OPEN Research Support

MD, subspecialized in pediatric surgery, PhD
Mark Bremholm Ellebæk
Surgical department OUH

Projekt styring
Projekt status    Open
Data indsamlingsdatoer
Start 01.09.2021  
Slut 31.01.2023  

Neuroendocrine tumors in children and adolescents

Short summary

Some children are diagnosed with a rare form of cancer (neuroendocrine tumors, "NET"). Very little is known about NET in children. The disease can present itself with various unspecific symptoms and is often diagnosed incidentally during or after appendectomy for acute appendicitis. NET is most commonly found in the appendix but can appear in several areas in the body including lungs. Early recognition of the disease is important because surgical treatment in most cases can cure the child.


Neuroendocrine tumores (NET) is a common term referring to tumors derived from neuroendocrine cells, which can appear in several areas of the body including lung, breast and the gastrointestinal tract (1). NET are usually rare tumors, but nonetheless there has been observed an increase in incidence amongst the adult population in recent decades (2). The exact incidence among children and adolescents is not well defined due to a number of relatively few studies based on small sample sizes.

One study has estimated an incidence at 5,4 per 1 million children each year (3) and another study has reported an incidence at 1,14 per 1 million children each year in regards to NET specifically found in appendix (4). NET can present with an array of various unspecific symptoms such as coughing, abdominal discomfort or weight loss. Oftentimes NET will be asymptomatic, which easily results in NET going undetected at the initial clinical presentation (1; 5).

Despite their rarity, NET is considered one of the most common found malignancies in the gastrointestinal tract among children and adolescents (6). The most common localization for NET among this patient group is the appendix, which almost always is an incidental finding during pathological examination in conjunction with appendectomies (4; 7; 8).

Outside the appendix, NET can be found in the lungs, pancreas, colon, small intestine and ventricle among others (3). In the lungs NET is considered to be the most commonly found primary lung cancer among children (9).

NET are often benign, though metastasizing can occur, which can influence prognosis. Defining all NET under the same classification system can be proven difficult due to NET covering a heterogenous group of tumors, but basic characteristics such as tumor proliferationrate and local spread to nearby anatomical structures can give an overall insight in prognosis (10).

In instances with appendiceal NET it is relevant to discuss the surgical course of action so far. Appendectomy alone is not always considered enough to be curative among some patients. With these patients a secondary surgery is performed in the form of an extensive right-sided hemicolectomy (RHC). Due to the lack of standardized guidelines regarding secondary surgery among pediatric patients with NET in the appendix it is relevant to assess the surgical interventions done so far and evaluate follow-up and outcome of the procedures.

The aethiology of NET is not well understood, but can be associated with hereditary conditions such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1), Von Hippel-Lindau syndrome (VHL), tuberous sclerosis, lynch syndrome and familial adenomatos polyposis (FAP) (3; 5)

Due to the generally low quantity of studies regarding NET among children and the young, further investigation in this area could be highly relevant in improving the understanding of the illness and hopefully aid in better diagnostics in the future. Furthermore, evaluation of surgical practice so far is important to consider which treatment ensures best prognosis and outcome for the patients.

The study aims to investigate a cohort of patients under 18 of years when diagnosed with NET in the past 26 years in Denmark. Our goal is to:

1) Investigate the incidence of NET in children and adolescents in Denmark

2) Evaluate patient and tumor characteristics plus outcome among children and adolescents with NET

3) Determine which criteria should result in an extra, extensive surgery with a right-sided hemicolectomy in regards to children with identified appendiceal NET

4) Investigate tumor predisposition in patients who had confirmed NET during childhood

Description of the cohort

The study is a nationwide retrospective register-based research project. Patients aged 0-18 years of age when identified with NET during 1995 to 2020 are included in the study.

Inclusion criteria:

1) Patients of both genders aged 0-18 when identified with NET during the years 1995-2020.

2) NET found in the entire body, pathologically verified by immunostaining.

Exclusion criteria:

1) Tumors that do not live up to the diagnosis for NET regarding histopathological features.

2) Patients above the age 18 when found with NET.

Data and biological material

Data collected retrospectively: preoperative biomarkers in blood and urine, scans, information regarding primary and secondary surgery, pathology reports, information regarding other health issues at time of diagnosis or after, information regarding medical treatment and follow-up regime. Old tissue samples will be collected and stained for the neuroendocrine tumor markers that are used as standard panel today. The material will be returned immediately after.

Collaborating researchers and departments

H.C. Andersen Childrens Hospital OUH

  • Mathias Rathe, MD, PhD

Department of pathology OUH

  • Lene Gaardsmand Christensen, MD

Publications associated with the project

Farooqui ZA, Chauhan A. Neuroendocrine Tumors in Pediatrics. Glob Pediatr Health. 2019 Jul 22;6:2333794X19862712.

Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015 Feb 15;121(4):589-97.

Diets IJ, Nagtegaal ID, Loeffen J, de Blaauw I, Waanders E, Hoogerbrugge N, Jongmans MC. Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition. Br J Cancer. 2017 Jan 17;116(2):163-168.

Parkes SE, Muir KR, al Sheyyab M, Cameron AH, Pincott JR, Raafat F, Mann JR. Carcinoid tumours of the appendix in children 1957-1986: incidence, treatment and outcome. Br J Surg. 1993 Apr;80(4):502-4.

Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia. 2017 Dec;19(12):991-1002.

Shaw PA. The topographical and age distributions of neuroendocrine cells in the normal human appendix. J Pathol. 1991 Jul;164(3):235-9.

Boxberger N, Redlich A, Böger C, Leuschner I, von Schweinitz D, Dralle H, Vorwerk P. Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer. 2013 Jan;60(1):65-70.

De Lambert G, Lardy H, Martelli H, Orbach D, Gauthier F, Guérin F. Surgical Management of Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Retrospective French Multicenter Study of 114 Cases. Pediatr Blood Cancer. 2016 Apr;63(4):598-603.

Potter SL, HaDuong J, Okcu F, Wu H, Chintagumpala M, Venkatramani R. Pediatric Bronchial Carcinoid Tumors: A Case Series and Review of the Literature. J Pediatr Hematol Oncol. 2019 Jan;41(1):67-70.

Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010 Aug;39(6):707-12.