January 17, 2007

Malignant Carcinoid Syndrome

Synonyms and related keywords: carcinoid tumors, metastases, gastroenteropancreatic tumors


Background: Malignant carcinoid syndrome is the constellation of symptoms typically exhibited by patients with metastases from carcinoid tumors. These tumors usually secrete excessive amounts of the hormone serotonin. The carcinoid tumors arise from neuroendocrine cells, which are widespread in the human body, especially in the organs derived from the primitive intestine. In 1907, Oberndorfer called a group of small, benign-appearing tumors karzinoide tumoren (carcinoid). The name was chosen to separate these tumors from ordinary malignancies, but, by the 1950s, the fact that carcinoids could be malignant was obvious.

These intensely vascularized tumors follow the so-called "rule of one third," which states that one third of the tumors are multiple, one third of those in the GI tract are located in the small bowel, one third have a second malignancy, and one third metastasize. In fact, some of the tumors produce hormones excessively, causing a condition known as malignant carcinoid syndrome. This syndrome is characterized by hot red flushing of the face, severe and debilitating diarrhea, and asthma attacks. Malignant carcinoid syndrome occurs in less than 10% of patients with a carcinoid tumor. Typically, 90% of cases of carcinoid tumors originate from the distal ileum or appendix (the embryologic midgut) and represent 90% of appendiceal tumors.

Tumors arising from the foregut and hindgut are considered atypical; however, tumors can originate from any cell of the amine precursor uptake and decarboxylation system and, therefore, produce several intestinal hormones. Most of these tumors produce 5-hydroxytryptamine, which, in physiological conditions, is taken up and stored in the platelets while the excesses are inactivated from the liver and lung and transformed into 5-hydroxyindoleacetic acid (5-HIAA).

In order of frequency, carcinoids may occur in the appendix (35%), ileum (28%), rectum (13%), and bronchi (13%). Incidence is less than 1% in the pancreas, gallbladder, liver, larynx, testes, and ovaries; however, these tumors have a high incidence of metastases and spread through the mesenterial lymph nodes and portal vein. Carcinoids do not produce the malignant carcinoid syndrome until they are no longer confined to the small bowel or mesentery, perhaps because of the liver breakdown of tumor products. After spreading to the liver, carcinoids can metastasize to the lungs, bone, skin, or almost any organ. Ovarian carcinoids may be considered exceptions. In fact, a patient with ovarian teratomas, whose secretory products enter into the systemic circulation, may present with this syndrome without liver metastasis.

If a patient is thought to have carcinoid syndrome, blood and urine tests must be performed to determine levels of bioactive substances secreted by carcinoid tumors. Imaging studies also must be performed to detect the sites of either primary tumors or metastases. Carcinoid tumors and related syndromes may be a part of multiple endocrine neoplasia.

Pathophysiology: Pathophysiology is closely related to the sites of the primary tumors. When these tumors spread to the liver, patients usually begin to develop malignant carcinoid syndrome. In fact, this syndrome develops when vasoactive substances produced by a carcinoid tumor escape hepatic degradation and gain access into the systemic circulation.

Carcinoids arising in the stomach usually are associated with low acid production, determining a condition termed hypochlorhydria or achlorhydria. Rarely does this condition become malignant, and it never causes metastases; yet, sometimes this condition may produce histamine. The carcinoid tumors arising in the lung generally produce serotonin, gastrin, adrenocorticotropic hormone (ACTH), and histamine. Carcinoids that primarily develop outside the appendix more often are malignant, while tumors developing in the appendix usually are benign if smaller than 2 cm in diameter. Rectal carcinoid tumors often produce polypeptides (PPs), polypeptide Y, neuropeptide Y, and other peptides, but none of the patients with this disease location has symptoms related to the production of these molecules. Few of these patients have liver metastases, and despite liver metastases, these patients do not have any hormone-related symptoms.

Tryptophan is an amino acid that is used by the body to build up niacin and several proteins. Physiologically, serotonin causes vasodilation and also determines increased blood clotting, stimulating platelet aggregation (diffuse intravascular coagulation [DIC]); however, serotonin is converted to 5-HIAA in the body. The carcinoids also may produce PPs and amines, as follows:

  • 5-HIAA
  • Chromogranin-A
  • Neurokinin-A
  • Bradykinin
  • Tachykinin
  • Several hormones affecting steroid production (ACTH, atrial natriuretic hormone)
  • Parathyroid and thyroid hormones
  • Gastrin
  • Motilin
  • Vasoactive intestinal polypeptide
  • Pancreatic PP
  • Insulin
  • Glucagon

The above reported molecules are responsible for the extreme symptoms of this condition. For example, the reason some patients develop a heart disease is not definitively known, but the serotonin produced by the tumor probably is involved. The bronchial constriction, which accounts for the asthmalike attacks, seems related to the tumoral tachykinins. Also, symptoms may relate to overproduction of PPs in the pro-opiomelanocortin family (eg, endorphin, enkephalin). Frequently, the enteric blood supply is impaired, which is caused by the desmoplastic reaction of mesenterial peritoneum and determines kinking and angulation of the loops of the small bowel, with consequent bowel obstruction.


  • In the US: The incidence of carcinoids is probably 7-8 cases per year, but this approximation is underestimated because many patients never develop the related syndrome.
  • Internationally: Carcinoid tumors account for 50-55% of all gastroenteropancreatic tumors. The reported incidence of new cases of malignant carcinoid syndrome found yearly is 7-13 (average is 5) cases per 1,000,000 individuals. This number probably is underestimated because a large number of patients do not develop the related syndrome. Carcinoid syndrome is discovered in approximately 1-2 appendectomy cases per 200-300 per year. These tumors also are observed in 0.5-0.75% of all autopsic dissections.

Mortality/Morbidity: Tumors that are smaller than 1 cm in diameter rarely metastasize, while lesions larger than 2 cm often metastasize. The presence of a few small metastases to the liver is associated with a longer life expectancy. Morbidity is related to vasoactive amine production. The survival rate usually correlates inversely with the levels of daily urinary 5-HIAA excretion. Death usually is caused by cardiac or hepatic failure and by complications associated with tumor growth. An increased risk of death is associated with high plasma levels in neuropeptide K and chromogranin A, the location of the tumor in the large bowel, the advanced stage of the disease, and a contemporary second malignancy. Mucus-producing tumors developing in the appendix also have some malignant characteristics.

Race: No racial prevalence is known.

Sex: This syndrome affects men and women equally, with a male-to-female ratio of 1:1.

Age: Carcinoids occur most frequently in patients aged 50-70 years. Age at diagnosis ranges from 10-93 years (mean age 55 y).


History: Carcinoid tumors grow slowly. The symptoms are ill defined, occur after several years, and then may be neglected for a long time before being properly diagnosed. In fact, these tumors often are asymptomatic but may present as acute appendicitis or chronic pain of the right lower abdominal quadrant. For this reason, the condition frequently is misdiagnosed as an irritable bowel syndrome. Alcohol intolerance and weight loss also may be associated conditions. The patient's history is very important. Severity of symptoms varies. Symptoms may be spontaneous, although they can be precipitated by some foods and beverages (eg, alcohol), pharmacologic agents, and physical or emotional stress.

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, hasten diagnosis.

Causes: As with many other cancers, the exact cause is unknown. Malignant carcinoid syndrome generally does not appear to be hereditary.


Intestinal Motility Disorders
Irritable Bowel Syndrome
Ogilvie Syndrome
Tumor Lysis Syndrome

Other Problems to be Considered:

Sprue, nontropical
Bowel obstruction


Lab Studies:

Imaging Studies:

Other Tests:


Histologic Findings: In 1963, Williams and Sandler began to anatomically and clinically classify the carcinoid tumors according to embryologic origin from the foregut, midgut, or hindgut. Grossly, these tumors appear as submucosal or intramural masses, and they usually are single but may be multiple. After fixation, the tumor mass appears yellow or brownish, small, and firm. The intestinal mucosa over the tumor often is intact. Submucosal infiltration, often extending beyond the muscularis propria, is the rule.

Histologically, the tumor consists of uniform small cells arranged as islands separated by a fibrous stroma. Cells show a scant pink cytoplasm that is finely granulated and stippled with small round nuclei and small nucleoli. Several patterns can be observed in carcinoid tumors (ie, trabecular and tubular arrangements may be present and include intraluminal mucin). All carcinoids react positively with antichromogranin A antibodies and usually Masson staining, which indicates serotonin production and is positive in midgut primary tumors.

Staging: No internationally accepted staging system exists for carcinoid tumors.


Medical Care: Systemic therapy should be used to control humorally mediated symptoms when the cancer spreads elsewhere. Initially, interferons and octreotide are useful in approximately 40% of patients. Histamine blockers also may be useful. Diarrhea generally responds to standard antidiarrheal medications, but serotonin antagonists should be administered, if necessary, to control diarrhea and malabsorption. Severe and prolonged carcinoid crises associated with bronchial or stomach carcinoids may respond to corticosteroid treatment. Therapy with MIBG recently has been considered but is only experimental; however, administering a radioactive somatostatin analogue (In-111 DTPA-D-Phe1 octreotide) is a form of internal radiation therapy, which hopefully is strong enough to kill the tumor cells.

Surgical Care: Complete surgical removal of all tumor tissues is the best treatment when feasible because this may result in a complete and permanent cure. The aim of surgical therapy is to reduce the tumor mass and obtain symptom remission. Performing a curative resection, mass debulking, or hepatic embolization is possible. Although palliation often is brief and frequently associated with substantial morbidity, debulking hepatic metastases may palliate systemic symptoms.

  • Other surgical techniques, ablative but nonresective, include cryosurgery and percutaneous alcohol injections.
  • For patients with silent disease and symptomatic carcinoid heart disease, valve replacement should be considered.

Consultations: Consult with either a cardiologist or pneumologist for cardiac and respiratory assessment.

Diet: In patients with malignant carcinoid syndrome, diarrhea and weight loss are severe problems that need to be controlled.

  • The major nutrients are absorbed easily and do not exacerbate the diarrhea, while most vegetables are very irritating.
  • Patients with very severe diarrhea should be careful to not become dehydrated or low in vitamins (nicotinamide and niacin supplements are very useful and must be prescribed), potassium, magnesium, iron, and essential elements.
  • Always recommend increased protein in the diet.

Activity: Mild (not stressful) physical activity is not harmful and is possible if desired. No intense physical activities are allowed.


Today, somatostatin is rarely administered because of its poor half-life, and octreotide is considered the drug of choice worldwide for treating both carcinoids and related malignant syndromes. In patients with diffuse metastases, antiproliferative drugs may be useful for symptom palliation.

Drug Category: Antisecretory/GI agents -- Are used to reduce blood levels of GH and IGF-I in patients with an inadequate response to surgery, radiation, and bromocriptine.
Drug Name
Octreotide (Sandostatin) -- Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has many other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.
Adult Dose100 mcg SC tid/qid (most common effective dose); may administer direct IV over 5 min in emergency
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay reduce effects of cyclosporine; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dosage adjustments
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsAdverse effects primarily related to altered GI motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; because of alteration in counter-regulatory hormones (insulin, glucagon, GH), hypoglycemia or hyperglycemia may be observed; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; due to inhibition of TSH secretion, hypothyroidism also may occur; caution with renal impairment; cholelithiasis may occur
Drug Category: Antineoplastic agents -- Inhibit cell growth and proliferation
Drug Name
Doxorubicin (Adriamycin) -- Anthracycline antibiotic that can intercalate with DNA, affecting many DNA functions, including synthesis. Administered IV and distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. Does not cross blood-brain barrier and is excreted primarily in bile. May be helpful in symptom palliation for patients with progressive disease.
Adult Dose60-75 mg/m2 IV single dose q3-4wk; total dose not to exceed 550 mg/m2
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; severe CHF; cardiomyopathy; preexisting myelosuppression; impaired cardiac function; complete cumulative doses of daunorubicin, doxorubicin, and idarubicin
InteractionsIncreased toxicity with cyclophosphamide, cyclosporine, mercaptopurine, verapamil, streptozocin, paclitaxel, and progesterone; phenobarbital decreases effect; decreased toxicity with digoxin; decreases phenytoin levels
Pregnancy D - Unsafe in pregnancy
PrecautionsMay produce severe local toxicity in irradiated tissues, even when the 2 therapies are not administered concomitantly; caution in patients who have received radiotherapy
Cardiomyopathy is a well-known characteristic of doxorubicin; monitor for drug-induced cardiomyopathy; mortality rate is higher than 50% once cardiomyopathy has developed
Reddish stain of urine (it is not blood in urine)
Drug Name
Streptozocin, streptozotocin (Zanosar) -- Cell-cycle phase-nonspecific antineoplastic agent that alkylates DNA, causing interstrand cross-linking. Also inhibits DNA synthesis by blocking incorporation of DNA precursor and inhibiting cell proliferation. May be helpful in symptom palliation for patients with progressive disease. Dosage is related to body surface area. May cause a complete remission of disease. Administration must be suspended only when desired response or toxicity occurs. Streptozocin may determine severe nephrotoxic effects.
Adult Dose500 mg/m2 IV for 5 consecutive d q4-6wk
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity, renal disease
InteractionsIncreased nephrotoxicity with loop diuretics, aminoglycosides, or amphotericin B; increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced hyperglycemia with corticosteroids
Pregnancy X - Contraindicated in pregnancy
PrecautionsIrreversible nephrotoxicity can occur; destabilizes control in patients with diabetes mellitus
Drug Name
Fluorouracil, 5-FU (Adrucil) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with RNA synthesis and function. Has some effect on DNA. Useful in symptom palliation for patients with progressive disease.
Adult Dose15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity, bone marrow suppression, and serious infection; topical administration contraindicated in pregnancy
InteractionsIncreased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Pregnancy D - Unsafe in pregnancy
PrecautionsNausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment
Drug Name
Cisplatin (Platinol) -- Inhibits DNA synthesis and thus cell proliferation by causing DNA crosslinks and denaturation of double helix. May help with symptom palliation for patients with progressive disease.
Adult Dose20-40 mg/m2 IV qd for 3-5 d q3wk; alternatively, 20-120 mg/m2 IV single dose q3wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity, preexisting renal insufficiency, myelosuppression, hearing impairment
InteractionsIncreases toxicity of bleomycin and ethacrynic acid
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur
Drug Name
Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle. May help with symptom palliation for patients with progressive disease.
Adult Dose100 mg/m2 IV on days 3-5 in combination with other antineoplastic agents; dosage varies with protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration may cause death; breastfeeding
InteractionsMay prolong effects of warfarin and increase clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy D - Unsafe in pregnancy
PrecautionsBleeding and severe myelosuppression may occur
Drug Category: Interferons -- Are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.
Drug Name
Interferon-alpha, INF-alpha (Roferon-A, Intron-A) -- Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Therapeutic trials in selected patients.
Adult DoseExperimental therapeutic application; not established; administered SC; avoid intradermal injection
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsTheophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, and compromised CNS; avoid breastfeeding
Drug Category: H1 antihistamines -- Act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth-muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.
Drug Name
Cyproheptadine (Periactin) -- Competitively inhibits H1 receptor, which mediates bronchial constriction, smooth-muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias. Prevents histamine release in blood vessels and is more effective in preventing histamine response than in reversing it. May be useful in patients with syndromes sustained by histamine-producing tumors.
Adult Dose5-20 mg/d PO; not to exceed 0.5 mg/kg/d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity, narrow-angle glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction, lower respiratory tract symptoms
InteractionsPotentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsCaution in patients with a predisposition to urinary retention, history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties and may inhibit expectoration and sinus drainage
Drug Category: H2-receptor antagonists -- The combination of H1 and H2 antagonists may be useful in chronic idiopathic urticaria not responding to H1 antagonists alone. Also may be useful for itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis (IV).
Drug Name
Ranitidine (Zantac) -- Competitive and reversible H2-receptor blockers. Highly selective antagonists that do not affect the H1 receptors and may be administered contemporary to H1-receptor antagonists. May be useful for treatment of severe itching, flushing, and urticaria.
Adult Dose150 mg PO qd/qid; not to exceed 600 mg/d; alternatively, 50 mg IV/IM q3-6h; not to exceed 400 mg/d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsCaution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment
Drug Category: Alpha2-adrenergic agonists -- These agents improve the hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. Useful in reducing some symptoms of malignant carcinoid syndrome (eg, diarrhea, hypertension, tachycardia).
Drug Name
Clonidine (Catapres) -- Stimulate alpha2 adrenoreceptors in brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.
Adult Dose0.1-0.2 mg PO q8h
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsTricyclic antidepressants inhibit hypotensive effects; coadministration of with beta-blockers may potentiate bradycardia; tricyclic antidepressants may enhance hypertensive response associated with abrupt clonidine withdrawal; hypotensive effects are enhanced by narcotic analgesics
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairment; abrupt discontinuation may cause rebound hypertension


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