Extra-appendiceal Neuroendocrine Neoplasms in Children – Data from the GPOH-MET 97 Study

Abstract

Background:

Neuroendocrine neoplasms (NEN) in children are rare. In Germany, children with NEN of the gastroenteropancreatic system are prospectively registered since 1997. The objective of this study was to evaluate diagnostics, treatment and outcome in children with extra-appendiceal NEN.

Method:

Clinical data of 39 patients with NEN registered in the GPOH-MET 97 trial from 1997 to 2012 were analyzed. Children with NEN of the appendix were excluded.

Results:

14 patients with pancreatic, 12 patients with bronchial, 6 patients with gastrointestinal, 2 patients with nasopharyngeal and 5 patients with NEN of unknown primary were registered. About half of the patients had localized disease and rather low grade tumors, including all bronchial NEN, 5 of 14 pancreatic and 2 of 6 gastrointestinal tumors. Metastatic disease and high grade tumors were stated in cases with nasopharyngeal tumors, NEN of unknown ­primary and in part of pancreatic and gastrointestinal NEN. Complete surgical resection was performed in patients with localized NEN with an overall survival of 100%. In contrast, overall survival in metastatic disease was 26%.

Conclusions:

Outcome in children with low grade NEN and localized disease is excellent. Management of high grade tumors and metastatic disease remains challenging. Establishing international registries is inevitable for further improvements.

Zusammenfassung

Hintergrund:

Neuroendokrine Neoplasien (NEN) im Kindesalter sind selten. In Deutschland werden Kinder mit NEN des Gastroenteropankreatischen Systems prospektiv in der GPOH-MET-97-Studie erfasst. In der vorliegenden Auswertung sollten Diagnostik, Therapie und Prognose von Kindern mit diesen Tumoren untersucht werden. NEN der Appendix wurden von der Analyse ausgeschlossen.

Methode:

Ausgewertet wurden die Daten von 39 Patienten mit NEN, die von 1997 bis 2012 erfasst wurden.

Ergebnisse:

In die GPOH-MET-Studie wurden 14 Patienten mit NEN des Pankreas, 12 Patienten mit NEN der Lunge, 6 Patienten mit NEN des Gastrointestinaltraktes, 2 Patienten mit NEN des Nasopharynx und 5 Patienten mit unklarem Primarius gemeldet. Die Hälfte der Patienten wies bei Diagnosestellung keine Metastasen auf bzw. hatte eher niedriggradige Tumoren. Hierzu zählten alle bronchialen NEN, 5 von 14 der pan­kreatischen und 4 von 6 der gastrointestinalen NEN. Die übrigen Patienten wiesen Metastasen bzw. eher hochgradig maligne Tumoren auf. Eine komplette Resektion war bei allen Patienten mit lokalisierter Erkrankung möglich. Diese Kinder zeigten ein Gesamtüberleben von 100%. Bei Patienten mit metastasierten NEN betrug das Gesamtüberleben 26%.

Schlussfolgerung:

Für NEN ohne Metastasen fand sich nach kompletter chirurgischer Resektion eine ausgezeichnete Prognose. Tumorgra­ding und Ausdehnung der Erkrankung bei Diagnosestellung zeigten Einfluss auf das Ge­samtüberleben. Die Versorgung von Patienten mit metastasierten NEN bleibt eine Herausforderung. Hier ist die Etablierung internatio­naler Register eine notwendige Voraussetzung, um Fortschritte zu erzielen.

Schlüsselwörter

neuroendokrine Neoplasie - Karzinoide - neuroendokrine Tumoren - neuroendokrine Karzinome

Key words

neuroendocrine neoplasia - carcinoid tumor - neuroendocrine tumor - neuroendocrine carcinoma

• References

• 1 WHO . Classification of Tumours of the Digestive System. In: Bosman F, Carneiro F, Hruban R, Theise N. eds Lyon, France: IARC Press; 2010
• 2 Al-Qahtani AR, Di LM, Yazbeck S. Endobronchial tumors in children: Institutional experience and literature review. J Pediatr Surg 2003; 38: 733-736
• 3 Boxberger N, Redlich A, Boger C et al. Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 2013; 60: 65-70
• 4 Brecht IB, Schneider DT, Kloppel G et al. Malignant pancreatic tumors in children and young adults: evaluation of 228 patients identified through the Surveillance, Epidemiology, and End Result (SEER) database. Klin Padiatr 2011; 223: 341-345
• 5 Broaddus RR, Herzog CE, Hicks MJ. Neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) presenting at extra-appendiceal sites in childhood and adolescence. Arch Pathol Lab Med 2003; 127: 1200-1203
• 6 Capovilla M, Kambouchner M, Bernier M et al. Late cerebellar relapse of a juvenile bronchial carcinoid. Clin Lung Cancer 2007; 8: 339-341
• 7 Curtis JM, Lacey D, Smyth R et al. Endobronchial tumours in childhood. Eur J Radiol 1998; 29: 11-20
• 8 De GU, Fanini F, Amadori D et al. Tumorlets in familial history of bronchopulmonary carcinoid. J Thorac Oncol 2011; 6: 1613-1614
• 9 Faiss S, Pape UF, Bohmig M et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors – the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003; 21: 2689-2696
• 10 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
• 11 Fauroux B, Aynie V, Larroquet M et al. Carcinoid and mucoepidermoid bronchial tumours in children. Eur J Pediatr 2005; 164: 748-752
• 12 Ferguson MK, Landreneau RJ, Hazelrigg SR et al. Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardiothorac Surg 2000; 18: 156-161
• 13 Hartmann C, Weinel P, Schmid H et al. Oxaliplatin, irinotecan, and gemcitabine: a novel combination in the therapy of progressed, relapsed, or refractory tumors in children. J Pediatr Hematol Oncol 2011; 33: 344-349
• 14 Howell DL, O’Dorisio MS. Management of neuroendocrine tumors in children, adolescents, and young adults. J Pediatr Hematol Oncol 2012; 34 (Suppl 2): S64-S68
• 15 Klimstra DS, Modlin IR, Coppola D et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39: 707-712
• 16 Kvols LK, Brendtro KL. The North American Neuroendocrine Tumor Society (NANETS) guidelines: mission, goals, and process. Pancreas 2010; 39: 705-706
• 17 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934-959
• 18 Navalkele P, O’Dorisio MS, O’Dorisio TM et al. Incidence, survival, and prevalence of neuroendocrine tumors versus neuroblastoma in children and young adults: nine standard SEER registries, 1975–2006. Pediatr Blood Cancer 2011; 56: 50-57
• 19 Oberg K, Hellman P, Ferolla P et al. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 (Suppl 7): vii120-vii123
• 20 Oberg K, Knigge U, Kwekkeboom D et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl 7): vii124-vii130
• 21 Pavel M, Baudin E, Couvelard A et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95: 157-176
• 22 Pavel ME, Hainsworth JD, 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. Lancet 2011; 378: 2005-2012
• 23 Raymond E, Dahan L, Raoul JL et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501-513
• 24 Redlich A, Boxberger N, Strugala D et al. Systemic Treatment of Adrenocortical Carcinoma in Children: Data from the German GPOH-MET 97 Trial. Klin Padiatr 2012; 224: 366-371
• 25 Rindi G, Kloppel G, Alhman H et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449: 395-401
• 26 Rindi G, Kloppel G, Couvelard A et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007; 451: 757-762
• 27 Rizzardi G, Marulli G, Calabrese F et al. Bronchial carcinoid tumours in children: surgical treatment and outcome in a single institution. Eur J Pediatr Surg 2009; 19: 228-231
• 28 Roby BB, Drehner D, Sidman JD. Pediatric tracheal and endobronchial tumors: an institutional experience. Arch Otolaryngol Head Neck Surg 2011; 137: 925-929
• 29 Salazar R, Wiedenmann B, Rindi G et al. ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: an update. Neuroendocrinology 2012; 95: 71-73.
• 30 Spunt SL, Pratt CB, Rao BN et al. Childhood carcinoid tumors: the St Jude Children’s Research Hospital experience. J Pediatr Surg 2000; 35: 1282-1286
• 31 Wang LT, Wilkins Jr EW, Bode HH. Bronchial carcinoid tumors in pediatric patients. Chest 1993; 103: 1426-1428
• 32 Wong KK, Waterfield RT, Marzola MC et al. Contemporary nuclear medicine imaging of neuroendocrine tumours. Clin Radiol 2012; 67: 1035-1050
• 33 Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-523
• 34 Zhuge Y, Cheung MC, Yang R et al. Pediatric intestinal foregut and small bowel solid tumors: a review of 105 cases. J Surg Res 2009; 156: 95-102