Carcinoid Syndrome

• Fred F. Ferri, M.D.

 Basic Information

Definition

Carcinoid syndrome is a symptom complex characterized by paroxysmal vasomotor disturbances, diarrhea, and bronchospasm. It is caused by the action of amines and peptides (serotonin, bradykinin, histamine) produced by tumors arising from neuroendocrine cells.

Synonyms

1. Flush syndrome

2. Argentaffinoma syndrome

ICD-10CM CODES
E34.0	Carcinoid syndrome

Epidemiology & Demographics

Incidence

1. •

   Carcinoid tumors are found incidentally in 0.5% to 0.75% of autopsies.

2. •

   Carcinoid tumors are principally found in the following organs: appendix (40%); small bowel (20%; 15% in the ileum); rectum (15%); bronchi (12%); esophagus, stomach, and colon (10%); and ovary, biliary tract, and pancreas (3%). Table E1 summarizes the relative frequencies of selected carcinoid tumors and their prevalence of metastases and carcinoid syndrome.

   TABLEE1 Relative Frequencies of Selected Carcinoid Tumors and Their Prevalence of Metastases and Carcinoid Syndrome
   From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

   	% of all Carcinoidsa	% with Metastases	% with Carcinoid Syndrome
   Gastric	2-6	22-31	10
   Small intestinalb	10-28	14-71	3-13
   Appendiceal	2-38	2-35	<1
   Colonic	4-10	60-71	5
   Rectal	10-19	3-14	<1
   Pancreatic	<1	66-100	Up to 100
   Tracheal/bronchial/pulmonary	85	13	13

3. •

   The incidence of carcinoids is 2.47 to 4.48/100,000, depending on race and sex, and is highest in black men. The overall incidence has increased over the last 30 years due in part to improved diagnostic modalities.

4. •

   Carcinoid tumors can be classified using the WHO classification as follows:

   1. 1.

      WHO I: Well-differentiated, <2 cm diameter, low proliferation index (<2%), confined to mucosa and submucosa

   2. 2.

      WHO II: Differentiated, >2 cm diameter, invasive growth, high proliferation index (2% to 15%)

   3. 3.

      WHO III: Poorly differentiated carcinomas with metastases and proliferation index >15%

Physical Findings & Clinical Presentation

1. •

   Cutaneous flushing (75% to 90%)

   1. 1.

      The patient usually has red-purple flushes starting in the face, then spreading to the neck and upper trunk (Fig. E1).

      

   2. 2.

      The flushing episodes last from a few minutes to hours (longer-lasting flushes may be associated with bronchial carcinoids).

   3. 3.

      Flushing may be triggered by emotion, alcohol, or foods or may occur spontaneously.

   4. 4.

      Dizziness, tachycardia, and hypotension may be associated with the cutaneous flushing.

2. •

   Diarrhea (>70%): often associated with abdominal bloating and audible peristaltic rushes

3. •

   Intermittent bronchospasm (25%): characterized by severe dyspnea and wheezing

4. •

   Facial telangiectasia

5. •

   Tricuspid insufficiency, pulmonic stenosis from carcinoid heart lesions

Etiology

1. •

   Carcinoid syndrome is caused by neoplasms originating from neuroendocrine cells.

2. •

   Carcinoid tumors do not usually produce the syndrome unless liver metastases are present or the primary tumor does not involve the gastrointestinal tract.

Diagnosis (Fig. E2)

Differential Diagnosis

1. •

   Flushing: Carcinoid syndrome must be distinguished from idiopathic flushing (IF); patients with IF more often are female, are younger, and have a longer duration of symptoms; palpitations, syncope, and hypotension occur primarily in patients with IF. Additional causes of flushing that need to be ruled out are menopause, medications (niacin, nitrates), alcohol, renal cell carcinoma, medullary cancer of thyroid, VIPoma, mastocytosis, and chronic use of food additives (nitrites, sulfites)

2. •

   Diarrhea: IBD, IBS, laxative abuse, infectious colitis

3. •

   Bronchospasm: asthma, foreign body, GERD, lung neoplasm

Laboratory Tests

1. •

   The biochemical marker for carcinoid syndrome is increased 24-hr urinary 5-hydroxyindoleacetic acid, a metabolite of serotonin (5-hydroxytryptamine).

2. •

   False elevations can be seen with ingestion of certain foods (bananas, pineapples, eggplant, avocados, walnuts) and certain medications (acetaminophen, caffeine, guaifenesin, reserpine); therefore patients should be on a restricted diet and avoid these medications when the test is ordered.

3. •

   Falsely low results can occur with use of alcohol, aspirin, MAO inhibitors, and St. John’s wort.

4. •

   Liver function studies are an unreliable indicator of liver involvement.

Imaging Studies

1. •

   CT scan of chest is useful to detect bronchial carcinoids.

2. •

   CT scan or MRI of abdomen or a liver and spleen radionuclide scan is useful to detect liver metastases (palpable in >50% of cases).

3. •

   Iodine-123–labeled somatostatin can detect carcinoid endocrine tumors with somatostatin receptors.

4. •

   Scanning with radiolabeled octreotide (Fig. E3) can visualize previously undetected or metastatic lesions.

   

5. •

   PET scan.

Treatment

Nonpharmacologic Therapy

Avoidance of ethanol ingestion (may precipitate flushing)

General Rx

1. •

   Surgical resection of the tumor can be curative if the tumor is localized or palliative and results in prolonged asymptomatic periods if metastases are present. Surgical manipulation of the tumor can, however, cause severe vasomotor abnormalities and bronchospasm (carcinoid crisis).

2. •

   Percutaneous embolization and ligation of the hepatic artery can decrease the bulk of the tumor in the liver and provide palliative treatment of tumors with hepatic metastases.

3. •

   Cytotoxic chemotherapy: combination chemotherapy with 5-fluorouracil and streptozocin can be used in patients with unresectable or recurrent carcinoid tumors; however, it has only limited success. Fig. E4 describes a therapeutic algorithm for treatment of metastatic carcinoid tumor.

   

4. •

   Control of clinical manifestations:

   1. 1.

      Somatostatin analogues (octreotide and lanreotide) are effective for both flushing and diarrhea in most patients. Telotristat ethyl, a tryptophan hydroxylase inhibitor is FDA approved for use in combination with somatostatin analogues (SSA) for diarrhea inadequately controlled with SSA.

   2. 2.

      Flushing may be controlled by the combination of H₁– and H₂-receptor antagonists (e.g., diphenhydramine 25 to 50 mg PO q6h and ranitidine 150 mg bid).

   3. 3.

      Diarrhea may respond to diphenoxylate with atropine (Lomotil).

   4. 4.

      Bronchospasm can be treated with aminophylline and/or albuterol.

5. •

   Nutritional support: supplemental niacin therapy may be useful to prevent pellagra because the tumor uses dietary tryptophan for serotonin synthesis, resulting in a nutritional deficiency in some patients.

6. •

   Interferon alfa may be useful as an additive to control symptoms unresponsive to somatostatin analogues.

7. •

   Echocardiography and monitoring for right-sided congestive heart failure are recommended for patients with unresectable disease because endocardial fibrosis, involving predominantly the endocardium, chordae, and valves of the right side of the heart, can occur.

Disposition

Carcinoids of the appendix and rectum have a low malignancy potential and rarely produce the clinical syndrome; metastases are also uncommon if the size of the primary lesion is <2 cm in diameter. Table E2 summarizes the 5-year survival rates of selected carcinoid tumors by stage.

Related Content

1. Carcinoid Syndrome (Patient Information)