Malignant Carcinoid Syndrome Clinical Presentation

  • Author: Luigi Santacroce, MD; Chief Editor: Jules E Harris, MD   more...
 
Updated: Jan 27, 2012
 

History

Carcinoid tumors grow slowly, and symptoms may not occur for several years, if at all. When symptoms do develop, they are ill defined and may be neglected for a long time before being properly diagnosed. In some cases, carcinoid tumors present as acute appendicitis or chronic pain in the lower right abdominal quadrant. For this reason, the condition is frequently misdiagnosed as irritable bowel syndrome.[18] Alcohol intolerance and weight loss also may be associated manifestations. Severity of symptoms varies. Onset of symptoms may be spontaneous or may be precipitated by certain foods and beverages (eg, alcohol), pharmacologic agents, and physical or emotional stress.

  • Diarrhea is common, as is flushing of the face and neck.[19] These manifestations result from tumoral hormone production; however, even if a carcinoid tumor produces these molecules, some patients do not experience any symptoms.
  • Right heart problems may develop because the tricuspid valve is stenosed by serotonin action, causing shortness of breath after a few years.
  • Other common problems include the following:
    • Asthma
    • Wheezing
    • Dyspnea
    • Palpitations
    • Low blood pressure
    • Fatigue
    • Dizziness
    • Asthenia
  • Uncommon symptoms include the following:
    • Myopathy
    • Arthritis
    • Arthralgias
    • Irritability, aggression, and lack of impulse control; these have been linked with low levels of plasma tryptophan and presumably with low brain serotonin.[15]
  • Flushing is a phenomenon of transient vasodilation causing reddening of the face, head, neck, and the upper chest and epigastric areas.[20]
    • Flushing is the most frequent symptom and may be brief (eg, 2-5 min) or may last for several hours, usually in later disease stages.
    • Flushing may be accompanied by tachycardia, while the blood pressure usually falls or does not change.
    • Malignant carcinoid syndrome is not a cause of sustained hypertension, and a rise in blood pressure during flushing is rare.
    • In addition to cutaneous vasodilation, some patients also develop telangiectasia, primarily on the face and neck, which is most marked in the malar area.
  • Intestinal obstruction may result from the primary tumor or from the sclerosing reaction in the surrounding mesentery. Necrosis of hepatic tumor masses may produce a typical acute syndrome with fever, abdominal pain, tenderness, and leukocytosis.
Next

Physical

Wheezing, facial telangiectasis with cyanosis and edema, pallor, flushing, macular erythema, and periorbital edema, accompanied by hepatomegaly, pellagralike skin lesions, steatorrhea, and chronic diarrhea, all suggest the diagnosis.

  • During chest examination, a pulmonary systolic and diastolic heart murmur may be heard if cardiac involvement is present. Cardiac involvement is associated with pulmonic valve stenosis and/or tricuspid insufficiency.[21]
  • Bronchospasms, which cause asthmalike attacks, are generally most pronounced during flushing attacks. Bronchospasms are a less common sign of malignant carcinoid syndrome but may be severe.
  • Any sign of niacin deficiency (pellagra) must be investigated carefully.[22]
  • Debilitating diarrhea is common and may have a secretory component.
    • As many as 20 episodes of diarrhea per day are possible and cause marked debilitation due to fluid, electrolyte, and protein depletion.
    • The diarrhea persists with fasting, fails to disappear when the patient is fed intravenously, and is usually accompanied by flushing; however, diarrhea occurs alone in approximately 15% of patients.
    • Abdominal borborygmi and cramping or pain may be present. When severe, malabsorption may occur and may even cause death.
  • Primary tumors seldom cause gastrointestinal bleeding.
  • Hepatomegaly from metastases is usually present, but extensive metastatic liver involvement may occur before liver function test results become abnormal.
  • Carcinoid heart disease is reported in approximately 50-60% of all patients with malignant carcinoid syndrome and is severe in approximately 25%.
    • Carcinoid heart disease occurs primarily on the right side of the heart but may involve the left side to a minimal degree.
    • Fibrous deposits adhering to the surface of the valvular endocardium may occur as part of this condition.[23]
    • Thickening of the endocardium of the cardiac chambers and papillary muscles and thickening and deformation of the valve cusps and chordae tendineae can lead to heart failure, influencing valvular function and causing regurgitation, stenosis, or combined functional lesions.
    • The tricuspid valve is affected most commonly.
Previous
Next

Causes

  • As with many other cancers, the exact cause is unknown. Malignant carcinoid syndrome does not generally appear to be hereditary.
  • A study of genetic alterations in small bowel carcinoid tumors found that loss of all or most of chromosome 18 was the most common finding. Heterozygosity was also lost on chromosome arms 9p and 16q. Although the amplitude of observed gains was modest in comparison with those reported in some other tumor types, one focal region of recurrent gain on 14q mapped to the locus of the gene encoding the antiapoptotic protein DAD1.[24]
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Luigi Santacroce, MD  Assistant Professor, Medical School, State University at Bari, Italy

Disclosure: Nothing to disclose.

Coauthor(s)

Laura Diomede  University of Bari School of Medicine, Italy

Disclosure: Nothing to disclose.

Lodovico Balducci, MD  Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute

Disclosure: Nothing to disclose.

Specialty Editor Board

Sanjiv S Agarwala, MD  Chief of Oncology and Hematology, St Luke's Cancer Center, St Luke's Hospital and Health Network; Professor, Temple University Shool of Medicine

Sanjiv S Agarwala, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Head and Neck Surgery, American Society of Clinical Oncology, Eastern Cooperative Oncology Group, and European Society for Medical Oncology

Disclosure: BMS Honoraria Speaking and teaching; Novartis Consulting fee Consulting; Merck Consulting fee Consulting

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD  Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research

Disclosure: GlobeImmune Salary Consulting

References

  1. Bendelow J, Apps E, Jones LE, et al. Carcinoid syndrome. Eur J Surg Oncol. Mar 2008;34(3):289-96. [Medline].

  2. Feldman JM. Carcinoid tumors and syndrome. Semin Oncol. Sep 1987;14(3):237-46. [Medline].

  3. Feldman JM. Carcinoid tumors and the carcinoid syndrome. Curr Probl Surg. Dec 1989;26(12):835-85. [Medline].

  4. Lubarsch O. Ueber den primaren Krebs des Ileum, nebst Bemerhunge uber das gleichzeitge Vorkommen von Krebs und Tuberculose. Virchows Arch. 1888;111:280-317.

  5. Oberndorfer S. Uber die "kleinen Dunndarm Carcinome". Verh Dtsch Ges Pathol. 1907;11:113—6.

  6. Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-Hydroxytryptamine. Nature. 1952;169:800-1.

  7. Gosset A, Masson P. Tumeurs endocinne de l'appendice. Presse Med. 1914;22:237-40.

  8. Masson, P. Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of appendicular mucosa. Am J Patholol. 1928;4:181-212.

  9. Ahlman H. Midgut carcinoid tumors. Surg Annu. 1986;18:65-93. [Medline].

  10. Papadogias D, Makras P, Kossivakis K, et al. Carcinoid syndrome and carcinoid crisis secondary to a metastatic carcinoid tumour of the lung: a therapeutic challenge. Eur J Gastroenterol Hepatol. Dec 2007;19(12):1154-9. [Medline].

  11. Bonaros N, Muller S, Bonatti J, et al. Primary ovarian carcinoid heart disease curatively treated with a two-stage procedure. Thorac Cardiovasc Surg. Oct 2007;55(7):467-9. [Medline].

  12. Chaowalit N, Connolly HM, Schaff HV, et al. Carcinoid heart disease associated with primary ovarian carcinoid tumor. Am J Cardiol. May 15 2004;93(10):1314-5. [Medline].

  13. Bhattacharyya S, Davar J, Dreyfus G, et al. Carcinoid heart disease. Circulation. Dec 11 2007;116(24):2860-5. [Medline].

  14. Cunningham JL, Janson ET, Agarwal S, Grimelius L, Stridsberg M. Tachykinins in endocrine tumors and the carcinoid syndrome. Eur J Endocrinol. Sep 2008;159(3):275-82. [Medline].

  15. Russo S, Boon JC, Kema IP, Willemse PH, den Boer JA, Korf J, et al. Patients with carcinoid syndrome exhibit symptoms of aggressive impulse dysregulation. Psychosom Med. May-Jun 2004;66(3):422-5. [Medline]. [Full Text].

  16. Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG. Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol. Sep 2001;12(9):1295-300. [Medline]. [Full Text].

  17. Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand A. Jul 1976;84(4):322-30. [Medline].

  18. Wilson HM. Chronic subacute bowel obstruction caused by carcinoid tumour misdiagnosed as irritable bowel syndrome: a case report. Cases J. Jan 22 2009;2(1):78. [Medline].

  19. Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc. 2000;21(1):21-4. [Medline].

  20. Kleyn CE, Lai-Cheong JE, Bell HK. Cutaneous manifestations of internal malignancy: diagnosis and management. Am J Clin Dermatol. 2006;7(2):71-84. [Medline].

  21. Monsegu J, Algayres JP, Ciribilli JM, et al. [Tricuspid insufficiency disclosing carcinoid syndrome]. Rev Med Interne. 1994;15(9):593-6. [Medline].

  22. Shah GM, Shah RG, Veillette H, Kirkland JB, Pasieka JL, Warner RR. Biochemical assessment of niacin deficiency among carcinoid cancer patients. Am J Gastroenterol. Oct 2005;100(10):2307-14. [Medline].

  23. Banzali FM Jr, Tiwari AK, Frantz R, et al. Valvular heart disease caused by carcinoid syndrome: emphasis on the use of intraoperative transesophageal echocardiography. J Cardiothorac Vasc Anesth. Dec 2007;21(6):855-7. [Medline].

  24. Kulke MH, Freed E, Chiang DY, Philips J, Zahrieh D, Glickman JN, et al. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer. Jul 2008;47(7):591-603. [Medline].

  25. Granerus G, Lindell SE, Waldenstrom J, et al. Histamine metabolism in carcinoidosis. Lancet. Jun 4 1966;1(7449):1267-8. [Medline].

  26. Campana D, Nori F, Piscitelli L, Morselli-Labate AM, Pezzilli R, Corinaldesi R, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors?. J Clin Oncol. May 20 2007;25(15):1967-73. [Medline].

  27. Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J. Usefulness of N-terminal pro-brain natriuretic peptide as a biomarker of the presence of carcinoid heart disease. Am J Cardiol. Oct 1 2008;102(7):938-42. [Medline].

  28. Sinzinger H, Renner F, Granegger S. Unsuccessful iodine-131 MIBG imaging of carcinoid tumors and apudomas. J Nucl Med. Jul 1986;27(7):1221-2. [Medline].

  29. Garg S, Bourantas CV, Nair RK, Alamgir F. Carcinoid syndrome diagnosed by echocardiography. Int J Cardiol. Feb 11 2009;[Medline].

  30. Bastarrika G, Cao MG, Cano D, et al. Magnetic resonance imaging diagnosis of carcinoid heart disease. J Comput Assist Tomogr. Nov-Dec 2005;29(6):756-9. [Medline].

  31. Sinha V, Dyer P, Shuvro RC, Geh JI, Karandikar S. Case of carcinoid crisis following a fine-needle biopsy of hepatic metastasis. Eur J Gastroenterol Hepatol. Jan 2009;21(1):101-3. [Medline].

  32. Joensuu H, Kumpulainen E, Grohn P. Treatment of metastatic carcinoid tumour with recombinant interferon alfa. Eur J Cancer. 1992;28A(10):1650-3. [Medline].

  33. [Best Evidence] Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, 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. Oct 1 2009;27(28):4656-63. [Medline].

  34. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. Dec 10 2011;378(9808):2005-12. [Medline].

  35. Hodul P, Malafa M, Choi J, et al. The role of cytoreductive hepatic surgery as an adjunct to the management of metastatic neuroendocrine carcinomas. Cancer Control. Jan 2006;13(1):61-71. [Medline].

  36. Eller R, Frazee R, Roberts J. Gastrointestinal carcinoid tumors. Am Surg. Jul 1991;57(7):434-7. [Medline].

  37. Farndon JR. The carcinoid syndrome: methods of treatment and recent experience with hepatic artery ligation and infusion. Clin Oncol. Dec 1977;3(4):365-75. [Medline].

  38. Codd JE, Drozda J, Merjavy J. Palliation of carcinoid heart disease. Arch Surg. Sep 1987;122(9):1076-7. [Medline].

  39. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation. Dec 11 2007;116(24):2860-5. [Medline].

  40. Chambers AJ, Pasieka JL, Dixon E, Rorstad O. The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors. Surgery. Oct 2008;144(4):645-51; discussion 651-3. [Medline].

  41. Bernheim AM, Connolly HM, Rubin J, Møller JE, Scott CG, Nagorney DM, et al. Role of hepatic resection for patients with carcinoid heart disease. Mayo Clin Proc. Feb 2008;83(2):143-50. [Medline].

  42. Gregor M. Therapeutic principles in the management of metastasising carcinoid tumors: drugs for symptomatic treatment. Digestion. 1994;55 Suppl 3:60-3. [Medline].

  43. Kleyn CE, Lai-Cheong JE, Bell HK. Cutaneous manifestations of internal malignancy: diagnosis and management. Am J Clin Dermatol. 2006;7(2):71-84. [Medline].

  44. Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (includingcarcinoid) tumours. Gut. Jun 2005;54 Suppl 4:iv:1-16. [Medline].

  45. Patients, Caregivers, and Friends. The Carcinoid Foundation. Available at www.carcinoid.org/index.shtml. Accessed September 27, 2009.

  46. Jabbour-Khoury S, Dabbous A, al-Jazzar M, et al. Anesthetic management of a patient having a carcinoid syndrome. Middle East J Anesthesiol. Oct 2003;17(3):435-47. [Medline].

  47. Anderson AS, Krauss D, Lang R. Cardiovascular complications of malignant carcinoid disease. Am Heart J. Oct 1997;134(4):693-702. [Medline].

  48. Anthony LB, Martin W, Delbeke D, et al. Somatostatin receptor imaging: predictive and prognostic considerations. Digestion. 1996;57 Suppl 1:50-3. [Medline].

  49. Bhattacharyya S, Toumpanakis C, Caplin ME, et al. Analysis of 150 patients with carcinoid syndrome seen in a single year at one institution in the first decade of the twenty-first century. Am J Cardiol. Feb 1 2008;101(3):378-81. [Medline].

  50. Bourgault C, Bergeron S, Bogaty P, et al. A most unusual acute coronary syndrome. Can J Cardiol. Apr 2006;22(5):429-32. [Medline].

  51. de Diego C, Marcos Alberca P, Cabrera JA, et al. Pathognomonic echocardiographic features of carcinoid syndrome. Clin Cardiol. Mar 2006;29(3):134. [Medline].

  52. [Guideline] de Herder WW, O'Toole D, Rindi G. ENETS Consensus Guidelinesfor the Diagnosis and Treatment of Neuroendocrine Gastrointestinal TumorsPart 2 - Midgut and Hindgut Tumors. Neuroendocrinology. 2008;87.

  53. Di Lucca J, Mahé E, Saiag P. [Severe acrocyanosis in carcinoid syndrome]. Ann Dermatol Venereol. Nov 2007;134(11):895-6. [Medline].

  54. Farling PA, Durairaju AK. Remifentanil and anaesthesia for carcinoid syndrome. Br J Anaesth. Jun 2004;92(6):893-5. [Medline].

  55. Feldman JM. Histaminuria from histamine-rich foods. Arch Intern Med. Nov 1983;143(11):2099-102. [Medline].

  56. Frilling A, Rogiers X, Knofel WT, et al. Liver transplantation for metastatic carcinoid tumors. Digestion. 1994;55 Suppl 3:104-6. [Medline].

  57. González O, Alberca MT, Santonja C. Echocardiographic diagnosis of carcinoid disease: exceptional evolution after ovarian tumor resection without cardiac surgery. Eur J Echocardiogr. Dec 2007;8(6):497-500. [Medline].

  58. Hodgson HJ. Controlling the carcinoid syndrome. BMJ. Nov 12 1988;297(6658):1213-4. [Medline].

  59. Jaber WA, Klarich KW. Images in cardiovascular medicine. Carcinoid heart disease. Circulation. Feb 21 2006;113(7):e160-1. [Medline].

  60. Jagernauth S, Patel A, Baig K, et al. Fungal endocarditis of the eustachian valve in carcinoid heart disease: a case report. J Heart Valve Dis. Nov 2007;16(6):631-3. [Medline].

  61. Lee KJ, Connolly HM, Pellikka PA. Carcinoid pulmonary valvulopathy evaluated by real-time 3-dimensional transthoracic echocardiography. J Am Soc Echocardiogr. Apr 2008;21(4):407.e1-2. [Medline].

  62. Majeed F, Porter TR, Tarantolo S, et al. Carcinoid crisis and reversible right ventricular dysfunction after embolization in untreated carcinoid syndrome. Eur J Echocardiogr. Oct 2007;8(5):386-9. [Medline].

  63. Mansencal N, Mitry E, Forissier JF, et al. Assessment of patent foramen ovale in carcinoid heart disease. Am Heart J. May 2006;151(5):1129.e1-6. [Medline].

  64. Maton PN. The carcinoid syndrome. JAMA. Sep 16 1988;260(11):1602-5. [Medline].

  65. Merino J, Zuluaga A, Gutierrez-Tejero F, et al. Pure testicular carcinoid associated with intratubular germ cell neoplasia. J Clin Pathol. Dec 2005;58(12):1331-3. [Medline].

  66. Mignon M. Natural history of neuroendocrine enteropancreatic tumors. Digestion. 2000;62 Suppl 1:51-8. [Medline].

  67. [Best Evidence] Moller JE, Pellikka PA, Bernheim AM, et al. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation. Nov 22 2005;112(21):3320-7. [Medline].

  68. Mollet NR, Dymarkowski S, Bogaert J. MRI and CT revealing carcinoid heart disease. Eur Radiol. Dec 2003;13 Suppl 4:L14-8. [Medline].

  69. Park SB, Kim JK, Cho KS. Imaging findings of a primary bilateral testicular carcinoid tumor associated with carcinoid syndrome. J Ultrasound Med. Mar 2006;25(3):413-6. [Medline].

  70. Robertson RG, Geiger WJ, Davis NB. Carcinoid tumors. Am Fam Physician. 2006;74(3):429-34. [Full Text].

  71. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol. Mar 1 2005;89(3):151-60. [Medline].

  72. Rosenberg JM, Welch JP. Ileal tumor causing carcinoid syndrome without hepatic metastases. Arch Surg. Apr 1984;119(4):485. [Medline].

  73. Shapiro RS, Shafir M, Sung M, et al. Cryotherapy of metastatic carcinoid tumors. Abdom Imaging. May-Jun 1998;23(3):314-7. [Medline].

  74. Somak R, Shramana M, Vijay S, et al. Primary carcinoid tumor of the ovary: a case report. Arch Gynecol Obstet. Jan 2008;277(1):79-82. [Medline].

  75. Stella M, Decian F, Mithieux F, et al. Ileal carcinoid with liver metastasis presenting after ten years with abdominal mass and right heart failure: report of a case. Tumori. Jan-Feb 2006;92(1):83-5. [Medline].

  76. van der Horst-Schrivers AN, Wymenga AN, Links TP, et al. Complications of midgut carcinoid tumors and carcinoid syndrome. Neuroendocrinology. 2004;80 Suppl 1:28-32. [Medline].

  77. Yeo CJ, Couse NF, Zinner MJ. Serotonin and substance P stimulate intestinal secretion in the isolated perfused ileum. Surgery. Jan 1989;105(1):86-92. [Medline].

  78. Zeitlin IJ. Kinin release in the carcinoid syndrome. Lancet. Nov 1971;2(7732):1040. [Medline].

 
Previous
Next
 
A section (on the right) of an intestinal carcinoid mass arising from the mucosa (150 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a carcinoid mass (350 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a rare lymph node metastasis from adenocarcinoid tumor (250 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.