eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Malignant Carcinoid Syndrome

Author: Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Coauthor(s): Laura Diomede, University of Bari School of Medicine, Italy; Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Contributor Information and Disclosures

Updated: Aug 7, 2008

Introduction

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.

A section (on the right) of an intestinal carcino...

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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A section (on the right) of an intestinal carcino...

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.


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

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.

More on Malignant Carcinoid Syndrome

Overview: Malignant Carcinoid Syndrome
Differential Diagnoses & Workup: Malignant Carcinoid Syndrome
Treatment & Medication: Malignant Carcinoid Syndrome
Follow-up: Malignant Carcinoid Syndrome
Multimedia: Malignant Carcinoid Syndrome
References
Further Reading
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Further Reading

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.

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Keywords

malignant carcinoid syndrome, malignant carcinoid tumor, carcinoid tumors, cancer metastases, cancer metastasis, serotonin excess, neuroendocrine tumors, intestinal tumors, gastroenteropancreatic tumors, facial flushing, diarrhea, asthma

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Contributor Information and Disclosures

Author

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Disclosure: Nothing to disclose.

Coauthor(s)

Laura Diomede, University of Bari School of Medicine, Italy
Disclosure: Nothing to disclose.

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Medical Editor

Sanjiv S Agarwala, MD, Chief of Oncology and Hematology, St Luke's Cancer Center, St Luke's Hospital and Health Network; Associate Professor of Cancer Biology, University of Pennsylvania
Sanjiv S Agarwala, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Head and Neck Surgery, Eastern Cooperative Oncology Group, and European Society for Medical Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

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