Malignant carcinoid syndrome is the constellation of symptoms typically exhibited by patients with metastases from carcinoid tumors.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.
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 This finding, built on research conducted in the first half of the 20th century, is 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
In 1928, Masson established characterization of carcinoids as argentaffin cell tumors.8
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 of patients have a second malignancy, and one third of these tumors metastasize. In addition, some of these 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 carcinoid tumors originate from the distal ileum or appendix (the embryologic midgut9 ); carcinoid tumors 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 physiologic conditions, is taken up and stored in the platelets while the excesses are inactivated in 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, tumors in these locations frequently metastasize and spread through the mesenteric lymph nodes (and portal vein.
The main clinical characteristics of the carcinoids arising in the digestive tract that most often cause malignant carcinoid syndrome are as follows:
Gastric carcinoid tumors are sporadic in 15-25% of cases, usually solitary and larger than 1 cm, arising in normal-appearing mucosa from enterochromaffin-like 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 over 50% have pernicious anemia. 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.
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.
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 there are regional metastases, and 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.
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.
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 presents as 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% 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.
Clinical
History
Carcinoid tumors grow slowly, and symptoms may not occur for several years, if at all. When symptoms do develop, they are ill defined and may be neglected for a long time before being properly diagnosed. In some cases, carcinoid tumors present as acute appendicitis or chronic pain in the lower right abdominal quadrant. For this reason, the condition is frequently misdiagnosed as irritable bowel syndrome.18 Alcohol intolerance and weight loss also may be associated manifestations. Severity of symptoms varies. Onset of symptoms may be spontaneous or may be precipitated by certain foods and beverages (eg, alcohol), pharmacologic agents, and physical or emotional stress.
Diarrhea is common, as is flushing of the face and neck.19 These manifestations result from tumoral hormone production; however, even if a carcinoid tumor produces these molecules, some patients do not experience any symptoms.
Right heart problems may develop 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
Dizziness
Asthenia
Uncommon symptoms include the following:
Myopathy
Arthritis
Arthralgias
Irritability, aggression, and lack of impulse control; these have been linked with low levels of plasma tryptophan and presumably with low brain serotonin.15
Flushing is a phenomenon of transient vasodilation causing reddening of the face, head, neck, and the upper chest and epigastric areas.20
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 vasodilation, 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.
