BASICS
DESCRIPTION
- Cluster of symptoms related to release of bioactive humoral mediators by carcinoid tumors, including
- Cutaneous flushing
- Diarrhea
- Bronchospasm
- Carcinoid tumors represent a diverse range of neoplasms and present with multiple clinical characteristics depending on the site of origin, hormone production, and level of differentiation.
- Most carcinoid tumors are found in the GI tract (67%) and bronchi (25%) (1).
- Tumors can arise almost anywhere.
- Classic carcinoid syndrome if liver metastasis has occurred. The liver inactivates bioactive tumor products, but metastases can release these amines, peptides, and prostaglandins directly into hepatic veins and then into the systemic circulation.
- Carcinoid tumors can occur without the accompanying carcinoid syndrome.
- The term carcinoid has fallen out of favor due to lack of specificity; neuroendocrine tumor (NET) is favored (e.g., small intestine NET).
- Metastases relates to tumor size: incidence of metastases is <15% with tumor smaller than 1 cm but rises to 95% with tumors larger than 2 cm (2).
EPIDEMIOLOGY
Incidence
- Incidence rates for gastroenteropancreatic (GEP) NETs are roughly 2.5 to 5 cases per 100,000.
- About 0.5% of all malignant diseases are neuroendocrine (carcinoid) tumors originating in the GI or bronchopulmonary systems.
- Incidence and prevalence have increased substantially over several decades; perhaps due to advances in imaging.
- Carcinoid syndrome is more common in midgut intestinal tumors (rates as high as 50%); less common with bronchial carcinoids
Prevalence
True prevalence rates of carcinoid tumors are difficult to determine because they are often asymptomatic.
ETIOLOGY AND PATHOPHYSIOLOGY
- Tumors arise from enterochromaffin (neuroendocrine) cells of the aerodigestive tract.
- Common symptoms are linked to bioactive products secreted by tumors
- Serotonin, kallikrein, prostaglandins, and histamine are common examples.
- Other tumor products include biogenic amines (e.g., serotonin, histamine), peptides (e.g., substance P, vasoactive intestinal polypeptide [VIP], atrial wide natriuretic peptide), tachykinins (e.g., kallikrein, neuropeptide K), and prostaglandins.
- Serotonin contributes to diarrhea (stimulating motility and inhibiting GI absorption), flushing, and bronchospasm and right-sided cardiac findings (tricuspid valve or pulmonary valve dysfunction secondary to valvular endothelial fibrosis).
- Cardiac findings are typically right-sided because the lungs inactivate mediators passing through the pulmonary circulation.
- Kallikrein contributes to flushing by generating bradykinin, a vasodilator.
- Histamine can cause flushing, pruritus, and possibly peptic ulcers.
- Prostaglandins can cause bronchospasm and affect GI motility.
Genetics
Multiple genes may be associated: point mutations, deletions, methylation, and chromosomal loss and gain.
RISK FACTORS
- African Americans have a higher incidence.
- Age >50 years
COMMONLY ASSOCIATED CONDITIONS
- Multiple endocrine neoplasia type 1 (MEN1)
- von Hippel-Landau syndrome
- Neurofibromatosis type 1
DIAGNOSIS
HISTORY
- Most carcinoid tumors are asymptomatic and discovered incidentally at imaging, endoscopy, surgery, or autopsy.
- Due to nonspecific presentation, the average time to diagnosis is 9 years.
- Most commonly misdiagnosed as irritable bowel syndrome (IBS) (3).
- Note timing, frequency, and precipitating factors associated with the following:
- Flushing (85%)
- Diarrhea (80%)
- Abdominal pain
- Bowel obstruction
- Bronchospasm/wheezing (10-20%)
- Symptoms of carcinoid heart disease (especially right-sided heart failure)
- Often precipitated by exertion or certain food/drink (foods high in tyramine; ethanol)
- Flushing
- Sudden onset; facial or upper torso, lasts 5 to 10 minutes, intermittent throughout the day, commonly after stress, alcohol, anesthesia, or tyramine-containing foods
PHYSICAL EXAM
- Hypotension, tachycardia (when symptomatic)
- Often, no significant findings
- Pellagra; dermatitis (secondary niacin deficiency)
- Venous telangiectasia
- Examine for signs of right-sided heart failure (murmur).
- Bronchospasm (bronchial carcinoid)
DIFFERENTIAL DIAGNOSIS
- Flushing: alcohol, (including disulfiram reaction), menopause, anaphylaxis, hot drinks, spicy foods, emotional distress, medications (e.g., niacin, nitrates, diltiazem), pheochromocytoma, VIPoma, mastocytosis, autonomic epilepsy, medullary carcinoma of the thyroid
- Diarrhea: gastroenteritis, infectious colitis, laxative misuse, irritable bowel, inflammatory bowel disease, malabsorption, among many others
- Bronchospasm: asthma, pulmonary edema, foreign body, postnasal drip syndrome, COPD
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA); sensitivity and specificity near 90%
- Many foods (e.g., avocado, chocolate, tomatoes, bananas, nuts) and medications (e.g., acetaminophen, nicotine, caffeine) can alter test results; review dietary restrictions with patients before testing.
- Serum chromogranin A (CgA) levels have a reported sensitivity of 75-85% and specificity of 84-95%; higher plasma CgA levels are associated with poorer prognosis. Follow levels to monitor treatment response; 40% false-positive rate in patients with multiple myeloma (4).
- All carcinoid tumors should be stained for CgA on pathology examination (5).
- Serum serotonin concentration if 24-hour urine-5-HIAA test is nondiagnostic
- Pancreatic polypeptide (PP) levels have sensitivity of 54% in functioning tumors and 57% in non-functioning; however, when combined with CgA, the sensitivity increased to 94-96% depending on tumor (2).
- Epinephrine provocation test has a reported sensitivity of nearly 100%.
- 11Indium-labeled octreotide scintigraphy scans provide functional data; sensitivity for small intestine NETs with symptoms is >90% (6)[B].
- Abdominal, multiphase, contrast-enhanced CT to localize tumor after positive test (sensitivity is 44-55%)
- MRI, endoscopic US, and PET scans with targeted tracers (e.g., 18F-DOPA) have shown promise to aid tumor localization as well.
- Upper and lower GI endoscopies in gastroduodenal and ileocolonic tumors; ileal submucosal location limits endoscopic detection.
- Barium enema examination in cecum, right colon, and hindgut tumors.
- Small bowel enteroscopy, MR enterography, and video capsule endoscopy to visualize small bowel
- Liver metastases are evaluated by CT or MRI.
- Diagnostic angiography has fallen out of favor but is still employed when noninvasive imaging studies are equivocal and surgery or chemoembolization is contemplated (particularly in hepatic metastatic cases) (4).
Test Interpretation
- Historically, carcinoid tumors were classified by embryologic site of origin (e.g., foregut, midgut, hindgut), affinity for silver staining, and morphology.
- More recent WHO classification guidelines are based on degree of differentiation and site of origin.
TREATMENT
Surgical resection is usually first line for small and localized tumors and alleviation of any obstructive symptoms. Surgical cure is almost impossible in the presence of intra-abdominal and widespread metastases (5). Treatment has evolved slowly due to lack of uniform classification, delayed diagnosis, and limited therapeutic options. Multidisciplinary treatment including endocrinology, oncology, GI, and/or surgery depending on size and location of tumors.
MEDICATION
First Line
- Somatostatin in analogues (SAs): typically octreotide and lanreotide (reduces the diarrhea and flushing in at least 80% of patients) and, more recently, pasireotide (4)[B]. SAs control symptoms well. Refractory symptoms requiring dose escalation, increased dose frequency, or use of subcutaneous octreotide shots occur in up to 40% of patients within 6 to 18 months (1).
- Interferon-α can be added for symptoms refractory to SAs; improves risk of progressive disease and median survival but associated with more common adverse effects
- Chemotherapy with fluorouracil, doxorubicin, etoposide, cisplatin, and streptozocin (3) is used for poorly differentiated, rapidly progressive metastatic carcinoid tumors; no consensus on a standardized regimen.
- Studies currently assessing benefits of tyrosine kinase inhibitors and vascular endothelial growth factor antibodies
- For patients with milder symptoms, initial therapy may be aimed at symptom control alone: antidiarrheals, avoiding triggers for flushing (e.g., alcohol, spicy foods), and albuterol for bronchoconstriction. Antihistamines may also provide some relief for a histamine-secreting tumor.
SURGERY/OTHER PROCEDURES
- Surgery is the treatment for solitary tumors. If the disease is extensive, surgery may play a role depending on extent and location of the metastases.
- Hepatic metastases may be treated with hepatic artery embolization, chemoembolization, radioembolization, radiofrequency ablation, and cryoablation.
- Liver transplant is rarely performed for extensive hepatic disease.
- Future therapies: peptide-receptor radionuclide therapy with radiolabeled somatostatin analogues (2), to deliver radioactivity directly to somatostatin receptor-expressing tissues; not yet readily available
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Carcinoid tumors are associated with development of a second primary tumor due to tumorigenic activity of bioactive products. Patients with carcinoid tumors of the GI tract should be evaluated for a second primary malignancy, which occurs in 12-46% of cases.
DIET
Patients should avoid food and drinks that provoke symptoms (e.g., alcohol, caffeine, spicy foods).
PATIENT EDUCATION
- The Carcinoid Cancer Foundation: http://www.carcinoid.org/
- Caring for Carcinoid Foundation: http://www.caringforcarcinoid.org/
PROGNOSIS
- Prognosis varies depending on the site of origin, histologic features, and extent (stage) of disease.
- 5-year survival for early-stage disease >90%; with distant metastases, 5-year survival decreases to 40-50%.
- Presence of the carcinoid syndrome in patients with neuroendocrine tumors is a negative prognostic factor; estimated median survival rates: 5 to 8 years for these patients
- Metastatic disease generally is incurable; surgical debulking in selected patients may improve symptoms and extend survival.
COMPLICATIONS
- 10-30% of patients with carcinoid syndrome develop valvular heart disease (tricuspid regurgitation or pulmonary stenosis).
- Carcinoid crisis is cardiovascular collapse due to massive release of bioactive products from a carcinoid tumor resulting in vascular instability, profound flushing, and altered mental status.
- Carcinoid crisis can be induced by surgical manipulation of the tumor, anesthesia, chemotherapy, or hepatic artery embolization. Treatment includes immediate infusion of plasma and octreotide.
REFERENCES
11 Giovacchini G, Nicolas G, Forrer F. Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors. Anticancer Agents Med Chem. 2012;12(5):526-542.22 Wolin EM, Hu K, Hughes G, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study. Cancer Chemother Pharmacol. 2013;72(2):387-395.33 Kunz PL. Carcinoid and neuroendocrine tumors: building on success. J Clin Oncol. 2015;33(16):1855-1863.44 Oberg KE. The management of neuroendocrine tumours: current and future medical therapy options. Clin Oncol (R Coll Radiol). 2012;24(4):282-293.55 Liu EH, Solorzano CC, Katznelson L, et al. AACE/ACE disease state clinical review: diagnosis and management of midgut carcinoids. Endocr Pract. 2015;21(5):534-545.66 Salyers WJ, Vega KJ, Munoz JC, et al. Neuroendocrine tumors of the gastrointestinal tract: case reports and literature review. World J Gastrointest Oncol. 2014;6(8):301-310.
ADDITIONAL READING
- Coan KE, Gray RJ, Schlinkert RT, et al. Metastatic carcinoid tumors-are we making the cut? Am J Surg. 2013;205(6):642-646.
- Heller MT, Shah AB. Imaging of neuroendocrine tumors. Radiol Clin North Am. 2011;49(3):528-548.
- Kidd M, Modlin IM. Small intestinal neuroendocrine cell pathobiology: "˜carcinoid' tumors. Curr Opin Oncol. 2011;23(1):45-52.
- Kulke MH, Benson ABIII, Bergsland E, et al. Neuroendocrine tumors. J Natl Compr Canc Netw. 2012;10(6):724-764.
- Liu EH, Solorzano CC, Katznelson L, et al. AACE/ACE disease state clinical review: diagnosis and management of midgut carcinoids. Endocr Pract. 2015;21(5):534-545.
- Modlin IM, Pavel M, Kidd M, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169-188.
- Pusceddu S, De Braud F, Festinese F, et al. Evolution in the treatment of gastroenteropancreatic-neuroendocrine neoplasms, focus on systemic therapeutic options: a systemic review. Future Oncol. 2015;11(13):1947-1959.
- Srirajaskanthan R, Shanmugabavan D, Ramage JK. Carcinoid syndrome. BMJ. 2010;341:c3941.
- Strosberg JR, Weber JM, Feldman M, et al. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol. 2013;31(3):420-425.
CODES
ICD10
- E34.0 Carcinoid syndrome
- D3A.8 Other benign neuroendocrine tumors
ICD9
- 259.2 Carcinoid syndrome
- 209.60 Benign carcinoid tumor of unknown primary site
SNOMED
- Carcinoid syndrome (disorder)
- neuroendocrine tumor (disorder)
CLINICAL PEARLS
- <10% of carcinoid tumors produce symptoms therefore a delay in diagnosis is common. Often misdiagnosed as IBS.
- Major symptoms are diarrhea, flushing, and wheezing.
- Diagnosis established with elevated serum CgA levels and elevated 24-hour urine 5-HIAA.
- Somatostatin-receptor scintigraphy, CT, MRI, and barium enema help localize the tumor.