Key Facts

Carcinoid syndrome results from secretion of vasoactive substances (serotonin, histamine, bradykinin, prostaglandins) by well-differentiated neuroendocrine tumours. Syndrome only manifests when secretory products reach the systemic circulation, usually implying hepatic metastases.

Epidemiology

• Neuroendocrine tumours: incidence ~5-7 per 100,000 per year in the UK
• Carcinoid syndrome occurs in ~10% of all NET patients
• Most common primary sites: small bowel (midgut) > lung > appendix > rectum
• Median age at diagnosis: 55-65 years

Aetiology

• Most commonly from midgut (small bowel) NETs with hepatic metastases
• Hindgut NETs (rectum, sigmoid) rarely produce carcinoid syndrome
• Bronchial NETs can cause syndrome without liver metastases (secretion directly into systemic circulation)
• Ovarian NETs can also cause syndrome via systemic drainage

Pathophysiology

• Tumour cells produce serotonin (5-HT), histamine, bradykinin, prostaglandins, tachykinins
• Normally, portal venous drainage allows hepatic metabolism of serotonin (first-pass effect)
• Liver metastases bypass this → systemic serotonin release
• Serotonin causes diarrhoea (intestinal motility), fibrosis (cardiac valves), and bronchoconstriction
• Flushing is mediated primarily by bradykinin and tachykinins rather than serotonin
• Tryptophan diversion to serotonin synthesis can cause pellagra (niacin/B3 deficiency)

Flushing (90%)

• Episodic, dry flushing of face, neck, upper chest
• Lasts seconds to minutes
• Triggered by alcohol, stress, exercise, certain foods (cheese, chocolate)
• In bronchial NETs: more prolonged, purplish, with periorbital oedema

Diarrhoea (70%)

• Secretory (watery) diarrhoea, often with cramping
• May be explosive, 10-20 episodes/day
• Not relieved by fasting

Cardiac Disease (Hedinger Syndrome)

• Right-sided valve disease (serotonin-mediated fibrosis)
• Tricuspid regurgitation (most common) and pulmonary stenosis
• Left-sided valves usually spared (serotonin metabolised in lungs)
• Present in 20-50% of patients with carcinoid syndrome

Bronchospasm (15%)

• Wheezing and dyspnoea
• Can be severe during carcinoid crisis

Red Flags

• Carcinoid crisis: severe flushing, hypotension, tachycardia, bronchospasm – can be fatal; triggered by anaesthesia, tumour manipulation, or biopsy
• Signs of pellagra: diarrhoea, dermatitis, dementia (niacin deficiency from tryptophan depletion)
• Progressive right heart failure symptoms (peripheral oedema, hepatomegaly, JVP elevation)

Bedside

• Cardiovascular examination (right heart murmurs)
• Hepatomegaly assessment

Bloods

• Chromogranin A: elevated in most NETs (non-specific but useful for monitoring)
• Serum serotonin: may be elevated but less specific
• FBC: may show anaemia
• LFTs: if liver metastases present
• NT-proBNP: screen for cardiac involvement

Urine

• 24-hour urinary 5-HIAA: gold standard biochemical test (sensitivity 70-75%, specificity >95%)
• Avoid serotonin-rich foods for 3 days before collection (bananas, avocado, walnuts, tomatoes)

Imaging

• CT thorax/abdomen/pelvis: staging, identify primary tumour and metastases
• Gallium-68 DOTATATE PET/CT: somatostatin receptor imaging – most sensitive for well-differentiated NETs
• Echocardiography: assess for carcinoid heart disease (tricuspid regurgitation, pulmonary stenosis)
• MRI liver: characterise hepatic metastases

Special Tests

• Octreotide scan (Octreoscan): if DOTATATE PET unavailable
• Histology: Ki-67 index for grading (G1: <3%, G2: 3-20%, G3: >20%)
• CT enterography/capsule endoscopy: for small bowel primary

Non-pharmacological

• Avoid triggers: alcohol, stress, strenuous exercise, serotonin-rich foods
• Nutritional support: niacin supplementation to prevent pellagra
• NET specialist MDT management

Pharmacological

• Somatostatin analogues (first-line):
  • Octreotide LAR 20-30mg IM monthly (PROMID trial – improved PFS in midgut NETs)
  • Lanreotide Autogel 120mg SC monthly (CLARINET trial – improved PFS)
  • Rescue doses: octreotide 100-200 mcg SC for breakthrough symptoms
• Telotristat ethyl 250mg TDS (oral tryptophan hydroxylase inhibitor) – add-on for inadequately controlled diarrhoea (TELESTAR trial)
• PRRT (peptide receptor radionuclide therapy): Lutetium-177 DOTATATE (NETTER-1 trial) for somatostatin receptor-positive progressive disease
• Everolimus 10mg OD (RADIANT-4 trial – improved PFS in non-functional NETs)
• Interferon-alpha: second-line for symptom control
• Pre-operative carcinoid crisis prevention: IV octreotide 50-100 mcg bolus, avoid suxamethonium and morphine

Surgical/Interventional

• Surgical resection of primary tumour and liver metastases where feasible
• Hepatic artery embolisation/TACE: for liver-predominant disease
• Radiofrequency ablation: for small hepatic metastases
• Valve replacement surgery: for significant carcinoid heart disease

Referral Criteria

• All NETs should be managed in ENETS Centre of Excellence or specialist NET MDT
• Carcinoid heart disease → cardiology
• Consider PRRT referral if progressive disease on somatostatin analogues

• 5-year survival for metastatic midgut NETs: 60-75%
• Well-differentiated NETs (G1/G2) have much better prognosis than poorly differentiated (G3)
• Carcinoid heart disease present in 20-50% and is a major cause of morbidity
• Median survival with carcinoid syndrome: 8-12 years with modern treatment
• PRRT can provide significant improvement in PFS and quality of life
• Carcinoid crisis has significant mortality if not prevented/managed

NET Grading (WHO 2019)

Landmark Trials in NET Management