Carcinoid Syndrome Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: While the underlying neuroendocrine tumours (NETs) are uncommon, carcinoid syndrome represents a severe systemic manifestation. A house officer must recognise it to prevent or manage a life-threatening carcinoid crisis, often precipitated by surgery, anaesthesia, or even a biopsy.
High-Yield Definition: Carcinoid syndrome is a constellation of signs and symptoms mediated by the systemic release of serotonin, bradykinin, and other vasoactive substances from well-differentiated neuroendocrine tumours, most commonly after they have metastasised to the liver. (Source: UpToDate, StatPearls).
Clinical One-Liner: Think of this in any patient with the bizarre triad of flushing, diarrhoea, and wheezing, especially if you find incidental liver mets.
II. Etiology & Risk Factors
Etiology: The syndrome is caused by functional NETs (carcinoid tumours) that secrete vasoactive hormones. For the syndrome to occur, these hormones must bypass hepatic first-pass metabolism. This happens in two main scenarios:
Midgut NETs (small intestine, appendix) with liver metastases: This is the classic and most common cause (>90%). The liver can no longer metabolise the serotonin produced by the large tumour bulk in the metastases.
Primary NETs with direct systemic venous drainage: E.g., lung/bronchial or ovarian carcinoids, which drain directly into the systemic circulation, bypassing the portal system.
Risk Factors: Primarily genetic. Look out for a family history suggestive of:
Multiple Endocrine Neoplasia type 1 (MEN1)
Neurofibromatosis type 1 (NF1)
Von Hippel-Lindau syndrome (VHL)
III. Quick Pathophysiology
It's simple. The NET produces massive amounts of serotonin from tryptophan. Normally, the liver metabolises this via monoamine oxidase. When you have extensive liver mets, this serotonin floods the systemic circulation.
Serotonin Overload leads to:
GI Tract: Increased motility -> secretory diarrhoea, cramping.
Heart: Fibroblast stimulation -> fibrous plaques on the right-sided heart valves (tricuspid and pulmonary) -> Carcinoid Heart Disease. The lungs metabolise serotonin, protecting the left heart.
Kallikrein & Bradykinin release leads to:
Vasodilation: Cutaneous flushing (the classic hallmark).
Bronchoconstriction: Wheezing.
IV. Classification
The classification is based on the embryological origin of the primary NET, which influences the hormone profile and clinical features.
Foregut (Lung, stomach, pancreas): Flushing can be prolonged and purplish. Often secrete histamine. 5-HIAA may be normal.
Midgut (Jejunum, ileum, appendix, caecum): The classic cause. Produces high levels of serotonin. Flushing is erythematous and lasts minutes.
Hindgut (Distal colon, rectum): Rarely functional and almost never cause carcinoid syndrome.
V. Clinical Assessment
🚩 Red Flags & Immediate Actions:
Carcinoid Crisis: This is an iatrogenic or stress-induced emergency.
Sign/Symptom: Profound, refractory hypotension OR severe hypertension, intense flushing, bronchospasm, altered mental status.
Action: Stop the offending procedure/agent immediately. Administer a bolus of IV Octreotide (e.g., 100-500 mcg IV). Call your senior and anaesthesiology for support.
Reason: Massive, uncontrolled release of vasoactive mediators leading to circulatory collapse.
History:
Key Diagnostic Clues (Classic Triad):
Cutaneous Flushing: Often the first and most common symptom. Ask about duration, colour (pink, red, purple), and triggers (alcohol, cheese, stress, certain foods).
Secretory Diarrhoea: Watery, non-bloody, can be explosive. Not relieved by fasting. Can cause severe electrolyte imbalance.
Bronchospasm: Presents as wheezing or shortness of breath. Less common than the other two.
Symptom Breakdown by Frequency:
Common (>75%): Cutaneous flushing, secretory diarrhoea.
Less Common (10-20%): Intermittent bronchospasm, right-sided heart failure symptoms (leg oedema, ascites) from carcinoid heart disease.
Rare (<10%): Pellagra (niacin deficiency due to tryptophan diversion to serotonin), telangiectasias (late sign).
Pertinent Negatives:
Absence of flushing makes classic carcinoid syndrome highly unlikely.
Absence of diarrhoea.
No history of urticaria or pruritus (distinguishes from anaphylaxis).
Physical Examination (OSCE Approach):
General Inspection: Patient may appear anxious. Look for the characteristic flush on the face, neck, and upper chest. Note any signs of cachexia or respiratory distress.
Vitals: Can be normal between episodes. During a flush, may see tachycardia and hypotension.
Disease-Specific Examination:
Skin: Look for telangiectasias over the malar area. Note the colour and distribution of any active flushing.
Cardiovascular: Auscultate for murmurs. The classic findings are a pansystolic murmur of tricuspid regurgitation and an ejection systolic murmur of pulmonary stenosis. Check JVP and for peripheral oedema.
Respiratory: Auscultate for expiratory wheeze.
Abdomen: Palpate for hepatomegaly, which suggests liver metastases.
Pertinent Negatives: Normal cardiac and respiratory exams between episodes. No hepatomegaly (though this doesn't rule out micrometastases).
Clinical Pearl: Provoking a flush with alcohol or a small meal can be diagnostic, but should only be done cautiously in a monitored setting as it can precipitate a severe episode.
VI. Diagnostic Workflow
Differential Diagnosis:
Anaphylaxis:
Points For: Flushing, bronchospasm, hypotension.
Points Against: Presence of urticaria and angioedema. Usually a clear temporal link to an allergen.
How to Differentiate: Serum tryptase level (elevated in anaphylaxis and mastocytosis).
Pheochromocytoma:
Points For: Episodic flushing, palpitations, hypertension.
Points Against: Flushing in pheochromocytoma is usually associated with pallor and sweating. Diarrhoea is uncommon.
How to Differentiate: 24-hour urinary metanephrines.
Mastocytosis:
Points For: Flushing, abdominal cramps, diarrhoea.
Points Against: Often associated with pruritus, urticaria, and dermatographism.
How to Differentiate: Serum tryptase, bone marrow biopsy.
Investigations Plan:
Bedside / Initial: ECG (may show right heart strain in late disease), vital signs monitoring.
First-Line Labs & Imaging:
Biochemical: The single most important test is a 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). The patient must avoid serotonin-rich foods (bananas, walnuts, pineapple) for 3 days prior.
Blood: Chromogranin A (CgA) is a sensitive but non-specific marker for NETs.
Imaging: Triple-phase CT scan of the abdomen and pelvis is crucial to identify the primary tumour (often in the small bowel) and assess the extent of liver metastases. A CT thorax is needed to look for lung primaries.
Confirmatory / Gold Standard:
Functional Imaging: Gallium-68 DOTATATE PET/CT is now the gold standard for staging, as it identifies somatostatin receptor-positive tumours with very high sensitivity. An Octreoscan (Indium-111 pentetreotide) is an older alternative if DOTATATE is unavailable.
Histopathology: Biopsy of a metastatic lesion (usually liver) confirms the diagnosis of a well-differentiated NET.
VII. Staging & Severity Assessment
Severity is assessed based on the frequency and intensity of symptoms, the level of 24-hour urinary 5-HIAA, and the burden of disease on imaging. The underlying NET is staged using the standard AJCC TNM system. An echocardiogram is mandatory to screen for and stage carcinoid heart disease.
VIII. Management Plan
A. Principle of Management:
Symptom Control: Inhibit hormone release.
Tumour Control: Reduce the tumour burden.
B. Immediate Stabilisation (Carcinoid Crisis):
A/B: High-flow oxygen. Salbutamol nebuliser for bronchospasm. Be cautious as it can cause tachycardia.
C: Secure IV access. Start IV Octreotide 100-500 mcg bolus, followed by an infusion of 50-100 mcg/hour. Give IV fluids for hypotension. Vasopressors may be needed but can paradoxically worsen the crisis; use with extreme caution and senior guidance.
D/E: Monitor GCS, check blood glucose.
C. Definitive Treatment (The Ward Round Plan):
First-Line (Symptom Control):
Somatostatin Analogues (SSAs): This is the cornerstone. They inhibit hormone release from the tumour.
Octreotide LAR: 20-30 mg deep intramuscular injection every 4 weeks.
Lanreotide Autogel: 90-120 mg deep subcutaneous injection every 4 weeks.
Second-Line (Symptom Control):
Telotristat ethyl: A tryptophan hydroxylase inhibitor that reduces serotonin production. Used for diarrhoea refractory to SSAs.
Tumour-Directed Therapy:
Surgery: Resection of the primary tumour and curative-intent resection of liver metastases if feasible. Even palliative "debulking" of liver metastases can significantly improve symptoms.
Liver-Directed Therapy: For unresectable liver metastases - trans-arterial chemoembolization (TACE) or radioembolization (TARE).
Systemic Therapy (for progressive disease):
Peptide Receptor Radionuclide Therapy (PRRT): Lutetium-177 DOTATATE. A form of targeted radiation delivered to somatostatin receptor-positive cells. Available in select centres in Malaysia.
Targeted Therapy: Everolimus (mTOR inhibitor) or Sunitinib (tyrosine kinase inhibitor) can be used for progressive, non-functional or functional pancreatic/gut NETs.
D. Long-Term & Discharge Plan:
Regular follow-up with endocrinology/oncology.
Continuation of monthly SSA injections.
Dietary advice: Avoid trigger foods (spicy food, high-tyramine foods like aged cheese, and alcohol).
Serial monitoring with CgA, 24-hr 5-HIAA, and imaging.
Regular echocardiograms to monitor for carcinoid heart disease.
IX. Complications
Immediate: Carcinoid crisis.
Short-Term: Severe dehydration and electrolyte disturbances from diarrhoea.
Long-Term:
Carcinoid Heart Disease: Right-sided valve fibrosis leading to right heart failure. High mortality if untreated. Valve replacement surgery may be required.
Mesenteric Fibrosis: Can cause bowel obstruction or ischemia.
Pellagra: Niacin (Vitamin B3) deficiency. Presents with dermatitis, dementia, diarrhoea.
X. Prognosis
Prognosis depends heavily on the primary site, grade of the tumour, and the extent of metastases. With modern management (SSAs, PRRT), the median survival for patients with distant midgut NETs is now over 10 years. The presence of carcinoid heart disease is a poor prognostic factor.
XI. How to Present to Your Senior
"Sir/Madam, I'm calling about Patient [Name], IC [Number], in Ward [X], Bed [Y].
Situation: This is a patient with known metastatic neuroendocrine tumour who has just developed acute-onset flushing, severe diarrhoea, and wheezing with a blood pressure of 80/50 mmHg.
Background: He was scheduled for a liver biopsy this morning. His baseline medications include monthly Lanreotide.
Assessment: My impression is that he is in a carcinoid crisis, likely precipitated by the stress of the impending procedure.
Recommendation: I have administered a stat bolus of 100mcg IV Octreotide and started high-flow oxygen. I would like to start an octreotide infusion and send bloods including electrolytes. Request your presence to review the patient urgently."
XII. Summary & Further Reading
Top 3 Takeaways:
Suspect carcinoid syndrome with the triad of flushing, diarrhoea, and wheezing, especially with liver lesions.
The key initial diagnostic test is a 24-hour urinary 5-HIAA. The gold standard for staging is a Ga-68 DOTATATE PET/CT.
Management hinges on somatostatin analogues (Octreotide/Lanreotide) for symptoms and treating the underlying tumour. Always be prepared to manage a carcinoid crisis.
Key Resources:
UpToDate: "Clinical features of carcinoid syndrome" and "Treatment and prognosis of the carcinoid syndrome".
