Author's Accepted Manuscript
GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN Paul R.V. Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP
www.elsevier.com/locate/sempedsurg
PII: DOI: Reference:
S1055-8586(14)00009-2 http://dx.doi.org/10.1053/j.sempedsurg.2014.03.007 YSPSU50473
To appear in:
Seminars in Pediatric Surgery
Cite this article as: Paul R.V. Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP, GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN, Seminars in Pediatric Surgery, http://dx.doi.org/ 10.1053/j.sempedsurg.2014.03.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#6 GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN Paul R V Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP Professor of Pediatric Surgery, University of Oxford and Director of the Oxford Islet Transplant Programme Address for Correspondence: Academic Pediatric Surgery Unit, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headley Way, OXFORD OX3 9RZ UNITED KINGDOM Abstract
1
Neuroendocrine tumours (NETs) (previously termed carcinoids) are slow growing tumors of the neuroendocrine system. They can occur anywhere within the body but are most commonly found in the mid‐gut. This review is therefore, confined to a discussion of gastroenteropancreatic NETS (GEP‐NETS). GEP‐NETS may be asymptomatic and found incidentally (eg during appendicectomy), or can present with symptoms either attributable to the site of the primary tumor, or attributable to the secretion of serotonin and other substances from metastatic carcinoid disease (carcinoid syndrome). Symptoms of carcinoid syndrome include facial flushing, diarrhea, wheezing, colicky abdominal pain, and edema. Surgical resection offers the only curative treatment for neuroendocrine tumours, although peptide hormone analogues can be used to control carcinoid symptoms. Guidelines exist to determine when further surgical resection is required when NETs (carcinoids) are found incidentally during appendicetomy. A multi‐disciplinary approach is essential for the management of all children with these rare and challenging tumors. Keywords: Neuroendocrine tumor, Carcinoid, Pancreas, Appendix, GEP‐NET Introduction Neuroendocrine tumours (NETs) are slow growing tumors that arise from cells within the neuroendocrine system. They are rare, with a reported overall incidence of 2‐3 per 100,000 persons per year (1), and the incidence seems to be increasing (2) (3) (4). The incidence of NETs varies amongst different ethnic groups, with African‐Americans having the highest reported incidence of 6.5 per 100,000 per year (2). In children, NETs can occur anywhere within the body,
2
including the lungs (5), bronchial tree (6), thymus (7), testis (8), and thyroid (5), but are most commonly found within the gastrointestinal tract and the pancreas (gastrenteropancreatic NETS or GEP‐NETs). According to the Surveillance, Epidemiology, and End Results (SEER) Programme in the United States (1, 3), and the Norwegian Registry of Cancer (NRC) (2), GEP‐NETS comprise over 50% of NETs in all patients, and up to 67% of all NETs in the United States in patients of Afro‐Caribbean origin. This overview is confined to a discussion of GEP‐NETs. Terminology and Classification There has been considerable confusion over recent years with regards the nomenclature and classification of NETs. Previously, NETs were referred to as 'carcinoids', a term first introduced in 1907 by the German pathologist Siegfried Oberndorfer, to describe 'carcinoma‐like' tumours that were benign in behaviour but that demonstrated the microscopic features of malignancy ('karzinoide') (9). However, once it was realised that all NETs can become fully malignant, the term 'neuroendocrine tumors' was introduced to describe the common cell origin of these anatomically varied tumors. Unfortunately, the term carcinoid had become well established and it is still often used interchangeably with the term NETs by many clinicians. In 2000, the World Health Organisation (WHO) attempted to clarify the term carcinoid, maintaining it for certain benign NETs in certain locations (10). Other groups (including many paediatric surgeons) confine the term carcinoid to well‐differentiated NETs of the gastrointestinal tract. More recent guidelines on NETs however, have called for the cessation of the term carcinoid tumor altogether, and for NETs to be classified by anatomical location,
3
clinical syndrome, and degree of tumor differentiation (11) (12). The term carcinoid would then be used solely in the context of the 'carcinoid syndrome' (see below). In 2010, an updated WHO Classification was introduced (WHO 2010) (13) with some fundamental differences from the WHO 2000 Classification (10) (11). WHO 2010 takes into account the fact that all NETs can become malignant and classifies NETs according to grade and stage, and simply uses the terms neurendocrine tumor and neuroendocrine carcinoma (see Figure 1). Pathology NETs are an example of a 'small blue cell tumor'. All NETs demonstrate positive reactions to markers of neuroendocrine tissue, including neuron‐specific enolase, synaptophysin, and chromgranin (14) (15) (16). GEP‐NETs vary in other histological features according to their anatomical location. Midgut NETs are characterised by positive silver staining (argentaffin positive), whereas foregut and hindgut NETs are argentaffin negative. Under elecron microscopy, some NETs are found to have numerous neurosecretory granules containing different substances including serotonin, histamine, corticotropin, dopamine, and kallikrein (14) (15). Indeed, NETs were previously referred to as APUDomas because they often demonstrated Amine Precursor Uptake and Decarboxylation to produce active amines such as serotonin and catecholamines. Release of these substances (especially serotonin) into the systemic circulation is responsible for the clinical features of carcinoid syndrome (see below).
4
Previously, the embryological origin of NETs was believed to be from cells migrating in from the neural crest. However, this is no longer believed to be the case. Indeed, it is now postulated that the origin of NETs in the gut and pancreas is from pluripotential progenitor cells that develop a neuroendocrine phenotype (12). As stated above, both the 2000 and 2010 WHO 2010 classifications of NETs distinguish NETs based on their degree of differentiation (10)(13). The 2000 WHO system included the 3 groups: well‐differentiated neuroendocrine tumors, well‐differentiated (low grade) neuroendocrine carcinomas, and poorly differentiated (high grade) neuroendocrine carcinomas (10). The WHO 2010 Classification includes a three‐tier tumor grading system that is based on mitotic count or Ki‐67 index (17) (Ki67 antigen is a nuclear protein expressed by proliferating cells). G1 is defined as a mitotic count of 20 mitoses / 10 HPF AND / OR ki‐67 index of >20% (13). Staging is either by the WHO TNM system or by the ENETS TNM system depending on the anatomical location (18) (19). Aetiology The precise etiology of GEP‐NETs is unclear. The majority are sporadic, but some are associated with specific inherited familial syndromes including Multiple
5
Endocrine Neoplasia (MEN) 1, MEN 2, von Hippel‐Lindau, neurofibromatosis type 1, tuberous sclerosis, and Carney complex (20) (21). In addition to the genetic mutations identified with the familial syndromes above, a number of novel genetic mutations have been identified in association with pancreatic NETs (18). One in six well‐differentiated pancreatic NETs have mutations in the mTOR pathway genes (including TSC2, PTEN, and PUK3CA (19). In addition, about 40% of pancreatic NETs are associated with mutations in the ATRX and DAXX genes that are part of a recently discovered cancer pathway (22). These genetic mutations are distinct from those previously identified in pancreatic adenocarcinoma. Clinical Presentation Depending on whether or not they secrete serotonin and the other substances described above, GEP‐NETs are classified clinically as being either functioning or non‐functioning. Functioning GEP‐NETs present with symptoms and signs specific to the substances they produce (eg pancreatic insulinomas etc). The classic clinical presentation associated with functioning GEP‐NETs, particularly those of the midgut, is termed carcinoid syndrome (see below). Non‐functioning GEP‐NETs on the other hand, can be either asymptomatic and found incidentally (eg during appendicectomy), or symptomatic due to local effects of the primary tumor. Both the local and systemic effects of GEP‐NETs can vary according to the anatomical site of the tumor.
6
Carcinoid syndrome The symptoms of carcinoid syndrome include facial flushing, diarrhea, wheezing, colicky abdominal pain, and edema. It occurs in up to 5% of all NETs and in about 20% of patients with well‐differentiated GEP‐NETs of the midgut. Carcinoid syndrome associated with midgut GEP‐NETS usually occurs when the disease has metastasised to the liver, whereas NETs in other anatomical locations (eg the lung) do not have to have metastasised in order to produce it. This is because serotonin released into the portal circulation is metabolised to inactive products within the liver, whereas NETs that secrete directly into the systemic circulation result in the full effects of the substance secreted. This also explains why GEP‐ NETs that have locally invaded the retroperitoneum, can also result in the carcinoid syndrome, as in that situation the venous drainage bypasses the liver. Carcinoid syndrome is less frequently seen in patients with primary GEP‐NETSs in other anatomical sites, and indeed rectal NETs are very rarely associated with the carcinoid syndrome (11). The cluster of symptoms and signs of carcinoid syndrome described above can be accompanied by right upper quadrant pain resulting from the local pressure of the hepatic metastases. 'Carcinoid crisis' is an acute and severe form of carcinoid syndrome usually triggered by anaesthetic induction or manual handling / manipulation of a functional NET tumor (23). Carcinoid crisis is extremely rare in children. Pancreatic NETs
7
Pancreatic NETs (PNETs ‐ to be distinguished from the same acronym for primitive neuroectodermal tumors) represent about a third of all GEP‐NETs. They are frequently multi‐focal. The majority (up to 60%) of PNETs are non‐ functioning (24). Non‐functioning PNETs can be large and often present late. Indeed, about 50% of non‐functioning PNETs have metastasised by the time of clinical presentation (11). Symptoms may be due to the local effects of the pancreatic mass and / or the hepatic metastases. Both the nomenclature and clinical presentation of the most common functioning PNETs depend on which pancreatic hormone is predominantly being secreted (see Table 2). Diarrea and diabetes mellitus are two of the commonest presenting features of all these tumors. Insulinomas are the commonest functioning PNET tumor in children (as opposed to gastrinomas in adults). They present with symptoms of hyperinsulinism. Depending on the age of the child, clinical presentation includes sweating, weakness, unconsciousness, and confusion. Symptoms are improved with feeding. Gastrinomas present with diarrhoea and / or peptic ulceration (Zollinger‐Elison syndrome), whereas glucagonomas present with weight loss, diabetes mellitus, diarrea, and necrolytic migratory erythema. VIPomas present with profuse diarrea and marked hypokalaemia. Finally, somatostatinomas present with weight loss, diarrea, steatorrhea, and diabetes mellitus. Rarer functioning PNETs include those secreting adrenocorticotropic hormone
(ACTH), corticotropin‐releasing hormone (CRH) parathyroid hormone‐related peptide, growth hormone‐ releasing hormone (GHRH), gonadotropin‐releasing hormone (CRH) and, calcitonin (GRF).
8
Gastric NETs Gastric NETs in childhood are very rare (25). Three distinct types of gastric NET are recognised overall, namely those associated with chronic atrophic gastritis type A (CAG‐A), those associated with hypergastrinaemia and the Zollinger‐ Ellison syndrome, and those that are sporadic (16). CAG‐A NETs represent about three quarters of gastric NETs in adults, but usually present after the fifth decade of life. They are slow growing and tend to metastasise rarely. Gastric NETs associated with the Zollinger‐Ellison syndrome are still rare, but are more common in childhood than CAG‐As. They are primarily associated with MEN1 (16). Up to 25% of gastric NETS are sporadic. They are usually solitary and large, and have frequently metastasised by the time of presentation. Small Bowel NETs In adult series, small bowel NETs represent about 30% of all small bowel tumours. The ileum is the commonest site for small bowel NETs in both adults and children (26) (27) (28). Small bowel NETs tend to be multi‐focal and aggressive in nature. Most patients present with local lymphatic spread, and many present with distant metastases. Carcinoid syndrome is commonly associated with these lesions.
9
Appenidceal NETs Appendiceal NETs are the commonest type of GEP‐NETs encountered in the paediatric age group (29) (30) (31). They represent 16% of malignant NETs in children in the SEER registry (27). Less than 10% of appendiceal NETs present with symptoms, with the vast majority being found incidentally within histological specimens following either emergency or interval appendicetomy (16). About seventy five percent of appendiceal carcinoids are found within the appendiceal tip with less than 10% being found in the base. It has been reported that up to 0.7% of appendicetomy specimens in adults contain a GEP‐NET (32), whereas this figure seems to be lower (0.08%) in children (30). Although the majority of appendiceal NETs are non‐functioning, they can present with the carcinoid syndrome. Tumor size is highly predictive of outcome and helps dictate whether additional surgery or adjuvant treatment is required following the incidental finding of appendiceal NET (see below). There is also a theory that appendiceal NETs can / do regress spontaneously with age (16). Colonic and Rectal NETs Although colonic and rectal NETs are also very rare in children, according to the SEER database, they represent 34% of all solid tumours of the colon and rectum(33). Colonic and rectal NETs rarely present with carcinoid syndrome, and indeed colonic NETs usually contain glucagon and other substances rather than serotonin. Approximately 50% of rectal NETs are found incidentally during routine endocsopy, whereas colonic NETs often present with pain, anorexia, and
10
weight loss (16). About 75% of colonic NETs are found in the right colon (16) (33). Diagnosis Diagnosis is based on a combination of clinical presentation, detection of circulating NET secretions, and a range of different imaging techniques (11). Tissue diagnosis by histopathology then confirms the diagnosis. Children with a family history of MEN1 or who are known to have a genetic predisposition to developing GEP‐NETs, should be screened for possible tumors. There is however, an ongoing debate concerning at what age screening should commence. Biochemical Tests Measuring the specific secretions produced by functioning GEP‐NETS helps make the diagnosis of GEP‐NET in the first place, as well as being a useful way of monitoring tumor progression and resolution following treatment (34). In addition, there are a number of less‐specific substances that are produced by many GEP‐NETs regardless of their anatomical location and regardless of whether they are clinically functional tumors. These include pancreatic polypeptide which is produced by more than 30% of GEP‐NETs, and also chromogranin A (CgA) (11) (35). However, care has to be taken to recognise that CgA is also elevated in patients with atrophic gastritis, renal insufficiency, and who are on treatment with proton pump inhibitors (36).
11
Imaging Diagnostic imaging consists of a combination of routine and specialist radiological and nuclear investigations (11) (36). Most NETs require a multi‐ modality approach for accurate localisation and staging. Cross‐sectional imaging (CT and MRI) plays an important role in initial localisation, as does somatostatin receptor scinitgraphy (SSRS). MIBG Scintigraphy can be useful in diagnosing GEP‐NETs that do not take up somatostatin analogues. Gallium‐68 PET / CT is recommended for locating an unknown primary and is the most sensitive modality for assessing metastatic tumors. Flexible endoscopy enables visualisation of some gastric and rectal tumors and can enable tissue samples to be taken. Capsule endoscopy has been used in some adults to visualise GEP‐ NETs in the small bowel, but precise localisation of tumors using this method can be difficult (37). Endoscopic ultrasound can be useful for detecting pancreatic GEP‐NETs, and intra‐operative ultrasound can help identify tumour extent and the presence of multifocal disease at the time of surgery. Management Consensus guidelines exist for the management of many GEP‐NETs (11) (36). It is therefore, important that children with these rare tumours are managed by multi‐disciplinary teams with expertise in the diagnosis and treatment of NETs. One of the problems however, is that most of the guidelines have been based on NETs in adults, and some aspects (eg recommendations based on tumor size)
12
need to be carefully considered in the context of a young child. For instance, a 2cm tumor in an child is proportionately larger and more significant than the same sized tumor in an adult, and modified recommendations for children are currently not widely available. However, the same principles of treatment apply for children. Surgical treatment Complete surgical resection offers the only curative treatment for neuroendocrine tumours. A detailed account of individual procedures for GEP‐ NETs in different locations is beyond the scope of this review. However, radical resection may be required, and the tendency to multi‐focal disease must always be taken into account in planning surgical treatment. When non‐resectable or metastatic disease is present, surgery aimed at ablating or debulking the tumor burden can significantly improve length of patient survival, and it can contribute considerably to quality of life (36). The use of novel intraoperative techniques, such as radio‐frequency ablation and cryotherapy, have further aided the surgical treatment of advanced disease. Surgical recommendations following incidental appendiceal NET identified post interval or emergency appendicectomy As stated above, incidental GEP‐NETs identified within appendix specimens following either emergency or interval appendicectomy, are the most common NETs encountered by paediatric surgeons. One of the treatment dilemmas is
13
when to consider additional surgical resection once an incidental appendiceal NET has been diagnosed. The recommendations currently adopted in most centres, are based on the fact that well differentiated NETs
GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN Paul R.V. Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP
www.elsevier.com/locate/sempedsurg
PII: DOI: Reference:
S1055-8586(14)00009-2 http://dx.doi.org/10.1053/j.sempedsurg.2014.03.007 YSPSU50473
To appear in:
Seminars in Pediatric Surgery
Cite this article as: Paul R.V. Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP, GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN, Seminars in Pediatric Surgery, http://dx.doi.org/ 10.1053/j.sempedsurg.2014.03.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#6 GASTROENTEROPANCREATIC NEUROENDOCRINE (CARCINOID) TUMORS IN CHILDREN Paul R V Johnson MBChB MD FRCS(Eng) FRCS (Edin) FRCS (Paed.Surg) FAAP Professor of Pediatric Surgery, University of Oxford and Director of the Oxford Islet Transplant Programme Address for Correspondence: Academic Pediatric Surgery Unit, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headley Way, OXFORD OX3 9RZ UNITED KINGDOM Abstract
1
Neuroendocrine tumours (NETs) (previously termed carcinoids) are slow growing tumors of the neuroendocrine system. They can occur anywhere within the body but are most commonly found in the mid‐gut. This review is therefore, confined to a discussion of gastroenteropancreatic NETS (GEP‐NETS). GEP‐NETS may be asymptomatic and found incidentally (eg during appendicectomy), or can present with symptoms either attributable to the site of the primary tumor, or attributable to the secretion of serotonin and other substances from metastatic carcinoid disease (carcinoid syndrome). Symptoms of carcinoid syndrome include facial flushing, diarrhea, wheezing, colicky abdominal pain, and edema. Surgical resection offers the only curative treatment for neuroendocrine tumours, although peptide hormone analogues can be used to control carcinoid symptoms. Guidelines exist to determine when further surgical resection is required when NETs (carcinoids) are found incidentally during appendicetomy. A multi‐disciplinary approach is essential for the management of all children with these rare and challenging tumors. Keywords: Neuroendocrine tumor, Carcinoid, Pancreas, Appendix, GEP‐NET Introduction Neuroendocrine tumours (NETs) are slow growing tumors that arise from cells within the neuroendocrine system. They are rare, with a reported overall incidence of 2‐3 per 100,000 persons per year (1), and the incidence seems to be increasing (2) (3) (4). The incidence of NETs varies amongst different ethnic groups, with African‐Americans having the highest reported incidence of 6.5 per 100,000 per year (2). In children, NETs can occur anywhere within the body,
2
including the lungs (5), bronchial tree (6), thymus (7), testis (8), and thyroid (5), but are most commonly found within the gastrointestinal tract and the pancreas (gastrenteropancreatic NETS or GEP‐NETs). According to the Surveillance, Epidemiology, and End Results (SEER) Programme in the United States (1, 3), and the Norwegian Registry of Cancer (NRC) (2), GEP‐NETS comprise over 50% of NETs in all patients, and up to 67% of all NETs in the United States in patients of Afro‐Caribbean origin. This overview is confined to a discussion of GEP‐NETs. Terminology and Classification There has been considerable confusion over recent years with regards the nomenclature and classification of NETs. Previously, NETs were referred to as 'carcinoids', a term first introduced in 1907 by the German pathologist Siegfried Oberndorfer, to describe 'carcinoma‐like' tumours that were benign in behaviour but that demonstrated the microscopic features of malignancy ('karzinoide') (9). However, once it was realised that all NETs can become fully malignant, the term 'neuroendocrine tumors' was introduced to describe the common cell origin of these anatomically varied tumors. Unfortunately, the term carcinoid had become well established and it is still often used interchangeably with the term NETs by many clinicians. In 2000, the World Health Organisation (WHO) attempted to clarify the term carcinoid, maintaining it for certain benign NETs in certain locations (10). Other groups (including many paediatric surgeons) confine the term carcinoid to well‐differentiated NETs of the gastrointestinal tract. More recent guidelines on NETs however, have called for the cessation of the term carcinoid tumor altogether, and for NETs to be classified by anatomical location,
3
clinical syndrome, and degree of tumor differentiation (11) (12). The term carcinoid would then be used solely in the context of the 'carcinoid syndrome' (see below). In 2010, an updated WHO Classification was introduced (WHO 2010) (13) with some fundamental differences from the WHO 2000 Classification (10) (11). WHO 2010 takes into account the fact that all NETs can become malignant and classifies NETs according to grade and stage, and simply uses the terms neurendocrine tumor and neuroendocrine carcinoma (see Figure 1). Pathology NETs are an example of a 'small blue cell tumor'. All NETs demonstrate positive reactions to markers of neuroendocrine tissue, including neuron‐specific enolase, synaptophysin, and chromgranin (14) (15) (16). GEP‐NETs vary in other histological features according to their anatomical location. Midgut NETs are characterised by positive silver staining (argentaffin positive), whereas foregut and hindgut NETs are argentaffin negative. Under elecron microscopy, some NETs are found to have numerous neurosecretory granules containing different substances including serotonin, histamine, corticotropin, dopamine, and kallikrein (14) (15). Indeed, NETs were previously referred to as APUDomas because they often demonstrated Amine Precursor Uptake and Decarboxylation to produce active amines such as serotonin and catecholamines. Release of these substances (especially serotonin) into the systemic circulation is responsible for the clinical features of carcinoid syndrome (see below).
4
Previously, the embryological origin of NETs was believed to be from cells migrating in from the neural crest. However, this is no longer believed to be the case. Indeed, it is now postulated that the origin of NETs in the gut and pancreas is from pluripotential progenitor cells that develop a neuroendocrine phenotype (12). As stated above, both the 2000 and 2010 WHO 2010 classifications of NETs distinguish NETs based on their degree of differentiation (10)(13). The 2000 WHO system included the 3 groups: well‐differentiated neuroendocrine tumors, well‐differentiated (low grade) neuroendocrine carcinomas, and poorly differentiated (high grade) neuroendocrine carcinomas (10). The WHO 2010 Classification includes a three‐tier tumor grading system that is based on mitotic count or Ki‐67 index (17) (Ki67 antigen is a nuclear protein expressed by proliferating cells). G1 is defined as a mitotic count of 20 mitoses / 10 HPF AND / OR ki‐67 index of >20% (13). Staging is either by the WHO TNM system or by the ENETS TNM system depending on the anatomical location (18) (19). Aetiology The precise etiology of GEP‐NETs is unclear. The majority are sporadic, but some are associated with specific inherited familial syndromes including Multiple
5
Endocrine Neoplasia (MEN) 1, MEN 2, von Hippel‐Lindau, neurofibromatosis type 1, tuberous sclerosis, and Carney complex (20) (21). In addition to the genetic mutations identified with the familial syndromes above, a number of novel genetic mutations have been identified in association with pancreatic NETs (18). One in six well‐differentiated pancreatic NETs have mutations in the mTOR pathway genes (including TSC2, PTEN, and PUK3CA (19). In addition, about 40% of pancreatic NETs are associated with mutations in the ATRX and DAXX genes that are part of a recently discovered cancer pathway (22). These genetic mutations are distinct from those previously identified in pancreatic adenocarcinoma. Clinical Presentation Depending on whether or not they secrete serotonin and the other substances described above, GEP‐NETs are classified clinically as being either functioning or non‐functioning. Functioning GEP‐NETs present with symptoms and signs specific to the substances they produce (eg pancreatic insulinomas etc). The classic clinical presentation associated with functioning GEP‐NETs, particularly those of the midgut, is termed carcinoid syndrome (see below). Non‐functioning GEP‐NETs on the other hand, can be either asymptomatic and found incidentally (eg during appendicectomy), or symptomatic due to local effects of the primary tumor. Both the local and systemic effects of GEP‐NETs can vary according to the anatomical site of the tumor.
6
Carcinoid syndrome The symptoms of carcinoid syndrome include facial flushing, diarrhea, wheezing, colicky abdominal pain, and edema. It occurs in up to 5% of all NETs and in about 20% of patients with well‐differentiated GEP‐NETs of the midgut. Carcinoid syndrome associated with midgut GEP‐NETS usually occurs when the disease has metastasised to the liver, whereas NETs in other anatomical locations (eg the lung) do not have to have metastasised in order to produce it. This is because serotonin released into the portal circulation is metabolised to inactive products within the liver, whereas NETs that secrete directly into the systemic circulation result in the full effects of the substance secreted. This also explains why GEP‐ NETs that have locally invaded the retroperitoneum, can also result in the carcinoid syndrome, as in that situation the venous drainage bypasses the liver. Carcinoid syndrome is less frequently seen in patients with primary GEP‐NETSs in other anatomical sites, and indeed rectal NETs are very rarely associated with the carcinoid syndrome (11). The cluster of symptoms and signs of carcinoid syndrome described above can be accompanied by right upper quadrant pain resulting from the local pressure of the hepatic metastases. 'Carcinoid crisis' is an acute and severe form of carcinoid syndrome usually triggered by anaesthetic induction or manual handling / manipulation of a functional NET tumor (23). Carcinoid crisis is extremely rare in children. Pancreatic NETs
7
Pancreatic NETs (PNETs ‐ to be distinguished from the same acronym for primitive neuroectodermal tumors) represent about a third of all GEP‐NETs. They are frequently multi‐focal. The majority (up to 60%) of PNETs are non‐ functioning (24). Non‐functioning PNETs can be large and often present late. Indeed, about 50% of non‐functioning PNETs have metastasised by the time of clinical presentation (11). Symptoms may be due to the local effects of the pancreatic mass and / or the hepatic metastases. Both the nomenclature and clinical presentation of the most common functioning PNETs depend on which pancreatic hormone is predominantly being secreted (see Table 2). Diarrea and diabetes mellitus are two of the commonest presenting features of all these tumors. Insulinomas are the commonest functioning PNET tumor in children (as opposed to gastrinomas in adults). They present with symptoms of hyperinsulinism. Depending on the age of the child, clinical presentation includes sweating, weakness, unconsciousness, and confusion. Symptoms are improved with feeding. Gastrinomas present with diarrhoea and / or peptic ulceration (Zollinger‐Elison syndrome), whereas glucagonomas present with weight loss, diabetes mellitus, diarrea, and necrolytic migratory erythema. VIPomas present with profuse diarrea and marked hypokalaemia. Finally, somatostatinomas present with weight loss, diarrea, steatorrhea, and diabetes mellitus. Rarer functioning PNETs include those secreting adrenocorticotropic hormone
(ACTH), corticotropin‐releasing hormone (CRH) parathyroid hormone‐related peptide, growth hormone‐ releasing hormone (GHRH), gonadotropin‐releasing hormone (CRH) and, calcitonin (GRF).
8
Gastric NETs Gastric NETs in childhood are very rare (25). Three distinct types of gastric NET are recognised overall, namely those associated with chronic atrophic gastritis type A (CAG‐A), those associated with hypergastrinaemia and the Zollinger‐ Ellison syndrome, and those that are sporadic (16). CAG‐A NETs represent about three quarters of gastric NETs in adults, but usually present after the fifth decade of life. They are slow growing and tend to metastasise rarely. Gastric NETs associated with the Zollinger‐Ellison syndrome are still rare, but are more common in childhood than CAG‐As. They are primarily associated with MEN1 (16). Up to 25% of gastric NETS are sporadic. They are usually solitary and large, and have frequently metastasised by the time of presentation. Small Bowel NETs In adult series, small bowel NETs represent about 30% of all small bowel tumours. The ileum is the commonest site for small bowel NETs in both adults and children (26) (27) (28). Small bowel NETs tend to be multi‐focal and aggressive in nature. Most patients present with local lymphatic spread, and many present with distant metastases. Carcinoid syndrome is commonly associated with these lesions.
9
Appenidceal NETs Appendiceal NETs are the commonest type of GEP‐NETs encountered in the paediatric age group (29) (30) (31). They represent 16% of malignant NETs in children in the SEER registry (27). Less than 10% of appendiceal NETs present with symptoms, with the vast majority being found incidentally within histological specimens following either emergency or interval appendicetomy (16). About seventy five percent of appendiceal carcinoids are found within the appendiceal tip with less than 10% being found in the base. It has been reported that up to 0.7% of appendicetomy specimens in adults contain a GEP‐NET (32), whereas this figure seems to be lower (0.08%) in children (30). Although the majority of appendiceal NETs are non‐functioning, they can present with the carcinoid syndrome. Tumor size is highly predictive of outcome and helps dictate whether additional surgery or adjuvant treatment is required following the incidental finding of appendiceal NET (see below). There is also a theory that appendiceal NETs can / do regress spontaneously with age (16). Colonic and Rectal NETs Although colonic and rectal NETs are also very rare in children, according to the SEER database, they represent 34% of all solid tumours of the colon and rectum(33). Colonic and rectal NETs rarely present with carcinoid syndrome, and indeed colonic NETs usually contain glucagon and other substances rather than serotonin. Approximately 50% of rectal NETs are found incidentally during routine endocsopy, whereas colonic NETs often present with pain, anorexia, and
10
weight loss (16). About 75% of colonic NETs are found in the right colon (16) (33). Diagnosis Diagnosis is based on a combination of clinical presentation, detection of circulating NET secretions, and a range of different imaging techniques (11). Tissue diagnosis by histopathology then confirms the diagnosis. Children with a family history of MEN1 or who are known to have a genetic predisposition to developing GEP‐NETs, should be screened for possible tumors. There is however, an ongoing debate concerning at what age screening should commence. Biochemical Tests Measuring the specific secretions produced by functioning GEP‐NETS helps make the diagnosis of GEP‐NET in the first place, as well as being a useful way of monitoring tumor progression and resolution following treatment (34). In addition, there are a number of less‐specific substances that are produced by many GEP‐NETs regardless of their anatomical location and regardless of whether they are clinically functional tumors. These include pancreatic polypeptide which is produced by more than 30% of GEP‐NETs, and also chromogranin A (CgA) (11) (35). However, care has to be taken to recognise that CgA is also elevated in patients with atrophic gastritis, renal insufficiency, and who are on treatment with proton pump inhibitors (36).
11
Imaging Diagnostic imaging consists of a combination of routine and specialist radiological and nuclear investigations (11) (36). Most NETs require a multi‐ modality approach for accurate localisation and staging. Cross‐sectional imaging (CT and MRI) plays an important role in initial localisation, as does somatostatin receptor scinitgraphy (SSRS). MIBG Scintigraphy can be useful in diagnosing GEP‐NETs that do not take up somatostatin analogues. Gallium‐68 PET / CT is recommended for locating an unknown primary and is the most sensitive modality for assessing metastatic tumors. Flexible endoscopy enables visualisation of some gastric and rectal tumors and can enable tissue samples to be taken. Capsule endoscopy has been used in some adults to visualise GEP‐ NETs in the small bowel, but precise localisation of tumors using this method can be difficult (37). Endoscopic ultrasound can be useful for detecting pancreatic GEP‐NETs, and intra‐operative ultrasound can help identify tumour extent and the presence of multifocal disease at the time of surgery. Management Consensus guidelines exist for the management of many GEP‐NETs (11) (36). It is therefore, important that children with these rare tumours are managed by multi‐disciplinary teams with expertise in the diagnosis and treatment of NETs. One of the problems however, is that most of the guidelines have been based on NETs in adults, and some aspects (eg recommendations based on tumor size)
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need to be carefully considered in the context of a young child. For instance, a 2cm tumor in an child is proportionately larger and more significant than the same sized tumor in an adult, and modified recommendations for children are currently not widely available. However, the same principles of treatment apply for children. Surgical treatment Complete surgical resection offers the only curative treatment for neuroendocrine tumours. A detailed account of individual procedures for GEP‐ NETs in different locations is beyond the scope of this review. However, radical resection may be required, and the tendency to multi‐focal disease must always be taken into account in planning surgical treatment. When non‐resectable or metastatic disease is present, surgery aimed at ablating or debulking the tumor burden can significantly improve length of patient survival, and it can contribute considerably to quality of life (36). The use of novel intraoperative techniques, such as radio‐frequency ablation and cryotherapy, have further aided the surgical treatment of advanced disease. Surgical recommendations following incidental appendiceal NET identified post interval or emergency appendicectomy As stated above, incidental GEP‐NETs identified within appendix specimens following either emergency or interval appendicectomy, are the most common NETs encountered by paediatric surgeons. One of the treatment dilemmas is
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when to consider additional surgical resection once an incidental appendiceal NET has been diagnosed. The recommendations currently adopted in most centres, are based on the fact that well differentiated NETs
