Carcinoid Syndrome

Carcinoid syndrome is a clinical syndrome caused by systemic release of vasoactive substances from a functioning, serotonin secreting neuroendocrine tumour, most commonly of small intestinal origin. Serotonin is the principal mediator, alongside others including histamine, tachykinins and prostaglandins.

The syndrome characteristically occurs only once hepatic metastatic disease has developed. The liver normally metabolises the great majority of serotonin released from a gastrointestinal primary via the portal circulation, before it reaches the systemic circulation. A primary tumour confined to the gastrointestinal tract therefore does not typically produce systemic carcinoid syndrome.

Primary bronchial or ovarian carcinoid tumours are the exception. They drain directly into the systemic venous circulation, bypass hepatic first pass metabolism, and can produce systemic symptoms without hepatic metastasis.

Pathophysiology

• Systemically released serotonin and other mediators produce flushing, diarrhoea, bronchospasm, and, over time, carcinoid heart disease. Each symptom reflects the effect of the causative mediators at their target tissues.
• Carcinoid heart disease is fibrotic thickening of the right sided heart valves (tricuspid and pulmonary). It is believed to result from chronic exposure of the right heart to high circulating serotonin concentrations before pulmonary metabolism. It produces predominantly tricuspid regurgitation and pulmonary stenosis.
• The left heart is typically protected by pulmonary clearance of serotonin. The exceptions are a significant right to left cardiac shunt or, rarely, a primary bronchial carcinoid, which bypass this pulmonary filtering.
• Niacin (vitamin B3) deficiency, and associated pellagra, can occur in longstanding carcinoid syndrome. Dietary tryptophan is diverted towards serotonin synthesis at the expense of normal niacin production.

• Episodic flushing, typically of the face and upper trunk, is a core presenting symptom. It is often triggered by alcohol, certain foods, emotional stress or physical exertion. It occurs together with watery diarrhoea and abdominal cramping.
• Bronchospasm, producing wheeze and dyspnoea, occurs in a proportion of patients.
• Carcinoid heart disease develops over the course of longstanding disease. It produces progressive right heart failure (peripheral oedema, raised jugular venous pressure, and, in more advanced disease, ascites) from the underlying valvular pathology.
• Carcinoid crisis is a severe, acute exacerbation of the syndrome, and a life threatening emergency. Features are profound flushing, severe bronchospasm, marked haemodynamic instability (hypotension or, less commonly, hypertension) and altered consciousness. Anaesthesia, tumour manipulation during surgery, or other significant physiological stressors can precipitate it. It needs specific preventive measures and prompt treatment.
• Because of the association with hepatic metastatic disease, hepatomegaly and right upper quadrant discomfort frequently accompany the syndrome. They reflect the advanced, metastatic stage typically present when systemic carcinoid syndrome becomes apparent.

• Twenty four hour urinary 5-hydroxyindoleacetic acid (5-HIAA), the principal serotonin metabolite, is the standard biochemical test, and elevated levels support the diagnosis. To avoid false positive results, patients should avoid dietary sources of serotonin precursors (including bananas, tomatoes, avocados and certain nuts) and interfering medications in the days before collection.
• Serum chromogranin A is non-specific for carcinoid syndrome. It supports the general diagnosis of neuroendocrine tumour and monitoring of disease burden, following the principles under neuroendocrine neoplasms generally.
• Cross sectional and somatostatin receptor imaging localise the primary tumour and characterise the extent of metastatic disease. This is essential for confirming the diagnosis and for treatment planning. The principles are as under neuroendocrine neoplasms and pancreatic neuroendocrine tumours.
• Echocardiography is essential in every patient with confirmed or suspected carcinoid syndrome, to assess for carcinoid heart disease. Confirmed valvular involvement has significant implications for symptom management and, where significant, for surgical valve intervention.

• Somatostatin analogues (octreotide or lanreotide, given as long acting depot injections) are first line. They suppress hormone release from the tumour and control flushing and diarrhoea in the great majority of patients. Short acting subcutaneous octreotide is available for breakthrough symptoms and for acute management around procedures or surgery.
• Telotristat ethyl, a tryptophan hydroxylase inhibitor that reduces serotonin synthesis, is an effective add on for diarrhoea not adequately controlled with a somatostatin analogue alone. It targets serotonin overproduction by a complementary mechanism.
• Carcinoid crisis prevention requires prophylactic intravenous octreotide before any anaesthesia, surgery, or other procedure that could precipitate tumour mediator release in a patient with known carcinoid syndrome. This is an essential perioperative precaution. Intravenous octreotide is also used to treat an established crisis, alongside general haemodynamic support.
• Carcinoid heart disease with significant valvular dysfunction and heart failure symptoms warrants consideration of cardiac surgical valve replacement in appropriately selected patients. This is typically tricuspid valve replacement, with pulmonary valve intervention where significant pulmonary stenosis or regurgitation is also present. Symptoms and survival improve with successful surgery in this population.
• The decision and timing are individualised through cardiology and oncology multidisciplinary discussion, given the overall disease context and prognosis.
• Niacin supplementation is given where deficiency is identified or suspected, given the risk of pellagra in longstanding disease.
• Management of the underlying neuroendocrine tumour follows the general principles under neuroendocrine neoplasms. Options include peptide receptor radionuclide therapy, surgical debulking, or liver directed therapy for hepatic metastatic disease. The goal is to reduce the overall tumour and hormone secreting burden, complementing the symptomatic control from somatostatin analogues and adjunctive medical therapy.