I. What every physician needs to know.
The carcinoid syndrome is characterized by symptoms that may include intermittent flushing (90% of patients), diarrhea (70%), abdominal pain (40%), right-sided heart disease (30%), and wheezing (15%). Carcinoid tumors are neuroendocrine tumors of the amine precursor uptake decarboxylase cells (APUD cells) of the gastrointestinal tract, bronchi, pancreas, biliary tract, or thymus.
The majority of carcinoid tumors are discovered incidentally with only about 10% demonstrating hormonal activity. Symptomatic tumors cause the carcinoid syndrome through release of numerous bioactive substances including serotonin and histamine.
The carcinoid syndrome occurs when the capacity of the liver to metabolize the secreted bioactive substances is bypassed (liver metastases, bronchial tumors, ovarian tumors) or overwhelmed (extremely large carcinoid tumors). Carcinoid tumors causing carcinoid syndrome are typically slow growing with vague symptoms including abdominal discomfort present for years (median 9.2 years) before a diagnosis is made.
Confirmatory tests for carcinoid syndrome include urinary 5-hydroxyindoleacetic acid (5-HIAA) and/or plasma chromogranin A levels. Radiolabeled octreotide imaging (also termed serotonin receptor scintigraphy or SRS) allows localization of the responsible carcinoid tumor and an assessment of the extent of disease.
Long-term consequences of the carcinoid syndrome include fibrosis with cardiac valvular (particularly right-sided involvement) abnormalities. Fibrosis may also affect the small bowel mesentery or the lungs. Rarely, carcinoid tumors result in skin findings similar to scleroderma.
Management includes surgery for localized disease, hepatic artery embolization for control of liver metastases and chronic administration of octreotide or its analogues for symptom control.
II. Diagnostic Confirmation: Are you sure your patient has carcinoid syndrome?
Typical symptoms for carcinoid syndrome include the following: episodic flushing, abdominal pain, diarrhea, wheezing, and dyspnea.
24-hour urine 5-HIAA elevation, typically greater than 100 mg/day (523 micromol/day) OR plasma chromogranin A level that is elevated (diagnostic ranges are dependent on particular assays, so should be confirmed with laboratory).
Octreotide scan provides localization of suspected carcinoid tumor, but should not be done unless 5-HIAA or chromogranin A are elevated. The exception is when a bronchial carcinoid or gastric carcinoid tumor is suspected in which case the whole blood serotonin level may be elevated instead of 5-HIAA or chromogranin A.
A. History Part I: Pattern Recognition:
Episodic flushing is the key symptom, although bronchial carcinoids typically present with wheezing and dyspnea as major symptoms.
Flushing is usually confined to the face, neck and upper trunk. Midgut (small bowel, appendix) carcinoid tumors cause the classic carcinoid flush that is best described as cyanotic. The flush lasts 30 seconds to 30 minutes. Although the flush may be spontaneous, precipitating factors include anesthesia, defecation, eating, medications including adrenergic agonists, and palpation of the liver.
Classically, foregut (gastric, bronchial) carcinoid tumors cause distinctive flushing syndromes. The gastric carcinoid flush is described as bright salmon pink or cherry red, patchy and well demarcated and is associated with intense pruritis. The bronchial flush may be much more severe and prolonged, associated with hypotension, tachycardia, periorbital edema, and salivation along with diarrhea and severe bronchoconstriction.
Other presentations of the carcinoid syndrome include newly diagnosed tricuspid or pulmonic valve cardiac disease, late onset asthma, profuse secretory diarrhea, circulatory collapse with induction of anesthesia, or paradoxical response to beta-agonists.
B. History Part 2: Prevalence:
Carcinoid syndrome is a rare disorder. The incidence of carcinoid tumors is estimated at 2 per 100,000. About 30-40% of patients with small bowel carcinoid tumors develop carcinoid syndrome, while the tumors of other origins are much less likely to cause carcinoid syndrome. The syndrome normally manifests between the fifth and seventh decades of life.
A family history of multiple endocrine neoplasia Type 1 (MEN-1) increases the risk of carcinoid tumor.
C. History Part 3: Competing diagnoses that can mimic carcinoid syndrome.
The differential diagnosis is primarily that of episodic flushing and includes the following:
Alcohol plus chlorpromazine or disulfiram
Medullary carcinoma of the thyroid
VIPoma (vasoactive intestinal peptide)
A careful history will help exclude drugs or medications as a cause of recurrent flushing. Observation of the flush itself is key to eliminating the other diagnoses on the list.
Physical Examination Findings.
Findings that would increase the likelihood of carcinoid syndrome include the following:
Observation of the typical face, neck and upper trunk flush.
Features of rosacea (seen in patients following years of flushing).
Systolic murmur along the lower left sternal border suggestive of tricuspid regurgitation.
Pellagra, due to increased utilization of tryptophan by the carcinoid tumor that results in reduced nicotinic acid production and niacin deficiency.
Twenty-four hour urine for 5-hydroxyindoleacetic acid
Normal excretion 2-8 mg/day
Operating characteristics: sensitivity 35-75%, specificity 88-100%
Causes of high 5-HIAA in addition to carcinoid tumors include the following:
Foods: avocado, banana, eggplant, walnuts, pecans, kiwi, pineapple, and plums.
Medications: acetaminophen, caffeine, guaifenesin, phenobarbital, reserpine, ephedrine, nicotine, methamphetamine, melphalan, methocarbamol, and mesalamine.
Causes of falsely low 5-HIAA include the following:
Drugs: ethanol, corticotropin, monoamine oxidase (MAO) inhibitors, imipramine, levodopa, aspirin, heparin, methyldopa, and isoniazid
Note: 5-HIAA is unreliable in diagnosing gastric or bronchial carcinoids. Whole blood serotonin levels may be helpful if these tumors are suspected.
Plasma chromogranin A levels
Normal range is dependent on specific kit used in assay.
Operating characteristics: sensitivity 53-68% and specificity 84-94%.
Multiple non-malignant causes of elevated chromogranin A levels include the following: chronic atrophic gastritis, liver cirrhosis, chronic hepatitis, pancreatitis, inflammatory bowel disease, heart failure, renal failure, hyperthyroidism, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis.
Proton pump inhibitors cause elevation of chromogranin A levels that normalize within 1-2 weeks of cessation of the drug.
Many other malignancies can cause elevation of chromogranin A levels.
Very high levels are most consistent with carcinoid syndrome.
This assay is useful in following patients with carcinoid tumors as the level correlates with burden of disease and recurrence.
Octreoscan (indium-111 labelled octreotide scan) also termed “serotonin receptor scintigraphy” (SRS) allows localization of carcinoid tumor(s).
Computed tomography (CT) or magnetic resonance imaging (MRI) scans may be useful in localization of carcinoid tumors and in detection of metastases, but the octreoscan is the imaging of choice.
Abdominal ultrasound, while not a useful initial diagnostic test, has a reasonable sensitivity for detection of hepatic metastases.
Positron emission tomography-computed tomography (PET-CT) using 18-fluoro-dihydroxyphenylalanine has shown promise in detection of carcinoid tumors but is not yet widely available.
Over-utilized or “wasted” diagnostic tests associated with this diagnosis:
Some authorities recommend a large “menu” of biochemical markers for the work-up of flushing including neurokinin A (NKA), thyrocalcitonin, pancreatic polypeptide, gastrin-releasing peptide, vasoactive intestinal peptide (VIP), substance P, and prostaglandin D2, E1, and F2. These assays have no validated role in diagnosing carcinoid syndrome.
The priority for management of this disorder is recognition and diagnosis with subsequent consultation with an experienced center for ongoing management.
Rarely for this already rare disorder, carcinoid syndrome may be first recognized in the operating room during an intervention for the tumor. In the setting of carcinoid crisis, characterized by marked flushing, profound hypotension, tachycardia, and bronchospasm, or in anticipation of surgery for a patient with known carcinoid syndrome, the principles of management are:
Avoid opioids (meperidine or morphine).
Avoid histamine-releasing neuromuscular relaxants (atracurium, mivacurium, d-tubocurarine).
Avoid exogenous catecholamines (epinephrine, norepinephrine, dopamine, isoproterenol) that cause mediator release from carcinoid cells.
Reduce release of endogenous catecholamines. Consider benzodiazepines for anxiety, avoid hypothermia.
Avoid vigorous abdominal scrubbing or palpation of the liver.
Octreotide should be used along with plasma infusion to treat hypotension. Regimens have included 300 micrograms intravenously as a bolus or 50-150mcg per hour as a continuous infusion.
See above for immediate management. In carcinoid crisis, calcium and catecholamines may worsen the syndrome by stimulating further release of vasoactive substances from the carcinoid tumor. Octreotide is the drug of choice in this circumstance.
Long-term management and surveillance.
Chromogranin A may be followed periodically as an objective measure for control of the disease. There are no clear-cut guidelines for frequency of measurement, although it is reasonable to use intervals of at least 3-4 months. This disorder should be managed with the input of a center with expertise in carcinoid syndrome. Consultants likely to have experience include neuroendocrinology and gastroenterology.
Initiated using short-acting injections then transitioned to long-acting preparation such as Sandostatin LAR beginning at a dose of 20 mg intramuscular (IM) monthly with increased dosing as required for control of symptoms.
A long-acting octreotide analogue that can be self-administered as a deep subcutaneous injection monthly.
Side effects of these agents include nausea, abdominal discomfort, bloating, loose stools, and malabsorption, all of which tend to improve with time. Octreotide increases the risk of gallstones due to delayed gallbladder emptying.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
No change in standard management.
B. Liver Insufficiency.
Likely to be related to extensive disease or to management of known metastatic disease to the liver, which may include hepatic artery embolization.
Recall the potential risk of vigorous palpation of a liver filled with carcinoid in precipitating carcinoid crisis.
C. Systolic and Diastolic Heart Failure
No change in management, but recall that as many as 50% of patients with carcinoid syndrome have cardiac involvement. Tricuspid regurgitation and pulmonic regurgitation are the most common findings, although coexistent tricuspid or pulmonic stenosis can also occur. Right heart failure occurs as a consequence of valvular disease. Left-sided involvement is much less common.
Echocardiography is indicated in evaluation for all patients with carcinoid syndrome.
D. Coronary Artery Disease or Peripheral Vascular Disease
No change in standard management.
E. Diabetes or other Endocrine issues
Octreotide may worsen glucose tolerance.
Carcinoid tumors may secrete adrenocorticotropic hormone (ACTH) or other hormones, although clinical findings should dictate further work-up.
There appears to be an increased risk for adenocarcinoma of primarily gastrointestinal origin in patients with carcinoid tumors, but screening strategies are not recommended beyond those appropriate for age.
G. Immunosuppression (HIV, chronic steroids, etc).
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD)
Consider that beta-agonists may precipitate release of vasoactive substances by carcinoid cells resulting in hypotensive response to therapy and ineffective bronchodilation. Octreotide has been reported to rapidly reverse bronchospasm in patients with carcinoid syndrome.
Bronchial carcinoids are a possible cause of late-onset “asthma”.
Persistent localized wheezing may be a clinical sign of a bronchial carcinoid.
I. Gastrointestinal or Nutrition Issues
Patients with carcinoid syndrome are at risk for peptic ulcer disease. Use of histamine H2 blocker should be considered, particularly for patients with gastric carcinoids.
Patients with carcinoid syndrome are at risk for niacin deficiency.
J. Hematologic or Coagulation Issues
No adjustments in management or associations.
K. Dementia or Psychiatric Illness/Treatment
No specific adjustments in management.
Confusion or stupor may occur during carcinoid crisis.
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
Calls for shortness of breath, wheezing, hypotension, profound flushing, or confusion should prompt urgent bedside evaluation as these symptoms may reflect carcinoid crisis.
Octreotide is the drug of choice for wheezing that worsens with inhaled bronchodilators or for hypotension refractory to volume expansion.
Caution for prescription of opiates for pain.
B. Hospital Discharge Considerations.
Patients can be discharged when blood pressure is stable and flushing episodes are adequately controlled for patient comfort. Contact should be established with a center with expertise in management.
C. Arranging for Clinic Follow-up
Assuming a new diagnosis of carcinoid syndrome, the patient should be seen in follow-up within 2 weeks, given the unusual nature of the problem, which will require education and referral to specialists, and possibly regional referral.
Plasma chromogranin A, if not done as part of the diagnostic work-up, should be ordered to provide a baseline estimate of “burden of disease”.
A transthoracic echocardiogram should be arranged to assess for right-sided cardiac valvular disease.
D. Prognosis and Patient Counseling.
Carcinoid tumors that are discovered incidentally (i.e., are not associated with carcinoid syndrome) confer a prognosis that is primarily dependent on the origin and evidence of metastasis. Surgical resection is indicated for localized tumors.
Carcinoid syndrome implies metastatic disease in the majority of patients. Estimated survival rates are 70% at 1 year, 53% at 3 years and 40% at 5 years. However, survival appears to be improving with multidisciplinary management that may include neuroendocrinology, oncology, surgery, interventional radiology, and cardiac surgery.
Patients should consider taking a multivitamin containing niacin in addition to the management of carcinoid syndrome itself.
E. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Peptic ulcer disease prophylaxis should be considered. Histamine H2 blockers are appropriate for this concern given the histamine produced by many carcinoid tumors.
Patients should alert caregivers to the diagnosis or possible diagnosis of carcinoid syndrome. A medic alert bracelet would be appropriate for patients with a confirmed diagnosis.
VI. What’s the evidence?
Bell, HK, Poston, GJ, Vora, J, Wilson, NJ. “Cutaneous manifestations of the malignant carcinoid syndrome”. . vol. 152. 2005. pp. 71-5.
Bendelow, J, Apps, E, Jones, LE, Poston, GJ. “Carcinoid syndrome”. . vol. 34. 2008. pp. 289-96.
Bhattacharyya, S, Toumpanakis, C, Caplin, ME, Davar, J. “Analysis of 150 patients with carcinoid syndrome seen in a single year at one institution in the first decade of the twenty-first century”. . vol. 101. 2008. pp. 378-81.
Crocetti, E, Paci, E. “Malignant carcinoids in the USA SEER 1992-1999. An epidemiological study with 6830 cases”. . vol. 12. 2008. pp. 191-4.
Fox, DJ, Khattar, RS. “Carcinoid heart disease: presentation, diagnosis, and management”. . vol. 90. 2004. pp. 1224-8.
Ghevariya, V, Malieckal, A, Ghevariya, N, Mazumder, M, Anand, S. “Carcinoid tumors of the gastrointestinal tract”. . vol. 102. 2009. pp. 1032-40.
Mancuso, K, Kaye, AD, Boudreaux, JP. “Carcinoid syndrome and perioperative anesthetic considerations”. . vol. 23. 2011. pp. 329-41.
Ramage, JK, Ahmed, A, Ardill, J. “Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)”. . vol. 61. 2012. pp. 6-32.
Srirajaskanthan, R, Shanmugabavan, D, Ramage, JK. “Carcinoid syndrome”. . vol. 341. 2010. pp. c3941
Vinik, AI, Silva, MP, Woltering, EA, Go, VL, Warner, R, Caplin, M. “Biochemical testing for neuroendocrine tumors”. . vol. 38. 2009. pp. 876-89.
O’Toole, D, Grossman, A, Gross, D. “ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers”. Neuroendocrinology. vol. 90. 2009. pp. 194
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has carcinoid syndrome?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic carcinoid syndrome.
- Physical Examination Findings.
- Imaging Studies
- Over-utilized or “wasted” diagnostic tests associated with this diagnosis:
- Immediate management.
- Long-term management and surveillance.
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes or other Endocrine issues
- F. Malignancy
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Hospital Discharge Considerations.
- C. Arranging for Clinic Follow-up
- D. Prognosis and Patient Counseling.
- E. Appropriate Prophylaxis and Other Measures to Prevent Readmission.