AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Background

Malignant carcinoid syndrome is the constellation of symptoms typically exhibited by patients with metastases from carcinoid tumors.^{1, 2, 3} Carcinoid tumors usually secrete excessive amounts of the hormone serotonin. Carcinoid tumors arise from neuroendocrine cells, which are widespread in the human body, especially in the organs derived from the primitive intestine.

In 1888 Lubarsch first described a carcinoid tumor,⁴ but Oberndorfer called a group of small, benign-appearing tumors karzinoide tumoren (carcinoid) for the first time in 1907.⁵

The name was chosen to separate these tumors from ordinary malignancies, but, by the 1950s, the fact that carcinoids could be malignant was obvious thanks to Erspamer and Asero (1952), who identified serotonin production by carcinoid tumors.⁶ Such result was possible thanks to a number of studies conducted in the first half of 20th century, summarized as follows: In 1914, Gosset and Masson demonstrated that carcinoid tumors might arise from enterochromaffin cells  (Kulchitsky cell) within glands of Lieberkühn using silver impregnation techniques,⁷ and, in 1928, Masson established characterization of carcinoids as argentaffin cell tumors.⁸

Then, in 1980, the World Health Organization (WHO) applied the term carcinoid to all tumors of the diffuse endocrine system (synonymous with amine precursor uptake and decarboxylation [APUD] and neuroendocrine cell system).

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 gastrointestinal (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 fewer than 10% of patients with a carcinoid tumor. Typically, 90% of cases of carcinoid tumors originate from the distal ileum or appendix (the embryologic midgut⁹) 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 (see Media file 3) 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,¹⁰ 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.^{11, 12}

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 are usually 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. Carcinoid tumors arising in the lung generally produce serotonin, gastrin, adrenocorticotropic hormone (ACTH), and histamine. Carcinoids that develop primarily outside the appendix are often malignant, while tumors developing in the appendix are usually 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 have 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. To date, it is well known that the carcinoids also may produce PPs and amines, as follows (in alphabetical order):

• Acid phosphatase
• α glycoprotein
• α1-antitrypsin
• Amylin
• Atrial natriuretic polypeptide
• Calbindin-D28k
• Catecholamines
• CGA/CGB
• Dopamine
• Fibroblast growth factor (FGF)
• Gastrin
• Gastrin-releasing peptide (bombesin)
• Glucagon/glicentin
• 5-Hydroxyindoleacetic acid (5-HIAA)
• 5-Hydroxytryptamine (5-HT)
• Histamine
• Insulin
• Kallikrein
• Motilin
• Neuron specific enolase (NSE)
• A-Neuropeptide
• K-Neuropeptide
• Neurotensin
• Pancreastatin
• Pancreatic polypeptide
• Platelet-dermal growth factor (PDGF)
• Prostaglandins
• Pyroglutamyl-glutamyl-prolinamide
• Secretin
• Serotonin
• Somatostatin
• Substance P
• Somatotropin release-inhibiting factor (SRIF)
• Tachykinins
• β-transforming growth factor (β-TGF)
• Vasoactive intestinal polypeptide (VIP)

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,¹³ but the serotonin produced by the tumor is probably involved. 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.

Frequency

United States

The incidence of carcinoids is probably 7-8 cases per year, but this approximation is underestimated because many patients never develop the related syndrome. Some researchers estimated real incidence may be 1-2 cases per 100,000 individuals.

International

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. One Swedish study reported an incidence of 8.4 cases per 100,000 people. This number is probably 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 are also 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 is usually 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.

Age

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

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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 are often asymptomatic but may present as acute appendicitis or chronic pain of the right lower abdominal quadrant. For this reason, the condition is frequently 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, or they can be precipitated by some foods and beverages (eg, alcohol), pharmacologic agents, and physical or emotional stress.

• Most patients have diarrhea and flushing of the face and neck because of tumoral hormone production; however, even if a carcinoid tumor produces these molecules, some patients do not experience any symptoms.
• Other patients develop right heart problems 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
  • Flushing¹⁴
  • Dizziness
  • Asthenia
  • Diarrhea
• Uncommon symptoms include the following:
• • Myopathy
  • Arthritis
  • Arthralgias
  • Changes in mental state
• Flushing is a phenomenon of transient vasodilation causing reddening of the face, head, neck, and the upper chest and epigastric areas.¹⁵
• • 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 vasodilatation, 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.

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.

• 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.¹⁶
• 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.
• 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.¹⁷
  • 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.

Causes

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

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Other Problems to be Considered

Sprue, nontropical
Bowel obstruction
Pellagra

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Lab Studies

• Hormones in blood and urine are measured to monitor the growth, activity, and eventual recurrence of the primary tumor.
• The biochemical diagnosis of carcinoid tumors is based on the measurement of the serotonin metabolite 5-HIAA in a 24-hour urine collection (normal value [NV] = 0-8.9 mg/d, NV plasma serotonin is 0.04-0.2 mg/mL).
• • Consumption of foods that contain serotonin can complicate the biochemical diagnosis of malignant carcinoid syndrome; in fact, the following foods contain an amount of serotonin that can produce abnormally elevated excretion of urinary 5-HIAA after ingestion:
  • • Spinach
    • Eggplant
    • Cheese (eg, parmesan, Roquefort)
    • Wine (chianti, burgundy)
    • Caffeine
    • Tomatoes
    • Kiwi fruit
    • Bananas
    • Walnuts
    • Pineapples
    • Red plums
    • Avocados
  • The following drugs may have the same effects:
  • • Isoniazid
    • Phenothiazine
    • Phenacetin
    • Monamine oxidase inhibitors
    • Acetaminophen
    • Fluorouracil
    • Iodine solutions
  • If dietary (or pharmaceutical) 5-hydroxyindoles are excluded, a urinary excretion of 5-HIAA of 25 mg/d is diagnostic of carcinoid. If the range value is 9-25 mg/d, the differential diagnosis includes carcinoid syndrome, nontropical sprue, or acute intestinal obstruction.
  • The measurement of other bioactive amines (eg, serotonin, catecholamines, histamine, histamine metabolites¹⁸) in the platelets, plasma, and urine of patients with carcinoid tumors is of interest but has less diagnostic value than an assay of the major metabolite of serotonin in the urine.
  • Some authors have used high-performance liquid chromatography and gas chromatography mass spectrometry to characterize carcinoids in several patients. According to these authors, the platelet serotonin level seems to have a higher sensitivity for the detection of carcinoid tumors and is more consistently elevated than urinary 5-HIAA, especially with tumors that are characterized by a low rate of serotonin production. However, in patients with a high rate of serotonin secretion, the platelet serotonin level reaches a maximum, whereas urinary 5-HIAA does not, indicating that the platelet compartment is saturable. Differing from urinary 5-HIAA, platelet serotonin is not influenced by the consumption of a serotonin-rich diet; therefore, the measurement of platelet serotonin should be preferred for making the primary diagnosis.
• Platelet serotonin levels are also monitored during different treatments to evaluate the effect of therapy.
• • According to a recent study, the sensitivity and specificity of plasma chromogranin A elevations in the diagnosis of peptide-producing endocrine neoplasms is 81% and 100%, respectively.
  • In hindgut carcinoid tumors, chromogranin A, alpha human chorionic gonadotropin (a-HCG), b-HCG, and PP must be included in the follow-up study.
  • For lung carcinoids, gastrin, ACTH, growth hormone (GH), a-HCG, and b-HCG are helpful, and levels of urinary 5-HIAA, chromogranin A, and tachykinins are useful in midgut carcinoid tumors.
• Apart from measuring daily urinary 5-HIAA secretion, determining the presence of other bioactive amines enables more sensitive detection and also may indicate specific measures in particular patients.
• Platelet aggregation test may show increased aggregation with certain agonists. This test helps to diagnose platelet dysfunction and to distinguish between inherited and acquired bleeding problems (eg, DIC occurring in some patients with malignant carcinoid syndrome). Platelet aggregation normally occurs within 3-5 minutes.
• Total proteins and the amino acid tryptophan are often low because of malabsorption. The reference range is 6-8.3 g/dL.
• Routine allergy test results are not usually positive in cases that simulate an anaphylactic attack.

Imaging Studies

• For the diagnosis of carcinoids, several diagnostic methods have been evaluated, including barium examinations, iodine-131 metaiodobenzylguanidine (MIBG) scanning¹⁹ and octreotide scanning, CT scan, angiography, and venous blood sampling with radioimmunoassay of tumor products.
• Scintigraphy
• • Scintigraphy with indium-111 diethylenetriamine pentaacetic acid (DTPA) octreotide (In-111 DTPA Octr), or OctreoScan, localizes the primary carcinoid and eventual recurrences, as well as other neuroendocrine tumors, with high sensitivity and specificity.
  • The development of this diagnostic tool, with a half-life of 3 days, allows for a scan after 24, 48, and 72 hours.
  • This diagnostic tool also has obviated many of the problems of differential diagnosis with other neuroendocrine tumors that are frequent, using iodine-131 MIBG or iodine-123 tyrosine 3 octreotide scanning.
  • False-negative results are possible in 2% of cases (the mean percentage of carcinoids without receptors).
  • A positive test result usually predicts a good patient response to treatment with octreotide.
  • When administering a radioactive somatostatin analogue (In-111 DTPA-D-Phe1 octreotide), some authors are attempting to provide internal radiation therapy, hoping to kill the tumor cells, but adverse effects actually limit the clinical application of this therapy.
• Radiography
• • Barium examination is rarely diagnostic but may show a benign-appearing submucosal lesion or a large bulky ulcerating mass with bowel deformity.
  • A smooth polyp observed in the terminal ileum should always be considered a probable carcinoid tumor.
  • The importance of angiography for carcinoid diagnosis has been decreased by the availability of the more recent imaging methods.
• CT scanning
• • CT scanning may be used to find the primary tumor or to check for any disease spread.
  • The primary carcinoids of the bowel are usually not observed on CT scanning; otherwise, this study allows the assessment of the extent of tumor spread to the mesentery and bowel wall and metastases to the lymph nodes and liver.
  • CT scanning typically shows a homogenous ill-defined mesenteric mass with calcifications.
  • A stellate or curvilinear fibrosis radiating from the mass, representing thickened neurovascular bundles and distorting surrounding bowel loops, is usually observed.
• MRI²⁰
• • Further studies with this diagnostic procedure are required before MRI can be considered a first-choice method for diagnosing and staging carcinoids and related syndromes.
  • Today, this study is very expensive and offers minimal diagnostic advantages.
• Positron emission tomography scanning
• • Positron emission tomography (PET) scanning is the more recent imaging tool used to detect carcinoids, but experience is very limited.
  • Either tryptophan or its metabolite 5-hydroxytryptophan (5-HTP) has been used as a tracer substance.
  • PET scanning seems to be capable of identifying carcinoid metastases to various sites, and it may be valuable in the follow-up care of treated patients.
  • According to initial reports, only C11-5-HTP is taken up in serotonin-producing tumors.
• Ultrasonography: Ultrasonographic examination of the abdomen is usually not the first diagnostic method; instead, it is used to further confirm the diagnosis and establish the site and extent of the disease.

Other Tests

• Several provocative tests have been developed for carcinoid syndrome.
• • The most recent test uses pentagastrin.
  • The traditional test uses alcohol (10 mL PO), calcium (10 mg/kg of calcium gluconate in 4 h), or catecholamines (norepinephrine 1-20 mcg).
  • These tests must be performed with caution because they can trigger crises.

Procedures

• A percutaneous or laparotomy biopsy may be performed, when possible, after the primary tumor and its eventual metastases are detected.
• Diagnostic and operative endoscopy of the lower and upper GI tract may be helpful for diagnosis.

Histologic Findings

In 1963, Williams and Sandler began to classify the carcinoid tumors anatomically and clinically according to embryologic origin from the foregut, midgut, or hindgut. Grossly, these tumors appear as submucosal or intramural masses (see Media files 1-2), and they are usually single but may be multiple. After fixation, the tumor mass appears yellow or brownish, small, and firm. The intestinal mucosa over the tumor is often 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. Two main histologic features are described by observing with 10 high-power fields, as follows:

• Typical, showing fewer than 2 mitoses per 2 mm² of viable tumor and lacking necrosis 
• Atypical, showing 2-10 mitoses per 2 mm² with or without foci of necrosis

Staging

No internationally accepted staging system exists for carcinoid tumors.

TREATMENT

Section 6 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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.²¹ Histamine blockers may also 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 has recently 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 is hopefully strong enough to kill the tumor cells.

• Somatostatin or its analog may prevent flushing and other endocrine manifestations. Octreotide is a synthetic somatostatin analog with high affinity for somatostatin receptors. Octreotide should be preferred to native somatostatin because of a longer half-life (average half-life of somatostatin is 2 min; that of octreotide is 2 h). Octreotide has demonstrated the ability to relieve symptoms in most patients, but tumor reduction is rarely observed.
• Patients benefit from specific drugs that either suppress production of vasoactive amines or block the peripheral effects. These agents include alpha-adrenergic blocking drugs, cyproheptadine, and H2-receptor blockers.
• Interferon-alpha may help control carcinoid symptoms or arrest tumor growth and reportedly can re-induce symptom control in patients in whom octreotide treatment has failed. Benefits are generally transient and accompanied by adverse effects.
• Radiotherapy or chemotherapy with streptozotocin, cisplatin, etoposide, and doxorubicin, either alone or in combination, has been used, and reports show some success; a good response occurs in only 20-30% of cases. The role of radiation therapy in the management of carcinoid tumors with distant metastasis is restricted to symptomatic palliation of the painful bone metastases. This therapy is not useful for treating liver metastases or for other nonskeletal tissues.  
• • Little evidence suggests that chemotherapy, either traditional or by continuous infusion, helps improve patient survival rates.
  • Failure to respond to one chemotherapy combination does not necessarily mean another combination will also be ineffectual.
  • The combination of interferon-alpha and continuous infusion of 5-fluorouracil (5-FU) has demonstrated antitumoral and antihormonal activity and can provide symptom palliation.

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 is often brief and frequently associated with substantial morbidity, debulking hepatic metastases may palliate systemic symptoms.

In fact, cytoreductive surgery has been reported to have the best impact on symptom regression and overall survival.²²

• An extensive surgical excision, including the adjacent mesentery, must be performed.
• • Surgery should always be considered in patients with large or extensive hepatic metastases involving surgically accessible areas of the liver.
  • For lesions in the distal ileum, a right hemicolectomy is necessary to remove the lymphatic drainage adequately.
  • For tumors located in the appendix that are smaller than 1.5 cm in diameter, appendectomy is suitable and curative in 100% of patients. The involvement of the mesoappendix does not alter the patient's prognosis, but the invasion of the cecum determines the need for more radical surgery (eg, right hemicolectomy with regional lymphadenectomy). Childhood carcinoids usually occur in the appendix, and the appendectomy results in a complete cure.
  • Rectal carcinoids, if smaller than 1.5 cm in diameter, should be treated with local excision; if rectal carcinoids are larger than 1.5 cm, they must be considered malignant and abdominoperineal resection (Miles operation) or low anterior resection should be performed.
• Hepatic transplantation has also been attempted in selected patients, with promising results; however, generalization for this treatment option, because it is extremely expensive and debilitating, is not possible without more long-term studies.
• Surgery should also be considered for resection of hepatic recurrence, even after previous resection, but only if the lesions are in an area where resection can be performed with minimal morbidity.
• • The whole intestine should be examined at the time of surgery to detect eventual multiple lesions.²³
  • Chemoembolization with hepatic artery infusion of 5-FU or doxorubicin, combined with embolization of the hepatic artery with collagen fibers, causes substantial tumor necrosis. This procedure reportedly decreases tumor bulk of liver metastases from carcinoid tumors by more than 50% in as many as 60% of patients.²⁴
  • Adverse effects of embolization are frequent and may be severe (see Tumor Lysis Syndrome).
• Other surgical techniques, ablative but nonresective, include cryosurgery and percutaneous alcohol injections.
• For any patient with controlled carcinoid symptoms and heart involvement, cardiac surgery must be considered for symptomatic carcinoid heart disease and must be performed by an experienced team (including medical, surgical, and anesthesiology experts) in order to provide the best management of this condition.^{25, 26}
• For patients with silent disease and symptomatic carcinoid heart disease, valve replacement should be considered.
• Related CME is available at An Aggressive Surgical Approach Leads to Long-Term Survival in Patients With Pancreatic Endocrine Tumors.

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 severe diarrhea should be careful to avoid dehydration or vitamin deficiency (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.

MEDICATION

Section 7 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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.²⁷

Related CME is available at FDA Safety Changes: Prempro/Premphase, Premarin Intravenous, Sandostatin.

Drug Category: Antisecretory/GI agents

These drugs are used to reduce blood levels of GH and IGF-I in patients with an inadequate response to surgery, radiation, and bromocriptine.

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation.

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 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 Category: H2-receptor antagonists

The combination of H1 and H2 antagonists may be useful in chronic idiopathic urticaria not responding to H1 antagonists alone. They may also be useful for itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis (IV).

Drug Category: Alpha2-adrenergic agonists

These agents improve the hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. They are useful in reducing some symptoms of malignant carcinoid syndrome (eg, diarrhea, hypertension, tachycardia).

FOLLOW-UP

Section 8 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Further Inpatient Care

A systematic psychotherapeutic intervention may be very helpful in patients with carcinoid.

Further Outpatient Care

As with inpatients, a systematic psychotherapeutic intervention may be very helpful.

In/Out Patient Meds

• Always assess the color of the urine. Dark brown or intensely yellow urine usually indicates dehydration, and sometimes fluids must be given intravenously to keep up with the fluids lost in the diarrhea.
• Also, obtain the patient's weight daily and replace the essential elements and vitamins, either by diet or by commercial supplements.
• Other clinical problems associated with carcinoid syndrome, such as tachycardia and asthmalike attacks, should be managed by a cardiologist and pulmonologist.
• Severe flushes may be treated with clonidine hydrochloride.
• Patient treatment must include avoidance of conditions or substances that cause flushing (eg, stress, alcohol, epinephrine, epinephrinelike drugs).

Deterrence/Prevention

Patients must avoid any physical and emotional stress and any food or drug that may trigger a crisis. For example, monamine oxidase inhibitors should be avoided because they can exacerbate the syndrome by inhibiting serotonin degradation.

Complications

• Hypotension related to massive vasodilation can increase the risk of falls and subsequent injuries.
• Increased platelet aggregation causes a high risk for strokes, deep venous thromboses, and similar disorders.
• Gastrointestinal bleeding is very rare. Bowel obstruction from tumor mass or, most frequently, from mesenterial adhesions, is also very rare.
• Right-sided heart failure is more frequent, as reported above.
• Analysis of catecholamines and associated metabolites show consistent elevation of dopamine, norepinephrine, and epinephrine metabolites in more than 30% of midgut carcinoids. This explains some adverse effects (eg, arrhythmias, perioperative carcinoid crisis) in patients in whom octreotide premedication is indicated.
• Usually, urinary levels of histamine metabolites are less elevated, but increased histamine production was found to be the cause of specific symptoms (eg, angioedema), which should be treated specifically.
• Acute renal failure after liver chemoembolization of carcinoid metastases is an infrequent but well-known complication.
• Risk of metastasis correlates with size of primary tumor, as follows:
• • Tumors £1 cm metastasize in only 2% of cases
  • Tumors 1-2 cm metastasize in 50% of cases
  • Tumors ³2 cm metastasize in 85% of cases

Prognosis

• The prognosis for patients with malignant carcinoid syndrome is relatively good compared to the prognosis for patients with other malignancies, but the prognosis for any treated patient with progressing, recurring, or relapsing disease is poor. The median survival rate after 5 years is 30-67%. Survival for 8.5 years and 23 years has been reported.
• In patients with malignant carcinoid syndrome who are cured with surgery, follow-up care does not need to be intense. For patients with advanced disease, follow-up care should be scheduled on a regular basis. The frequency of follow-up care depends on the general condition of patients and their disease. In each follow-up session, complementary to patient examination, blood tests, x-ray films, and other studies may need to be performed.
• Treatment options for carcinoid syndromes have prolonged life for many patients, but it is very important to understand the patient’s perception of symptoms and the influence of treatment may affect their quality of life as well as disease progression.^{28, 29}
• The incidence of metastasis is estimated at 1-2 cases per 100,000 affected people, and their best treatment remains controversial. Lymph nodes and liver are the most common sites of metastasis, less commonly bone and lung. Very rare is the involvement of distant sites (eg, ovary, orbit). Most patients with metastases are asymptomatic and have an indolent course. If untreated, survival at 5 years is 30%.

Patient Education

• Avoidance of any physical and emotional stress and any food or drug that may trigger a crisis is mandatory.
• For excellent patient education materials, see eMedicine's Cancer and Tumors Center.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Medical/Legal Pitfalls

Because malignant carcinoid syndrome may rapidly worsen once symptoms develop, early recognition of primary neuroendocrine tumors and avoidance of diagnostic errors are crucial. A rapid and correct diagnosis is very important to avoid legal claims.

Special Concerns

Malignant carcinoid syndrome can cause significant trouble during anesthesia,³⁰ such as blood pressure imbalance and bronchospasm. Some studies report a lower rate of occurrence and severity of such problems after the preoperative use of octreotide.

FURTHER READING

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

The main clinical characteristics of the carcinoids arising in the digestive tract that most frequently might determine a malignant carcinoid syndrome are as follows:

1. Gastric carcinoid tumors are sporadic in 15-25% of cases, usually solitary and larger than 1 cm, arising in normal-appearing mucosa from enterochromaffinlike cells in the gastric fundus. These tumors are generally located in the body or fundus of the stomach and identified endoscopically. A large number of patients have metastases at the time of presentation and have pernicious anemia in over 50% of cases. Gastric carcinoid tumors are more common in women during their sixth or seventh decade of life. It may be associated with atypical carcinoid syndrome manifested by flushing and mediated by histamine.
2. Carcinoid tumors of the small bowel arise from intraepithelial endocrine cells producing 5-HT and account for one third or fewer of small-bowel tumors. Often located in the distal ileum, these tumors are frequently multicentric and most patients present with metastases to the lymph nodes or liver. Although tumor size is an unreliable predictor of metastatic disease, the 5-year survival rate closely correlates with the stage of disease at presentation (35% of patients survive if one or more distant metastases are present, 65% for localized or regional disease). Patients usually present in the sixth or seventh decade of life, and 5-7% present with carcinoid syndrome.
3. Appendiceal carcinoids are the most common cancers of the appendix and arise from the subepithelial endocrine cells from the lamina propria and submucosa. In 75% of cases, appendiceal carcinoids are located at the tip. Fewer than 10% of appendiceal carcinoids are located at the base. Appendiceal carcinoids are most frequently diagnosed in women in the fourth or fifth decade of life, and 10% or more are symptomatic. Patients may often be misdiagnosed as having appendicitis. The tumor size is the best prognostic predictor, with a 5-year survival rate of 94% for patients with local disease, 85% if regional metastases, 34% if the patient has one or more distal metastases. It is noteworthy that more than 95% of appendiceal carcinoids are 2 cm or less, with rare metastases, while one third of tumors 2 cm or larger have either nodal or distant metastases. Carcinoid syndrome has been reported in patients with liver metastases.
4. Carcinoid tumors of the colon  account for 1% or fewer of colon tumors and usually arise from serotonin-producing epithelial endocrine cells present in the colon mucosa. Most of the affected patients are in the seventh decade of life and present with abdominal pain, anorexia, and weight loss. At the time of diagnosis, the average tumor diameter is approximately 5 cm and more than two thirds of patients have either nodal or distant disease. The 5-year survival rate is reported to be near 70% for local disease, 44% if regional metastases exist, and 20% in cases with distant metastases. The 5% of patients with metastatic disease show a malignant carcinoid syndrome.
5. Rectal carcinoid tumors are responsible for up to 2% of all rectal tumors. The disease usually affects persons in the sixth decade of life and most commonly present with rectal bleeding, pain, or constipation, while 50% of patients are asymptomatic with tumors found during routine endoscopy. Generally, the tumor cells contain glucagon and glicentin-related peptides rather than serotonin. The 5-year survival rate is 81% for patients with local disease, 47% for regional disease, and 18% for distant metastases. Note that patients rarely present with carcinoid syndrome, and the syndrome is closely related to tumor size.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Media file 1:  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.
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Media file 2:  A section of a carcinoid mass (350 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
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Media file 3:  A section of a rare lymph node metastasis from adenocarcinoid tumor (250 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• 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. Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc. 2000;21(1):21-4. [Medline].
15. 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].
16. Monsegu J, Algayres JP, Ciribilli JM, et al. [Tricuspid insufficiency disclosing carcinoid syndrome]. Rev Med Interne. 1994;15(9):593-6. [Medline].
17. 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].
18. Granerus G, Lindell SE, Waldenstrom J, et al. Histamine metabolism in carcinoidosis. Lancet. Jun 4 1966;1(7449):1267-8. [Medline].
19. 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].
20. 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].
21. Joensuu H, Kumpulainen E, Grohn P. Treatment of metastatic carcinoid tumour with recombinant interferon alfa. Eur J Cancer. 1992;28A(10):1650-3. [Medline].
22. 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].
23. Eller R, Frazee R, Roberts J. Gastrointestinal carcinoid tumors. Am Surg. Jul 1991;57(7):434-7. [Medline].
24. 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].
25. Codd JE, Drozda J, Merjavy J. Palliation of carcinoid heart disease. Arch Surg. Sep 1987;122(9):1076-7. [Medline].
26. Connolly HM, Pellikka PA. Carcinoid heart disease. Curr Cardiol Rep. Mar 2006;8(2):96-101. [Medline].
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