FRCA Notes

Carcinoid Syndrome

The curriculum asks for knowledge of 'the principles of the peri-operative management of the commoner complex cases including resection of neuroendocrine tumours e.g. carcinoid'.

It has yet to feature as an SAQ/CRQ, though is anecdotally more common viva fodder.

Resources

  • Carcinoid syndrome is (essentially) a paraneoplastic syndrome arising from carcinoid tumour secretory activity
  • The incidence is 3 in 100,000
  • Carcinoid tumours are slow-growing, neuroendocrine tumours of enterochromaffin (Kulchitsky) cells
  • They secrete a range of bioactive polypeptides, monoamines and prostaglandins
  • They arise from the different embryonic divisions of the gut:
    • Foregut: lungs (25%), bronchi (accounts for 2% of all lung cancer) or stomach (10%)
    • Midgut: jejunum or ileum (40%), appendix/caecum or proximal colon
    • Hindgut: distal colon and rectum (25%)

  • The most common site of metastases is the liver

Bioactive molecule secretion

  • Enterochromaffin cell tumours secrete a wide variety of active polypeptides
  • Although >40 different molecules may be secreted, the following are some of the commonest:
Neurotransmitters Vasoactive substances Others
Serotonin Histamine Corticotrophin
Dopamine Prostaglandins Kallikrein
Substance P Bradykinin Neurotensin
Neurokinin
  • Only 10% of patients with carcinoid tumours will experience carcinoid syndrome
    • The majority of these peptides are removed by 1st pass hepatic metabolism
    • Patients with metastatic disease (esp. hepatic) are more likely to experience symptoms

Downstream molecular pathway effects

  • There is increased dietary conversion of tryptophan to serotonin (70% converstion rate vs. normal rate of 1%)
  • Excess serotonin stimulates fibroblasts, leading to widespread fibrosis
  • Diversion of tryptophan metabolism can result in niacin deficiency (pellagra)
  • Niacin deficiency negatively impacts on protein synthesis, with consequent hypoalbuminaemia

  • Clinical features of carcinoid syndrome are typically intermittent and their presence often signifies metastatic disease
  • Triggers include:
    • Exercise
    • Alcohol
    • Coffee
    • Ingestion of high tyramine content foods e.g. blue cheese, chocolate

  • The classically described triad is diarrhoea, flushing and right heart failure, although there are multiple other features:

General symptoms (predominantly GI)

  • Paroxysmal facial flushing (85%; due to bradykinin and prostaglandins)
  • Lacrimation
  • Rhinorrhoea
  • Diarrhoea (80%)
  • Dyspepsia/peptic ulcer disease (histamine)
  • Wheeze / bronchospasm (10-20%; bradykinins)
  • Pruritus (histamine)
  • Abdominal bloating
  • Hypotension
  • Venous telangiectasia of the nose, upper lip and cheeks

Mass effect

  • Large tumours may present with symptoms of mass effect
  • Lung carcinoid tumours present typically e.g. haemoptysis, cough, recurrent infection
  • Gastrointestinal tumours can present with bowel obstruction

Carcinoid heart disease (up to 66%)

  • Classically causes right-sided fibrous thickening of the endocardium
    • This leads to retraction and fixation of the tricuspid valve leaflet
    • Consequent tricuspid (typically regurgitation) and pulmonary valvular disease ensues
    • The degree of fibrosis is related to the duration of exposure to high serotonin concentrations
  • Right sided disease is more common because the lungs filter out a large proportion of the bioactive molecules
  • Up to 10% have left sided cardiac disease too

  • Other cardiac features include:
    • RV failure
    • SVT or other dysrhythmia
    • Constrictive pericarditis

Other features

  • Widespread fibroblast activation causes fibrosis elsewhere, including:
    • Mesenteric fibrosis
    • Retroperitoneal fibrosis → possible ureteric obstruction
    • Penile fibrosis → Peyronie's disease

  • Hypoalbuminaemia and muscle wasting from altered protein metabolism

  • Niacin deficiency presents with rough scaly skin, glossitis, angular stomatitis and confusion

  • 24hr urinary 5-hydroxyindolacetic acid (5-HIAA)
    • This serotonin metabolite has a high specificity (100%) but lower sensitivity (73%)
    • False-positives can be generated by food (pineapples, bananas) or drugs (paracetamol, warfarin)

  • Serum chromogranin A
    • A glycoprotein secreted by neuroendocrine tumours
    • Higher sensitivity than 5-HIAA so may be more useful in screening

  • Imaging
    • TTE for right heart disease
    • CT abdomen with IV & oral contrast
    • MRI, particularly of the liver
    • Bronchoscopy for suspicion of lung disease
    • Endoscopy for suspicion of GI disease
    • Somatostatin-receptor scintigraphy (OctreoScan), which uses a radiolabelled octreotide analogue (111-indium pentetreotide) to detect tumours with a high level of somatostatin receptor expression

  • Surgical resection is the management of choice
  • Other measures include:
    • Chemo/radiotherapy
    • Transarterial chemoembolization (TACE), which involves infusing chemotherapy and embolizing material locally to the tumor via the hepatic arterial system
    • Octreotide

Octreotide

  • A somatostatin analogue, infused
  • Side-effects:
    • Prolonged QT
    • Cardiac conduction defects
    • Bradycardia
    • Vomiting

Perioperative management of the patient with carcinoid syndrome


  • Patients typically present for resection of either the primary tumour ± liver metastases
  • They may also require cardiac surgery to treat carcinoid heart disease, prior to primary tumour resection
  • Overall perioperative goals are to:
    • Identify and optimise possible complications of the disease
    • Minimise the risk of carcinoid crisis

History and examination

  • Full anaesthetic history:
    • Features of carcinoid syndrome
    • Features of carcinoid cardiac disease
    • History of diarrhoea and degree of dehydration
    • Features of bowel obstruction

  • Examination focused on cardiovascular system, particularly for right heart disease and degree of dehydration

Investigations

  • FBC
  • U&E; may have dyselectrolytaemia due to diarrhoea
  • LFT's; may have liver failure from metastatic disease (rare)
  • G&XM

  • ECG; right heart disease
  • CXR; lung lesions
  • TTE; right heart valvular disease

Avoiding carcinoid syndrome ± crisis

  • Even in patients without any symptoms of carcinoid syndrome, the anaesthetic and surgical stress can precipitate a carcinoid crisis
  • Minimising the potential ensuing cardiovascular instability is important
  • Management is with infusion of octreotide at 50μg/hr for at least 12hrs prior to surgery

Monitoring and access

  • AAGBI
  • Depth of anaesthesia monitoring e.g. BIS
  • Cardiac output monitoring
  • Arterial line
  • Central line

Anaesthetic technique

  • No demonstrable benefit of one technique over another
  • The overall goal is as stable a physiology as possible to reduce risk of carcinoid crisis
  • This involves:
    • Only manipulating airway once adequately deep anaesthetic and muscle relaxed
    • Avoiding histamine-releasing agents e.g. atracurium, morphine
    • Avoiding suxamethonium
    • Avoiding certain vasoactive drugs (see below)
  • Remifentanil has favourable characteristics

Carcinoid crises

  • Triggers include:
    • Anaesthetic stimulation e.g. laryngoscopy
    • Anaesthetic drugs, particularly histamine-releasing drugs, vasoactive drugs and suxamethonium
    • Surgical stimulation
    • Surgical tumour handling
    • Hypovolemia, hypoxia, hypothermia or hypercarbia

    Clinical features of carcinoid crisis under anaesthesia
    Hypertension (or labile BP)
    Hypotension
    Tachycardia
    Bronchospasm
    Raised ventilatory pressures
    Sweating

  • Management is with:
    • Octreotide as a 20-50μg bolus IV
    • Steroids
    • Anti-histamine
    • 5-HT antagonists e.g. ondansetron

  • One should avoid:
    • β2-agonists and theophylline in the treatment of bronchospasm; use ipratropium instead
    • Ephedrine and adrenergic agents in the treatment of bronchospasm or hypotension (see below)

Vasoactive drugs

  • The response to vasopressors in carcinoid syndrome is unpredictable
  • Adrenergic agents should be avoided
    • Noradrenaline and adrenaline can cause an exaggerated hypertensive response
    • Noradrenaline may activate kallikrein within the tumour, leading to bradykinin release and paradoxical vasodilation & hypotension with noradrenaline
    • Avoid ephedrine

  • Safe drugs include:
    • Vasopressin
    • Phenylephrine

Analgesia

  • Avoid morphine due to potential for (further) histamine release
  • Paracetamol is safe (although can raise 5-HIAA levels)
  • Thoracic epidural analgesia
    • The analgesic effect may reduce risk of carcinoid crisis by removing peri-operative pain
    • The drawback is that should it cause hypotension, there may be an exaggerated response to vasopressors used

  • Typically managed in an HDU environment due to:
    • Need for ongoing monitoring
    • Ongoing octreotide infusion
    • Management of thoracic epidural