Carcinoid Syndrome
Carcinoid syndrome is a hormonal disorder caused by the systemic release of vasoactive substances—primarily serotonin and tachykinins—from neuroendocrine tumors (NETs), typically occurring when midgut NETs metastasize to the liver or when venous drainage bypasses hepatic metabolism. 1
Pathophysiology
The syndrome develops when vasoactive compounds enter systemic circulation without being metabolized by the liver, which normally inactivates these substances during first-pass metabolism. 1, 2
This occurs in approximately 20% of patients with well-differentiated jejunal or ileal (midgut) NETs, almost always after liver metastases develop. 1
Carcinoid syndrome can also occur without liver metastases if direct retroperitoneal tumor involvement allows venous drainage to bypass the liver. 1, 2
The syndrome is very rare with rectal NETs and occurs less frequently with NETs from other origins. 1
In bronchopulmonary NETs, carcinoid syndrome occurs in only 1-5% of cases due to ectopic serotonin production. 1
Clinical Presentation
Classic Symptoms
Dry flushing (without sweating) occurs in 70% of patients, often affecting the upper thorax and sometimes accompanied by lacrimation and rhinorrhea. 1, 3
Secretory diarrhea occurs in 50% of patients, typically episodic rather than continuous. 1, 2
Intermittent abdominal pain occurs in 40% of patients, suggesting an episodic pattern of symptoms. 1, 2
Bronchospasm and wheezing occur less commonly, particularly with bronchopulmonary NETs. 1, 3
Chronic Complications
Carcinoid heart disease develops in chronic cases, involving fibrosis of the tricuspid and pulmonary valves on the right side of the heart, typically after the syndrome has been present for several years. 1, 3
This cardiac complication is extremely rare in carcinoids of lung origin. 1
Pellagra can occur rarely due to tryptophan depletion for serotonin synthesis. 3
Life-Threatening Emergency: Carcinoid Crisis
Carcinoid crisis is characterized by profound flushing, bronchospasm, tachycardia, and widely fluctuating blood pressure due to massive release of serotonin and vasoactive peptides. 1, 3, 4
This emergency is precipitated by anesthetic induction, intraoperative tumor manipulation, or invasive procedures such as embolization and radiofrequency ablation. 1, 4
The crisis can cause hemodynamic instability, severe hypotension unresponsive to standard vasopressor therapy, and may require ICU transfer. 4
Prevention with IV octreotide acetate is the only effective strategy, though no standardized protocols exist for dosing, timing, or administration schedules. 1, 4
Diagnostic Approach
Measure 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, with dietary restrictions to avoid interference from certain foods and medications. 1, 2
The urinary 5-HIAA test has approximately 88-90% specificity and 35% sensitivity. 1, 2
Measure serum chromogranin A, which is elevated in 75% of carcinoid tumors and has the highest reliability among NET biomarkers. 1
Neuron-specific enolase can be measured but has lower sensitivity (32.9%). 1
Radionuclide-labeled octreotide scintigraphy is helpful since up to 80% of bronchopulmonary NETs express somatostatin receptors. 1
Treatment Principles
Medical Management
Somatostatin analogs (octreotide and lanreotide) are first-line therapy, inducing symptomatic improvement in 65-72% and biochemical response in 45-46% of patients. 5, 6
Increasing the dose or frequency, or switching between somatostatin analogs, reduces flushing and/or diarrhea in 72-84% of cases. 5
Telotristat ethyl (250 mg three times daily with food) is FDA-approved for carcinoid syndrome diarrhea refractory to somatostatin analogs, reducing bowel movements by an average of 0.8 movements per day compared to placebo. 7
Telotristat works by inhibiting tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. 7
When using short-acting octreotide rescue therapy with telotristat, administer octreotide at least 30 minutes after telotristat to avoid drug interaction. 7
Interferon-alpha controls symptoms in 45-63% of cases. 5
Surgical and Interventional Approaches
Surgical resection is the only curative treatment and should be pursued whenever feasible, even for bronchial carcinoids. 1, 6
Liver-directed therapies improve symptoms in 82% of CS patients with liver-dominant disease based on retrospective institutional series. 5
Peptide receptor radionuclide therapy (PRRT) shows symptomatic improvement in patients with uncontrolled symptoms. 8, 5
Important Caveats
Chemotherapy and everolimus do not induce significant response in carcinoid syndrome symptoms, though everolimus combined with octreotide reduces urinary 5-HIAA more than octreotide alone. 8, 5
Patients should discontinue telotristat and contact their provider if they experience severe constipation or severe persistent/worsening abdominal pain. 7
The 500 mg three times daily dose of telotristat is not recommended due to lack of additional benefit and greater adverse reactions compared to the 250 mg dose. 7