Carcinoid syndrome refers to the array of symptoms 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.
Clinical presentation
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. Interestingly, if the primary tumor is from the GI tract, 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 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.
Diarrhea: 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.
Secondary restrictive cardiomyopathy: About 50% of patients have cardiac abnormalities
classically of the restrictive-type caused by serotonin-induced fibrosis of the valvular
endocardium, notably the tricuspid and pulmonary valves, called cardiac fibrosis. This results
in a heart with normal rhythm and contractility, but reduced preload and end-diastolic volume.
"TIPS" is an acronym for Tricuspid Insufficiency, Pulmonary Stenosis.
Abdominal pain: Due to desmoplastic reaction of the mesentery or hepatic metastases.
Pathophysiology Carcinoid tumors produce the vasoactive substance,
serotonin. 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, a pellagra-like syndrome, 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 receptors 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. 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, a degradation product of serotonin.
The biology of these tumors is interesting as it 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 levels of 5-HIAA, 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 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, performed on a PET/CT scanner is superior to conventional
Octreoscan. Usually on 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 and platelets serotonin 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 laparotomy
is the definitive way to localize the tumour.
Treatment For symptomatic relief of carcinoid syndrome:
octreotide) peptide receptor radionuclide therapy with
lutetium-177, yttrium-90 or indium-111 labelled to octreotate is highly effective
methysergide maleate cyproheptadine
Alternative treatment for qualifying candidates: Surgical resection of tumor and chemotherapy
Endovascular, Chemoembolization, targeted chemotherapy directly delivered to the liver
through special catheters mixed with embolic beads. For patients with liver metastases.
Uncertainties All aspects of this disease have significant
uncertainties. Patients frequently face disagreeing doctors and have to choose which doctors'
advice to follow, thereby effectively deciding their own treatment course. Disease progression
is difficult to ascertain because the disease can metastasize anywhere in the body, can
be too small to identify with any current technology, and surprises can await the surgeon
in the operating room. The markers, such as Chromogranin A, are generally poor signifiers.
Therefore, the patient and doctor must make decisions with few facts and few ways to test
the results of those decisions. Prognosis
Prognosis 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 syndrome
Flush syndrome See also
Carcinoid Neuroendocrine tumor
Kulchitsky cells Apudoma
Serotonin Syndrome References