Carcinoid syndrome
Encyclopedia
Carcinoid syndrome refers to the array of symptom
s that occur secondary to carcinoid tumors
. The syndrome includes flushing
and diarrhea
, and, less frequently, heart failure and bronchoconstriction
. It is caused by endogenous secretion of mainly serotonin
and kallikrein
.
becomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. This is the case when carcinoid tumors metastasize to the liver or they arise for example in the bronchus.
The most important clinical finding is flushing
of the skin, usually of the head and the upper part of thorax. Secretory diarrhea
and abdominal cramps are also characteristic features of the syndrome. When the diarrhea
is intensive it may lead to electrolyte disturbance and dehydration. Other associated symptoms are nausea
, and vomiting
. Bronchoconstriction
, which may be histamine
-induced, affects a smaller number of patients and often accompanies flushing.
About 50% of patients have cardiac abnormalities, caused by serotonin-induced fibrosis
of the tricuspid
and pulmonary
valves. Elevated levels of circulating serotonin have been associated with cardiac failure, due to fibrous deposits on the endocardium. These deposits are thought to be responsible for the fibrous degeneration of the valve apparatus. "TIPS" is an acronym for Tricuspid Insufficiency, Pulmonary Stenosis (fibrosis of tricuspid and pulmonary valves).
Abdominal pain is due to desmoplastic
reaction of the mesentery
or hepatic metastases.
Although the most common site of a carcinoid tumor is the appendix or terminal ileum, liver metastases, releasing serotonin directly into the systemic circulation are required for the carcinoid syndrome to occur. This is because serotonin
created by a GI carcinoid tumour and released into the hepatic portal system is broken down at the liver and does not reach the systemic circulation. However: If the tumor is bronchogenic in origin, then metastasis does not need to occur in order for carcinoid syndrome to occur.
. It is commonly, but incorrectly, thought that serotonin is the cause of the flushing. The flushing results from secretion of kallikrein
, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin. The latter is further converted to bradykinin
, one of the most powerful vasodilators known. Other components of the carcinoid syndrome are diarrhea (probably caused by serotonin), a pellagra
-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B3, niacin
, to the synthesis of 5-hydroxyindoles including serotonin), fibrotic lesions of the endocardium, particularly on the right side of the heart resulting in insufficiency of the tricuspid valve and, less frequently, the pulmonary valve and, uncommonly, bronchoconstriction. The pathogenesis of the cardiac lesions and the bronchoconstriction is unknown, but the former probably involves activation of serotonin 5-HT2B receptor
s by serotonin. When the primary tumor is in the gastrointestinal tract, as it is in the great majority of cases, the serotonin and kallikrein are inactivated in the liver; manifestations of carcinoid syndrome do not occur until there are metastases to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized
.
In most patients, there is an increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin
.
levels of 5-HIAA (5-hydroxyindoleacetic acid), the end product of serotonin metabolism. Patients with carcinoid syndrome usually excrete more than 25 mg of 5-HIAA per day. For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan, where indium-111 labelled somatostatin
analogues (octreotide
) are used in scintigraphy
for detecting tumors expressing somatostatin
receptors. Median detection rates with octreoscan are about 89%, in contrast to other imaging techniques such as CT scan and MRI with detection rates of about 80%. Gallium-68 labelled somatostatin analogues such as 68Ga-DOTA-Octreotate (DOTATATE), performed on a PET/CT scanner is superior to conventional Octreoscan. Usually on CT scan, one will note a spider-like/crab like change in the mesentery due to the fibrosis from the release of serotonin. 18F-FDG PET/CT, which evaluate for increased metabolism of glucose, may also aid in localizing the carcinoid lesion or evaluating for metastases. Chromogranin A
and platelets serotonin
are increased.
is the definitive way to localize the tumour.
Alternative treatment for qualifying candidates:
varies from individual to individual. It ranges from a 95% 5 year survival for localized disease to an 80% 5 year survival for those with liver metastases. The average survival time from the start of octreotide treatment has increased to about 12 years.
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s that occur secondary to carcinoid tumors
Carcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
. The syndrome includes flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, and, less frequently, heart failure and bronchoconstriction
Bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
. It is caused by endogenous secretion of mainly serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and kallikrein
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
.
Clinical presentation
The carcinoid syndrome occurs in approximately 10% of carcinoid tumors andbecomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. This is the case when carcinoid tumors metastasize to the liver or they arise for example in the bronchus.
The most important clinical finding is flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
of the skin, usually of the head and the upper part of thorax. Secretory diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and abdominal cramps are also characteristic features of the syndrome. When the diarrhea
is intensive it may lead to electrolyte disturbance and dehydration. Other associated symptoms are nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. Bronchoconstriction
Bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
, which may be histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
-induced, affects a smaller number of patients and often accompanies flushing.
About 50% of patients have cardiac abnormalities, caused by serotonin-induced fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
of the tricuspid
Tricuspid valve
The tricuspid valve, or right atrioventricular valve, is on the right dorsal side of the mammalian heart, between the right atrium and the right ventricle. The normal tricuspid valve usually has three leaflets and three papillary muscles. They are connected to the papillary muscles by the chordae...
and pulmonary
Pulmonary valve
The pulmonary valve is the semilunar valve of the heart that lies between the right ventricle and the pulmonary artery and has three cusps. Similar to the aortic valve, the pulmonary valve opens in ventricular systole, when the pressure in the right ventricle rises above the pressure in the...
valves. Elevated levels of circulating serotonin have been associated with cardiac failure, due to fibrous deposits on the endocardium. These deposits are thought to be responsible for the fibrous degeneration of the valve apparatus. "TIPS" is an acronym for Tricuspid Insufficiency, Pulmonary Stenosis (fibrosis of tricuspid and pulmonary valves).
Abdominal pain is due to desmoplastic
Desmoplasia
In medicine, a desmoplastic fibroma is a benign fibrous tumour of bone, affecting children and young adults, potentially resulting in cortical bone destruction. It can also occur in the hand....
reaction of the mesentery
Mesentery
In anatomy, the mesentery is the double layer of peritoneum that suspends the jejunum and ileum from the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity.-Mesentery :The...
or hepatic metastases.
Although the most common site of a carcinoid tumor is the appendix or terminal ileum, liver metastases, releasing serotonin directly into the systemic circulation are required for the carcinoid syndrome to occur. This is because serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
created by a GI carcinoid tumour and released into the hepatic portal system is broken down at the liver and does not reach the systemic circulation. However: If the tumor is bronchogenic in origin, then metastasis does not need to occur in order for carcinoid syndrome to occur.
Pathophysiology
Carcinoid tumors produce the vasoactive substance, serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
. It is commonly, but incorrectly, thought that serotonin is the cause of the flushing. The flushing results from secretion of kallikrein
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin. The latter is further converted to bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
, one of the most powerful vasodilators known. Other components of the carcinoid syndrome are diarrhea (probably caused by serotonin), a pellagra
Pellagra
Pellagra is a vitamin deficiency disease most commonly caused by a chronic lack of niacin in the diet. It can be caused by decreased intake of niacin or tryptophan, and possibly by excessive intake of leucine. It may also result from alterations in protein metabolism in disorders such as carcinoid...
-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B3, niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
, to the synthesis of 5-hydroxyindoles including serotonin), fibrotic lesions of the endocardium, particularly on the right side of the heart resulting in insufficiency of the tricuspid valve and, less frequently, the pulmonary valve and, uncommonly, bronchoconstriction. The pathogenesis of the cardiac lesions and the bronchoconstriction is unknown, but the former probably involves activation of serotonin 5-HT2B receptor
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
s by serotonin. When the primary tumor is in the gastrointestinal tract, as it is in the great majority of cases, the serotonin and kallikrein are inactivated in the liver; manifestations of carcinoid syndrome do not occur until there are metastases to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
.
In most patients, there is an increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
.
Diagnosis
With a certain degree of clinical suspicion, the most useful initial test is the 24 hour urineUrine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
levels of 5-HIAA (5-hydroxyindoleacetic acid), the end product of serotonin metabolism. Patients with carcinoid syndrome usually excrete more than 25 mg of 5-HIAA per day. For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan, where indium-111 labelled somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
analogues (octreotide
Octreotide
Octreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
) are used in scintigraphy
Scintigraphy
Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radioisotopes are taken internally, and the emitted radiation is captured by external detectors to form two-dimensional images...
for detecting tumors expressing somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
receptors. Median detection rates with octreoscan are about 89%, in contrast to other imaging techniques such as CT scan and MRI with detection rates of about 80%. Gallium-68 labelled somatostatin analogues such as 68Ga-DOTA-Octreotate (DOTATATE), performed on a PET/CT scanner is superior to conventional Octreoscan. Usually on CT scan, one will note a spider-like/crab like change in the mesentery due to the fibrosis from the release of serotonin. 18F-FDG PET/CT, which evaluate for increased metabolism of glucose, may also aid in localizing the carcinoid lesion or evaluating for metastases. Chromogranin A
Chromogranin A
Chromogranin A or parathyroid secretory protein 1 is a member of the granin family of neuroendocrine secretory proteins, i.e. it is located in secretory vesicles of neurons and endocrine cells...
and platelets serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
are increased.
Localization of tumour
Tumour localization may be extremely difficult. Barium swallow and follow-up examination of the intestine may occasionally show the tumour. Capsule video endoscopy has recently been used to localize the tumour. Often laparotomyLaparotomy
A laparotomy is a surgical procedure involving a large incision through the abdominal wall to gain access into the abdominal cavity. It is also known as coeliotomy.- Terminology :...
is the definitive way to localize the tumour.
Treatment
For symptomatic relief of carcinoid syndrome:- octreotideOctreotideOctreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
(a somatostatinSomatostatinSomatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
analogue that neutralizes serotonin and decreases urinary 5-HIAA) - peptide receptor radionuclide therapy (PRRT) with lutetium-177, yttrium-90Yttrium-90Yttrium-90 is a medically significant isotope of yttrium.It emits beta rays of 2.3 MeV.Yttrium-90 is a decay product of Strontium-90 which makes up about 5% of the Nuclear daughter isotopes when Uranium is fissioned....
or indium-111 labelled to octreotate is highly effective - methysergide maleate (antiserotonin agent but not used because of serious side effect of retroperitoneal fibrosis)
- cyproheptadineCyproheptadineCyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
(an antihistamineAntihistamineAn H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
drug)
Alternative treatment for qualifying candidates:
- Surgical resection of tumor and chemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
(5-FU and doxorubicin) - Endovascular, Chemoembolization, targeted chemotherapy directly delivered to the liver through special catheters mixed with embolic beads (particles that block blood vessels). For patients with liver metastases.
Prognosis
PrognosisPrognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
varies from individual to individual. It ranges from a 95% 5 year survival for localized disease to an 80% 5 year survival for those with liver metastases. The average survival time from the start of octreotide treatment has increased to about 12 years.
Synonyms
- Thorson-Bioerck syndrome
- Argentaffinoma syndrome
- Cassidy-Scholte sydrome
- Flush syndrome
See also
- CarcinoidCarcinoidCarcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
- Kulchitsky cells
- ApudomaApudomaIn pathology, an apudoma is an endocrine tumour that arises from an APUD cell from structures such as the ampulla of Vater, pancreas, and prostate.They are derived from neural crest cells.The term dates back to at least 1975....