Neuroendocrine tumours

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Neuroendocrine neoplasms range from indolent well-differentiated NETs to aggressive poorly differentiated neuroendocrine carcinomas; primary site, mitotic rate, Ki-67 index, somatostatin-receptor expression and hormone secretion all change management. Most NETs are sporadic and arise through site-specific alterations in chromatin regulation, cell-cycle control, mTOR signalling or DNA repair. MEN1, von Hippel–Lindau, neurofibromatosis type 1 and tuberous sclerosis increase particular pancreatic, duodenal, adrenal or other neuroendocrine tumours. Well-differentiated architecture can still be grade 1, 2 or 3 by mitoses and Ki-67, while poorly differentiated carcinoma is biologically distinct. Bioactive amines or peptides produce syndromes only when secreted, active and able to reach systemic circulation; many radiologically evident NETs are non-functioning.

Recognition depends on the tempo, host context and anatomical pattern rather than one isolated result. Incidental imaging, pain, jaundice, obstruction or metastasis is more common than a classic hormone syndrome across many NET sites. Episodic flushing and secretory diarrhoea, sometimes with bronchospasm, suggests systemic serotonin exposure and usually metastatic midgut disease. Documented hypoglycaemia, severe acid hypersecretion, necrolytic migratory erythema or watery diarrhoea suggests insulinoma, gastrinoma, glucagonoma or VIPoma. Investigation should answer immediate safety, diagnostic confirmation and extent in that order. Core biopsy with expert pathology Report well versus poorly differentiated morphology and grade on adequate tissue; small crushed samples can underestimate heterogeneity. Multiphase CT or MRI Arterial-phase imaging improves detection of hypervascular pancreatic and hepatic lesions; MRI is particularly sensitive for liver metastases. Somatostatin-receptor PET-CT Gallium-68 or fluorine-18 SSTR PET-CT is the reference functional study in receptor-expressing disease; low uptake can indicate dedifferentiation.

Management is determined by physiological urgency, disease extent, treatment intent and the person's priorities. The pathway moves through build an integrated net diagnosis, then plan site-specific curative treatment, then control metastatic receptor-positive net; each transition requires named multidisciplinary ownership. Follow-up must anticipate carcinoid heart disease, mesenteric ischaemia or obstruction, hormonal metabolic injury while measuring function and treatment toxicity.

Key points

Non-functioning mass is a pivotal clue in Neuroendocrine tumours: Incidental imaging, pain, jaundice, obstruction or metastasis is more common than a classic hormone syndrome across many NET sites.
Immediate priority in unstable Neuroendocrine tumours: Stabilise the physiological syndrome, obtain specialist endocrine-oncology input, use intravenous octreotide promptly for suspected carcinoid crisis and treat airway, shock, glucose, bleeding or obstruction through the relevant emergency pathway.
Core biopsy with expert pathology is used early to establish differentiation, primary-site markers, mitotic count and Ki-67 proliferation index. Report well versus poorly differentiated morphology and grade on adequate tissue; small crushed samples can underestimate heterogeneity.
Multiphase CT or MRI refines the next decision because arterial-phase imaging improves detection of hypervascular pancreatic and hepatic lesions; MRI is particularly sensitive for liver metastases.
Build an integrated NET diagnosis: Obtain expert pathology with differentiation, mitoses, Ki-67 and site markers, repeating biopsy if small tissue conflicts with clinical behaviour.
Plan site-specific curative treatment: Control hormone excess before anaesthesia and create a carcinoid-crisis plan for a functioning midgut or high-burden tumour.
A major avoidable harm is carcinoid heart disease; Fibrotic tricuspid regurgitation and pulmonary stenosis lead to right-heart failure and may require valve intervention before hepatic or oncological procedures.
A common diagnostic trap is menopause or mast-cell flushing: Flushing without secretory diarrhoea or raised syndrome-specific markers may be vasomotor, allergic, medicine-related or autonomic.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Sporadic genomic change

Most NETs are sporadic and arise through site-specific alterations in chromatin regulation, cell-cycle control, mTOR signalling or DNA repair.

Inherited syndromes

MEN1, von Hippel–Lindau, neurofibromatosis type 1 and tuberous sclerosis increase particular pancreatic, duodenal, adrenal or other neuroendocrine tumours.

Chronic gastric stimulation

Autoimmune atrophic gastritis and prolonged hypergastrinaemia promote selected gastric enterochromaffin-like-cell NETs with behaviour unlike sporadic high-grade gastric disease.

Poorly differentiated lineage

Neuroendocrine carcinomas carry marked genomic instability and TP53 or RB pathway disruption, behaving more like aggressive systemic carcinoma than indolent NET.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Differentiation and grade
Well-differentiated architecture can still be grade 1, 2 or 3 by mitoses and Ki-67, while poorly differentiated carcinoma is biologically distinct.
2
Hormone secretion
Bioactive amines or peptides produce syndromes only when secreted, active and able to reach systemic circulation; many radiologically evident NETs are non-functioning.
3
Hepatic bypass
Midgut serotonin usually causes systemic carcinoid syndrome after liver metastasis allows mediators to avoid first-pass metabolism, though bronchial and ovarian primaries are exceptions.
4
Somatostatin receptors
Many well-differentiated NETs express SSTR2, enabling functional imaging, symptom suppression by analogues and peptide-receptor radionuclide therapy.
5
Fibrotic signalling
Serotonin and growth mediators can cause mesenteric fibrosis and right-sided valvular plaque, leading to obstruction, ischaemia and heart failure independently of tumour size.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Non-functioning mass

Incidental imaging, pain, jaundice, obstruction or metastasis is more common than a classic hormone syndrome across many NET sites.

Carcinoid syndrome

Episodic flushing and secretory diarrhoea, sometimes with bronchospasm, suggests systemic serotonin exposure and usually metastatic midgut disease.

Functional pancreatic syndrome

Documented hypoglycaemia, severe acid hypersecretion, necrolytic migratory erythema or watery diarrhoea suggests insulinoma, gastrinoma, glucagonoma or VIPoma.

Carcinoid heart disease

Progressive exertional breathlessness, oedema, raised JVP and a right-sided murmur can reflect tricuspid and pulmonary valve fibrosis.

Carcinoid crisisRed flag

Profound flushing, bronchospasm, labile blood pressure and shock during tumour stress is an endocrine-oncology emergency.

High-grade behaviour

Rapid enlargement, weight loss, heavy liver burden and low receptor expression suggest aggressive grade 3 NET or neuroendocrine carcinoma.

Red flags requiring action

Episodic flushing, diarrhoea, wheeze and right-sided valvular symptoms suggest carcinoid syndrome.
Recurrent fasting confusion, seizure or low plasma glucose suggests an insulin-secreting pancreatic NET.
Multiple or refractory peptic ulcers with diarrhoea suggests gastrinoma and acid hypersecretion.
Severe abdominal pain, obstruction, mesenteric ischaemia or a fibrotic mesenteric mass requires urgent assessment.
A secretory NET patient becomes hypotensive, bronchospastic and flushed during anaesthesia, embolisation or tumour manipulation.
Rapid progression, bulky disease, very high Ki-67 or constitutional decline suggests poorly differentiated neuroendocrine carcinoma.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Core biopsy with expert pathologyFirst step
Why
Establish differentiation, primary-site markers, mitotic count and Ki-67 proliferation index.
Interpretation and limitations
Report well versus poorly differentiated morphology and grade on adequate tissue; small crushed samples can underestimate heterogeneity.
02
Multiphase CT or MRI
Why
Define primary anatomy, mesenteric complications, liver burden, nodes and resectability.
Interpretation and limitations
Arterial-phase imaging improves detection of hypervascular pancreatic and hepatic lesions; MRI is particularly sensitive for liver metastases.
03
Somatostatin-receptor PET-CT
Why
Stage receptor-positive well-differentiated NET and determine suitability for receptor-targeted treatment.
Interpretation and limitations
Gallium-68 or fluorine-18 SSTR PET-CT is the reference functional study in receptor-expressing disease; low uptake can indicate dedifferentiation.
04
FDG PET-CT
Why
Characterise aggressive biology when high grade, rapid progression or discordant receptor imaging is present.
Interpretation and limitations
High FDG uptake often marks poorer prognosis and may identify lesions that need biopsy rather than assuming uniform tumour biology.
05
Syndrome-directed biochemistry
Why
Confirm a clinically suspected secretory syndrome using the correct pre-analytical conditions.
Interpretation and limitations
Use plasma glucose with insulin, C-peptide and beta-hydroxybutyrate during hypoglycaemia, fasting gastrin with gastric context, or 5-HIAA for serotonin syndrome; do not order every hormone indiscriminately.
06
Echocardiography and NT-proBNP
Why
Detect carcinoid heart disease when serotonin secretion, symptoms or biomarker risk is present.
Interpretation and limitations
Assess right-sided valve structure and ventricular effect at baseline and surveillance intervals chosen by the specialist service.
07
Genetic assessment
Why
Identify an inherited syndrome when age, multiplicity, tumour site or family history raises suspicion.
Interpretation and limitations
Genetic results direct surveillance of other organs and relatives and can influence operative planning in MEN1-associated disease.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Menopause or mast-cell flushing

Flushing without secretory diarrhoea or raised syndrome-specific markers may be vasomotor, allergic, medicine-related or autonomic. In Neuroendocrine tumours, this distinction materially changes diagnostic assessment.

Irritable or inflammatory bowel disease

Chronic diarrhoea is common and must be phenotyped before attributing it to serotonin secretion. In Neuroendocrine tumours, this distinction materially changes diagnostic assessment.

Factitious or drug-related hypoglycaemia

Insulin, sulfonylurea and critical illness can mimic insulinoma; paired biochemical sampling during low glucose is decisive.

Pancreatic adenocarcinoma

A pancreatic mass with duct obstruction and hypovascular imaging follows a different tissue, surgical and systemic pathway.

Small-cell carcinoma

Poorly differentiated pulmonary or extrapulmonary neuroendocrine carcinoma requires urgent platinum-based management, distinct from somatostatin-receptor-positive NET. In Neuroendocrine tumours, this distinction materially changes diagnostic assessment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ClassifyBuild an integrated NET diagnosisFirst stepA biopsy, imaging finding or hormone syndrome suggests a neuroendocrine neoplasm.

1Obtain expert pathology with differentiation, mitoses, Ki-67 and site markers, repeating biopsy if small tissue conflicts with clinical behaviour.
2Stage with multiphase anatomical imaging and SSTR PET-CT for well-differentiated disease; add FDG PET when grade or tempo suggests aggressive biology.
3Confirm only clinically plausible hormone syndromes under correct conditions and offer genetics assessment when phenotype indicates inherited disease.

02LocalisedPlan site-specific curative treatmentA localised primary and regional disease can be removed with acceptable functional cost.

1Use organ- and site-specific surgery, balancing nodal clearance, pancreatic function, bowel blood supply and inherited multifocal disease.
2Control hormone excess before anaesthesia and create a carcinoid-crisis plan for a functioning midgut or high-burden tumour.
3Review final pathology, grade, margins and nodes and enter surveillance based on recurrence risk rather than one universal scan schedule.

03Well differentiatedControl metastatic receptor-positive NETDisease is unresectable or metastatic but remains well differentiated with somatostatin-receptor expression.

1Use a long-acting somatostatin analogue for carcinoid symptoms and tumour control in eligible gastroenteropancreatic NET.
2At progression, select peptide-receptor radionuclide therapy, everolimus, sunitinib, liver-directed treatment or chemotherapy by site, grade, receptor imaging and burden.
3Consider resection or ablation of selected dominant disease only when symptom, obstruction or durable-control benefit justifies procedure burden.

04High gradeTreat aggressive neuroendocrine diseasePathology shows poorly differentiated neuroendocrine carcinoma or a rapidly progressive grade 3 neoplasm.

1Review morphology, Ki-67, receptor and FDG imaging because grade 3 well-differentiated NET and neuroendocrine carcinoma need different systemic choices.
2Use platinum–etoposide promptly for appropriate poorly differentiated carcinoma, with tumour-lysis and marrow-risk planning.
3Integrate early symptom, nutritional and palliative support and reassess after a short interval because resistance and functional decline can be rapid.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Suppresses hormone secretion and slows growth in eligible somatostatin-receptor-positive well-differentiated NET.

Octreotide long-acting release

A common licensed starting regimen for functioning gastroenteropancreatic NET is 20 mg by deep intramuscular injection every 4 weeks; many specialist pathways use 30 mg every 4 weeks and titrate to symptoms and tumour control.

Establish tolerability with short-acting treatment when appropriate; monitor glucose, thyroid, gallbladder, bradycardia, gastrointestinal absorption and injection technique, and provide rescue short-acting octreotide for breakthrough symptoms.

Provides long-acting somatostatin-receptor activation for tumour and secretory control.

Lanreotide Autogel

Use 120 mg by deep subcutaneous injection every 28 days for antiproliferative treatment of eligible grade 1 or selected grade 2 gastroenteropancreatic NET, with interval adjustment only through the specialist protocol.

Monitor glucose, gallstones, thyroid function, heart rate and gastrointestinal effects; teach self- or partner-injection only after competency assessment.

Blocks mediator release during life-threatening carcinoid haemodynamic instability and accompanies standard shock and airway treatment.

Octreotide for carcinoid crisis

Give an immediate specialist-led intravenous bolus, commonly 50–100 micrograms, followed by infusion commonly starting at 50 micrograms/hour and titrated rapidly to haemodynamics and bronchospasm in monitored care.

Do not delay adrenaline and resuscitation when anaphylaxis is possible; monitor glucose, bradycardia and splanchnic or cardiac effects and seek NET anaesthetic expertise.

Inhibits peripheral serotonin synthesis and reduces bowel frequency when analogue therapy is optimised.

Telotristat ethyl

Use 250 mg orally three times daily with food in adults with carcinoid-syndrome diarrhoea inadequately controlled by a somatostatin analogue, under the commissioned specialist pathway.

Continue the somatostatin analogue, monitor constipation, abdominal pain, mood and liver tests, and stop urgently if severe constipation or obstructive symptoms develop.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Carcinoid heart disease

Fibrotic tricuspid regurgitation and pulmonary stenosis lead to right-heart failure and may require valve intervention before hepatic or oncological procedures.

Mesenteric ischaemia or obstruction

Desmoplastic reaction around a small bowel primary can tether bowel and vessels, producing pain, obstruction and infarction.

Hormonal metabolic injury

Hypoglycaemia, acid ulceration, severe diarrhoea and electrolyte loss cause neurological, bleeding, renal and nutritional harm. In Neuroendocrine tumours, this distinction materially changes complication assessment.

Carcinoid crisis

Anaesthesia, embolisation, surgery or spontaneous mediator release can cause bronchospasm and extreme haemodynamic instability. In Neuroendocrine tumours, this distinction materially changes complication assessment.

Liver failure

Diffuse hepatic replacement or repeated liver-directed therapy can impair reserve even when secretory symptoms temporarily improve.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Use the same anatomical and functional imaging framework to distinguish receptor-positive stability from aggressive discordant progression.
Trend the syndrome-specific marker only when it was validly elevated and correlates with symptoms; do not chase non-specific chromogranin A alone.
During somatostatin analogues, review stool frequency, flushing, weight, glucose, thyroid function, gallbladder symptoms and injection delivery.
Screen for carcinoid heart disease with symptoms, NT-proBNP and echocardiography at specialist intervals in significant serotonin secretion.
Before PRRT, track marrow, renal function, receptor uptake and cumulative radionuclide exposure with radiation-safety counselling.
Re-biopsy a rapidly growing or imaging-discordant site when transformation or grade heterogeneity would change treatment.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

NET is not one disease

Site, differentiation, grade, stage, hormone function and receptor expression each contribute information that cannot be replaced by the label neuroendocrine.

Biochemistry needs a syndrome

Non-specific hormone panels create false positives; sample the suspected pathway under its required fasting, medication and glucose conditions.

Two PET scans ask different questions

SSTR uptake supports receptor targeting, while FDG uptake exposes aggressive metabolism and biological heterogeneity.

Small primary, large consequence

A tiny ileal tumour can create extensive mesenteric fibrosis, obstruction, ischaemia and carcinoid heart disease.

Crisis planning precedes procedure

Anaesthesia, embolisation and tumour handling can trigger mediator release, so octreotide and haemodynamic plans belong in the procedural brief.

11Common pitfallsFrequent interpretation and management errors.

01
Treating all neuroendocrine neoplasms as indolent carcinoid tumours.
02
Ordering a broad hormone panel without a compatible syndrome.
03
Relying on chromogranin A despite proton-pump inhibitor or renal confounding.
04
Using SSTR imaging alone in rapidly progressive high-grade disease.
05
Missing carcinoid heart disease while focusing on abdominal imaging.
06
Taking a functioning tumour to anaesthesia without a crisis plan.