Medical Oncologist
Gastroenteropancreatic Neuroendocrine Neoplasms
GEP-NETs • Functioning tumours • Neuroendocrine carcinomas (NECs)
Gastrointestinal and pancreatic neuroendocrine neoplasms are not a single disease. They may arise in different organs — including the stomach, small intestine, pancreas, colon or rectum — and may differ substantially in biological behaviour, growth rate and treatment options.
Appropriate assessment considers not only the site of origin but also tumour differentiation, mitotic count and Ki-67, disease stage — that is, how far and where it has spread — somatostatin receptor expression and, where present, the production of hormones or other biologically active substances. In selected cases, particularly in pancreatic neuroendocrine tumours, additional information from the tumour’s molecular profile may contribute to a fuller understanding of the biology of the disease. Taken together, these data help define the behaviour of the tumour more accurately and guide the appropriate treatment strategy.
The same diagnosis of a “neuroendocrine tumour” may therefore represent very different disease and require a different treatment approach.
When can a specialist assessment be helpful?
In gastrointestinal and pancreatic neuroendocrine neoplasms, the treatment strategy may differ substantially according to the organ of origin, tumour differentiation and grade, somatostatin receptor expression and the previous course of the disease. Where there is uncertainty about the precise classification or an important treatment decision must be made, a comprehensive review of the medical record can be helpful.
In which organ did the tumour arise?
The site of the primary tumour is important because neuroendocrine tumours arising in different organs may have different biological behaviour, symptoms, molecular characteristics and treatment options.
Stomach
Gastric NETs are a heterogeneous group and may be associated with different mechanisms of hypergastrinaemia. Their classification, together with tumour size, grade, depth of invasion and the presence of metastatic disease, materially influences management.
Duodenum
Duodenal NETs have distinct characteristics and may be functioning or non-functioning. Their location, size, grade and any hormonal activity are relevant when choosing between an endoscopic, surgical or other treatment approach.
Small Intestine
Small-intestinal NETs, particularly those of the ileum, often have a relatively indolent course, but may be diagnosed after lymph-node or liver involvement has already developed. Some patients may develop carcinoid syndrome. Complete staging and functional imaging are particularly important when planning treatment.
Pancreas
Pancreatic NETs show marked biological heterogeneity and may be functioning or non-functioning. Grade, stage, somatostatin receptor expression and, in selected cases, the molecular profile contribute to the overall treatment assessment.
Rectum & Colon
Neuroendocrine neoplasms of the rectum and colon may behave very differently. Small, well-differentiated rectal NETs are often managed locally, whereas larger, higher-grade or poorly differentiated tumours require a different and often multimodal approach.
Appendix
Appendiceal neuroendocrine tumours are often found incidentally after appendicectomy. Further management depends on features including tumour size, grade, resection margins and other pathological findings; in many cases, the initial operation may be sufficient.
NET or NEC? What do differentiation and grade mean?
Differentiation and grade are not the same. Differentiation describes how closely the cancer cells retain the morphological features of a neuroendocrine tumour — how similar they remain to the healthy cell from which they arose — whereas grade estimates how actively the tumour is proliferating, principally on the basis of mitotic count and Ki-67.
A neuroendocrine tumour may therefore be well differentiated but G3 without being a neuroendocrine carcinoma (NEC). This distinction is important because the two categories have different biology and may require different treatment approaches.
Well-Differentiated NET
G1
Low rate of cellular proliferation — the tumour cells divide relatively slowly.
G2
Intermediate rate of cellular proliferation — the cells divide more rapidly than in a G1 tumour.
G3
High rate of cellular proliferation — the cells divide rapidly, but the tumour retains the morphology of a well-differentiated NET.
NET G3 tumours form a distinct biological category and are seen more often in the pancreas, although they may also arise elsewhere in the digestive tract.
Poorly Differentiated NEC
Neuroendocrine carcinomas (NECs) are high-grade, poorly differentiated neoplasms and are morphologically classified as small-cell or large-cell. They have different molecular biology and usually more aggressive clinical behaviour than well-differentiated NETs. NECs are high grade by definition and are not classified as G1, G2 or G3 in the same way as well-differentiated NETs.
NET G3 ≠ NEC
A high Ki-67 index alone is not sufficient to classify a tumour as an NEC. Accurate classification takes into account tumour morphology, mitotic count, Ki-67 and, in some diagnostically difficult cases, additional immunohistochemical or molecular features.
In pancreatic neuroendocrine tumours, for example, alterations in MEN1, DAXX or ATRX are more often found in well-differentiated NETs, whereas abnormal p53 expression or loss of RB1 is more characteristic of poorly differentiated NECs.
Functioning Neuroendocrine Tumours and Hormonal Syndromes
Some neuroendocrine tumours can secrete hormones or other biologically active substances in quantities that cause specific symptoms. These are described as functioning tumours. Diagnosis of a functioning syndrome is based not simply on the presence of a hormone within the tumour, but on the combination of characteristic symptoms and appropriate biochemical confirmation.
Recognising the hormonal syndrome is important because specific symptom management is often required alongside treatment of the tumour itself. Different syndromes may require different biochemical investigations, imaging and treatment strategies.
Carcinoid Syndrome
Carcinoid syndrome is caused by circulating biologically active substances, principally serotonin, and is seen more often in small-intestinal NETs. It may present with flushing, diarrhoea, abdominal symptoms or wheezing. Patients with established syndrome also require assessment for possible involvement of the heart valves (carcinoid heart disease).
Insulinoma
An insulinoma is a functioning pancreatic NET that causes inappropriate insulin secretion and episodes of hypoglycaemia. Symptoms may include sweating, tremor, tachycardia, confusion or even loss of consciousness, and often improve after glucose is taken.
Gastrinoma / Zollinger–Ellison Syndrome
Excess gastrin production increases gastric acid secretion and may lead to recurrent or multiple peptic ulcers, gastro-oesophageal reflux and diarrhoea. Gastrinomas may arise in the pancreas or duodenum and, in some cases, are associated with inherited syndromes such as MEN1.
Rarer Functioning Syndromes
Rarer functioning pancreatic NETs may secrete glucagon, VIP, somatostatin, ACTH or other hormones, producing different clinical presentations. Identification of the specific syndrome determines both the biochemical investigations required and the prompt management of symptoms.
Treatment Addresses Both the Tumour and the Hormonal Syndrome
In a functioning NET, the treatment strategy has two parallel aims: control of the disease and control of excessive hormone secretion and the symptoms it causes.
How are diagnosis and staging carried out?
Assessment of a neuroendocrine tumour is not based on a single test. The pathological diagnosis must be considered together with anatomical and functional imaging and, where indicated, specialist biochemical or molecular testing. The aim is to define accurately the type and biology of the tumour, its site of origin and the stage of disease — that is, how far and where it has spread.
1. Histological Diagnosis, Differentiation and Grade
Tissue examination is the basis of diagnosis. The pathologist assesses tumour morphology and differentiation, mitotic count and Ki-67 to determine the type and grade of the neoplasm. In some diagnostically difficult cases, additional immunohistochemical or molecular testing may be needed for accurate classification.
2. CT and MRI
CT and MRI are used to assess the primary tumour and the overall extent of disease. Selection of the appropriate technique depends on the site and the clinical question. MRI is particularly valuable for assessing the liver, while dedicated CT or MRI protocols may provide detailed evaluation of pancreatic and other GEP-NETs.
3. Endoscopy and Endoscopic Ultrasound
Depending on the site of origin, endoscopy may be central to both diagnosis and assessment of local extent. Endoscopic ultrasound (EUS) is particularly useful in selected tumours of the pancreas, stomach and duodenum, and may assist with tissue sampling or planning a treatment intervention.
4. SSTR PET/CT — Functional Imaging
Somatostatin receptor PET/CT imaging, for example with DOTATATE or DOTATOC, may demonstrate the overall distribution of SSTR-positive disease throughout the body. It has an important role in staging many well-differentiated NETs and provides essential information when somatostatin receptor-targeted treatment, such as PRRT, is being considered.
5. FDG PET/CT and Biological Heterogeneity
FDG PET/CT is not required for every NET. In selected cases — particularly where there is a higher grade, rapid progression or a discrepancy between the expected and observed behaviour of the disease — it may provide additional information about tumour metabolic activity and biological heterogeneity. Considered alongside SSTR imaging, it may identify different disease populations within the same patient.
Specialist Biochemical and Hormonal Testing
Where symptoms suggest a functioning syndrome, laboratory testing is directed towards the specific hormone or biologically active substance. Not every patient needs the same extensive hormonal investigations. Test selection should be based on the clinical presentation and on the type and site of the tumour.
Not Every Test Is Required for Every Patient
The appropriate diagnostic work-up depends on the site, differentiation and grade of the tumour, the stage of disease, symptoms and the specific treatment question.
How is the appropriate treatment selected?
There is no single treatment suitable for every neuroendocrine tumour. Selection depends on the organ of origin, differentiation and grade, the extent and rate of disease progression, symptoms, somatostatin receptor expression and treatments already received. It is also important to consider whether the treatment aim is cure, long-term disease control, rapid tumour shrinkage or control of a functioning syndrome. Treatment sequencing is often reassessed as the biology and extent of the disease change.
1. Surgical and Endoscopic Treatment
When disease is localised, surgical resection may offer definitive treatment. For small NETs at specific sites, such as the stomach, duodenum or rectum, endoscopic removal may be appropriate in selected cases. The extent of the intervention depends on the organ of origin, tumour size, grade, depth of invasion and the presence of lymph-node or metastatic disease.
2. Somatostatin Analogues
Somatostatin analogues, such as octreotide and lanreotide, are used in many well-differentiated NETs. They may help control both tumour growth and, in functioning tumours, hormonal hypersecretion and its symptoms. Somatostatin receptor expression and the overall biology of the tumour are considered when selecting this treatment.
PRRT — Peptide Receptor Radionuclide Therapy
In patients with well-differentiated, SSTR-positive GEP-NETs, PRRT with ^177Lu-DOTATATE may be an important treatment option. SSTR PET/CT is used to confirm that the disease expresses the treatment target adequately. The place of PRRT in the treatment sequence depends on grade, previous treatment, the extent of disease and its rate of progression.
4. Targeted Systemic Therapies
Medicines that inhibit specific pathways involved in tumour growth may be used in advanced, progressive, well-differentiated NETs. Everolimus has an established role in pancreatic NETs and selected non-functioning gastrointestinal NETs, while sunitinib is an option specifically for progressive pancreatic NETs. Cabozantinib is now also an approved European treatment option for previously treated, advanced, well-differentiated pancreatic and extra-pancreatic NETs.
5. Chemotherapy
Chemotherapy has an important role in selected well-differentiated NETs, particularly pancreatic tumours and disease with a higher grade, more rapid progression or a need for substantial tumour shrinkage. The regimen and its place in the treatment sequence are individualised according to disease biology and previous treatments.
6. Local Treatments and Management of Metastases
In selected patients, particularly where disease is mainly confined to the liver or to a limited number of sites, local treatment approaches may be used. These include surgery, thermal ablation or cryoablation, intra-arterial liver treatments and, in appropriate cases, stereotactic radiotherapy. They are selected as part of the overall treatment strategy rather than in isolation.
7. Neuroendocrine Carcinomas (NECs)
Poorly differentiated neuroendocrine carcinomas (NECs) are a distinct biological entity and are managed differently from well-differentiated NETs. In metastatic disease, a platinum agent combined with etoposide is a principal first-line treatment option, while later-line treatment depends on response, duration of disease control and tumour characteristics. In selected cases, molecular testing may identify clinically actionable features.
Appropriate treatment sequencing is as important as the choice of each individual treatment
Several treatment options are often available for neuroendocrine tumours. The central question is not only which treatment can be used, but when, in what sequence and with what treatment aim. The strategy is reassessed as the extent, rate of progression and biology of the disease change.
Molecular Features and Emerging Research Directions
Pancreatic neuroendocrine tumours In well-differentiated pancreatic NETs, frequent alterations have been described in genes such as MEN1, DAXX and ATRX, as well as in genes involved in mTOR signalling. These alterations relate to mechanisms including chromatin regulation, telomere maintenance and control of cell growth, demonstrating that pancreatic NETs form a molecularly heterogeneous group of tumours. DAXX / ATRX and telomere maintenance Loss of DAXX or ATRX function is associated in a subset of pancreatic NETs with the alternative lengthening of telomeres (ALT) mechanism. These features have important biological and research value, but they are not currently used as established routine biomarkers for selecting a specific systemic treatment. NET G3 and NEC: different molecular biology Molecular analysis may also provide additional support in diagnostically difficult cases when distinguishing a well-differentiated NET G3 from a poorly differentiated NEC. Alterations in the MEN1/DAXX/ATRX axis are more frequent in pancreatic NETs, whereas TP53 and RB1 abnormalities are much more common in pancreatic NECs. Morphology, however, remains fundamental to diagnosis, and molecular features are interpreted within the overall pathological context. An important distinction: somatic and germline variants Finding a MEN1 alteration within the tumour itself does not in itself mean that the patient has inherited MEN1 syndrome. An acquired (somatic) alteration confined to the cancer cells is different from a germline variant present in all cells of the body. Where the personal or family history raises suspicion, specialist genetic counselling and germline testing may be required. Large genomic studies have confirmed that a subset of PanNETs is associated with inherited genetic alterations. Molecular information does not replace histological diagnosis, Ki-67, imaging or the clinical picture. It provides an additional layer of information that, in selected cases, may help improve understanding of disease biology, inform differential diagnosis and support the assessment of potential research or treatment options.
Frequently Asked Questions
Scientific References & Clinical Guidelines
WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine Tumours. WHO Classification of Tumours, 5th ed., Volume 10. IARC; 2025. Panzuto F, et al. ENETS 2023 guidance paper for gastroduodenal NETs G1–G3. J Neuroendocrinol. 2023. Kos-Kudła B, et al. ENETS 2023 guidance paper for nonfunctioning pancreatic NETs. J Neuroendocrinol. 2023. Hofland J, et al. ENETS 2023 guidance paper for functioning pancreatic NET syndromes. J Neuroendocrinol. 2023. Lamarca A, et al. ENETS 2024 guidance paper for well-differentiated small-intestinal NETs. J Neuroendocrinol. 2024. Rinke A, et al. ENETS 2023 guidance paper for colorectal neuroendocrine tumours. J Neuroendocrinol. 2023. ENETS 2023 guidance paper for appendiceal NETs. J Neuroendocrinol. 2023. ENETS 2023 guidance paper for digestive neuroendocrine carcinoma. J Neuroendocrinol. 2023. European Medicines Agency. Lutathera — EPAR. Current EU indication for ^177Lu-DOTATATE. European Medicines Agency. Cabometyx — EPAR. Current EU indication including previously treated advanced well-differentiated pNET/epNET.
Second Opinion & Medical Record Review
In neuroendocrine neoplasms, a treatment decision often depends on combining several pieces of information: precise histological classification, grade and Ki-67, the extent and biological behaviour of the disease, functional imaging and treatments already received.
In a complex or rare case, a comprehensive review of the medical record may help confirm the diagnosis and plan the next steps in treatment.