Carcinoid Tumors RUSSELL G. ROBERTSON, M.D., Northwestern University, Chicago, Illinois WILLIAM J. GEIGER, M.D., and NANCY B. DAVIS, M.D. Medical College of Wisconsin, Milwaukee, Wisconsin

Carcinoid tumors are rare, slow-growing neuroendocrine that often are indolent and may not become clinically apparent until there has been metastatic spread or evidence of carci- noid syndrome. Recent evidence has revealed that the overall incidence of carcinoid tumors has been steadily increasing, and although the disease was thought to be relatively benign, it is now considered one of increasing . Carcinoid tumors derive from different embryonic divi- sions of the gut: foregut carcinoid tumors commonly originate in the , bronchi, or ; carcinoid tumors in the , , or proximal large bowel; and hindgut carcinoid tumors in the distal colon or . , although rare, is most associ- ated with midgut carcinoid tumors. The diagnosis of a carcinoid tumor often is coincidental with performed for another reason. Treatment and prognosis are dependent on the location of the primary tumor and the degree and extent of at the time of diagnosis. (Am Fam Physician 2006;74:429-34. Copyright © 2006 American Academy of Family Physicians.)

arcinoid tumors are rare, slow- greater than 2 percent but less than 15 per- growing tumors that originate in cent); poorly differentiated endocrine car- the cells of the neuroendocrine sys- cinoma (PI greater than 15 percent); mixed tem. The nerve cells rarely undergo exocrine-endocrine tumors; and tumor-like C or neoplastic transformation, lesions. Table 12,4,5 provides an overview of whereas cells in the endocrine and in the incidence rate, average age at onset, asso- disseminated sites in the mucous membranes ciated symptoms, likelihood of metastasis, and skin may undergo a transformation com- and commonness of carcinoid syndrome monly known as carcinoid tumors.1 There for carcinoid tumors in different locations are three main areas of origin for carcinoid of the body. tumors: foregut carcinoid tumors start in the Carcinoid tumors pose a diagnostic chal- lungs, bronchi, or stomach; midgut carcinoid lenge because they often are asymptomatic. tumors start in the small intestine, appendix, The overall prevalence of carcinoid tumors or proximal large bowel; and hindgut carci- in the United States is estimated to be one noid tumors start in the distal colon or rec- to two cases per 100,000 persons.3,4 Because tum.2 The appendix is the most common site many carcinoid tumors are indolent, their of carcinoid tumors, followed by the rectum, true prevalence may be higher.5 Data derived , lungs, bronchi, and stomach.3 from a five-decade analysis of 13,715 carci- Historically, the classification and distribu- noid tumors revealed an overall increase in tion of carcinoid tumors has been according incidence over the past 30 years, with 67.2 per- to their derivation from different embry- cent of patients having a five-year survival rate onic divisions of the gut. More recently, regardless of the site of the tumor.2 Prognosis the World Health Organization varies widely depending on the location and presented new classifications of stage of the tumor.1,2 The disease is considered There has been an overall gastroenteropancreatic neuro- to be more aggressive and to have a worse increase in incidence of car- endocrine neoplasms1 based on prognosis than was thought previously.2 cinoid tumors over the past their malignant potential: well- 30 years, with 67.2 percent differentiated endocrine tumor Clinical Presentation of patients having a five- (proliferation index [PI] less Many carcinoid tumors are found during year survival rate. than 2 percent); well-differen- surgery for other reasons, usually at appen- tiated endocrine (PI dectomy or surgery for acute pancreatitis,

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Evidence Clinical recommendation rating References

5-Hydroxyindoleacetic acid and serum chromogranin A are C 13, 17 recommended as initial tests for patients with vasoactive symptoms and suspected carcinoid tumors. A multimodal approach is recommended for imaging and may include C 13 CT, MRI, receptor scintography using indium-111 labeled , and endoscopic ultrasonography. Patients with carcinoid tumors of the should be C 21, 22 evaluated for second primary malignancy.

CT = computed tomography; MRI = magnetic resonance imaging. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 363 or http://www.aafp.org/afpsort.xml.

but also surgery for bowel obstruction or CARCINOID SYNDROME diseases of the female reproductive tract.6,7 A carcinoid tumor often is only considered If there are symptoms, they usually are after the onset of carcinoid syndrome, which vague, nonspecific, and organ-related, typically does not occur until the tumor has causing relatively long delays in diagnosis. metastasized to the lungs or .9 The symp- The average time from symptom onset toms of carcinoid syndrome include to diagnosis is more than nine years.8 (pale, purplish, or red), (watery Symptoms from the tumor can range from and explosive), tachycardia or hypotension, mild abdominal discomfort to intermit- bronchospasm, telangiectasia, and right- tent intestinal obstruction.9 Occasionally, sided disease or failure.1,9,10 Symptoms a carcinoid tumor can be the lead point for often are precipitated by exertion or by an intermittent intestinal intussuception.9 eating or drinking (especially items high in These tumors characteristically present at tyramine [e.g., blue cheeses, chocolate] or age 50 to 60.8 ethanol [e.g., red wine]).1,9,10

TABLE 1 Characteristics of Carcinoid Tumors by Location

Approximate age Carcinoid Location Percent at presentation Symptoms Metastasis at diagnosis syndrome (%)

Rectum 26 60 Rectal , pain, Tumor size < 1 cm: < 5 constipation 5 percent Tumor size > 2 cm: majority Small intestine 25 60 to 70 Abdominal pain, small bowel Majority present with 5 to 7 obstruction metastasis, usually to lymph nodes or liver Lungs, bronchi, 23 50 Recurrent pneumonia, cough, < 15 percent < 5 and trachea hemoptysis, chest pain Appendix 12 40 to 50 Appendicitis caused by tumor < 5 percent < 5 presence; incidental discovery during other pelvic procedures Stomach 7 60 to 70 Anemia, abdominal pain < 10 percent 5 to 10; also Zollinger-Ellison syndrome Colon 7 70 Pain, anorexia, weight loss > 66 percent < 5

Information from references 2, 4, and 5.

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Carcinoid tumors contain many neuro- Diagnosis secretory granules that are capable of the Although a significant percentage of car- synthesis, storage, and release of substances, cinoid tumors are innocuous at the time including , histamine, prostaglan- of presentation, there are useful diagnostic dins, kallikrein, bradykinins, substance P, techniques that facilitate identification and gastrin, corticotrophin, and neuron-specific localization. Because the presentation varies enolase.9,11 The most prominent of these with the embryologic origin of the tumor, substances is serotonin (i.e., 5-hydroxytryp- there are differing approaches to the diagno- tamine). Degradation of 5-hydroxytrypta- sis. The indolent nature of carcinoid tumors mine results in 5-hydroxyindoleacetic acid makes test selection complex. For patients (5-HIAA), which is excreted in the urine. with vasoactive symptoms, measuring the When released in the systemic circulation, urinary excretion of 5-HIAA and serum 5-hydroxytryptamine can result in the chromogranin A level is recommended.13 For symptoms of carcinoid syndrome; the exci- those with symptoms of bowel dysmotility tation of smooth muscle leads to increased syndromes, computed tomography (CT) and gastrointestinal motility, bronchoconstric- magnetic resonance imaging (MRI) may be tion, platelet aggregation, or vascular con- helpful and often will note the coincidental striction and dilatation.12 presence of hepatic metastases that may be The lungs and liver metabolize many of the first clue as to the presence of the primary the substances secreted by carcinoid tumors, tumor.9,11 thus preventing their release into the sys- temic circulation until metastases develop.9 URINALYSIS The syndrome is variable: patients may not The biochemical properties of carcinoid have all symptoms, and the symptoms may tumors reflect the presence of neurosecre- vary in intensity and timing.9 Carcinoid tory granules that these tumors share with syndrome occurs in only 10 percent of all other similarly classified tumors referred to patients with carcinoid tumors,8 and it is as (Amine Precursor Uptake and most often associated with midgut tumors.5 Decarboxylation).14 Carcinoid tumors are Table 210 is a differential diagnosis of carci- classified as biochemically typical or atypical noid syndrome symptoms. based on the presence of high levels of sero- Although the exact secreted substance tonin in so-called typical tumors.15 The best responsible for the flushing is uncertain and controversial, the diarrhea seems to be largely caused by excessive serotonin in TABLE 2 the system.8,9 Bronchospasm may be medi- Differential Diagnosis of Carcinoid Syndrome ated by serotonin and bradykinin, although this has not been definitively delineated.8 Flushing Right-sided is thought Menopausal syndrome; pheochromocytoma; mastocytosis; benign to be caused by prolonged high serum lev- cutaneous flushing; medullary of the thyroid; ingestants els of serotonin and is therefore a later (e.g., food, drugs) complication. Patients with carcinoid heart Wheezing disease demonstrate higher levels of serum Asthma; anaphylaxis; pulmonary edema; bronchial foreign body serotonin and urine 5-HIAA than other Diarrhea patients with carcinoid syndrome.6 Endo- Gastroenteritis; inflammatory bowel disease; infectious colitis; laxative cardial fibrosis is the underlying abuse that results in thickened and contracted Heart valve symptoms heart valves, producing the most common Rheumatic heart disease; subacute bacterial endocarditis; dilated cardiomyopathy; ischemic heart disease with papillary muscle lesions of pulmonic stenosis and tricuspid dysfunction insufficiency. Left-side heart valves usually are less affected because of the metabolism Information from reference 10. of serotonin in the lungs.9,11

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known metabolite of serotonin in carcinoid of neuroendocrine tumors.8 There is some tumors is 5-HIAA. In a 24-hour sample, the new evidence that indicates that positron urinary level of 5-HIAA is the test most com- emission tomography (PET) may be useful monly used in the endocrine work-up of car- in the diagnosis of neuroendocrine tumors cinoid tumors. Despite its popularity, it lacks as well.19 Somatostatin receptor scintigraphy the sensitivity and specificity for the diagno- with indium-111 labeled octreotide is supe- sis of carcinoid tumors because 5-HIAA may rior to CT scans for localizing the primary not be elevated in atypical carcinoids and can tumor site and to MIBG scans in the diag- be elevated in other conditions nosis of carcinoid tumors, with a 60 percent such as tropical sprue, celiac sensitivity and a greater than 90 percent Carcinoid syndrome occurs disease, Whipple’s disease, and sensitivity in patients with symptoms of car- in only 10 percent of small bowel obstruction, and cinoid syndrome.13,20 patients with neuroendo- can be caused by ingestion of crine tumors. foods high in serotonin, or cer- Second Primary Malignancy tain medications.16 In a patient with a known carcinoid tumor of the gastrointestinal tract, there is an SERUM ANALYSIS additional concern about a second primary Although a number of other tumor markers malignancy. The rate of second primary have been investigated for carcinoid tumor malignancy with carcinoid tumors ranges overproduction, serum analysis of chromo- from 12 to 46 percent, with an average of granin A, a glycoprotein that is secreted with 17 percent, which is significant when com- other by neuroendocrine tumors, pared with rates of second primary malig- appears to be the most promising, with speci- nancy in other , where 2.3 percent of ficity approaching 95 percent and sensitivity patients undergoing surgery and 8.1 percent for carcinoid tumors approaching 80 per- of autopsied patients have a second pri- cent. A 40 percent false-positive rate has been mary malignancy.20,21 Most second primary seen in patients with multiple myeloma.17 present concurrently and are more aggressive, resulting in -medi- DIAGNOSTIC IMAGING ated death.22 The most common sites for Diagnostic imaging techniques may be second primary malignancies are the gastro- relative to the origin and the degree of intestinal tract, genitourinary tract, and dissemination at the time of diagnosis. A or bronchial system.21 multimodal approach is recommended, using combinations of imaging studies Treatment depending on the suspected site of the Treatment decisions for patients with carci- tumor.13 Barium contrast studies or CT may noid tumors are complex and related to the detect mucosal thickening, a submucosal location of the primary tumor and whether or mass, or luminal narrowing.8,18 CT is an not metastasis has occurred. The main treat- excellent technique to show the mesenteric ment options and approaches are outlined extension of tumors and liver metastases. in Table 3.1,23 Options include surgery, che- Carcinoids that have infiltrated have a char- motherapy, and radiation with somatostatin acteristic CT appearance that is spiculated analogues such as octreotide (Sandostatin) with a stellate pattern.8 The appearance of or alpha-interferon.15,24,25 Further discussion carcinoids with MRI seems to resemble that of treatment options for carcinoid tumors is seen with CT.8 Endoscopic ultrasonography available in a recent British guideline,13 the is also an imaging option.13 series by Oberg and colleagues,26 and the National Comprehensive Cancer Network NUCLEAR MEDICINE Guidelines (http://www.nccn.org).27 Patients Meta-iodobenzylguanidine (MIBG) is a with carcinoid tumors should be referred to structural analogue to norepinephrine, and subspecialists who have expertise in its diag- I-labeled MIBG can be used for the detection nosis, staging, and treatment.

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TABLE 3 General Treatment Options for Malignant Carcinoid Tumors

Carcinoid tumor Surgical resection if possible: Hepatic metastases dominant: long-acting somatostatin analogues; hepatic artery embolization or ligation with or without interferon, with or without Systemic spread: chemotherapy or interferon or long-acting somatostatin analogues Carcinoid syndrome Systematic progression through treatment options: Heart disease: diuretics, long-acting somatostatin analogues, occasional valvular replacement Flushing: avoid precipitating food and alcohol; 5-HT3-receptor antagonist; long-acting somatostatin analogues; interferon; hepatic artery embolization or ligation with or without interferon, with or without chemotherapy Diarrhea: antidiarrheal agents; 5-HT3-receptor antagonist; long-acting somatostatin analogues; interferon; hepatic artery embolization or ligation with or without interferon, with or without chemotherapy Wheezing: selective bronchodilators; long-acting somatostatin analogues; interferon; hepatic artery embolization or ligation with or without interferon, with or without chemotherapy

5-HT3 = serotonin receptor subtype 5-hydroxytryptamine-3. Information from references 1 and 23.

Prognosis Internal Medicine at the Medical College of Wisconsin, Milwaukee. She graduated from the University of Texas Most patients with carcinoid tumors seek at Houston and completed her residency in internal treatment for metastatic disease.24 The prog- medicine and a fellowship in hematology/ at nosis for patients with these tumors is vari- the University of Chicago, Chicago, Ill. able and related to the site of the primary Address correspondence to Russell G. Robertson, M.D., tumor, the presence of metastatic disease, Feinburg School of Medicine, Northwestern University, and time of diagnosis. Importantly, the most 710 N. Lakeshore Dr., Room 1415, Chicago, IL 60611 (e-mail: [email protected]). Reprints are not common cause of carcinoid syndrome is available from the authors. metastatic liver disease arising from a small bowel carcinoid tumor. For these patients, The authors thank Sean Wall, M.D., and Andrew Stock, M.D., at Columbia-St. Mary’s Family Practice Residency 3 the prognosis is uniformly poor. Program, for research done for the preparation of the manuscript. The Authors Author disclosure: Nothing to disclose. RUSSEL G. ROBERTSON, M.D., is professor and chair of the Department of Family Medicine at the Feinberg School of Medicine at Northwestern University, Chicago, Ill. He is a REFERENCES graduate of Wayne State University School of Medicine in Detroit, Mich., and completed his family medicine 1. Oberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, residency at the Grand Rapids (Mich.) Family Medicine Gustafsen J, et al. Guidelines for the management of Residency Program. gastroenteropancreatic neuroendocrine tumors (includ- ing bronchopulmonary and thymic neoplasms). Part WILLIAM J. GEIGER, M.D., is associate professor in the I-general overview. Acta Oncol 2004;43:617-25. Department of Family and Community Medicine at the 2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of Medical College of Wisconsin and program director of the 13,715 carcinoid tumors. Cancer 2003;97:934-59. Columbia-St. Mary’s Family Practice Residency Program in 3. Godwin JD II. Carcinoid tumors. An analysis of 2,837 Milwaukee. He is a graduate of the Ohio State University cases. Cancer 1975;36:560- 9. School of Medicine in Columbus and completed his family 4. Modlin IM, Sandor A. An analysis of 8305 cases of medicine residency at Akron (Ohio) City Hospital. carcinoid tumors. Cancer 1997;79:813-29. NANCY B. DAVIS, M.D., is assistant professor in the 5. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med division of neoplastic diseases in the Department of 1999;340:858-68.

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6. Goede AC, Caplin ME, Winslet MC. Carcinoid tumour and the alpha-subunit of glycoprotein hormones. of the appendix. Br J Surg 2003;90:1317-22. J Clin Endocrinol Metab 1997;82:2622-8. 7. Mayoral W, Salcedo J, Al-Kawas F. Ampullary carcinoid 18. Picus D, Glazer HS, Levitt RG, Husband JE. Computed tumor presenting as acute pancreatitis in a patient with tomography of abdominal carcinoid tumors. AJR Am von Recklinghausen’s disease: case report and review J Roentgenol 1984;143:581-4. of the literature. Endoscopy 2003;35:854-7. 19. Sundin A, Eriksson B, Bergstrom M, Langstrom B, 8. Horton KM, Kamel I, Hofmann L, Fishman EK. Carcinoid Oberg K, Orlefors H. PET in the diagnosis of neuroen- tumors of the small bowel: a multitechnique imaging docrine tumors. Ann N Y Acad Sci 2004;1014:246-57. approach. AJR Am J Roentgenol 2004;182:559-67. 20. Kaltsas G, Korbonits M, Heintz E, Mukherjee JJ, Jen- 9. de Vries H, Verschueren RC, Willemse PH, Kema IP, de kins PJ, Chew SL, et al. Comparison of somatostatin Vries EG. Diagnostic, surgical and medical aspect of the analog and meta-iodobenzylguanidine radionuclides midgut carcinoids. Cancer Treat Rev 2002;28:11-25. in the diagnosis and localization of advanced neu- 10. Metcalfe DD. Differential diagnosis of the patient with roendocrine tumors. J Clin Endocrinol Metab 2001; unexplained flushing/anaphylaxis. Allergy Asthma Proc 86:895-902. 2000;21:21-4. 21. Habal N, Sims C, Bilchik AJ. Gastrointestinal carcinoid 11. Graham GW, Unger BP, Coursin DB. Perioperative man- tumors and second primary malignancies. J Surg Oncol agement of selected endocrine disorders. Int Anesthe- 2000;75:310-6. siol Clin 2000;38:31-67. 22. Gerstle JT, Kaufman GL Jr, Koltun WA. The incidence, 12. Hage R, de la Riviere AB, Seldenrijk CA, van den Bosch management, and outcome of patients with gastroin- JM. Update in pulmonary carcinoid tumors: a review testinal carcinoids and second primary malignancies. article. Ann Surg Oncol 2003;10:697-704. J Am Coll Surg 1995;180:427-32. 13. Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Gross- 23. Jensen RT, Doherty GM. Carcinoid tumors and the man A, et al., for the UKNETwork for Neuroendocrine carcinoid syndrome. In: DeVita VT Jr, Hellman S, Tumours. Guidelines for the management of gastro- Rosenberg SA, eds. Cancer: Principles & Practice of enteropancreatic neuroendocrine (including carcinoid) Oncology. 7th ed. Philadelphia, Pa.: Lippincott Wil- tumours. Gut 2005;54 (suppl 4):iv1-16. liams & Wilkins, 2005:1559-74. 14. Pearse AG. The APUD concept and produc- 24. Oberg K. Carcinoid tumors: molecular genetics, tumor tion. Clin Endocrinol Metab 1980;9:211-22. biology, and update of diagnosis and treatment. Curr Opin Oncol 2002;14:38-45. 15. Pasieka JL, McKinnon JG, Kinnear S, Yelle CA, Numerow L, Paterson A, et al. Carcinoid syndrome 25. Oberg K. Chemotherapy and biotherapy in the symposium on treatment modalities for gastrointes- treatment of neuroendocrine tumors. Ann Oncol tinal carcinoid tumours: symposium summary. Can 2001;12(suppl 2):S111-4. J Surg 2001:44;25-32. 26. Oberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, 16. Roberts LJ, Anthony LB, Oates JA. Disorders of vasodila- Gustafsen J, et al; for the Nordic NE Tumour Group. tor hormones; carcinoid syndrome and mastocytosis. Guidelines for the management of gastroenteropan- In: Williams RH, Wilson JD, eds. Williams Textbook creatic neuroendocrine tumours (including broncho- of Endocrinology. 9th ed. Philadelphia, Pa.: Saunders, pulmonary and thymic neoplasms). Part II-specific NE 1998:1711-20. tumour types. Acta Oncol 2004;43:626-36. 17. Nobels FR, Kwekkeboom DJ, Coopmans W, Schoen- 27. National Comprehensive Cancer Network. Carcinoid makers CH, Lindemans J, De Herder WW, et al. tumors. In: NCCN practice guidelines in oncology – Chromogranin A as serum marker for neuroendocrine v.2.2005. Neuroendocrine tumors. Accessed March 2, neoplasia: comparison with neuron-specific enolase 2006, at: http://www.nccn.org/professionals/physician _gls/PDF/neuroendocrine.pdf.

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