Elsevier

The Lancet Oncology

Volume 9, Issue 1, January 2008, Pages 61-72
The Lancet Oncology

Review
Gastroenteropancreatic neuroendocrine tumours

https://doi.org/10.1016/S1470-2045(07)70410-2Get rights and content

Summary

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

Introduction

Although neuroendocrine tumours (NETs) have been regarded as fairly rare diseases, the US Surveillance Epidemiology and End Results (SEER) database suggests that their prevalence has increased substantially over the past three decades as awareness and diagnostic techniques have improved. However, analyses of UK and US databases also suggest no improvement in outcome over a similar period. On the basis of this database information, the US National Cancer Institute and US congressional committee for the National Institutes of Health appropriations have elevated NET disease and carcinoid tumours to number two in the priority for funding, after autism. Furthermore, the National Cancer Institute has mandated a summit conference to address the current status of the disease and to give recommendations for development of strategies for early diagnosis, identification of new targets, and effective management. Here, we review NETs from a biological and clinical perspective, and we give recommendations that take into account current scientific and clinical limitations that need to be addressed to facilitate improvement in management and outcome.

Section snippets

Nomenclature

Tumours that are derived from the diffuse neuroendocrine system of the gastrointestinal tract and pancreas are fairly rare. They share some common clinical features, frequently have unpredictable and unusual biological behaviour, and frequently present late after delayed diagnosis. Targeted treatment is limited and management challenging because little is known about the cell biology and mechanistic regulation of these tumours.1

The understanding of gastroenteropancreatic (GEP) NETs has remained

Epidemiology

GEP NETs are substantially rarer than adenocarcinomas; incidence is about 2·5 to 5 cases per 100 000.4 About 0·46% of all malignant diseases are so-called carcinoid tumours of bronchopulmonary or gastrointestinal origin.4 The incidence and prevalence of carcinoid tumours has increased substantially (figure 2), which may partly reflect increased diagnosis of benign and incidentally identified lesions due to increased availability of advanced endoscopic and radiological imaging. Clinical

Cell biology of gut neuroendocrine cells

Neuroendocrine cells occur throughout the length of the gut, and are the largest group of hormone-producing cells in the body (table 1).8 They derive from local multipotent gastrointestinal stem cells, rather than by migration from the neural crest as first thought.3 The mechanisms that underlie differentiation of cells of the diffuse endocrine-cell system are poorly understood. Transcription factors with a role in neuroendocrine-cell differentiation include protein atonal homolog 1 and

Animal studies and cell lines

Animals that develop NETs and cell lines derived from human NETs might give insight into the pathogenesis of human GEP NET disease and enable rational development of molecularly targeted therapies, particularly if molecular pathogenesis in animals or cell lines mimics that of human GEP NETs. To date, preclinical findings have not successfully translated to the clinic, and most studies have had substantial limitations.

For example, expression of simian virus 40 (SV40) T antigen under the control

Molecular genetics

Studies have shown that the development of foregut, midgut, and hindgut NETs might involve different genes that are associated with distinct abnormalities, including point mutations, deletions, methylation, and chromosomal losses and gains.25, 26, 27

Foregut NETs have frequent deletions and mutations of the menin gene, encoding a protein of 610 aminoacids. Menin mutations cause most cases of MEN1 and a small proportion of sporadic foregut and non-gastrointestinal endocrine tumours. Menin is

Pathology

The 2000 WHO classification of endocrine tumours30 clearly defined NET phenotypes by degree of differentiation, with specific related clinicopathological features according to tumour site of origin. Although this framework is helpful—especially for stomach, pancreatic, and duodenal tumours30, 31—definitions of hyperplastic and dysplastic lesions and associated prognostic features are absent for the ileum and colon, and lesions of uncertain behaviour are poorly defined.

Furthermore, there is

Clinical presentation

GEP NETs are fairly rare: diagnosis needs a high index of suspicion. These tumours synthesise, store, and secrete various peptides and neuroamines that might produce distinct syndromes.26, 32 Most GEP NETs are sporadic, but they can be multiple and part of a familial syndrome such as MEN1, von Hippel-Lindau syndrome, and neurofibromatosis type 1.

Clinical presentation depends on the site of the primary tumour and whether they are so-called functioning tumours—ie, whether the peptides secreted

Biochemical and tissue markers

Diagnosis of NETs is based on clinical presentation, hormone assays, and pathology. Some biochemical markers that are identifiable in body fluids suggest specific tumours, whereas others are common to several GEP NET types (table 2).32, 33 Correlation of serum markers with symptomatology and lesion location is important to facilitate accurate diagnosis.

For carcinoid tumours of the gastrointestinal tract, the breakdown product of serotonin, 5-hydroxyindoleacetic acid, can be measured in a urine

Topographic diagnosis

Assessment of the location and extent of GEP NETs is crucial for management. Commonly used imaging modalities include: conventional radiology (ie, transabdominal ultrasonography, CT, and MRI); selective angiography, with or without hormonal sampling; nuclear imaging (eg, somatostatin-receptor scintigraphy [SRS] with single photon emission CT [SPECT], and bone scanning); endoscopic ultrasonography; and various intraoperative methods (figure 5). No technique is 100% sensitive, and multiple

Treatment

Treatment should be highly individualised based on the diverse range of tumour burden and symptoms. The best therapeutic choice for individual patients will depend on whether the main aim of treatment is to slow tumour growth or ameliorate symptoms by inhibition of the secretion of bioactive agents. Critical assessment of every treatment option is difficult because of the limited number of patients in a centre and the inability to classify accurately a heterogeneous group of lesions.

Conclusion

GEP NETS are unusual and fairly rare neoplasms. Although recognised for at least a century, they remain orphan tumours, about which little is known. Disappointingly, survival of patients with NETs has not changed appreciably over the past three decades in either the USA4 or UK.78 Improved cell lines and models are needed to define their derivation, biology, behaviour, and growth potential.

Many different types of physicians manage GEP NETs, including endocrinologists, gastroenterologists,

Search strategy and selection criteria

Data for this review were identified by searches of MEDLINE and PubMed, and references from relevant articles using the search terms “Neuroendocrine” or “carcinoid” and “tumor”. Abstracts and reports from meetings were included only when they related directly to previously published work. Data published from Jan 1, 1970, to June 30, 2007, were included.

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