Carcinoid Syndrome

1. Topic Overview (Clinical Overview)

Summary

Carcinoid Syndrome is a clinical syndrome caused by the systemic release of vasoactive substances—primarily Serotonin (5-HT)—from Neuroendocrine Tumours (NETs). NETs most commonly arise in the midgut (Appendix, Ileum), but can occur in the foregut (Lung, Stomach) or hindgut (Rectum). The syndrome typically only manifests when the tumour has metastasised to the liver, allowing serotonin to bypass hepatic first-pass metabolism and enter the systemic circulation. Cardinal features include paroxysmal flushing, secretory diarrhoea, wheezing (bronchospasm), and right-sided valvular heart disease (Carcinoid Heart Disease). Diagnosis is by measuring 24-hour Urinary 5-HIAA (a serotonin metabolite) and Chromogranin A. Treatment involves Somatostatin Analogues (Octreotide, Lanreotide) to control symptoms, surgical resection where possible, Peptide Receptor Radionuclide Therapy (PRRT) for advanced disease, and perioperative Octreotide to prevent Carcinoid Crisis. [1,2,3]

Key Facts

• Tumour Origin: Midgut NETs (Appendix, Ileum) most common to cause syndrome. [1]
• Syndrome Appears: Usually only after Liver Metastases (Hepatic first-pass metabolism bypassed). 10% of NET patients develop the syndrome. [2,3]
• Secreted Substances: Serotonin (5-HT), Histamine, Bradykinin, Prostaglandins, Tachykinins (Substance P). [4]
• Classic Triad: Flushing (63-94%), Diarrhoea (68-84%), Bronchospasm (4-18%). [2]
• Heart: Carcinoid Heart Disease occurs in 40-50% of patients with chronic carcinoid syndrome. Right-sided valve fibrosis (Tricuspid Regurgitation, Pulmonary Stenosis). Left heart spared because lungs metabolise serotonin. [5,6]
• Diagnosis: 24h Urinary 5-HIAA (sensitivity 73%, specificity 88-100%), Chromogranin A (elevated in 60-90% of NETs). [7,8]
• Treatment: Somatostatin Analogues (Octreotide/Lanreotide). PRRT (Lu-177 DOTATATE) for progressive disease. Surgery for resectable disease. [9,10,11]

Clinical Pearls

"No Liver Mets = No Syndrome (Usually)": Serotonin from gut NETs is cleared by hepatic first-pass metabolism. Carcinoid syndrome typically only occurs when there are liver metastases (or a lung/ovarian primary, which drains directly to systemic circulation). [2]

"Right Heart Valve Fibrosis – Left Heart Spared": Serotonin is metabolised by monoamine oxidase (MAO) in the lungs. Valves exposed before the lungs (Tricuspid, Pulmonary) undergo fibrotic changes from chronic serotonin exposure. Left-sided valves (Mitral, Aortic) are protected. Patent foramen ovale or bronchopulmonary shunts can allow left-sided involvement. [5,6]

"Avoid the Crisis": Carcinoid Crisis (Severe flushing, Hypotension, Bronchospasm, Arrhythmias) is triggered by anaesthesia, surgery, tumour manipulation, or embolisation procedures. Prevent with prophylactic IV Octreotide infusion starting pre-operatively. Mortality can reach 50% without treatment. [12,13]

"Tryptophan Thievery": NETs consume up to 60% of dietary Tryptophan to synthesise Serotonin. This can cause Pellagra (Niacin deficiency – 3Ds: Dermatitis, Diarrhoea, Dementia) in severe cases with high tumour burden. [14]

"5-HIAA False Positives": Dietary serotonin-rich foods (bananas, avocados, walnuts, tomatoes, pineapples) and medications (SSRIs, tramadol, acetaminophen) can falsely elevate urinary 5-HIAA. Patients must avoid these 48-72 hours before collection. [7]

Why This Matters Clinically

Carcinoid syndrome typically indicates metastatic disease, requiring multidisciplinary management. Early recognition allows initiation of somatostatin analogues that dramatically improve quality of life and may prolong survival. Annual echocardiographic screening can detect carcinoid heart disease early, allowing timely cardiac intervention. Prophylactic octreotide prevents potentially fatal carcinoid crisis during surgery or interventional procedures. [2,3,9]

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2. Epidemiology

Incidence and Prevalence

• NET Incidence: 6.98 per 100,000 per year in the USA (2012 SEER data). Incidence has increased 6.4-fold over past 40 years due to improved detection and increased awareness. [15]
• Carcinoid Syndrome: Occurs in 10-18% of all NETs, and in 8-10% of patients with midgut NETs. [2,3]
• Age: Median age at diagnosis 60-65 years. Rare in children. [15]
• Sex: Slight male predominance (M:F ratio 1.2:1). [15]
• Prevalence: Estimated 170,000 people in USA living with NETs (35 per 100,000). [15]

Tumour Origin and Syndrome Frequency

Geographic Variation

• Higher incidence in Caucasian populations compared to African American or Asian populations. [15]
• Incidence highest in North America and Northern Europe.

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3. Pathophysiology

Molecular Pathophysiology: Serotonin Synthesis and Metabolism

Normal Serotonin Pathway

Carcinoid Syndrome Pathophysiology

1. Excessive Serotonin Production: Neuroendocrine tumour cells overexpress Tryptophan Hydroxylase (TPH-1), resulting in unregulated serotonin synthesis. Up to 60% of dietary tryptophan is diverted to serotonin production (normally less than 1%). [4]
2. First-Pass Hepatic Metabolism Bypass:
   • Gut NETs without liver mets: Serotonin drains via portal vein → Liver MAO degrades serotonin → 5-HIAA. No systemic symptoms.
   • Gut NETs with liver metastases: Tumour cells in liver parenchyma secrete serotonin directly into hepatic veins → Bypasses portal clearance → Systemic circulation → Syndrome manifests. [2]
   • Lung/Ovarian NETs: Drain directly to systemic circulation, bypassing liver. Syndrome can occur without liver metastases. [2]
3. Multi-Hormone Secretion: NETs secrete multiple vasoactive substances beyond serotonin, contributing to symptom heterogeneity. [4]

Carcinoid Heart Disease: Molecular Mechanisms

Carcinoid Heart Disease (CHD) occurs in 40-50% of patients with prolonged carcinoid syndrome. [5,6]

Detailed Molecular Pathogenesis

Right-Sided Predominance: Why Left Heart Spared

Exceptions for Left-Sided CHD (< 10% of cases):

Carcinoid Heart Disease: Screening and Surveillance

Who to Screen:

• ALL patients with carcinoid syndrome (mandatory annual echo)
• All patients with elevated 5-HIAA (even without symptoms)
• Before valve surgery or major NET surgery

Screening Protocol:

Echocardiographic Severity Grading (Tricuspid Regurgitation):

EROA = Effective Regurgitant Orifice Area

Risk Factors for Developing CHD:

• High 5-HIAA levels: 3× upper limit normal (HR 2.5-3.0). [7]
• Long duration of syndrome: 5 years untreated (HR 2.0)
• Elevated plasma serotonin: 1000 ng/mL
• Elevated NT-proBNP: 300 pg/mL (marker, not causative)
• High tumour burden: Extensive liver metastases (50%)
• Midgut primary: Higher serotonin secretion vs foregut/hindgut

Prevention and Slowing Progression:

• Early SSA treatment: Reduces serotonin exposure. May slow CHD progression (not proven to prevent).
• Optimise SSA dosing: Aim for 5-HIAA < 2× upper limit normal if possible.
• Surveillance: Early detection allows timely medical and surgical intervention.

Other Secreted Vasoactive Substances

Tryptophan Depletion and Pellagra

• Excessive serotonin synthesis consumes dietary tryptophan.
• Niacin (Vitamin B3) is normally synthesised from tryptophan (60 mg tryptophan → 1 mg niacin).
• Pellagra develops when tryptophan is shunted to serotonin synthesis → niacin deficiency.
• Classic Triad of Pellagra: Dermatitis (photosensitive rash), Diarrhoea, Dementia.
• Occurs in less than 5% of carcinoid syndrome patients, usually with large tumour burden and 5-HIAA > 200 mg/24h. [14]

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4. Clinical Presentation

Classic Symptoms

Flushing (63-94% of patients) [2,3]

Triggers:

Comprehensive Medication Triggers to Avoid:

• Anaesthetic agents: Suxamethonium (succinylcholine), thiopental sodium, desflurane
• Muscle relaxants: Atracurium, mivacurium (histamine-releasing)
• Opioids: Morphine, pethidine (meperidine) – histamine-releasing. Prefer fentanyl, remifentanil.
• Sympathomimetics: Ephedrine, pseudoephedrine, phenylephrine (direct vasopressors safer)
• Catecholamine releasers: Adrenaline, noradrenaline (in carcinoid crisis; may worsen)
• Chemotherapy: Can trigger crisis from tumour lysis. Give prophylactic octreotide.

Safe Alternatives for Anaesthesia:

• Induction: Propofol (controversial; some avoid, some use), etomidate
• Maintenance: Sevoflurane, isoflurane
• Muscle relaxants: Rocuronium, vecuronium (non-histamine-releasing)
• Analgesia: Fentanyl, remifentanil, alfentanil (synthetic opioids, no histamine release)
• Vasopressors (if needed): Vasopressin (preferred; no catecholamine release), phenylephrine

Diarrhoea (68-84% of patients) [2,3]

• Character: Secretory, watery, high-volume (up to 20 bowel movements per day in severe cases).
• Mechanism: Serotonin-induced increased intestinal motility and secretion. Prostaglandin contribution.
• Timing: Non-bloody. Can be intermittent or continuous.
• Nutritional Impact: Malabsorption, weight loss, electrolyte disturbances (hypokalemia, hypomagnesemia).

Bronchospasm and Wheezing (4-18% of patients) [2,3]

• Serotonin and Tachykinin-mediated bronchoconstriction.
• Can mimic asthma. Often under-recognised.
• More common during flushing episodes or carcinoid crisis.

Abdominal Pain (30-50% of patients) [2]

• From primary tumour: Bowel obstruction, intussusception, mesenteric ischaemia.
• From mesenteric fibrosis: Desmoplastic reaction around mesenteric vessels → vascular insufficiency, ischaemia.
• From liver metastases: Capsular distension, hepatic ischaemia.

Carcinoid Heart Disease (40-50% of chronic syndrome patients) [5,6]

Clinical Presentation

Examination Findings

• Pansystolic murmur at lower left sternal edge (Tricuspid Regurgitation). Increases with inspiration (Carvallo's sign).
• Ejection systolic murmur at upper left sternal edge (Pulmonary Stenosis).
• Giant V waves in JVP (severe Tricuspid Regurgitation).
• Hepatomegaly, pulsatile liver (Tricuspid Regurgitation).
• Peripheral oedema, ascites (Right heart failure).

Pellagra (less than 5% of cases) [14]

• Dermatitis: Photosensitive rash in sun-exposed areas (Casal's necklace). Hyperpigmentation, scaling.
• Diarrhoea: Watery, secretory (may be difficult to distinguish from carcinoid diarrhoea).
• Dementia: Confusion, memory loss, psychosis (late finding).
• Fourth D: Death (if untreated).

Carcinoid Crisis [12,13]

Definition: Life-threatening episode of severe symptoms triggered by surgical stress, anaesthesia, tumour manipulation, or embolisation procedures.

Triggers

• Anaesthetic induction (propofol, thiopental)
• Surgical manipulation of tumour
• Liver embolisation (transarterial chemoembolisation)
• Chemotherapy
• Catecholamine-releasing drugs (succinylcholine)

Clinical Features

Mortality

• 50% without treatment. [12]
• less than 5% with prophylactic octreotide. [13]

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5. Clinical Examination

Systematic Examination Approach

General Inspection

Cardiovascular Examination

Respiratory Examination

Abdominal Examination

Skin Examination

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6. Differential Diagnosis

Flushing

Diarrhoea

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7. Investigations

Biochemical Diagnosis

24-Hour Urinary 5-HIAA [7,8]

• Gold Standard for Carcinoid Syndrome Diagnosis.
• Sensitivity: 73%. Specificity: 88-100%. [7]
• Normal Range: < 40 µmol/24h (< 8 mg/24h in USA units).
• Diagnostic Threshold: 73 µmol/24h (14 mg/24h) highly suggestive. Levels 2-3× upper limit normal are diagnostic.
• Correlation: Higher levels correlate with greater tumour burden, increased risk of CHD, and worse prognosis. [7]

Comprehensive 5-HIAA Testing Protocol:

Pre-Collection Patient Instructions (CRITICAL – 48-72h before and during collection):

Collection Protocol:

1. Patient Education: Provide written list of dietary and medication restrictions 48-72 hours before collection starts.
2. Collection Container: Laboratory-provided container with acid preservative (6N HCl or acetic acid). Keep refrigerated.
3. Start Time: Discard first morning void. Note exact start time.
4. Collection Period: Collect ALL urine for exactly 24 hours.
5. End Time: Include first morning void on day 2 (24h after start). Note exact end time.
6. Volume: Measure and record total volume (important for calculation).
7. Transport: Deliver to laboratory within 24 hours. Keep refrigerated.
8. Documentation: Complete form with:
   • Current medications (especially SSRIs, PPIs)
   • Dietary compliance
   • Renal function (eGFR)

Interpretation:

Special Considerations:

• Hindgut NETs (Rectum): Often do NOT produce serotonin → 5-HIAA normal despite NET.
• Early Disease: Small tumour burden may have normal or borderline 5-HIAA.
• On SSAs: 5-HIAA typically reduced 40-60% with treatment. Use to monitor response.
• Renal Impairment: May have reduced excretion → falsely low. Check plasma serotonin if eGFR < 30.

Troubleshooting False Results:

• Unexpectedly high 5-HIAA: Review diet diary. Repeat after strict dietary restriction. Check medication list.
• Normal 5-HIAA despite clinical suspicion: Consider plasma serotonin, chromogranin A, repeat collection, or non-serotonin-secreting NET (foregut/hindgut).

Chromogranin A (CgA) [8]

• General NET biomarker. Elevated in 60-90% of NETs.
• Not specific for carcinoid syndrome. Elevated in other NETs (pancreatic NETs, phaeochromocytoma).
• Utility: Tumour burden marker. Monitoring treatment response. Prognosis (higher levels = worse outcome).

Interfering Factors and False Positives:

Chromogranin A Testing Protocol:

1. Fasting: 8-hour fast recommended (reduces GI stimulation).
2. Stop PPIs: Discontinue 14 days before test if clinically safe. If not possible, interpret with caution or use Chromogranin B.
3. Stop H2 antagonists: 48-72 hours before.
4. Venepuncture technique: Avoid haemolysis. Use appropriate tube (serum or EDTA plasma, depending on assay).
5. Assay method: Multiple commercial assays available with different reference ranges. Ensure same assay used for serial monitoring.
6. Interpretation:
   • Normal: < 100 µg/L (varies by assay)
   • Mildly elevated (100-500 µg/L): Consider interfering factors. May be non-NET cause.
   • Markedly elevated (500 µg/L): Highly suggestive of NET (especially if PPI stopped and renal function normal).
   • Very high (1000 µg/L): Indicates high tumour burden. Poor prognostic marker.

Alternative if on PPI: Chromogranin B (less affected by PPIs) or Pancreastatin (CgA fragment, more specific).

Other Biomarkers

Baseline Investigations for Complications

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Imaging

Cross-Sectional Imaging

Functional Imaging (Somatostatin Receptor Imaging)

68Ga-DOTATATE PET/CT [17,18]

• Gold Standard for NET imaging.
• Mechanism: Gallium-68 labelled somatostatin analogue binds to somatostatin receptors (SSTR2, SSTR5) on NET cells.
• Sensitivity: 90-100% for midgut NETs. [17]
• Advantages: Whole-body staging, detects occult primary, superior to CT/MRI for small lesions and extrahepatic metastases, guides PRRT eligibility.
• Reporting: Krenning score (0-4) quantifies SSTR expression. Score ≥2 indicates PRRT eligibility.
• False Positives: Granulomatous disease (sarcoidosis, tuberculosis), thyroid tissue, spleen, pituitary, adrenals (physiological uptake).

Alternative: Octreotide Scan (111-Indium Octreotide Scintigraphy)

• Older modality. Lower sensitivity than 68Ga-DOTATATE PET/CT.
• Now largely replaced by PET/CT where available.

Echocardiography [5,6]

• Indication: All patients with carcinoid syndrome (screening for CHD). Annual if syndrome present. 6-monthly if CHD detected.
• Findings:
  • "Tricuspid Regurgitation: Thickened, retracted, fixed leaflets. Severe regurgitation common."
  • "Pulmonary Stenosis/Regurgitation: Leaflet thickening, commissural fusion."
  • "Right Atrial/Ventricular Dilatation: Secondary to volume overload."
  • "Plaque-like endocardial thickening: Pathognomonic."
• Severity Grading: Quantitative assessment of regurgitant volume, effective regurgitant orifice area (EROA).
• Left Heart Assessment: Assess for PFO (bubble study if left-sided involvement suspected).

Cardiac MRI

• Superior to echocardiography for assessing right ventricular function, quantifying regurgitant volumes.
• Useful pre-operative planning for valve surgery.

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Endoscopy and Histology

Colonoscopy and Ileoscopy

• Visualise terminal ileum (common primary site).
• Biopsy if lesion identified.
• Histology: Neuroendocrine tumour. Chromogranin A, Synaptophysin positive (immunohistochemistry).

Upper GI Endoscopy (OGD)

• For foregut NETs (gastric, duodenal).

Capsule Endoscopy

• If primary site not identified on CT/endoscopy, consider for small bowel primary.

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Grading and Staging

WHO 2019 Classification (Ki-67 Proliferation Index) [19]

Note: G3 NETs are divided into well-differentiated G3 NET (better prognosis, responsive to SSAs/PRRT) vs poorly-differentiated G3 Neuroendocrine Carcinoma (aggressive, requires platinum-based chemotherapy).

TNM Staging (AJCC 8th Edition)

Staging varies by primary site (small bowel, lung, pancreas, etc.). Generally:

• Stage I-II: Localised disease. Resectable.
• Stage III: Regional lymph node involvement.
• Stage IV: Distant metastases (liver, bone, peritoneum).

Carcinoid syndrome almost always indicates Stage IV disease (liver metastases).

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8. Management

Multidisciplinary Team (MDT) Approach

Essential specialists:

• Endocrinology: Hormone management, somatostatin analogues.
• Medical Oncology: Systemic therapy, PRRT, chemotherapy.
• Surgical Oncology: Resection of primary, liver metastases, cytoreductive surgery.
• Interventional Radiology: Liver-directed therapies (embolisation).
• Cardiology: CHD management, valve surgery.
• Anaesthetics: Carcinoid crisis prevention.
• Nutrition/Dietetics: Malnutrition, pellagra prevention.
• Palliative Care: Symptom control, end-of-life planning.

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Medical Management: Symptom Control

Somatostatin Analogues (SSAs) [9,20,21]

First-Line for Symptom Control. SSAs inhibit hormone secretion from NET cells.

Efficacy:

• Symptom control: 60-80% of patients experience reduction in flushing and diarrhoea. [9]
• Biochemical response: 40-60% reduction in 5-HIAA levels. [9]
• Tumour control: PROMID and CLARINET trials showed anti-proliferative effect (prolonged PFS). [20,21]

Detailed SSA Treatment Protocol

Initiation:

1. Baseline Assessments:

   • 24h urinary 5-HIAA, Chromogranin A
   • Symptom diary (flushing episodes/day, bowel movements/day)
   • Imaging (CT or 68Ga-DOTATATE PET/CT)
   • Echocardiography
   • HbA1c, LFTs (including GGT, ALP)
   • Ultrasound gallbladder (baseline for gallstone surveillance)

2. Starting Dose:

   • Octreotide LAR: 20 mg IM every 4 weeks (deep gluteal injection)
   • Lanreotide Autogel: 90 mg SC every 4 weeks (deep SC injection, abdomen/thigh)
   • Bridge with short-acting octreotide: 100-200 µg SC TDS for first 2 weeks (until long-acting formulation reaches steady state)

3. Patient Education:

   • Injection site rotation
   • Expected effects (symptom improvement within days to 2 weeks)
   • Adverse effects (loose stools initially → constipation/steatorrhoea later)
   • Gallstone risk
   • Need for regular monitoring

Dose Escalation Strategy:

Dose Escalation Options:

• Octreotide LAR: Increase 20mg → 30mg → 40mg (off-label, max dose)
• Lanreotide: Increase 90mg → 120mg every 4 weeks
• Shorten interval: Give every 3 weeks instead of 4 weeks (off-label)
• Add short-acting: Octreotide 100-200 µg SC BD-TDS for breakthrough symptoms

Monitoring Schedule:

Adverse Effects Management:

Treatment Failure (Inadequate Control Despite Max Dose SSA):

• Recheck compliance: Injection timing, technique
• Measure SSA levels (trough octreotide or lanreotide levels if available)
• Add telotristat ethyl: 250mg PO TDS (for refractory diarrhoea)
• Consider disease progression: Repeat imaging, check 5-HIAA/CgA trend
• Escalate to PRRT: If progressive disease on imaging

Adjunctive Symptom Control

For Diarrhoea:

For Flushing:

• Optimise SSA dosing.
• Avoid triggers (alcohol, stress, tyramine-rich foods).
• Cyproheptadine (antihistamine, anti-serotonin): 4 mg PO TDS. Limited efficacy.
• Phenoxybenzamine (α-blocker): For refractory cases. 10-20 mg PO BD.

For Bronchospasm:

• Inhaled bronchodilators: Salbutamol, ipratropium.
• SSA optimisation.

For Pellagra:

• Nicotinamide (Niacin): 50-100 mg PO TDS. Avoid nicotinic acid form (can trigger flushing).
• High-protein diet: Increase dietary tryptophan availability.

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Surgical Management

Indications for Surgery

• Resectable primary tumour (even if metastatic disease present): Debulking reduces hormone secretion, prevents bowel obstruction.
• Resectable liver metastases: Curative intent if less than 70% liver involvement, bilobar disease may still be resectable.
• Symptomatic bowel obstruction/bleeding: From primary tumour.

Surgical Approaches

Pre-Operative Preparation:

• Mandatory: Prophylactic IV Octreotide infusion (50-100 µg/hr) starting 12-24 hours pre-operatively, continued intra-operatively and 48 hours post-operatively. [12,13]
• Cardiac assessment: Echocardiography. If severe CHD, consider valve surgery before or concurrent with tumour resection.
• Gallbladder: Consider prophylactic cholecystectomy if on long-term SSAs and undergoing laparotomy.

Intra-Operative Considerations:

• Avoid drugs that trigger carcinoid crisis: Suxamethonium (succinylcholine), morphine, atracurium.
• Use short-acting agents: Propofol (controversial, some avoid), remifentanil, rocuronium.
• Octreotide bolus (100-500 µg IV) immediately available for crisis.

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Liver-Directed Therapies

For unresectable liver metastases:

Transarterial Embolisation (TAE) / Chemoembolisation (TACE)

• Mechanism: Liver metastases derive blood supply predominantly from hepatic artery. Embolisation causes tumour necrosis.
• Chemoembolisation: Addition of chemotherapy (doxorubicin, streptozocin) to embolisation.
• Efficacy: Symptom control in 60-80%. Radiological response 30-50%. Duration 12-24 months.
• Complications: Post-embolisation syndrome (fever, pain, nausea). Carcinoid crisis risk (requires prophylactic octreotide). Liver abscess (rare).

Selective Internal Radiation Therapy (SIRT) / Radioembolisation

• Mechanism: Yttrium-90 (Y-90) microspheres delivered via hepatic artery → localised radiation to liver mets.
• Efficacy: Similar to TACE. May have fewer systemic side effects.

Radiofrequency Ablation (RFA) / Microwave Ablation (MWA)

• For small (less than 3 cm), limited liver metastases.
• Percutaneous or laparoscopic approach.

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Peptide Receptor Radionuclide Therapy (PRRT) [10,11]

NETTER-1 Trial (2017): Landmark Phase 3 RCT. [10]

Mechanism

• Lu-177 DOTATATE (Lutathera): Lutetium-177 radiolabelled somatostatin analogue.
• Binds to somatostatin receptors (SSTR2) on NET cells → delivers targeted β-radiation → tumour cell death.

Indications

• Progressive, well-differentiated, somatostatin receptor-positive (SSTR+) midgut NETs.
• 68Ga-DOTATATE PET/CT: Krenning score ≥2 (tumour uptake ≥ liver uptake) required.
• Adequate organ function: Creatinine clearance > 50 mL/min, bone marrow reserve.

Protocol

• 4 cycles of Lu-177 DOTATATE (7.4 GBq per cycle) given every 8 weeks (total treatment duration 6 months).
• Co-administered with amino acid infusion (lysine, arginine) to protect kidneys.

Efficacy (NETTER-1 Trial) [10]

• Progression-Free Survival: Not reached in PRRT arm vs 8.4 months in control (high-dose octreotide).
• Objective Response Rate: 18% (PRRT) vs 3% (control).
• Overall Survival: Median not reached at interim analysis. Estimated OS benefit ~40 months.

Adverse Effects

• Haematological: Lymphopenia (common), anaemia, thrombocytopenia (10-15%). Myelodysplastic syndrome/leukaemia (less than 2%, long-term risk).
• Renal: Nephrotoxicity (5-10%). Monitor creatinine, creatinine clearance.
• Hepatic: Transaminitis (10-20%).
• Nausea/Vomiting: Common during infusion.

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Systemic Targeted Therapies

Everolimus (mTOR Inhibitor) [23,24]

• RADIANT-3 (2011): Pancreatic NETs. PFS 11 months (everolimus) vs 4.6 months (placebo). [23]
• RADIANT-4 (2016): Non-functional GI/lung NETs. PFS 11 months (everolimus) vs 3.9 months (placebo). [24]
• Dose: 10 mg PO daily.
• Indications: Progressive, well-differentiated NETs. Often used after PRRT.
• Adverse Effects: Stomatitis (mucositis), pneumonitis (interstitial lung disease), hyperglycaemia, immunosuppression, rash.

Sunitinib (Multi-Kinase Inhibitor)

• Indication: Progressive pancreatic NETs.
• Dose: 37.5 mg PO daily (continuous).
• Adverse Effects: Hypertension, diarrhoea, hand-foot syndrome, hypothyroidism.

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Chemotherapy

Indication: Poorly-differentiated Neuroendocrine Carcinoma (G3 NEC) with high Ki-67 > 55%.

Regimen

• Platinum-based: Cisplatin + Etoposide (EP regimen).
  • Cisplatin 80 mg/m² IV Day 1.
  • Etoposide 100 mg/m² IV Days 1-3.
  • Cycle every 3 weeks.
• Alternative: Carboplatin + Etoposide (if cisplatin contraindicated).
• Response Rate: 40-60% in poorly-differentiated NEC. Minimal benefit in well-differentiated NETs.

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Carcinoid Crisis: Emergency Management [12,13]

Prevention (Pre-Operative)

• IV Octreotide infusion: 50-100 µg/hr starting 12-24 hours pre-op. Continue intra-op and 48 hours post-op.
• Communication: Alert anaesthetics, ICU, surgical teams.
• Avoid triggers: Catecholamine-releasing drugs (suxamethonium, morphine, atracurium).

Acute Crisis Management

Carcinoid Crisis Management Algorithm:

Phase 1: Recognition (within 30 seconds)

Phase 2: Immediate Interventions (within 1 minute)

Phase 3: Ongoing Management (within 5 minutes)

Phase 4: Refractory Hypotension (if MAP < 65 despite fluids + octreotide)

⚠️ DO NOT USE (may worsen crisis):

• ❌ Adrenaline/Epinephrine: Triggers further NET hormone release. May worsen crisis.
• ❌ Dobutamine: β-agonist may stimulate tumour.
• ❌ Dopamine: Unpredictable effects on NET.

Phase 5: Refractory Bronchospasm

Phase 6: Disposition

• ICU/HDU admission: All carcinoid crises require critical care monitoring.
• Continue octreotide infusion: 50-200 µg/hr for minimum 48-72 hours post-crisis.
• Monitoring: Continuous ECG, arterial line, hourly obs, fluid balance, serial lactate.
• Wean vasopressors: Gradually once haemodynamically stable 6 hours.
• Transition to long-acting SSA: Once stable, restart octreotide LAR or lanreotide.
• Investigate precipitant: Tumour progression? Inadequate SSA dosing? New metastases?

Post-Crisis Review:

1. Document crisis: Timing, triggers, response to octreotide, vasopressors used.
2. Increase baseline SSA: If on octreotide LAR 20mg monthly → escalate to 30mg. If on 30mg → consider adding short-acting octreotide TDS.
3. Future surgery: Higher-dose prophylaxis (100-200 µg/hr octreotide from 24h pre-op).
4. Patient counselling: Medical alert bracelet. Carry crisis management card.

Mortality:

• 50% without octreotide treatment. [12]
• < 5% with prompt octreotide and supportive care. [13]

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Carcinoid Heart Disease: Cardiac Management [5,6]

Medical Management

Surgical Management: Valve Replacement

Indications:

• Severe symptomatic Tricuspid Regurgitation (NYHA Class III-IV symptoms).
• Progressive right ventricular dilatation/dysfunction.
• Consideration: Valve surgery has high operative mortality (5-15%) in carcinoid patients. [6]

Valve Choice:

• Bioprosthetic valves preferred (risk of recurrent carcinoid valve disease on prosthesis, but less than native valve progression).
• Mechanical valves: Require anticoagulation. Risk of thromboembolic complications.

Pre-Operative Preparation:

• Mandatory IV Octreotide infusion (carcinoid crisis risk).
• Optimise volume status: Careful diuresis pre-operatively.
• MDT planning: Cardiac surgery, anaesthetics, endocrinology.

Outcomes:

• 5-year survival post valve surgery: 50-70%. [6]
• Significant improvement in functional status (NYHA class) in survivors.

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9. Complications

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10. Prognosis & Outcomes

Survival Data

5-Year Survival by Stage (SEER Data 2012-2018) [15]:

Carcinoid Syndrome-Specific Survival:

• Metastatic Midgut NET with Carcinoid Syndrome: Median survival 8-12 years (with modern therapy including SSAs, PRRT). [2,3]
• With Carcinoid Heart Disease: Median survival reduced to 4-6 years if untreated CHD. [6]
• Post-Valve Replacement for CHD: 5-year survival 50-70%. [6]

Prognostic Factors

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Follow-Up Schedule

Patients with Carcinoid Syndrome (Stage IV)

Patients Post-Curative Resection (Stage I-III)

• Clinical review and Chromogranin A every 6 months for 5 years, then annually.
• CT Abdomen/Pelvis annually for 5 years.
• 68Ga-DOTATATE PET/CT if Chromogranin A rising or symptoms recur.

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Nutritional and Lifestyle Management

Dietary Modifications

Avoid 5-HIAA Test Interference (48-72h before collection):

• Bananas, avocados, kiwi, pineapples, plums, tomatoes, eggplant, walnuts, pecans.

Trigger Avoidance (to reduce flushing):

• Alcohol (especially red wine): Major trigger. Advise abstinence or minimal consumption.
• Tyramine-rich foods: Aged cheese, cured meats, fermented foods.
• Spicy foods: Capsaicin can trigger flushing.

Nutritional Support:

• High-protein diet: Increase tryptophan availability (reduces pellagra risk).
• Niacin supplementation: Nicotinamide 50-100 mg PO TDS (preventative if high tumour burden, therapeutic if pellagra present).
• Pancreatic enzyme replacement: If steatorrhoea from SSAs (Creon 25,000-50,000 units with meals).
• Multivitamins: B-complex, Vitamin D, Iron if deficient.
• Dietitian referral: For malabsorption, weight loss, or complex dietary management.

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Patient Education and Counselling

Key Counselling Points

1. Symptom Control: "The monthly injection (somatostatin analogue) should significantly reduce your flushing and diarrhoea. Most patients notice improvement within days to weeks."

2. Heart Monitoring: "We will do yearly heart scans (echocardiogram) because the hormones from the tumour can affect your heart valves over time. Early detection allows us to manage this."

3. Surgery Safety: "If you ever need any operation, even a dental procedure under general anaesthesia, tell your doctors you have Carcinoid Syndrome. You need a special drip (octreotide) to prevent a dangerous reaction called carcinoid crisis."

4. Avoid Triggers: "Alcohol, especially red wine, and extreme stress can trigger flushing. Try to minimise these. Some foods like aged cheese may also trigger symptoms."

5. Long-Term Condition: "This is a chronic condition, but many people live well for many years, even decades, with proper treatment. The tumours often grow slowly."

6. MDT Care: "You will be looked after by a team including cancer specialists (oncologists), hormone doctors (endocrinologists), and sometimes heart doctors (cardiologists) and surgeons."

7. Emergency Alert: "Carry a medical alert card or wear a bracelet stating you have Carcinoid Syndrome and require octreotide in emergencies."

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Patient FAQs

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Common Clinical Pitfalls

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11. Evidence & Guidelines

Key International Guidelines

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Landmark Trials

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12. Exam Scenarios & Viva Questions

Scenario 1: Diagnostic Challenge

Stem: A 58-year-old woman presents with a 6-month history of episodic dry facial flushing (lasting 2-3 minutes), watery diarrhoea (8-10 bowel movements per day), and intermittent wheeze. She has a palpable liver (span 16 cm). Echocardiogram shows moderate Tricuspid Regurgitation with thickened tricuspid valve leaflets.

Question 1: What is the likely diagnosis?

• Answer: Carcinoid Syndrome secondary to metastatic Neuroendocrine Tumour (likely midgut primary with liver metastases).

Question 2: How would you confirm the diagnosis?

• Answer:
  1. 24-hour Urinary 5-HIAA (avoid dietary/medication interference 48-72h before).
  2. Chromogranin A (general NET biomarker).
  3. CT Chest/Abdomen/Pelvis (identify primary tumour, assess liver metastases).
  4. 68Ga-DOTATATE PET/CT (whole-body staging, assess SSTR expression for PRRT eligibility).
  5. Confirm with histology if biopsy feasible (colonoscopy/ileoscopy if primary suspected in ileum).

Question 3: What is the significance of the tricuspid regurgitation?

• Answer: Carcinoid Heart Disease. Chronic serotonin exposure causes fibrotic thickening of tricuspid valve leaflets → regurgitation. Occurs in 40-50% of chronic carcinoid syndrome patients. Requires annual echocardiography screening. May require valve replacement if severe and symptomatic.

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Scenario 2: Pathophysiology

Stem: Why does Carcinoid Syndrome typically only occur when there are liver metastases?

Answer:

• First-Pass Hepatic Metabolism: Midgut NETs secrete serotonin into the portal circulation → Liver contains monoamine oxidase (MAO) which metabolises serotonin to 5-HIAA → Serotonin is cleared before reaching systemic circulation → No symptoms.
• Liver Metastases: Tumour cells within liver parenchyma secrete serotonin directly into hepatic veins → Bypasses portal clearance → Serotonin enters systemic circulation → Syndrome manifests (flushing, diarrhoea, bronchospasm, CHD).
• Exceptions: Lung NETs or ovarian NETs drain directly to systemic circulation, bypassing liver → Syndrome can occur without liver metastases.

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Scenario 3: Carcinoid Heart Disease Pathophysiology

Stem: What cardiac lesions are seen in Carcinoid Heart Disease, and why is the left heart typically spared?

Answer:

• Right-Sided Valves Affected:
  • "Tricuspid Valve: Regurgitation (90-95% of CHD). Leaflet thickening, retraction, fixation."
  • "Pulmonary Valve: Stenosis and/or regurgitation (50-80% of CHD). Leaflet thickening."
• Left Heart Spared:
  • Serotonin from hepatic veins passes through right heart → exposed to high concentrations.
  • Blood then passes through lungs → Pulmonary vascular endothelium contains monoamine oxidase (MAO) → Metabolises ~90% of serotonin to 5-HIAA.
  • Left-sided valves (Mitral, Aortic) are protected by lung metabolism.
• Exceptions for Left-Sided Involvement (less than 10% of CHD):
  • "Patent Foramen Ovale (PFO): Right-to-left shunt bypasses lungs."
  • "Bronchopulmonary shunts: Direct arteriovenous connections."
  • "Very high serotonin levels: Overwhelm lung clearance capacity."
  • "Primary lung NET: Serotonin secreted post-pulmonary circulation."

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Scenario 4: Carcinoid Crisis Prevention

Stem: A patient with known carcinoid syndrome requires emergency laparotomy for bowel obstruction. How do you prevent Carcinoid Crisis?

Answer:

1. Pre-Operative Communication: Alert anaesthetics, ICU, surgical team. Provide patient's NET history, current medications.
2. IV Octreotide Infusion: Start 50-100 µg/hr IV 12-24 hours pre-operatively. Continue during surgery and for 48 hours post-operatively.
3. Octreotide Bolus Available: Have 100-500 µg IV bolus drawn up and immediately available in theatre for crisis.
4. Avoid Trigger Drugs:
   • Avoid: Suxamethonium (succinylcholine), morphine, atracurium (release histamine/catecholamines).
   • Use: Short-acting agents (propofol - controversial, remifentanil, rocuronium).
5. Fluid Management: Adequate IV hydration. Invasive monitoring (arterial line) for haemodynamic instability.
6. Vasopressor Choice: If hypotension occurs, use Vasopressin (does not trigger catecholamine release). Avoid adrenaline/noradrenaline initially.
7. Post-Operative Care: ICU/HDU monitoring. Continue octreotide infusion 48h post-op.

If Carcinoid Crisis Occurs:

• Immediate IV Octreotide bolus 100-500 µg. Repeat every 5-10 minutes.
• Increase infusion rate to 100-200 µg/hr.
• Vasopressin for refractory hypotension.
• Nebulised bronchodilators (salbutamol, ipratropium).
• Halt tumour manipulation if intra-operative.

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Scenario 5: PRRT Indications

Stem: A 62-year-old man with metastatic ileal NET and carcinoid syndrome has been on octreotide LAR 30 mg monthly for 2 years. Recent CT shows progressive liver metastases. 5-HIAA rising from 120 to 250 µmol/24h. 68Ga-DOTATATE PET/CT shows avid SSTR uptake (Krenning score 3-4) in liver lesions. Creatinine 85 µmol/L. Hb 12.5 g/dL, Platelets 180.

Question: Is he eligible for PRRT? What are the benefits?

Answer:

• Yes, eligible for PRRT (Lu-177 DOTATATE).
• Criteria Met:
  1. Progressive disease (radiological progression, rising 5-HIAA).
  2. Well-differentiated NET (ileal primary, likely G1/G2).
  3. SSTR-positive on 68Ga-DOTATATE PET/CT (Krenning score ≥2, his is 3-4).
  4. Adequate organ function: Creatinine clearance > 50 mL/min (estimated ~80 mL/min), adequate bone marrow (Hb > 9, Platelets > 75).
• Expected Benefits (NETTER-1 Trial):
  • "PFS: Not reached (vs 8.4 months with high-dose octreotide alone)."
  • "Objective Response Rate: 18% (vs 3%)."
  • "Symptom improvement: Reduction in flushing, diarrhoea (from reduced 5-HIAA)."
  • "OS benefit: Estimated median OS ~40 months from PRRT initiation."
• Protocol: 4 cycles of Lu-177 DOTATATE (7.4 GBq) every 8 weeks. Total duration 6 months.

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13. Triage: When to Refer

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14. Patient/Layperson Explanation

What is Carcinoid Syndrome?

Carcinoid Syndrome is caused by a type of slow-growing tumour called a Neuroendocrine Tumour (NET). These tumours release hormones, especially serotonin, into your bloodstream. Normally, your liver filters out these hormones, but when the tumour has spread to your liver, the hormones enter your whole body and cause symptoms.

What are the symptoms?

• Flushing: Sudden redness of the face and neck, lasting a few minutes. It feels warm but you don't sweat.
• Diarrhoea: Frequent, urgent, watery loose stools. Can happen many times a day.
• Wheezing: Difficulty breathing, like asthma.
• Heart problems: Over time, the hormones can damage the valves on the right side of your heart, causing breathlessness and swelling in your legs.

How is it diagnosed?

• Urine test: A 24-hour urine collection measures a substance called 5-HIAA, which is high in carcinoid syndrome.
• Blood test: Chromogranin A is a marker for neuroendocrine tumours.
• Scans: CT scans and special PET scans (68Ga-DOTATATE) to see where the tumour is and how much has spread.
• Heart scan (Echocardiogram): To check if your heart valves are affected.

How is it treated?

1. Monthly injections (Octreotide or Lanreotide): These block the hormone release and control your flushing and diarrhoea. Most people feel much better within days to weeks.
2. PRRT (Peptide Receptor Radionuclide Therapy): If the tumour is growing despite injections, a radioactive medicine (Lu-177 DOTATATE) can target and kill the tumour cells. It's given as 4 infusions over 6 months.
3. Surgery: If possible, surgeons can remove the tumour and areas of spread in the liver.
4. Tablets (Everolimus): For tumours that keep growing, a daily tablet can slow them down.
5. Heart treatment: If your heart valves are damaged, you may need heart medications (water tablets) or, in severe cases, valve replacement surgery.

Important Safety Information

• Alert for Surgery: Always tell any doctor or dentist that you have Carcinoid Syndrome. If you need surgery or even a procedure under anaesthesia, you must have a special drip (octreotide) to prevent a dangerous reaction.
• Avoid Alcohol: Alcohol, especially red wine, can trigger severe flushing. It's best to avoid it.
• Yearly Heart Checks: You need a heart scan (echocardiogram) every year to check your heart valves.

What is the outlook?

• Many people with carcinoid syndrome live for many years (often 10-20 years or more) with good treatment.
• The tumours usually grow slowly.
• Modern treatments like monthly injections, PRRT, and surgery can keep the disease controlled for a long time.

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Scenario 6: Biochemical Interpretation

Stem: A 55-year-old woman presents with episodic flushing and diarrhoea. She is taking omeprazole 20mg daily for reflux. Chromogranin A is 850 µg/L (normal < 100). 24h urinary 5-HIAA is 45 µmol/24h (normal < 40).

Question 1: How do you interpret these results?

• Answer:
  • "Chromogranin A elevated: Suggests NET, BUT patient is on PPI (omeprazole). PPIs cause up to 10-fold elevation in CgA via hypergastrinaemia and ECL cell hyperplasia."
  • "5-HIAA borderline: Marginally elevated (45 vs normal < 40). Could be false positive from dietary interference, or true positive."
  • "Action: "
    1. Stop PPI for 2 weeks if clinically safe (or switch to H2 antagonist).
    2. Repeat 24h 5-HIAA with strict dietary restriction (avoid serotonin-rich foods 48-72h before).
    3. Repeat CgA off PPI.
    4. CT chest/abdomen/pelvis to look for NET.
    5. If cannot stop PPI, measure Chromogranin B (less affected by PPIs).

Question 2: She stops omeprazole. Repeat CgA after 2 weeks is 180 µg/L. Repeat 5-HIAA (with dietary restriction) is 125 µmol/24h. What now?

• Answer:
  • CgA remains elevated (though lower than 850 → confirms PPI effect).
  • 5-HIAA now clearly elevated (125 vs < 40) → diagnostic of carcinoid syndrome.
  • "Next steps: Imaging (CT + 68Ga-DOTATATE PET/CT), echocardiography, initiate somatostatin analogue, refer to NET MDT."

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Scenario 7: CHD Surveillance

Stem: A 60-year-old man with metastatic ileal NET and carcinoid syndrome has been on octreotide LAR 30mg monthly for 3 years. Symptoms well controlled. 5-HIAA stable at 80 µmol/24h. He has not had an echocardiogram for 18 months.

Question: What is the risk, and what should be done?

• Answer:
  • "Risk: Carcinoid heart disease develops in 40-50% of patients with chronic carcinoid syndrome. Insidious onset. May be asymptomatic until severe TR/PS."
  • "Guideline: Annual echocardiography is mandatory for all patients with carcinoid syndrome. [26]"
  • "Action: "
    1. Urgent echocardiogram (within 2 weeks).
    2. NT-proBNP (if elevated, higher risk of CHD).
    3. If echo shows CHD (any TR/PS), increase frequency to 6-monthly.
    4. If severe CHD (severe TR or PS), refer to cardiology for valve surgery consideration.
  • "Audit standard: 90% of carcinoid syndrome patients should have annual echo."

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Scenario 8: Medication Counselling

Stem: A patient with carcinoid syndrome controlled on lanreotide 120mg monthly needs an urgent appendicectomy for acute appendicitis.

Question: What specific pre-operative management is required?

• Answer:
  1. Immediate communication: Inform anaesthetist and surgeon about carcinoid syndrome.
  2. IV Octreotide infusion: Start 50-100 µg/hr IV immediately (ideally 12-24h pre-op if time allows, but in emergency start as soon as possible). Continue during surgery and 48 hours post-operatively.
  3. Octreotide bolus available: Draw up 100-500 µg IV bolus for immediate use in theatre if carcinoid crisis occurs.
  4. Avoid trigger drugs:
     • Avoid: Suxamethonium, morphine, atracurium (histamine/catecholamine releasers).
     • Use: Propofol/etomidate for induction. Rocuronium for paralysis. Fentanyl/remifentanil for analgesia.
  5. Vasopressor choice: If hypotension, use vasopressin (not adrenaline).
  6. Post-operative: ICU/HDU monitoring. Continue octreotide infusion 48h. Restart lanreotide once eating/drinking.

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Additional Clinical Pearls

Pearl 1: "The Borderline 5-HIAA Dilemma"

• 5-HIAA 40-73 µmol/24h is borderline. Do not dismiss.
• Action: Repeat with strict dietary compliance. Check medications (SSRIs, paracetamol). Consider plasma serotonin. If high clinical suspicion (classic symptoms, NET on imaging), treat as carcinoid syndrome even if 5-HIAA borderline.

Pearl 2: "Not All NETs Secrete Serotonin"

• Hindgut NETs (rectal): Usually non-functional. 5-HIAA normal. No carcinoid syndrome. Often diagnosed incidentally on colonoscopy or with obstructive symptoms.
• Foregut NETs (gastric, lung): May secrete histamine > serotonin → bright red, patchy flushing (vs dry violaceous midgut flush). 5-HIAA may be normal or mildly elevated.
• Pancreatic NETs: Often secrete other hormones (insulin, gastrin, VIP) → different syndromes (insulinoma, gastrinoma, VIPoma).

Pearl 3: "High 5-HIAA = High CHD Risk"

• 5-HIAA 300 µmol/24h (3× upper limit normal) → high risk of carcinoid heart disease. [7]
• Action: If 5-HIAA this high, order echocardiogram immediately (don't wait for annual screening). Check NT-proBNP. Escalate SSA dosing aggressively.

Pearl 4: "Carcinoid Crisis Can Occur Spontaneously"

• Most cases are peri-operative, BUT 5-10% occur spontaneously (stress, infection, tumour necrosis, progression). [12]
• Trigger: Rapid tumour growth, embolisation, chemotherapy, or idiopathic.
• Management: Same as peri-operative crisis (IV octreotide bolus + infusion, vasopressin if needed, ICU).

Pearl 5: "Foregut vs Midgut Flushing – Key Difference"

Pearl 6: "NT-proBNP as CHD Screening Tool"

• NT-proBNP 300 pg/mL in carcinoid syndrome patient → sensitive marker for CHD. [5]
• Use: If NT-proBNP rising on serial measurements → order echocardiogram early (don't wait for annual).
• Advantage: Blood test, easy, can be done 6-monthly as adjunct to annual echo.

Pearl 7: "Telotristat Ethyl – When to Use"

• Indication: Refractory carcinoid syndrome diarrhoea despite maximum dose SSA. [22]
• Mechanism: Tryptophan hydroxylase inhibitor → reduces serotonin synthesis.
• Dose: 250mg PO TDS.
• Evidence: TELESTAR trial: 43% reduction in bowel movements vs 20% placebo. [22]
• When NOT to use: If SSA dose not optimised (escalate SSA first).

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15. Quality Markers: Audit Standards

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16. Historical Context

Timeline of Discovery

• 1888 – Otto Lubarsch: First described a small bowel neuroendocrine tumour (called "carcinoid" meaning "carcinoma-like" due to indolent behaviour).
• 1907 – Siegfried Oberndorfer: Coined the term "Karzinoide" (Carcinoid) to describe tumours that were histologically malignant but clinically less aggressive than typical carcinomas.
• 1952 – Björck, Thorson, and Waldenström: First comprehensive description of Carcinoid Syndrome as a clinical entity (flushing, diarrhoea, right-sided heart disease, bronchospasm). Linked syndrome to midgut carcinoid tumours. "Hedinger Syndrome" in European literature.
• 1953 – Serotonin Identified: Lembeck identified serotonin (5-HT) in carcinoid tumours. Explained the mechanism of symptoms.
• 1961 – 5-HIAA Urinary Test: Measurement of urinary 5-HIAA established as diagnostic test.
• 1979 – Octreotide Developed: Bauer et al. synthesised octreotide, the first long-acting somatostatin analogue. Revolutionised symptom control.
• 1988 – Octreotide Scan (SRS): 111-Indium Octreotide scintigraphy introduced for NET imaging.
• 2000s – PRRT Development: Lu-177 and Y-90 labelled somatostatin analogues developed for targeted radiotherapy.
• 2009 – PROMID Trial: Demonstrated anti-proliferative effect of octreotide LAR (prolonged PFS in midgut NETs).
• 2014 – CLARINET Trial: Lanreotide showed PFS benefit in non-functional NETs.
• 2017 – NETTER-1 Trial: Landmark trial. Lu-177 DOTATATE (PRRT) significantly prolonged PFS in midgut NETs. Led to FDA/EMA approval of Lutathera.
• 2018 – Telotristat Ethyl Approved: First tryptophan hydroxylase inhibitor for refractory carcinoid syndrome diarrhoea.

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17. References

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2. Sultana Q, Kar J, Verma A, et al. A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management. J Clin Med. 2023;12(15):5138. PMID: 37568540

3. Halperin DM, Shen C, Dasari A, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18(4):525-534. PMID: 28238593

4. Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169-188. PMID: 19845567

5. Jin C, Sharma AN, Thevakumar B, et al. Carcinoid Heart Disease: Pathophysiology, Pathology, Clinical Manifestations, and Management. Cardiology. 2021;146(1):65-73. PMID: 33070143

6. Gustafsson BI, Hauso O, Drozdov I, Kidd M, Modlin IM. Carcinoid heart disease. Int J Cardiol. 2008;129(3):318-324. PMID: 18571250

7. Rossi RE, Lavezzi E, Jaafar S, et al. Urinary 5-Hydroxyindolacetic Acid Measurements in Patients with Neuroendocrine Tumor-Related Carcinoid Syndrome: State of the Art. Cancers (Basel). 2023;15(16):4065. PMID: 37627093

8. Oberg K, Modlin IM, De Herder W, et al. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol. 2015;16(9):e435-e446. PMID: 26370353

9. Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e490s. PMID: 30133596

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12. Condron ME, Pommier SJ, Pommier RF. Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis. Surgery. 2016;159(1):358-365. PMID: 26454675

13. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and outcomes of abdominal surgery for metastatic carcinoid tumours. Br J Anaesth. 2001;87(3):447-452. PMID: 11517130

14. Shah GM, Shah RG, Veillette H, et al. Biochemical assessment of niacin deficiency among carcinoid cancer patients. Am J Gastroenterol. 2005;100(10):2307-2314. PMID: 16181384

15. Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. PMID: 28448665

16. Sundin A, Arnold R, Baudin E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging. Neuroendocrinology. 2017;105(3):212-244. PMID: 28355596

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18. Hope TA, Bergsland EK, Bozkurt MF, et al. Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors. J Nucl Med. 2018;59(1):66-74. PMID: 28935835

19. Konukiewitz B, Jesinghaus M, Kasajima A, Klöppel G. Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls. Virchows Arch. 2022;480(2):247-257. PMID: 34647171

20. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663. PMID: 19704057

21. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233. PMID: 25014687

22. Kulke MH, Hörsch D, Caplin ME, et al. Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. J Clin Oncol. 2017;35(1):14-23. PMID: 27918724

23. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523. PMID: 21306238

24. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977. PMID: 26703889

25. Hellman P, Hessman O, Akerström G, et al. Surgical strategy for large or malignant endocrine pancreatic tumors. World J Surg. 2000;24(11):1353-1360. PMID: 11038206

26. Pavel M, O'Toole D, Costa F, et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology. 2016;103(2):172-185. PMID: 26731013

27. Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas. 2017;46(6):707-714. PMID: 28609356

28. Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. PMID: 32272208

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. If you have symptoms of carcinoid syndrome, please seek medical attention.