Carcinoid syndrome is a
paraneoplastic syndrome comprising the
signs and
symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
s that occur secondary to
carcinoid tumors
A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) ...
. The syndrome includes
flushing
Flushing may refer to:
Places
* Flushing, Cornwall, a village in the United Kingdom
* Flushing, Queens, New York City
** Flushing Bay, a bay off the north shore of Queens
** Flushing Chinatown (法拉盛華埠), a community in Queens
** Flushing ...
and
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, and less frequently,
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
and
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.
Causes
The condition has a number of causes, the most common bei ...
.
It is caused by endogenous secretion of mainly
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
and
kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
.
Signs and symptoms
The carcinoid syndrome occurs in approximately 5% of carcinoid tumors
and becomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. If the primary tumor is from the gastrointestinal tract (hence releasing serotonin into the
hepatic portal circulation), carcinoid syndrome generally does not occur until the disease is so advanced that it overwhelms the liver's ability to metabolize the released serotonin.
* Flushing: The most important clinical finding is
flushing
Flushing may refer to:
Places
* Flushing, Cornwall, a village in the United Kingdom
* Flushing, Queens, New York City
** Flushing Bay, a bay off the north shore of Queens
** Flushing Chinatown (法拉盛華埠), a community in Queens
** Flushing ...
of the skin, usually of the head and the upper part of thorax.
* Diarrhea: It may be associated with abdominal cramping. This symptom is due to the action of serotonin,
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, and
gastrin
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin ...
* Abdominal pain: It is due to
hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
, small bowel obstruction or lack of oxygen to small bowel.
*
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.
Causes
The condition has a number of causes, the most common bei ...
, which may be
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
or serotonin-induced, affects about 15% of those having carcinoid syndrome and often accompanies flushing, sneezing, and shortness of breath.
* Carcinoid heart disease: About 19% to 60% of the those affected by carcinoid syndrome develop carcinoid heart disease. Serotonin induces fibrosis in valves of the right heart especially
tricuspid valve
The tricuspid valve, or right atrioventricular valve, is on the right dorsal side of the mammalian heart, at the superior portion of the right ventricle. The function of the valve is to allow blood to flow from the right atrium to the right vent ...
.
Pathophysiology
Carcinoid tumors produce several vasoactive substances, most prominently serotonin. It is commonly thought that serotonin is the cause of the flushing, but this is only partially correct.
The flushing also results from secretion of
kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
, the enzyme that catalyzes the conversion of
kininogen Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.
Types o ...
to lysyl-bradykinin. The latter is further converted to
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
, one of the most powerful
vasodilators
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction ...
known.
Other components of the carcinoid syndrome are diarrhea (probably caused by the increased serotonin, which greatly increases peristalsis, leaving less time for fluid absorption), a
pellagra
Pellagra is a disease caused by a lack of the vitamin niacin (vitamin B3). Symptoms include inflamed skin, diarrhea, dementia, and sores in the mouth. Areas of the skin exposed to either sunlight or friction are typically affected first. Over t ...
-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B
3 niacin
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...
, which is needed for NAD production, to the synthesis of serotonin and other 5-hydroxyindoles), 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-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the ''HTR2B'' gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytrypta ...
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
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the
bronchi
A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...
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
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
.
In most patients, there is an increased urinary excretion of
5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin.
The biology of these tumors differs from many other tumor types. Ongoing research on the biology of these tumors may reveal new mechanisms for tumor development.
Diagnosis
With a certain degree of clinical suspicion, the most useful initial test is the 24-hour
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
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.
Imaging
For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan, where
indium-111
Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days.
Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target (112Cd(p,2n) ...
labelled
somatostatin
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
analogues (
octreotide
Octreotide, sold under the brand name Sandostatin among others, 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. It was ...
) are used in
scintigraphy
Scintigraphy (from Latin ''scintilla'', "spark"), also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally and ...
for detecting tumors expressing
somatostatin
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
receptors. Median detection rates with octreoscan are about 89%, in contrast to other imaging techniques such as
CT scan and
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
with detection rates of about 80%.
Gallium-68
Natural gallium (31Ga) consists of a mixture of two stable isotopes: gallium-69 and gallium-71. The most commercially important radioisotopes are gallium-67 and gallium-68.
Gallium-67 (half-life 3.3 days) is a gamma-emitting isotope (the gamma r ...
labelled somatostatin analogues such as
68Ga-DOTA-Octreotate (DOTATATE), performed on a PET/CT scanner is superior to conventional Octreoscan.
Usually, on a CT scan, a spider-like/crab-like change is visible 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 or parathyroid secretory protein 1 (gene name CHGA) is a member of the granin family of neuroendocrine secretory proteins. As such, it is located in secretory vesicles of neurons and endocrine cells such as islet beta cell secretory ...
and platelets serotonin are increased.
Transthoracic echocardiogram
A transthoracic echocardiogram (TTE) is the most common type of echocardiogram, which is a still or moving image of the internal parts of the heart using ultrasound. In this case, the probe (or ultrasonic transducer) is placed on the chest or abdo ...
shows valve thickening and reduction in mobility of the valves. Cardiac MRI is useful in showing ventricular anatomy and function.
Localization of tumour
Tumour localization may be extremely difficult. Barium swallow and follow-up examination of the intestine may occasionally show the tumor. Capsule video endoscopy has recently been used to localize the tumor. Often
laparotomy
A laparotomy is a surgical procedure involving a surgical incision through the abdominal wall to gain access into the abdominal cavity. It is also known as a celiotomy.
Origins and history
The first successful laparotomy was performed without ane ...
is the definitive way to localize the tumour. Another form of localizing a tumor is the octreoscan. A tracer agent of Indium 111 is injected into a vein where then the tumors absorb the radionuclide Indium 111 and become visible on the scanner. Only the tumors absorb the somatostatin agent Indium 111 making the scan highly effective.
Treatment
For symptomatic relief of carcinoid syndrome:
*
Octreotide
Octreotide, sold under the brand name Sandostatin among others, 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. It was ...
(a
somatostatin
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
analogue which decreases the secretion of serotonin by the tumor and, secondarily, decreases the breakdown product of serotonin (
5-HIAA))
*
Telotristat ethyl
Telotristat ethyl (USAN, brand name Xermelo) is a prodrug of telotristat, which is an inhibitor of tryptophan hydroxylase. It is formulated as telotristat etiprate — a hippurate salt of telotristat ethyl.
On February 28, 2017, the U.S. Food a ...
(Xermelo) along with a somatostatin analogue in patients not responding to somatostatin analogue monotherapy.
It is a
tryptophan hydroxylase
Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aro ...
inhibitor and reduces the production of serotonin.
*
Peptide receptor radionuclide therapy (PRRT) with
lutetium-177
Naturally occurring lutetium (71Lu) is composed of one stable isotope 175Lu (97.41% natural abundance) and one long-lived radioisotope, 176Lu with a half-life of 3.78 × 1010 years (2.59% natural abundance). Thirty-five radioisotopes have been ch ...
,
yttrium-90
Yttrium-90 () is an isotope of yttrium. Yttrium-90 has found a wide range of uses in radiation therapy to treat some forms of cancer.
Decay
undergoes β− decay to zirconium-90 with a half-life of 64.1 hours and a decay energy of 2.28 M ...
or
indium-111
Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days.
Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target (112Cd(p,2n) ...
labeled to
octreotate is highly effective
*
Methysergide maleate (antiserotonin agent but not used because of the serious side effect of
retroperitoneal fibrosis
Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It may present wi ...
)
*
Cyproheptadine
Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine, first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.
It was patented in 1959 an ...
(an
antihistamine
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...
drug with
antiserotonergic effects)
Alternative treatment for qualifying patients:
*
Surgical
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
resection of tumor and
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
(
5-FU and
doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used togeth ...
)
*Endovascular, chemoembolization, targeted chemotherapy directly delivered to the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
through special catheters mixed with embolic beads (particles that block blood vessels), used for patients with
liver metastases.
Uncertainties
Disease progression is difficult to ascertain because the disease can
metastasize
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
anywhere in the body and can be too small to identify with any current technology. Markers of the condition such as chromogranin-A are imperfect indicators of disease progression.
Prognosis
Prognosis
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
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.
See also
*
Carcinoid
A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) ...
*
Neuroendocrine tumor
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lun ...
*
Small intestine neuroendocrine tumor
*
Kulchitsky cells
Enterochromaffin (EC) cells (also known as Kulchitsky cells) are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal reg ...
*
Apudoma
In pathology, an apudoma is an endocrine tumour that arises from an APUD cell from structures such as the ampulla of Vater. They were historically thought to be derived from neural crest cells, but this has since been shown to be untrue (see ne ...
*
Serotonin Syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high ...
References
Further reading
*
*
External links
{{DEFAULTSORT:Carcinoid Syndrome
Paraneoplastic syndromes
Syndromes affecting the gastrointestinal tract