Diagnosis is carcinoid syndrome due to a metastatic small bowel neuroendocrine tumor.
1. Definition
Carcinoid syndrome is a hormonal syndrome caused by systemic exposure to serotonin and other vasoactive substances released by neuroendocrine tumors. It is characterized primarily by flushing and secretory diarrhea, with possible bronchospasm and carcinoid heart disease.
In gastrointestinal neuroendocrine tumors, carcinoid syndrome usually develops after liver metastases allow tumor-derived mediators to reach the systemic circulation without complete hepatic metabolism.
2. Etiology
1. Small intestinal neuroendocrine tumors, particularly ileal or other midgut tumors, are the most common cause
o Carcinoid syndrome usually occurs when liver metastases are present
2. Bronchopulmonary neuroendocrine tumors
o May cause carcinoid syndrome without liver metastases because secreted products enter the systemic circulation directly
3. Ovarian neuroendocrine tumors
o May also cause carcinoid syndrome without liver metastases
4. Less commonly:
o Pancreatic neuroendocrine tumors
o Other foregut or unknown-primary neuroendocrine tumors
3. Pathophysiology
1. Neuroendocrine tumors may secrete:
o Serotonin
o Tachykinins
o Histamine
o Prostaglandins
o Other vasoactive peptides and amines
2. Secretory products from gastrointestinal tumors normally enter the portal circulation and are metabolized by the liver
3. Liver metastases allow large amounts of vasoactive substances to reach the systemic circulation
4. Serotonin contributes particularly to:
o Increased intestinal secretion and motility causing diarrhea
o Fibrotic changes contributing to carcinoid heart disease
5. Multiple vasoactive mediators contribute to:
o Flushing
o Bronchospasm
6. Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which can be measured in urine or plasma
7. Chronic diversion of tryptophan toward serotonin synthesis may reduce niacin synthesis and contribute to niacin deficiency or pellagra
4. Clinical Features
4.1 Classic Features
1. Episodic flushing
o Usually affects the face, neck, and upper chest
o May be triggered by alcohol, stress, exercise, or certain foods
2. Secretory watery diarrhea
3. Crampy abdominal pain
4. Bronchospasm or wheezing
5. Tachycardia or blood pressure fluctuations may occur during episodes
4.2 Carcinoid Heart Disease
1. Chronic exposure to circulating vasoactive substances causes fibrous plaque deposition on right-sided cardiac valves and endocardium
2. Tricuspid regurgitation is common
o May produce a holosystolic murmur at the left lower sternal border
3. Pulmonary valve stenosis and/or regurgitation may occur
4. Advanced disease may cause right-sided heart failure
5. The left side of the heart is usually relatively spared because vasoactive substances are metabolized in the lungs
6. Left-sided involvement may occur with:
o Patent foramen ovale or another right-to-left shunt
o Very high circulating mediator levels
o Bronchopulmonary neuroendocrine tumors
4.3 Other Features
1. Weight loss
2. Malnutrition
3. Fatigue
4. Niacin deficiency or pellagra
o Dermatitis
o Diarrhea
o Neurocognitive changes
5. Mesenteric fibrosis associated with small intestinal neuroendocrine tumors
o May cause bowel obstruction, ischemia, or abdominal pain
5. Diagnosis
5.1 Biochemical Testing
1. Twenty-four-hour urinary 5-HIAA is a standard biochemical test for suspected carcinoid syndrome
2. Because of biological and collection variability, two 24-hour urine collections are preferred
3. Patients should follow laboratory instructions regarding foods and medications that may interfere with 5-HIAA measurement
o Serotonin-rich foods and certain medications can produce misleading results
4. Plasma or serum 5-HIAA is an alternative where validated and available
5. Chromogranin A
o May reflect neuroendocrine tumor burden
o Is nonspecific
o Does not reliably distinguish patients with from those without carcinoid syndrome
5.2 Imaging
1. Multiphasic contrast-enhanced CT or MRI is used for localization, staging, and assessment of liver metastases
2. Somatostatin receptor PET/CT, typically using a radiolabeled somatostatin analogue such as 68Ga-DOTATATE, is preferred for:
o Whole-body staging
o Detection of somatostatin receptor-positive disease
o Determining suitability for peptide receptor radionuclide therapy
3. Older somatostatin receptor scintigraphy has lower sensitivity and is generally used only when SSTR PET is unavailable
5.3 Histology and Tumor Grading
1. Tissue diagnosis confirms a neuroendocrine tumor
2. Neuroendocrine differentiation is supported by markers such as:
o Synaptophysin
o Chromogranin
3. Tumor grade is determined using:
o Mitotic rate
o Ki-67 proliferation index
5.4 Cardiac Evaluation
1. NT-proBNP should be assessed in patients with carcinoid syndrome when carcinoid heart disease is suspected or screening is appropriate
2. Transthoracic echocardiography is the key imaging test for carcinoid heart disease
3. Echocardiography evaluates:
o Tricuspid valve thickening and reduced mobility
o Tricuspid regurgitation
o Pulmonary valve involvement
o Right ventricular size and function
4. ENETS uses NT-proBNP >260 pg/mL as a threshold prompting echocardiographic assessment
5. Clinical suspicion or an abnormal cardiac examination warrants echocardiography regardless of NT-proBNP
6. In this patient, the holosystolic murmur warrants transthoracic echocardiography even without an NT-proBNP result
6. Management
6.1 First-Line Symptom Control
1. Before attributing all diarrhea to carcinoid syndrome, evaluate for other potential causes, including:
o Pancreatic exocrine insufficiency
o Bile acid diarrhea
o Short bowel syndrome
o Intestinal ischemia
o Infection or other gastrointestinal disorders when clinically appropriate
2. Long-acting somatostatin analogues are first-line therapy for confirmed carcinoid syndrome
o Octreotide LAR
o Lanreotide
3. Somatostatin analogues reduce:
o Diarrhea
o Flushing
o Other hormone-mediated symptoms
4. They also have antiproliferative activity in well-differentiated neuroendocrine tumors
6.2 Supportive Treatment
1. Avoid identifiable flushing triggers, such as alcohol and certain foods
2. Correct dehydration and electrolyte abnormalities
3. Antidiarrheal therapy, such as loperamide, may be used as adjunctive treatment
4. Assess nutritional status and replace deficiencies, including niacin, when present
6.3 Persistent or Refractory Carcinoid Syndrome
1. Confirm adherence and optimize the dose or dosing interval of the somatostatin analogue
2. Reassess for alternative or contributing causes of diarrhea
3. Telotristat ethyl
o Inhibits tryptophan hydroxylase and reduces serotonin production
o Used for carcinoid syndrome diarrhea inadequately controlled by somatostatin analogue therapy
4. Additional tumor-directed therapy may improve refractory hormonal symptoms
6.4 Antitumor Therapy for Metastatic Disease
1. Peptide receptor radionuclide therapy with 177Lu-DOTATATE
o Recommended after progression on somatostatin analogue therapy in appropriate patients with somatostatin receptor-positive, well-differentiated metastatic gastrointestinal neuroendocrine tumors
2. Everolimus
o May be considered as an alternative systemic option for selected patients with progressive advanced neuroendocrine tumors, particularly when PRRT is unsuitable or the tumor is somatostatin receptor-negative
3. Treatment selection depends on:
o Tumor grade
o Somatostatin receptor expression
o Tumor burden
o Rate of progression
o Distribution of metastatic disease
o Previous treatment
6.5 Surgery and Liver-Directed Therapy
1. Surgical resection is preferred for localized resectable small intestinal neuroendocrine tumors
2. In metastatic disease, resection of the primary tumor or cytoreductive surgery may be considered in carefully selected patients
3. For liver-dominant metastatic disease, selected patients may benefit from:
o Transarterial embolization
o Transarterial chemoembolization
o Radioembolization
o Thermal ablation
o Surgical cytoreduction
4. Management should be individualized by a multidisciplinary neuroendocrine tumor team
6.6 Carcinoid Heart Disease
1. Optimize control of serotonin and other tumor-secreted mediators
2. Monitor with NT-proBNP and echocardiography
3. Treat right-sided heart failure when present
4. Valve replacement surgery should be considered in appropriately selected patients with severe symptomatic carcinoid valvular disease
6.7 Carcinoid Crisis
1. Carcinoid crisis is a potentially life-threatening episode characterized by severe hemodynamic instability, flushing, bronchospasm, and other manifestations of acute mediator release
2. It may occur during:
o Surgery
o Anesthesia
o Tumor manipulation
o Other invasive procedures
3. Evidence that prophylactic octreotide completely prevents carcinoid crisis is limited
4. Peri-procedural somatostatin analogue prophylaxis may be considered, particularly in patients with functional neuroendocrine tumors undergoing surgery or invasive procedures
5. The anesthesia and procedural teams should be prepared to recognize and immediately treat hemodynamic instability
6. Management may require:
o Appropriate intravenous fluids
o Vasoactive medications
o Intravenous octreotide as an adjunct
o Treatment of bronchospasm and other complications as clinically indicated
7. Key Clinical Insight
Episodic flushing + secretory diarrhea + wheezing + elevated 5-HIAA + small bowel neuroendocrine tumor + liver metastases = carcinoid syndrome
The holosystolic murmur at the left lower sternal border strongly suggests tricuspid regurgitation from carcinoid heart disease, so this patient requires cardiac assessment with transthoracic echocardiography, with NT-proBNP used as an additional biomarker.
References
1. Grozinsky-Glasberg S, Davar J, Hofland J, et al. European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease. J Neuroendocrinol. 2022;34(7):e13146. doi:10.1111/jne.13146. PMID: 35613326.
2. Perez K, Del Rivero J, Kennedy EB, et al. Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. JCO Oncol Pract. 2026;22(1):19-35. doi:10.1200/OP-25-00133. PMID: 40344544.
3. Del Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol. 2023;41(32):5049-5067. doi:10.1200/JCO.23.01529. PMID: 37774329.
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