Operationsindikationen bei neuroendokrinen Neoplasien des Pankreas

Zusammenfassung

Neuroendokrine Neoplasien des Pankreas (pNEN) haben aufgrund ihrer ansteigenden Inzidenz und Prävalenz eine zunehmende klinische Bedeutung. Ihr Erscheinungsbild variiert sehr stark, da manche dieser Tumoren Hormone sezernieren. Ihnen gemeinsam ist die Tendenz zur frühen Metastasierung. Dennoch ist die Tumorgröße, neben der Graduierung, ein wichtiger prognostischer Marker. Anhand einer systematischen Literaturrecherche und der Formulierung von konkreten Schlüsselfragen nach dem PICO-Schema sind Therapieempfehlungen formuliert worden. Durch die Befragung im Delphi-Verfahren unter den Mitgliedern der „Arbeitsgruppe Pankreas“ und der „Arbeitsgruppe Indikationsqualität“ der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie erstellten wir sodann evidenzbasierte Therapieempfehlungen für Patienten mit einem pNEN. Die chirurgische Resektion dieser Tumoren stellt das einzige potenzielle kurative Verfahren dar. Sporadische wie auch hereditäre pNEN > 2 cm stellen eine Operationsindikation dar, unabhängig von ihrer funktionellen Aktivität. Bei kleineren Tumoren kann u. U. auch ein abwartendes Verhalten indiziert sein. Anhand der aktuellen Daten ist eine Empfehlung hierzu aber nicht grundsätzlich zu geben und auch pNEN von 1 – 2 cm Größe sind daher eine relative Operationsindikation. Hereditäre pNEN stellen eine interdisziplinäre Herausforderung dar und diese Patienten sollten gemeinsam an einem Zentrum für neuroendokrine Tumoren betreut werden. Patienten mit Fernmetastasen sind nicht grundsätzlich als palliativ anzusehen, da neben der Metastasenchirurgie auch Debulking-Operationen indiziert sein können.

Abstract

Neuroendocrine neoplasms of the pancreas (pNEN) have an increasing incidence and prevalence. Thus, this entity is of increasing clinical significance. Patients with pNEN become clinically apparent due to different and unspecific symptoms. Some tumours secrete hormones and peptides and become clinically symptomatic. In general, these tumours can metastasise early and even small tumours lead to distant metastases. Nonetheless, primary tumour size and grading are important prognostic factors. On the basis of a systematic literature research and the formulation of key issues according to the PICO system, therapeutic concepts were established. These concepts were evaluated with a Delphi process among the members of the pancreas research group and the indications for surgery group of the German Society of General and Visceral Surgery. Thus this article gives an overview of the surgical treatment modalities and indications for the treatment of pNEN. Surgery is still the gold standard in treatment and the only potential chance of cure. Surgery is indicated for sporadic as well as hereditary pNEN > 2 cm independent of the functional activity. A so called “wait and see” strategy might be indicated in smaller pNEN; however, there is little evidence for this approach. In this respect, pNEN of 1 – 2 cm represent a surgical indication. The treatment of hereditary pNEN is challenging and should be interdisciplinary. Even in the case of distant metastases, a curative approach might be feasible and multimodal treatment is indicated.

Kernaussagen

• Die chirurgische Resektion von pNEN stellt das einzige kurative Verfahren dar.

• pNEN > 2 cm stellen eine OP-Indikation dar.

• pNEN < 2 cm können beobachtet oder operiert werden.

• Die hereditären und funktionellen pNEN sind von den nicht funktionellen sporadischen pNEN zu unterscheiden; ihre Therapie unterscheidet sich.

• Ein extrahepatisches Debulking kann indiziert sein, um eine zielgerichtete Therapie der hepatischen Metastasen zu ermöglichen.

• Die Metastasenchirurgie kann beim gut differenzierten pNEN nach interdisziplinärer Diskussion indiziert sein.

• Beim schlecht differenzierten pNEN ist eine Resektion nur dann indiziert, wenn Tumorfreiheit erzielt werden kann.

Schlüsselwörter

neuroendokrine Neoplasie - Pankreas - Operationsindikation - Pankreaschirurgie - Tumorgröße

Key words

neuroendocrine neoplasm - pancreas - operative indication - pancreatic surgery - tumour size

Publication History

Article published online:
29 June 2020

• Literatur

• 1 Boyar Cetinkaya R, Aagnes B, Thiis-Evensen E. et al. Trends in incidence of neuroendocrine neoplasms in Norway: a report of 16,075 cases from 1993 through 2010. Neuroendocrinology 2017; 104: 1-10 doi:10.1159/000442207
• 2 Yao JC, Eisner MP, Leary C. et al. Population-based study of islet cell carcinoma. Ann Surg Oncol 2007; 14: 3492-3500 doi:10.1245/s10434-007-9566-6
• 3 Crippa S, Partelli S, Zamboni G. et al. Incidental diagnosis as prognostic factor in different tumor stages of nonfunctioning pancreatic endocrine tumors. Surgery 2014; 155: 145-153 doi:10.1016/j.surg.2013.08.002
• 4 Lawrence B, Gustafsson BI, Chan A. et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40: 1-18 vii doi:10.1016/j.ecl.2010.12.005
• 5 McKenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg 2014; 3: 258-275 doi:10.3978/j.issn.2227-684X.2014.06.03
• 6 de Laat JM, Tham E, Pieterman CR. et al. Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. Eur J Endocrinol 2012; 167: 181-187 doi:10.1530/EJE-12-0210
• 7 Bartolini I, Bencini L, Risaliti M. et al. Current management of pancreatic neuroendocrine tumors: from demolitive surgery to observation. Gastroenterol Res Pract 2018; 2018: 9647247 doi:10.1155/2018/9647247
• 8 Choe J, Kim KW, Kim HJ. et al. What is new in the 2017 World Health Organization classification and 8th American Joint Committee on Cancer staging system for pancreatic neuroendocrine neoplasms?. Korean J Radiol 2019; 20: 5-17 doi:10.3348/kjr.2018.0040
• 9 Lloyd RV, Osamura RY, Klöppel G, Rosai J. WHO Classification of Tumours of endocrine Organs. 4th ed. Genf: IARC Press; 2017
• 10 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. Neuroendocrinology 2016; 103: 153-171 doi:10.1159/000443171
• 11 Rindi G, Falconi M, Klersy C. et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012; 104: 764-777 doi:10.1093/jnci/djs208
• 12 Bösch F, Hofmann K, Coenen M. et al. Surgical treatment of pNET – experience of a “high-volume” center. Surg Oncol 2018; 27: 409-414 doi:10.1016/j.suronc.2018.05.027
• 13 Miller HC, Drymousis P, Flora R. et al. Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease. World J Surg 2014; 38: 1353-1361 doi:10.1007/s00268-014-2451-0
• 14 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. JAMA Oncol 2017; 3: 1335-1342 doi:10.1001/jamaoncol.2017.0589
• 15 Bettini R, Partelli S, Boninsegna L. et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011; 150: 75-82 doi:10.1016/j.surg.2011.02.022
• 16 Mills L, Drymousis P, Vashist Y. et al. Tumour diameter is not reliable for management of non-secreting pancreatic neuroendocrine tumours. Endocr Connect 2017; 6: 876-885 doi:10.1530/EC-17-0293
• 17 Cherenfant J, Stocker SJ, Gage MK. et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013; 154: 785-791 doi:10.1016/j.surg.2013.07.004
• 18 Haynes AB, Deshpande V, Ingkakul T. et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg 2011; 146: 534-538 doi:10.1001/archsurg.2011.102
• 19 Hashim YM, Trinkaus KM, Linehan DC. et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETS). Ann Surg 2014; 259: 197-203 doi:10.1097/SLA.0000000000000348
• 20 Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 2013; 20: 2815-2821 doi:10.1245/s10434-013-3005-7
• 21 Halfdanarson TR, Rabe KG, Rubin J. et al. Pancreatic neuroendocrine tumors (PNETS): Incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008; 19: 1727-1733 doi:10.1093/annonc/mdn351
• 22 Tamburrino D, Spoletini G, Partelli S. et al. Surgical management of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab 2016; 30: 93-102 doi:10.1016/j.beem.2015.10.003
• 23 Garcia-Carbonero R, Capdevila J, Crespo-Herrero G. et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the national cancer registry of Spain (RGETNE). Ann Oncol 2010; 21: 1794-1803 doi:10.1093/annonc/mdq022
• 24 Sorbye H, Welin S, Langer SW. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study. Ann Oncol 2013; 24: 152-160 doi:10.1093/annonc/mds276
• 25 Garcia-Carbonero R, Sorbye H, Baudin E. et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 2016; 103: 186-194 doi:10.1159/000443172
• 26 Falconi M, Bartsch DK, Eriksson B. et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 2012; 95: 120-134 doi:10.1159/000335587
• 27 Reid MD, Balci S, Saka B. et al. Neuroendocrine tumors of the pancreas: current concepts and controversies. Endocr Pathol 2014; 25: 65-79 doi:10.1007/s12022-013-9295-2
• 28 Shah MH, Goldner WS, Halfdanarson TR. et al. NCCN guidelines insights: neuroendocrine and adrenal tumors, version 2.2018. J Natl Compr Canc Netw 2018; 16: 693-702 doi:10.6004/jnccn.2018.0056
• 29 Gratian L, Pura J, Dinan M. et al. Impact of extent of surgery on survival in patients with small nonfunctional pancreatic neuroendocrine tumors in the United States. Ann Surg Oncol 2014; 21: 3515-3521 doi:10.1245/s10434-014-3769-4
• 30 Partelli S, Cirocchi R, Crippa S. et al. Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms. Br J Surg 2017; 104: 34-41 doi:10.1002/bjs.10312
• 31 Sadot E, Reidy-Lagunes DL, Tang LH. et al. Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study. Ann Surg Oncol 2016; 23: 1361-1370 doi:10.1245/s10434-015-4986-1
• 32 Assi HA, Mukherjee S, Kunz PL. et al. Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: an 11-year analysis of the National Cancer Database. Oncologist 2020; 25: e276-e283 doi:10.1634/theoncologist.2019-0466
• 33 Chivukula SV, Tierney JF, Hertl M. et al. Operative resection in early stage pancreatic neuroendocrine tumors in the United States: are we over- or undertreating patients?. Surgery 2020; 167: 180-186 doi:10.1016/j.surg.2019.04.061
• 34 Chabot J. Editorial: Pancreatic neuroendocrine tumors: primum non nocere. Surgery 2016; 159: 348-349 doi:10.1016/j.surg.2015.08.037
• 35 Gooiker GA, Lemmens VE, Besselink MG. et al. Impact of centralization of pancreatic cancer surgery on resection rates and survival. Br J Surg 2014; 101: 1000-1005 doi:10.1002/bjs.9468
• 36 Hüttner FJ, Koessler-Ebs J, Hackert T. et al. Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms. Br J Surg 2015; 102: 1026-1036 doi:10.1002/bjs.9819
• 37 Sallinen V, Le Large TY, Galeev S. et al. Surveillance strategy for small asymptomatic non-functional pancreatic neuroendocrine tumors – a systematic review and meta-analysis. HPB (Oxford) 2017; 19: 310-320 doi:10.1016/j.hpb.2016.12.010
• 38 Cienfuegos JA, Salguero J, Nunez-Cordoba JM. et al. Short- and long-term outcomes of laparoscopic organ-sparing resection in pancreatic neuroendocrine tumors: a single-center experience. Surg Endosc 2017; 31: 3847-3857 doi:10.1007/s00464-016-5411-y
• 39 Hackert T, Hinz U, Fritz S. et al. Enucleation in pancreatic surgery: indications, technique, and outcome compared to standard pancreatic resections. Langenbecks Arch Surg 2011; 396: 1197-1203 doi:10.1007/s00423-011-0801-z
• 40 Jin JB, Qin K, Li H. et al. Robotic enucleation for benign or borderline tumours of the pancreas: a retrospective analysis and comparison from a high-volume centre in Asia. World J Surg 2016; 40: 3009-3020 doi:10.1007/s00268-016-3655-2
• 41 Shirota T, Nagakawa Y, Sahara Y. et al. Surgical resection of neuroendocrine tumors of the pancreas (pNETS) by minimally invasive surgery: the laparoscopic approach. Gland Surg 2018; 7: 12-19 doi:10.21037/gs.2017.11.06
• 42 Oberg K. Management of functional neuroendocrine tumors of the pancreas. Gland Surg 2018; 7: 20-27 doi:10.21037/gs.2017.10.08
• 43 Partelli S, Bartsch DK, Capdevila J. et al. ENETS consensus guidelines for standard of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology 2017; 105: 255-265 doi:10.1159/000464292
• 44 Cho MS, Kasi A. Zollinger Ellison syndrome. In: StatPearls. Treasure Island (FL); 2019. Im Internet (Stand: 13.05.2020): https://www.ncbi.nlm.nih.gov/books/NBK537344
• 45 Belei OA, Heredea ER, Boeriu E. et al. Verner-Morrison syndrome. Literature review. Rom J Morphol Embryol 2017; 58: 371-376
• 46 Mehrabi A, Fischer L, Hafezi M. et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas 2014; 43: 675-686 doi:10.1097/MPA.0000000000000110
• 47 Su AP, Ke NW, Zhang Y. et al. Is laparoscopic approach for pancreatic insulinomas safe? Results of a systematic review and meta-analysis. J Surg Res 2014; 186: 126-134 doi:10.1016/j.jss.2013.07.051
• 48 Jensen RT, Cadiot G, Brandi ML. et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 2012; 95: 98-119 doi:10.1159/000335591
• 49 Pavel M, OʼToole 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. Neuroendocrinology 2016; 103: 172-185 doi:10.1159/000443167
• 50 Bartsch DK, Albers M, Knoop R. et al. Enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1. Neuroendocrinology 2013; 98: 290-298 doi:10.1159/000357779
• 51 Norton JA, Foster DS, Ito T. et al. Gastrinomas: medical or surgical treatment. Endocrinol Metab Clin North Am 2018; 47: 577-601 doi:10.1016/j.ecl.2018.04.009
• 52 Norton JA, Foster DS, Blumgart LH. et al. Incidence and prognosis of primary gastrinomas in the hepatobiliary tract. JAMA Surg 2018; 153: e175083 doi:10.1001/jamasurg.2017.5083
• 53 Norton JA, Fraker DL, Alexander HR. et al. Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome. Ann Surg 2012; 256: 509-517 doi:10.1097/SLA.0b013e318265f08d
• 54 Norton JA, Fraker DL, Alexander HR. et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006; 244: 410-419 doi:10.1097/01.sla.0000234802.44320.a5
• 55 Bartsch DK, Waldmann J, Fendrich V. et al. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg 2012; 99: 1234-1240 doi:10.1002/bjs.8843
• 56 Akirov A, Larouche V, Alshehri S. et al. Treatment options for pancreatic neuroendocrine tumors. Cancers (Basel) 2019; 11: 828 doi:10.3390/cancers11060828
• 57 Ito T, Igarashi H, Jensen RT. Zollinger-Ellison syndrome: recent advances and controversies. Curr Opin Gastroenterol 2013; 29: 650-661 doi:10.1097/MOG.0b013e328365efb1
• 58 Kulke MH, Anthony LB, Bushnell DL. et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010; 39: 735-752 doi:10.1097/MPA.0b013e3181ebb168
• 59 Lopez CL, Falconi M, Waldmann J. et al. Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1. Ann Surg 2013; 257: 308-314 doi:10.1097/SLA.0b013e3182536339
• 60 Bösch F, Werner J, Angele MK. et al. [Oligometastases of neuroendocrine tumors-extent of surgery]. Chirurg 2018; 89: 516-522 doi:10.1007/s00104-018-0644-z
• 61 Frilling A, Modlin IM, Kidd M. et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 2014; 15: e8-e21 doi:10.1016/S1470-2045(13)70362-0
• 62 Bösch F, Ilhan H, Pfahler V. et al. Radioembolization for neuroendocrine liver metastases is safe and effective prior to major hepatic resection. Hepatobiliary Surg Nutr 2019;
• 63 Galleberg RB, Knigge U, Tiensuu Janson E. et al. Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas. Eur J Surg Oncol 2017; 43: 1682-1689 doi:10.1016/j.ejso.2017.04.010
• 64 Moggia E, Rouse B, Simillis C. et al. Methods to decrease blood loss during liver resection: a network meta-analysis. Cochrane Database Syst Rev 2016; (10) CD010683
• 65 Saito Y, Yamada S, Imura S. et al. A learning curve for laparoscopic liver resection: an effective training system and standardization of technique. Transl Gastroenterol Hepatol 2018; 3: 45 doi:10.21037/tgh.2018.07.03
• 66 Saxena A, Chua TC, Perera M. et al. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surg Oncol 2012; 21: e131-e141 doi:10.1016/j.suronc.2012.05.001
• 67 Elias D, Lefevre JH, Duvillard P. et al. Hepatic metastases from neuroendocrine tumors with a “thin slice” pathological examination: they are many more than you think. Ann Surg 2010; 251: 307-310 doi:10.1097/SLA.0b013e3181bdf8cf
• 68 Gibson WE, Gonzalez RS, Cates JMM. et al. Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract. Hum Pathol 2018; 79: 109-115 doi:10.1016/j.humpath.2018.05.006
• 69 Kennedy AS. Hepatic-directed therapies in patients with neuroendocrine tumors. Hematol Oncol Clin North Am 2016; 30: 193-207 doi:10.1016/j.hoc.2015.09.010