Carcinoid Syndrome

The most common clinical manifestation of neuroendocrine tumors1

"If the usual diagnostic tests [for IBS or other common GI disorders]—such as colonoscopy and upper endoscopy with the relevant biopsies—are unrevealing, this should raise the possibility of carcinoid syndrome, although it must be remembered that IBS is far more common than carcinoid syndrome." –Dr David C Metz

Carcinoid syndrome is believed to be caused by neurohormonal products, including serotonin, substance P, corticotrophin, histamine, dopamine, neurotensin, prostaglandins, kallikrein, and tachykinins, which can be released by an underlying tumor.2 It occurs in approximately 8% to 35% of patients with NETs.1 The most common signs and symptoms of carcinoid syndrome are flushing, diarrhea, abdominal cramping, and cardiac disease caused by valvular heart lesions.3 Some experts suggest that symptoms may be exacerbated by The 5 E's: eating, epinephrine, emotion, ethanol, and exercise.4,5

Adapted from Creutzfeldt W. World J Surg. 1996;20(2):126-131.

Focus: Four key symptoms of carcinoid syndrome

Chronic diarrhea and carcinoid syndrome

Chronic diarrhea is present in up to 80% of patients with carcinoid syndrome.3,6 There are many causes of chronic diarrhea7; however, certain characteristics may help associate this symptom with carcinoid syndrome and aid in a differential diagnosis.

The stools in diarrhea associated with carcinoid syndrome are watery and result from intestinal hypermotility and hypersecretion.3 The increase in gut motility in patients with carcinoid syndrome is likely to be caused by serotonin, which is released by certain types of NETs8 and stimulates small bowel and colonic secretions and motility.9,10

"A clue to carcinoid syndrome is that fasting does not reduce the diarrhea, because the increased motility and increased secretion are independent of intake." –Dr David C Metz

Another clue is that diarrhea may be nocturnal. Nocturnal diarrhea may be observed in other conditions (eg, IBD), but it is typically not seen in IBS.7 If IBD is suspected clinically, the patient can be evaluated endoscopically and/or radiologically. Note that there is limited information available in the literature on nocturnal diarrhea in carcinoid syndrome.11

Abdominal pain and carcinoid syndrome

Abdominal pain is a nonspecific symptom with many different potential causes. Diagnosing abdominal pain associated with carcinoid syndrome is difficult because there are no real distinguishing factors. In carcinoid syndrome, abdominal pain or discomfort may be due to gut hypermotility, obstructive-type symptoms or, rarely, intussusception of the neoplasm. Pain may also be due to serosal involvement of the neoplasm or stretching of the liver capsule because of large hepatic metastases.

Abdominal pain in carcinoid syndrome is intermittent12 and crampy,3 and occurs in approximately 40% to 51% of patients.3,8 Pain associated with diarrhea in carcinoid syndrome may be colicky9,13 and may not be relieved with defecation.14

Flushing and carcinoid syndrome

Flushing is the most common symptom of carcinoid syndrome and occurs in more than 90% of patients.9 Usually pink to red in color, flushing typically affects the face, neck, and upper trunk.8,9 Flushing in carcinoid syndrome is characteristically dry15—in women, this helps distinguish it from menopausal hot flashes, which are often associated with perspiration.16 The specific cause of flushing in carcinoid syndrome is unknown, although it has been shown to be preceded by a rise in substance P.17

Transient hypotension, headache, and bronchoconstriction may coincide with flushing in patients with carcinoid syndrome, particularly in those with foregut NETs.8 Physicians should consider that menopausal hot flashes are not associated with a fall in blood pressure.17

Cardiac disease and carcinoid syndrome

Cardiac disease is one of the most serious aspects of this disease, occurring in approximately two-thirds of patients with carcinoid syndrome.18

Cardiac manifestations usually develop late in neuroendocrine disease,9 when the right side of the heart is exposed to high levels of serotonin and other vasoactive substances released from hepatic metastases.19 This exposure is believed to result in fibrotic damage of the right heart endocardium and pulmonary and tricuspid valves.1,19,20

Left-sided heart disease is infrequent but has been observed in some patients.1,19

Carcinoid heart disease has been shown to be associated with increased levels of urinary 5-HIAA21,22 and can be detected with 2-dimensional echocardiographic and Doppler examinations.22

1. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol. 2005;89(3):151-160.
2. van der Lely AJ, de Herder WW. Carcinoid syndrome: diagnosis and medical management. Arq Bras Endocrinol Metab. 2005;49(5):850-860.
3. Creutzfeldt W. Carcinoid tumors: development of our knowledge. World J Surg. 1996;20(2):126-131.
4. Norheim I, Theodorsson-Norheim E, Brodin E, Öberg K. Tachykinins in carcinoid tumors: their use as a tumor marker and possible role in the carcinoid flush. 1986;63(3):605-612.
5. Grahame-Smith DG. What is the cause of the carcinoid flush? Gut. 1987;28(11):1413-1416.
6. von der Ohe MR, Camilleri M, Kvols LK, Thomforde GM. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329(15):1073-1078. Erratum in N Engl J Med. 1993;329(21):1592.
7. Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology. 1999;116(6):1464-1486.
8. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004;25(3):458-511.
9. McCormick D. Carcinoid tumors and syndrome. Gastroenterol Nurs. 2002;25(3):105-111.
10. Spiller R. Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signaling and metabolism in human disease. Neurogastroenterol Motil. 2007;19(suppl 2):25-31.
11. Wiedenmann B, Pape U-F. From basic to clinical research in gastroenteropancreatic neuroendocrine tumor disease—the clinician-scientist perspective. Neuroendocrinol. 2004;80(suppl 1):94-98.
12. Medline Plus Medical Encyclopedia. Carcinoid syndrome. http://www.nlm.nih.gov/medlineplus/ency/article
/000347.htm. Updated September 4, 2008. Accessed January 17, 2012.
13. Ghosh PK, O'Dorisio TM. Gastrointestinal hormones and carcinoid syndrome. In: Felig P, Frohman LA, eds. Endocrinology & Metabolism. 4th ed. New York, NY: McGraw-Hill; 2001:1317-1353.
14. Medline Plus Medical Encyclopedia. Irritable bowel syndrome. http://www.nlm.nih.gov/medlineplus/ency/
article/00246.htm. Updated August 22, 2008. Accessed May 7, 2009.
15. Martelli A, Ghiglioni D, Sarratud T, et al. Anaphylaxis in the emergency department: a paediatric perspective. Curr Opin Allergy Clin Immunol. 2008;8(4):321-329.
16. Jones NL, Judd HL. Menopause & postmenopause. In: DeCherney AH, Nathan L, eds. Current Obstetric & Gynecologic Diagnosis & Treatment. 9th ed. New York, NY: McGraw-Hill; 2002:1018-1040.
17. Vinik AI, Thompson N, Eckhauser F, Moattari AR. Clinical features of carcinoid syndrome and the use of somatostatin analogue in its management. Acta Oncologica. 1989;28(3):389-402.
18. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717-1751.
19. Møller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid disease. N Engl J Med. 2003;348(11):1005-1015.
20. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1559-1574.
21. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease: clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87(4):1188-1196.
22. Westberg G, Wängberg B, Ahlman H, Bergh CH, Beckman-Suurküla M, Caidahl K. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg. 2001;88(6):865-872.