Endoscopic diagnosis and treatment of gastrointestinal neuroendocrine tumors[J]. Chin J Gastrointest Surg, 2021, 24(10): 854-860.
[92]	PARTELLI S,, CIROCCHI R,, CRIPPA S, et al. Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms[J]. Br J Surg, 2017, 104(1): 34-41. doi: 10.1002/bjs.10312
[93]	KUO E J,, SALEM R R. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size[J]. Ann Surg Oncol, 2013, 20(9): 2815-2821. doi: 10.1245/s10434-013-3005-7
[94]	ZHANG X F,, XUE F,, DONG D H, et al. New nodal staging for primary pancreatic neuroendocrine tumors: a multi-institutional and national data analysis[J]. Ann Surg, 2021, 274(1): e28-e35.
[95]	SCHURR P G,, STRATE T,, RESE K, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience[J]. Ann Surg, 2007, 245(2): 273-281. doi: 10.1097/01.sla.0000232556.24258.68
[96]	JIN K Z,, XU J,, CHEN J, et al. Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: a consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET)[J]. Int J Oncol, 2016, 49(5): 1991-2000. doi: 10.3892/ijo.2016.3711
[97]	BERTANI E,, FAZIO N,, BOTTERI E, et al. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach[J]. Surgery, 2014, 155(4): 607-614. doi: 10.1016/j.surg.2013.12.024
[98]	DE JONG M C,, FARNELL M B,, SCLABAS G, et al. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis[J]. Ann Surg, 2010, 252(1): 142-148. doi: 10.1097/SLA.0b013e3181dbb7a7
[99]	OBERG K,, KVOLS L,, CAPLIN M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system[J]. Ann Oncol, 2004, 15(6): 966-973. doi: 10.1093/annonc/mdh216
[100]	HAN X,, LOU W H. Concomitant pancreatic neuroendocrine tumors in hereditary tumor syndromes: who, when and how to operate?[J]. J Pancreatol, 2019, 2(2): 48-53. doi: 10.1097/JP9.0000000000000016
[101]	RAZ D J,, NELSON R A,, GRANNIS F W, et al. Natural history of typical pulmonary carcinoid tumors: a comparison of nonsurgical and surgical treatment[J]. Chest, 2015, 147(4): 1111-1117. doi: 10.1378/chest.14-1960
[102]	KURUL I C,, TOPÇU S,, TAŞTEPE I, et al. Surgery in bronchial carcinoids: experience with 83 patients[J]. Eur J Cardiothorac Surg, 2002, 21(5): 883-887. doi: 10.1016/S1010-7940(02)00089-1
[103]	DIVISI D,, CRISCI R. Carcinoid tumors of the lung and multimodal therapy[J]. Thorac Cardiovasc Surg, 2005, 53(3): 168-172. doi: 10.1055/s-2005-837539
[104]	PHAN A T,, OBERG K,, CHOI J, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus)[J]. Pancreas, 2010, 39(6): 784-798. doi: 10.1097/MPA.0b013e3181ec1380
[105]	HUANG Y W,, YANG X D,, LU T, et al. Assessment of the prognostic factors in patients with pulmonary carcinoid tumor: a population-based study[J]. Cancer Med, 2018, 7(6): 2434-2441. doi: 10.1002/cam4.1515
[106]	BROWN L M,, COOKE D T,, JETT J R, et al. Extent of resection and lymph node assessment for clinical stage T_1aN₀M₀ typical carcinoid tumors[J]. Ann Thorac Surg, 2018, 105(1): 207-213. doi: 10.1016/j.athoracsur.2017.07.049
[107]	KNEUERTZ P J,, KAMEL M K,, STILES B M, et al. Incidence and prognostic significance of carcinoid lymph node metastases[J]. Ann Thorac Surg, 2018, 106(4): 981-988. doi: 10.1016/j.athoracsur.2018.05.044
[108]	DE LAAT J M,, PIETERMAN C R, et al.VAN DEN BROEK M F, Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients[J]. J Clin Endocrinol Metab, 2014, 99(9): 3325-3333. doi: 10.1210/jc.2014-1560
[109]	YE L,, WANG W,, OSPINA N S, et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: a single-centre study, systematic review and meta-analysis[J]. Clinical endocrinology, 2017, 87 (6): 706-16. doi: 10.1111/cen.13480
[110]	FRILLING A,, MODLIN I M,, KIDD M, et al. Recommendations for management of patients with neuroendocrine liver metastases[J]. Lancet Oncol, 2014, 15(1): e8-e21.
[111]	PARTELLI S,, BARTSCH D K,, CAPDEVILA J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours[J]. Neuroendocrinology, 2017, 105(3): 255-265. doi: 10.1159/000464292
[112]	LEWIS A,, RAOOF M,, ITUARTE P H G, et al. Resection of the primary gastrointestinal neuroendocrine tumor improves survival with or without liver treatment[J]. Ann Surg, 2019, 270(6): 1131-1137. doi: 10.1097/SLA.0000000000002809
[113]	PARTELLI S,, INAMA M,, RINKE A, et al. Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases[J]. Neuroendocrinology, 2015, 102(1/2): 68-76. doi: 10.1159/000431379
[114]	BERTANI E,, FAZIO N,, RADICE D, et al. Resection of the primary tumor followed by peptide receptor radionuclide therapy as upfront strategy for the treatment of G1-G2 pancreatic neuroendocrine tumors with unresectable liver metastases[J]. Ann Surg Oncol, 2016, 23(Suppl 5): 981-989. doi: 10.1245/s10434-016-5550-3
[115]	KEUTGEN X M,, NILUBOL N,, GLANVILLE J, et al. Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors[J]. Surgery, 2016, 159(1): 311-318. doi: 10.1016/j.surg.2015.05.042
[116]	CHEN L H,, CHEN J. Perspective of neo-adjuvant/conversion and adjuvant therapy for pancreatic neuroendocrine tumors[J]. J Pancreatol, 2019, 2(3): 91-99. doi: 10.1097/JP9.0000000000000023
[117]	VEZZOSI D,, BENNET A,, ROCHAIX P, et al. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies[J]. Eur J Endocrinol, 2005, 152(5): 757-767. doi: 10.1530/eje.1.01901
[118]	WOLTERING E A,, WRIGHT A E,, STEVENS M A, et al. Development of effective prophylaxis against intraoperative carcinoid crisis[J]. J Clin Anesth, 2016, 32: 189-193. doi: 10.1016/j.jclinane.2016.03.008
[119]	BAUDIN E,, CAPLIN M,, GARCIA-CARBONERO R, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2021, 32(4): 439-451. doi: 10.1016/j.annonc.2021.01.003
[120]	WOLIN E M,, BENSON III A B. Systemic treatment options for carcinoid syndrome: a systematic review[J]. Oncology, 2019, 96(6): 273-289. doi: 10.1159/000499049
[121]	BRODER M S,, BEENHOUWER D,, STROSBERG J R, et al. Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: a systematic literature review[J]. World J Gastroenterol, 2015, 21(6): 1945-1955. doi: 10.3748/wjg.v21.i6.1945
[122]	PAVEL M,, VALLE J W,, ERIKSSON B, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasms: systemic therapy-biotherapy and novel targeted agents[J]. Neuroendocrinology, 2017, 105(3): 266-280. doi: 10.1159/000471880
[123]	WOLIN E M,, JARZAB B,, ERIKSSON B, et al. Phase Ⅲ study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues[J]. Drug Des Devel Ther, 2015, 9: 5075-5086.
[124]	OBERG K. Interferon in the management of neuroendocrine GEP-tumors: a review[J]. Digestion, 2000, 62(Suppl 1): 92-97. doi: 10.1159/000051862
[125]	PAVEL M,, GROSS D J,, BENAVENT M, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial[J]. Endocr Relat Cancer, 2018, 25(3): 309-322. doi: 10.1530/ERC-17-0455
[126]	ITO T,, LEE L,, JENSEN R T. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies[J]. Expert Opin Pharmacother, 2016, 17(16): 2191-2205. doi: 10.1080/14656566.2016.1236916
[127]	DANIEL E,, AYLWIN S,, MUSTAFA O, et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients[J]. J Clin Endocrinol Metab, 2015, 100(11): 4146-4154. doi: 10.1210/jc.2015-2616
[128]	YUEN K C J,, WILLIAMS G,, KUSHNER H, et al. Association between mifepristone dose, efficacy, and tolerability in patients with cushing syndrome[J]. Endocr Pract, 2015, 21(10): 1087-1093. doi: 10.4158/EP15760.OR
[129]	RINKE A,, MÜLLER H H,, SCHADE-BRITTINGER C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group[J]. J Clin Oncol, 2009, 27(28): 4656-4663. doi: 10.1200/JCO.2009.22.8510
[130]	YAO J C,, PAVEL M,, LOMBARD-BOHAS C, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: Overall survival and circulating biomarkers from the randomized, phase Ⅲ RADIANT-3 study[J]. J Clin Oncol, 2016, 34(32): 3906-3913. doi: 10.1200/JCO.2016.68.0702
[131]	YAO J C,, FAZIO N,, SINGH S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study[J]. Lancet, 2016, 387(10022): 968-977. doi: 10.1016/S0140-6736(15)00817-X
[132]	KULKE M H,, RUSZNIEWSKI P,, VAN CUTSEM E, et al. A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial[J]. Ann Oncol, 2019, 30(11): 1846. doi: 10.1093/annonc/mdz219
[133]	PAVEL M E,, HAINSWORTH J D,, BAUDIN E, et al.Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study[J]. Lancet, 2011, 378(9808): 2005-2012. doi: 10.1016/S0140-6736(11)61742-X
[134]	PANZUTO F,, RINZIVILLO M,, SPADA F, et al. Everolimus in pancreatic neuroendocrine carcinomas G3[J]. Pancreas, 2017, 46(3): 302-305. doi: 10.1097/MPA.0000000000000762
[135]	FAIVRE S,, NICCOLI P,, CASTELLANO D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase Ⅲ randomized study[J]. Ann Oncol, 2017, 28(2): 339-343. doi: 10.1093/annonc/mdw561
[136]	CAPDEVILA J,, FAZIO N,, LÓPEZ C, et al. Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase Ⅱ TALENT trial (GETNE1509)[J]. J Clin Oncol, 2021, 39(20): JCO2003368.
[137]	PAVEL M,, O'TOOLE D,, COSTA F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site[J]. Neuroendocrinology, 2016, 103(2): 172-185. doi: 10.1159/000443167
[138]	CLEWEMAR ANTONODIMITRAKIS P, SUNDIN A,, WASSBERG C, et al. Streptozocin and 5-fluorouracil for the treatment of pancreatic neuroendocrine tumors: efficacy, prognostic factors and toxicity[J]. Neuroendocrinology, 2016, 103(3/4): 345-353. doi: 10.1159/000439086
[139]	CHATZELLIS E,, ANGELOUSI A,, DASKALAKIS K, et al. activity and safety of standard and prolonged capecitabine/temozolomide administration in patients with advanced neuroendocrine neoplasms[J]. Neuroendocrinology, 2019, 109 (4): 333-45. doi: 10.1159/000500135
[140]	LAMARCA A,, ELLIOTT E,, BARRIUSO J, et al. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: a lost cause?[J]. Cancer Treat Rev, 2016, 44: 26-41. doi: 10.1016/j.ctrv.2016.01.005
[141]	GARCIA-CARBONERO R,, SORBYE H,, BAUDIN E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas[J]. Neuroendocrinology, 2016, 103(2): 186-194. doi: 10.1159/000443172
[142]	SORBYE H,, WELIN S,, LANGER S W, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study[J]. Ann Oncol, 2013, 24(1): 152-160. doi: 10.1093/annonc/mds276
[143]	SORBYE H,, BAUDIN E,, PERREN A. The problem of high-grade gastroenteropancreatic neuroendocrine neoplasms: well-differentiated neuroendocrine tumors, neuroendocrine carcinomas, and beyond[J]. Endocrinol Metab Clin North Am, 2018, 47(3): 683-698. doi: 10.1016/j.ecl.2018.05.001
[144]	WELIN S,, SORBYE H,, SEBJORNSEN S, et al. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy[J]. Cancer, 2011, 117(20): 4617-4622. doi: 10.1002/cncr.26124
[145]	STROSBERG J,, MIZUNO N,, DOI T, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase Ⅱ KEYNOTE-158 study[J]. Clin Cancer Res, 2020, 26(9): 2124-2130. doi: 10.1158/1078-0432.CCR-19-3014
[146]	FAIVRE-FINN C,, SNEE M,, ASHCROFT L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial[J]. Lancet Oncol, 2017, 18(8): 1116-1125. doi: 10.1016/S1470-2045(17)30318-2
[147]	SKARLOS D V,, SAMANTAS E,, BRIASSOULIS E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase Ⅱ study of the Hellenic Cooperative Oncology Group (HeCOG)[J]. Ann Oncol, 2001, 12(9): 1231-1238. doi: 10.1023/A:1012295131640
[148]	HORN L,, MANSFIELD A S,, SZCZĘSNA A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J]. N Engl J Med, 2018, 379(23): 2220-2229. doi: 10.1056/NEJMoa1809064
[149]	PAZ-ARES L,, DVORKIN M,, CHEN Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial[J]. Lancet, 2019, 394(10212): 1929-1939. doi: 10.1016/S0140-6736(19)32222-6
[150]	EVANS W K,, SHEPHERD F A,, FELD R, et al. VP-16 and cisplatin as first-line therapy for small cell lung cancer[J]. J Clin Oncol, 1985, 3(11): 1471-1477. doi: 10.1200/JCO.1985.3.11.1471
[151]	OKAMOTO H,, WATANABE K,, NISHIWAKI Y, et al. Phase Ⅱ study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer[J]. J Clin Oncol, 1999, 17(11): 3540-3545. doi: 10.1200/JCO.1999.17.11.3540
[152]	NODA K,, NISHIWAKI Y,, KAWAHARA M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer[J]. N Engl J Med, 2002, 346(2): 85-91. doi: 10.1056/NEJMoa003034
[153]	SCHMITTEL A,, VON WEIKERSTHAL L F,, SEBASTIAN M, et al. A randomized phase Ⅱ trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer[J]. Ann Oncol, 2006, 17(4): 663-667. doi: 10.1093/annonc/mdj137
[154]	MOERTEL C G,, KVOLS L K,, O’CONNELL M J, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms[J]. Cancer, 1991, 68(2): 227-232. doi: 10.1002/1097-0142(19910715)68:2<227::AID-CNCR2820680202>3.0.CO;2-I
[155]	ZHANG P P,, LI J,, LI J,, et al. Etoposide and cisplatin versus irinotecan and cisplatin as the first-line therapy for patients with advanced, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma: a randomized phase 2 study[J]. Cancer, 2020, 126(Suppl 9): 2086-2092. doi: 10.1002/cncr.32750
[156]	FINE R L,, GULATI A P,, KRANTZ B A, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the Pancreas Center at Columbia University experience[J]. Cancer Chemother Pharmacol, 2013, 71(3): 663-670. doi: 10.1007/s00280-012-2055-z
[157]	OKITA N T,, KATO K,, TAKAHARI D, et al. Neuroendocrine tumors of the stomach: chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma[J]. Gastric Cancer, 2011, 14(2): 161-165. doi: 10.1007/s10120-011-0025-5
[158]	BAJETTA E,, CATENA L,, PROCOPIO G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?[J]. Cancer Chemother Pharmacol, 2007, 59(5): 637-642. doi: 10.1007/s00280-006-0306-6
[159]	LE D T,, DURHAM J N,, SMITH K N, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349): 409-413. doi: 10.1126/science.aan6733
[160]	HICKS R J,, KWEKKEBOOM D J,, KRENNING E, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues[J]. Neuroendocrinology, 2017, 105 (3): 295-309. doi: 10.1159/000475526
[161]	CARLSEN E A,, FAZIO N,, GRANBERG D, et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study[J]. Endocr Relat Cancer, 2019, 26(2): 227-239.
[162]	CARMONA-BAYONAS A,, JIMÉNEZ-FONSECA P,, LAMARCA Á, et al. Prediction of progression-free survival in patients with advanced, well-differentiated, neuroendocrine tumors being treated with a somatostatin analog: the GETNE-TRASGU study[J]. J Clin Oncol, 2019, 37(28): 2571-2580. doi: 10.1200/JCO.19.00980
[163]	WANG Y H,, LIN Y,, XUE L, et al. Relationship between clinical characteristics and survival of gastroenteropancreatic neuroendocrine neoplasms: a single-institution analysis (1995-2012) in South China[J]. BMC Endocr Disord, 2012, 12: 30. doi: 10.1186/1472-6823-12-30
[164]	FRILLING A,, LI J,, MALAMUTMANN E, et al. Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease[J]. Br J Surg, 2009, 96(2): 175-184. doi: 10.1002/bjs.6468
[165]	MOHAN H,, NICHOLSON P,, WINTER D C, et al. Radiofrequency ablation for neuroendocrine liver metastases: a systematic review[J]. J Vasc Interv Radiol, 2015, 26(7): 935-942.e1.
[166]	FAIRWEATHER M,, SWANSON R,, WANG J P, et al. Management of neuroendocrine tumor liver metastases: long-term outcomes and prognostic factors from a large prospective database[J]. Ann Surg Oncol, 2017, 24(8): 2319-2325. doi: 10.1245/s10434-017-5839-x
[167]	NORLÉN O,, STÅLBERG P,, ZEDENIUS J, et al. Outcome after resection and radiofrequency ablation of liver metastases from small intestinal neuroendocrine tumours[J]. Br J Surg, 2013, 100(11): 1505-1514. doi: 10.1002/bjs.9262
[168]	AKYILDIZ H Y,, MITCHELL J,, MILAS M, et al. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up[J]. Surgery, 2010, 148(6): 1288-1293. doi: 10.1016/j.surg.2010.09.014
[169]	STROSBERG J R,, CHEEMA A,, KVOLS L K. A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract[J]. Cancer Control, 2011, 18(2): 127-137. doi: 10.1177/107327481101800207
[170]	PERICLEOUS M,, CAPLIN M E,, TSOCHATZIS E, et al. Hepatic artery embolization in advanced neuroendocrine tumors: efficacy and long-term outcomes[J]. Asia Pac J Clin Oncol, 2016, 12(1): 61-69. doi: 10.1111/ajco.12438
[171]	刘一铭,, 连帆,, 周翔飞, 等. 肝动脉栓塞术联合长效奥曲肽降低中低级别神经内分泌瘤肝转移负荷的疗效及安全性分析[J]. 中华医学杂志, 2019, 99(15): 1142-1146.
	LIU Y M,, LIAN F,, ZHOU X F, et al. Safety and efficacy of transarterial embolization combined with octreotide LAR on reducing tumor burden for neuroendocrine tumor liver metastasis[J]. Natl Med J China, 2019, 99(15): 1142-1146.
[172]	刘海宽,, 陈文川,, 刘一铭, 等. 肝动脉栓塞术治疗42例低-中级别乏血供型神经内分泌肿瘤肝转移的近期疗效及安全性分析[J]. 中华介入放射学电子杂志, 2020, 8(2): 130-134.
	LIU H K,, CHEN W C,, LIU Y M, et al. Transarterial embolization in the treatment of 42 patients with low-to-intermediate grade neuroendocrine neoplasm liver metastasis with hypovascular pattern: an analysis of the short-term efficacy and safety[J]. Chin J Interv Radiol Electron Ed, 2020, 8(2): 130-134.
[173]	王于,, 陈洁. 胰腺神经内分泌肿瘤复杂肝转移的介入及药物治疗策略[J]. 协和医学杂志, 2020, 11(4): 389-394.
	WANG Y,, CHEN J. The management strategies of interventional therapy and drug therapy of complicated pancreatic neuroendocrine neoplasms with liver metastases[J]. Med J Peking Union Med Coll Hosp, 2020, 11(4): 389-394.
[174]	FRILLING A,, CLIFT A K. Therapeutic strategies for neuroendocrine liver metastases[J]. Cancer, 2015, 121(8): 1172-1186. doi: 10.1002/cncr.28760
[175]	DEL PRETE M,, FIORE F,, MODICA R, et al. Hepatic arterial embolization in patients with neuroendocrine tumors[J]. J Exp Clin Cancer Res, 2014, 33(1): 43. doi: 10.1186/1756-9966-33-43
[176]	ZENER R,, YOON H,, ZIV E, et al. Outcomes after transarterial embolization of neuroendocrine tumor liver metastases using spherical particles of different sizes[J]. Cardiovasc Intervent Radiol, 2019, 42(4): 569-576. doi: 10.1007/s00270-018-02160-y
[177]	ENGELMAN E S,, LEON-FERRE R,, NARAEV B G, et al. Comparison of transarterial liver-directed therapies for low-grade metastatic neuroendocrine tumors in a single institution[J]. Pancreas, 2014, 43(2): 219-225. doi: 10.1097/MPA.0000000000000030
[178]	SAXENA A,, CHUA T C,, BESTER L, et al. Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases[J]. Ann Surg, 2010, 251(5): 910-916. doi: 10.1097/SLA.0b013e3181d3d24a
[179]	BHAGAT N,, REYES D K,, LIN M D, et al. Phase Ⅱ study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury[J]. Cardiovasc Intervent Radiol, 2013, 36(2): 449-459. doi: 10.1007/s00270-012-0424-y
[180]	BEAN M B,, LIU Y,, JIANG R, et al. Small cell and squamous cell carcinomas of the head and neck: comparing incidence and survival trends based on surveillance, epidemiology, and end results (SEER) data[J]. Oncologist, 2019, 24(12): 1562-1569. doi: 10.1634/theoncologist.2018-0054
[181]	VAN DER LAAN T P, IEPSMA R,, WITJES M J, et al. Meta-analysis of 701 published cases of sinonasal neuroendocrine carcinoma: the importance of differentiation grade in determining treatment strategy[J]. Oral Oncol, 2016, 63: 1-9. doi: 10.1016/j.oraloncology.2016.10.002
[182]	POINTER K B,, KO H C,, BROWER J V, et al. Small cell carcinoma of the head and neck: an analysis of the National Cancer Database[J]. Oral Oncol, 2017, 69: 92-98. doi: 10.1016/j.oraloncology.2017.04.009
[183]	CHUN S G,, SIMONE C B, 2ND,, AMINI A, et al. American Radium Society appropriate use criteria: radiation therapy for limited-stage SCLC 2020[J]. J Thorac Oncol, 2021, 16 (1): 66-75. doi: 10.1016/j.jtho.2020.10.020
[184]	GRØNBERG B H,, KILLINGBERG K T,, FLØTTEN Ø, et al. High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial[J]. Lancet Oncol, 2021, 22(3): 321-331. doi: 10.1016/S1470-2045(20)30742-7
[185]	EXPERT PANEL THORACIC MALIGNANCIES:, HIGGINS K A,, SIMONE C B 2nd, et al. American Radium Society appropriate use criteria on radiation therapy for extensive-stage SCLC[J]. J Thorac Oncol, 2021, 16(1): 54-65. doi: 10.1016/j.jtho.2020.09.013
[186]	MAY M S,, KINSLOW C J,, ADAMS C, et al. Outcomes for localized treatment of large cell neuroendocrine carcinoma of the lung in the United States[J]. Transl Lung Cancer Res, 2021, 10(1): 71-79. doi: 10.21037/tlcr-20-374
[187]	WEGNER R E,, ABEL S,, HASAN S, et al. The role of adjuvant therapy for atypical bronchopulmonary carcinoids[J]. Lung Cancer, 2019, 131: 90-94. doi: 10.1016/j.lungcan.2019.03.022
[188]	UPRETY D,, HALFDANARSON T R,, MOLINA J R, et al. Pulmonary neuroendocrine tumors: adjuvant and systemic treatments[J]. Curr Treat Options Oncol, 2020, 21(11): 86. doi: 10.1007/s11864-020-00786-0
[189]	ZHAO Y,, GU H Y,, FAN L M, et al. Comparison of clinical features and survival between thymic carcinoma and thymic carcinoid patients[J]. Eur J Cardiothorac Surg, 2017, 52(1): 33-38. doi: 10.1093/ejcts/ezx037
[190]	CATTRINI C,, CERBONE L,, RUBAGOTTI A, et al. Prognostic variables in patients with non-metastatic small-cell neuroendocrine carcinoma of the bladder: a population-based study[J]. Clin Genitourin Cancer, 2019, 17(4): e724-e732.
[191]	LIM J H,, SUNDAR S. Prognosis of early stage small cell bladder cancer is not always dismal[J]. ESMO Open, 2019, 4(6): e000559.
[192]	NIU Q,, LU Y Y,, XU S G, et al. Clinicopathological characteristics and survival outcomes of bladder neuroendocrine carcinomas: a population-based study[J]. Cancer Manag Res, 2018, 10: 4479-4489. doi: 10.2147/CMAR.S175286
[193]	TEMPFER C B,, TISCHOFF I,, DOGAN A, et al. Neuroendocrine carcinoma of the cervix: a systematic review of the literature[J]. BMC Cancer, 2018, 18(1): 530. doi: 10.1186/s12885-018-4447-x
[194]	PANG L,, YANG H,, NING Y E, et al. Retrospective analysis of clinicopathological features and prognosis of gynecological small-cell carcinoma[J]. Cancer Manag Res, 2021, 13: 4529-4540. doi: 10.2147/CMAR.S314686
[195]	DONG M L,, GU X B,, MA T R, et al. The role of radiotherapy in neuroendocrine cervical cancer: SEER-based study[J]. Sci Prog, 2021, 104(2): 368504211009336.
[196]	LIN L M,, LIN Q,, LIU J, et al. Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix based on population analyses[J]. Cancer Med, 2020, 9(18): 6524-6532. doi: 10.1002/cam4.3326
[197]	BHATIA S,, STORER B E,, IYER J G, et al. Adjuvant radiation therapy and chemotherapy in merkel cell carcinoma: survival analyses of 6 908 cases from the national cancer data base[J]. J Natl Cancer Inst, 2016, 108(9): djw042.
[198]	ANDRUSKA N,, FISCHER-VALUCK B W,, MAHAPATRA L, et al. Association between surgical margins larger than 1 cm and overall survival in patients with Merkel cell carcinoma[J]. JAMA Dermatol, 2021, 157(5): 540-548. doi: 10.1001/jamadermatol.2021.0247
[199]	ANDRUSKA N,, MAHAPATRA L,, BRENNEMAN R J, et al. Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival[J]. Radiother Oncol, 2021, 155: 246-253. doi: 10.1016/j.radonc.2020.11.003
[200]	CHEN Y Y,, HAN D,, ZHU J Q, et al. A prospective and retrospective clinical controlled observation of Chinese herbal decoction (SMLJ01) for type 1 gastric neuroendocrine tumors[J]. Integr Cancer Ther, 2020, 19: 1534735420958488.
[201]	LAMB B W,, SEVDALIS N,, VINCENT C, et al. Development and evaluation of a checklist to support decision making in cancer multidisciplinary team meetings: MDT-QuIC[J]. Ann Surg Oncol, 2012, 19(6): 1759-1765. doi: 10.1245/s10434-011-2187-0
[202]	TAMAGNO G,, SHEAHAN K,, SKEHAN S J, et al. Initial impact of a systematic multidisciplinary approach on the management of patients with gastroenteropancreatic neuroendocrine tumor[J]. Endocrine, 2013, 44(2): 504-509. doi: 10.1007/s12020-013-9910-5

类型	发病率（10^-6/年）	分泌激素	常见部位	转移比例/%	主要症状
胰岛素瘤	1.00 ~ 32.00	胰岛素	胰腺	5 ~ 10	发作性低血糖症候群
胃泌素瘤	0.50 ~ 21.50	胃泌素	十二指肠、胰腺	50 ~ 60	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
胰高糖素瘤	0.01 ~ 0.10	胰高糖素	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	少见	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
产生ACTH的神经内分泌瘤	少见	ACTH	胰腺、胸腺	>90	库欣综合征
产生5-羟色胺的神经内分泌瘤	少见	5-羟色胺	小肠、肺、胰腺	>60	类癌综合征
产生生长激素的神经内分泌瘤	少见	生长激素	胰腺、肺	>60	肢端肥大症

分类/分级	分化	核分裂象（个/2 mm²）	Ki-67增殖指数/%
NET
G1	良好	<2	<3
G2	良好	2~20	3~20
G3	良好	>20	>20
NEC
LCNEC	差	>20	>20
SCNEC	差	>20	>20
MiNEN	差/良好	不一	不一

项目	TC	AC	LCNEC	SCLC
性别	女性好发	女性好发	男性好发	男性好发
核分裂象	<2个/2 mm²	2~10个/2 mm²	>10个/2 mm²（中位数70）	>10个/2 mm²（中位数80）
坏死	无	无/小斑片状	有	有
Ki-67增殖指数	小于5%	小于30%	30%~100%	30%~100%
TTF1	30%+,外周型	50%+,外周型	70%+	85%+
P40	阴性	阴性	阴性	阴性
非小细胞癌成分	无	无	切除标本中最高到25%	切除标本中最高到25%

肿瘤具有典型神经内分泌形态特点	TC	AC	LCNEC	SCNEC
肿瘤具有典型神经内分泌形态特点	低级别	中级别	高级别
核分裂象	<2个/2 mm²	2~10个/2 mm²	>10个/2 mm²（中位数45）	>10个/2 mm²（中位数110）
坏死	无	无/小斑片状	有	有

特征	1型ECL细胞NET	2型ECL细胞NET	3型NET
男性∶女性	0.4∶1.0	1.0∶1.0	2.8∶1.0
所占比例	80% ~ 90%	5% ~ 7%	10% ~ 15%
高胃泌素血症	是	是	否
胃窦G细胞增生	是	否	否
胃酸分泌	低胃酸/胃酸缺乏	高胃酸	正常
背景黏膜	萎缩性胃炎	壁细胞肥大/增生	无特异改变
ECL细胞增生	是	是	否
病理学分级	G1	G1	G1（罕见）
	G2（罕见）	G2（罕见）	G2
	G3（个别）		G3（罕见）
临床分期	Ⅰ ~ Ⅱ：95%	Ⅰ ~ Ⅱ：70%	Ⅰ ~ Ⅱ：38%
	Ⅲ：4%	Ⅲ：20%	Ⅲ：32%
	Ⅳ：1%	Ⅳ：10%	Ⅳ：30%
转移率	1% ~ 3%	10% ~ 30%	50%
5年生存率	~ 100%	60% ~ 90%	<50%