胰腺神经内分泌肿瘤外科治疗理念的四种转变

doi:10.19401/j.cnki.1007-3639.2022.09.002

摘要/Abstract

摘要：

胰腺神经内分泌肿瘤（pancreatic neuroendocrine neoplasm,pNEN）是一类具有高度异质性的肿瘤。外科手术是pNEN综合治疗的重要环节,但pNEN较低的发病率和较强的异质性导致其外科领域进展相对缓慢。在治疗理念上,pNEN的外科治疗策略逐渐由病情导向转变为预后导向,对肿瘤特征的评估更加依赖形态学联合分子病理学的方法。此外,pNEN手术治疗正在向个体化、微创化、精细化的方向发展,手术的介入时机也逐步拓展至患者的全诊疗周期。本文将结合国内外相关领域研究进展,分析现阶段pNEN外科治疗面临的问题与挑战,并探讨治疗理念的转变及潜在的突破方向。

关键词: 胰腺神经内分泌肿瘤, 外科治疗, 治疗理念

Abstract:

Pancreatic neuroendocrine neoplasm (pNEN) is highly heterogeneous. Surgery is an important part of the comprehensive treatment for pNEN, however, the low incidence and strong heterogeneity of the disease retard the progress of surgical treatment. In terms of treatment concepts, the therapeutic strategy of surgery may transform from condition-orientated to prognosis-orientated treatment, and the evaluation of tumor characteristics relies more on morphology combined with molecular pathology. In addition, pNEN surgical treatment is becoming individualized, minimally invasive and delicate, and the timing of surgical intervention has extended to the entire disease period. Based on the research progresses in related fields, we analyzed the issues and challenges and discussed the evolution in the surgical treatment concepts of pNEN.

Key words: Pancreatic neuroendocrine neoplasm, Surgical treatment, Treatment concept

中图分类号:

R735.9

王先泽, 吴文铭. 胰腺神经内分泌肿瘤外科治疗理念的四种转变[J]. 中国癌症杂志, 2022, 32(9): 765-771.

WANG Xianze, WU Wenming. Evolution in the surgical treatment concepts of pancreatic neuroendocrine tumors[J]. China Oncology, 2022, 32(9): 765-771.

参考文献 64

[1]	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
[2]	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.
[3]	CIVES M, STROSBERG J R. Gastroenteropancreatic neuroendocrine tumors[J]. CA Cancer J Clin, 2018, 68(6): 471-487. doi: 10.3322/caac.21493
[4]	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 pmid: 28448665
[5]	SCARPA A, CHANG D K, NONES K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours[J]. Nature, 2017, 543(7643): 65-71. doi: 10.1038/nature21063
[6]	刘大为. 一个值得深思的问题:重症治疗是病情导向抑或治疗目标导向[J]. 中华内科杂志, 2022, 61(6): 607-610.
	LIU D W. Target directed therapy in critical patients, to be or not to be[J]. Chin J Intern Med, 2022, 61(6): 607-610.
[7]	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(2022年版)[J]. 中国癌症杂志, 2022, 32(6): 545-579.
	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. doi: 10.19401/j.cnki.1007-3639.2022.06.010
[8]	KULKARNI R, KABIR I, HODSON J, et al. Impact of the extent of resection of neuroendocrine tumor liver metastases on survival: a systematic review and meta-analysis[J]. Ann Hepatobiliary Pancreat Surg, 2022, 26(1): 31-39. doi: 10.14701/ahbps.21-101
[9]	MEROLA E, FALCONI M, RINKE A, et al. Radical intended surgery for highly selected stage Ⅳ neuroendocrine neoplasms G3[J]. Am J Surg, 2020, 220(2): 284-289. doi: 10.1016/j.amjsurg.2020.03.009
[10]	MEROLA E, RINKE A, PARTELLI S, et al. Surgery with radical intent: is there an indication for G3 neuroendocrine neoplasms?[J]. Ann Surg Oncol, 2020, 27(5): 1348-1355. doi: 10.1245/s10434-019-08049-5 pmid: 31720931
[11]	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 pmid: 29746336
[12]	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. doi: 10.1097/SLA.0000000000003478
[13]	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
[14]	LUO G P, JAVED A, STROSBERG J R, et al. Modified staging classification for pancreatic neuroendocrine tumors on the basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society systems[J]. J Clin Oncol, 2017, 35(3): 274-280. doi: 10.1200/JCO.2016.67.8193 pmid: 27646952
[15]	ZHANG X F, XUE F, WU Z, et al. Development and validation of a modified eighth AJCC staging system for primary pancreatic neuroendocrine tumors[J]. Ann Surg, 2022, 275(6): e773-e780. doi: 10.1097/SLA.0000000000004039
[16]	WANG M, DING D, QIN T T, et al. New staging classification for pancreatic neuroendocrine neoplasms combining TNM stage and WHO grade classification[[J]. Cancer Lett, 2021, 518: 207-213. doi: 10.1016/j.canlet.2021.07.018
[17]	YAN J, YU S N, JIA C W, et al. Molecular subtyping in pancreatic neuroendocrine neoplasms: new insights into clinical, pathological unmet needs and challenges[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(1): 188367.
[18]	KAWASAKI K, TOSHIMITSU K, MATANO M, et al. An organoid biobank of neuroendocrine neoplasms enables genotype-phenotype mapping[J]. Cell, 2020, 183(5): 1420-1435.e21. doi: 10.1016/j.cell.2020.10.023 pmid: 33159857
[19]	SALLINEN V, HAGLUND C, SEPPÄNEN H. Outcomes of resected nonfunctional pancreatic neuroendocrine tumors: do size and symptoms matter?[J]. Surgery, 2015, 158(6): 1556-1563. doi: 10.1016/j.surg.2015.04.035
[20]	PAIK W H, LEE H S, LEE K J, et al. Malignant potential of small pancreatic neuroendocrine neoplasm and its risk factors: a multicenter nationwide study[J]. Pancreatology, 2021, 21(1): 208-214. doi: 10.1016/j.pan.2020.11.016 pmid: 33281058
[21]	MIRKIN K A, HOLLENBEAK C S, WONG J. Impact of chromogranin A, differentiation, and mitoses in nonfunctional pancreatic neuroendocrine tumors ≤ 2 cm[J]. J Surg Res, 2017, 211: 206-214. doi: 10.1016/j.jss.2016.12.033
[22]	HAN I W, PARK J, PARK E Y, et al. Fate of surgical patients with small nonfunctioning pancreatic neuroendocrine tumors: an international study using multi-institutional registries[J]. Cancers, 2022, 14(4): 1038. doi: 10.3390/cancers14041038
[23]	DE ROBERTIS R, MARIS B, CARDOBI N, et al. Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors?[J]. Eur Radiol, 2018, 28(6): 2582-2591. doi: 10.1007/s00330-017-5236-7 pmid: 29352378
[24]	PAIELLA S, LANDONI L, TEBALDI S, et al. Dual-tracer(⁶⁸Ga-DOTATOC and ¹⁸F-FDG-)-PET/CT scan and G1-G2 nonfunctioning pancreatic neuroendocrine tumors: a single-center retrospective evaluation of 124 nonmetastatic resected cases[J]. Neuroendocrinology, 2022, 112(2): 143-152. doi: 10.1159/000514809
[25]	HACKENG W M, BROSENS L A A, KIM J Y, et al. Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size[J]. Gut, 2022, 71(5): 961-973. doi: 10.1136/gutjnl-2020-322595
[26]	PEA A, YU J, MARCHIONNI L, et al. Genetic analysis of small well-differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases[J]. Ann Surg, 2020, 271(3): 566-573. doi: 10.1097/SLA.0000000000003022 pmid: 30339629
[27]	QUEVEDO R, SPREAFICO A, BRUCE J, et al. Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumor[J]. Genome Med, 2020, 12(1): 38. doi: 10.1186/s13073-020-00730-9 pmid: 32345369
[28]	TANG X, SHAO Y, YI X, et al. Metastatic timing and genetic heterogeneity in the evolution of a pancreatic neuroendocrine tumor[J]. Am J Gastroenterol, 2021, 116(4): 844-847.
[29]	RINDI G, METE O, UCCELLA S, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms[J]. Endocr Pathol, 2022, 33(1): 115-154. doi: 10.1007/s12022-022-09708-2 pmid: 35294740
[30]	TITAN A L, NORTON J A, FISHER A T, et al. Evaluation of outcomes following surgery for locally advanced pancreatic neuroendocrine tumors[J]. JAMA Netw Open, 2020, 3(11): e2024318.
[31]	GAO S Z, SHI X H, MA H Y, et al. The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection[J]. J Pancreatol, 2020, 3(4): 167-172.
[32]	WANG W Q, ZHANG W H, GAO H L, et al. A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors[J]. J Gastroenterol, 2021, 56(4): 395-405. doi: 10.1007/s00535-021-01777-0
[33]	PULVIRENTI A, JAVED A A, LANDONI L, et al. Multi-institutional development and external validation of a nomogram to predict recurrence after curative resection of pancreatic neuroendocrine tumors[J]. Ann Surg, 2021, 274(6): 1051-1057. doi: 10.1097/SLA.0000000000003579
[34]	CHAN C S, LADDHA S V, LEWIS P W, et al. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup[J]. Nat Commun, 2018, 9(1): 4158. doi: 10.1038/s41467-018-06498-2 pmid: 30315258
[35]	LAWRENCE B, BLENKIRON C, PARKER K, et al. Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer[J]. NPJ Genom Med, 2018, 3: 18. doi: 10.1038/s41525-018-0058-3 pmid: 30062048
[36]	HONG X F, QIAO S T, LI F Q, et al. Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system[J]. Gut, 2020, 69(5): 877-887. doi: 10.1136/gutjnl-2018-317233 pmid: 31462556
[37]	SADANANDAM A, WULLSCHLEGER S, LYSSIOTIS C A, et al. A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics[J]. Cancer Discov, 2015, 5(12): 1296-1313. doi: 10.1158/2159-8290.CD-15-0068 pmid: 26446169
[38]	YAO J, GARG A, CHEN D, et al. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials[J]. Endocr Relat Cancer, 2019, 26(4): 391-403. doi: 10.1530/ERC-18-0332
[39]	WEI M Y, XU J, HUA J, et al. From the immune profile to the immunoscore: signatures for improving postsurgical prognostic prediction of pancreatic neuroendocrine tumors[J]. Front Immunol, 2021, 12: 654660.
[40]	KIDD M, MODLIN I, ÖBERG K. Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms[J]. Nat Rev Clin Oncol, 2016, 13(11): 691-705. doi: 10.1038/nrclinonc.2016.85 pmid: 27273044
[41]	YOUNG K, STARLING N, SADANANDAM A. The molecular biology of pancreatic neuroendocrine neoplasms: challenges and translational opportunities[J]. Semin Cancer Biol, 2020, 61: 132-138. doi: S1044-579X(19)30291-3 pmid: 31577961
[42]	GAY-CHEVALLIER S, DE MESTIER L, PERINEL J, et al. Management and prognosis of localized duodenal neuroendocrine neoplasms[J]. Neuroendocrinology, 2021, 111(8): 718-727. doi: 10.1159/000508102
[43]	WANG R, MOHAPATRA S, JOVANI M, et al. Risk factors for lymph node metastasis and survival of patients with nonampullary duodenal carcinoid tumors treated with endoscopic therapy versus surgical resection: analysis of the Surveillance, Epidemiology, and End Results program[J]. Gastrointest Endosc, 2021, 93(6): 1384-1392. doi: 10.1016/j.gie.2020.12.012 pmid: 33347833
[44]	RIMBAŞ M, HORUMBĂ M, RIZZATTI G, et al. Interventional endoscopic ultrasound for pancreatic neuroendocrine neoplasms[J]. Dig Endosc, 2020, 32(7): 1031-1041. doi: 10.1111/den.13635
[45]	MELITA G, PALLIO S, TORTORA A, et al. Diagnostic and interventional role of endoscopic ultrasonography for the management of pancreatic neuroendocrine neoplasms[J]. J Clin Med, 2021, 10(12): 2638. doi: 10.3390/jcm10122638
[46]	WANG M, PENG B, LIU J H, et al. Practice patterns and perioperative outcomes of laparoscopic pancreaticoduodenectomy in China: a retrospective multicenter analysis of 1029 patients[J]. Ann Surg, 2021, 273(1): 145-153. doi: 10.1097/SLA.0000000000003190
[47]	WANG M, LI D W, CHEN R F, et al. Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours: a multicentre, open-label, randomised controlled trial[J]. Lancet Gastroenterol Hepatol, 2021, 6(6): 438-447. doi: 10.1016/S2468-1253(21)00054-6
[48]	TAMBURRINO D, PARTELLI S, RENZI C, et al. Systematic review and meta-analysis on laparoscopic pancreatic resections for neuroendocrine neoplasms (PNENs)[J]. Expert Rev Gastroenterol Hepatol, 2017, 11(1): 65-73. doi: 10.1080/17474124.2017.1253473
[49]	ZHANG H, LAN X, PENG B, et al. Is total laparoscopic pancreaticoduodenectomy superior to open procedure? A meta-analysis[J]. World J Gastroenterol, 2019, 25(37): 5711-5731. doi: 10.3748/wjg.v25.i37.5711
[50]	GIULIANI T, DE PASTENA M, PAIELLA S, et al. Pancreatic enucleation patients share the same quality of life as the general population at long-term follow-up: a propensity-score matched analysis[J]. Ann Surg, 2021. Online ahead of print.
[51]	HUANG J, YADAV D K, XIONG C J, et al. Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) versus open spleen-preserving distal pancreatectomy (OSPDP): a comparative study[J]. Can J Gastroenterol Hepatol, 2019, 2019: 9367868.
[52]	LI A Y, VISSER B C, DUA M M. Surgical indications and outcomes of resection for pancreatic neuroendocrine tumors with vascular involvement[J]. Cancers, 2022, 14(9): 2312. doi: 10.3390/cancers14092312
[53]	WANG X Z, CHUNG W Y, CORREA E, et al. The integration of artificial intelligence models to augment imaging modalities in pancreatic cancer[J]. J Pancreatol, 2020, 3(4): 173-180.
[54]	BARI H, WADHWANI S, DASARI B V M. Role of artificial intelligence in hepatobiliary and pancreatic surgery[J]. World J Gastrointest Surg, 2021, 13(1): 7-18. doi: 10.4240/wjgs.v13.i1.7 pmid: 33552391
[55]	HERNANDEZ VARGAS S, KOSSATZ S, VOSS J, et al. Specific targeting of somatostatin receptor subtype-2 for fluorescence-guided surgery[J]. Clin Cancer Res, 2019, 25(14): 4332-4342. doi: 10.1158/1078-0432.CCR-18-3312 pmid: 31015345
[56]	LAUWERENDS L J, VAN DRIEL P B A A, BAATENBURG DE JONG R J, et al. Real-time fluorescence imaging in intraoperative decision making for cancer surgery[J]. Lancet Oncol, 2021, 22(5): e186-e195. doi: 10.1016/S1470-2045(20)30600-8
[57]	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. doi: 10.1016/S1470-2045(13)70362-0
[58]	KAEMMERER D, TWRZNIK M, KULKARNI H R, et al. Prior resection of the primary tumor prolongs survival after peptide receptor radionuclide therapy of advanced neuroendocrine neoplasms[J]. Ann Surg, 2021, 274(1): e45-e53. doi: 10.1097/SLA.0000000000003237 pmid: 33030849
[59]	SPOLVERATO G, BAGANTE F, ALDRIGHETTI L, et al. Management and outcomes of patients with recurrent neuroendocrine liver metastasis after curative surgery: an international multi-institutional analysis[J]. J Surg Oncol, 2017, 116(3): 298-306. doi: 10.1002/jso.24670 pmid: 28513896
[60]	SQUIRES M H, WORTH P J, KONDA B, et al. Neoadjuvant capecitabine/temozolomide for locally advanced or metastatic pancreatic neuroendocrine tumors[J]. Pancreas, 2020, 49(3): 355-360. doi: 10.1097/MPA.0000000000001500
[61]	MURASE Y, KUDO A, AKAHOSHI K, et al. Surgery after sunitinib administration to improve survival of patients with advanced pancreatic neuroendocrine neoplasms[J]. Ann Gastroenterol Surg, 2021, 5(5): 692-700. doi: 10.1002/ags3.12458 pmid: 34585054
[62]	HIBI T, RELA M, EASON J D, et al. Liver transplantation for colorectal and neuroendocrine liver metastases and hepatoblastoma. Working group report from the ILTS transplant oncology consensus conference[J]. Transplantation, 2020, 104(6): 1131-1135. doi: 10.1097/TP.0000000000003118 pmid: 32217939
[63]	MORIS D, TSILIMIGRAS D I, NTANASIS-STATHOPOULOS I, et al. Liver transplantation in patients with liver metastases from neuroendocrine tumors: a systematic review[J]. Surgery, 2017, 162(3): 525-536. doi: 10.1016/j.surg.2017.05.006
[64]	MAZZAFERRO V, SPOSITO C, COPPA J, et al. The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors[J]. Am J Transplant, 2016, 16(10): 2892-2902. doi: 10.1111/ajt.13831 pmid: 27134017