Carcinoid Syndrome

Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and less frequently, heart failure, emesis and bronchoconstriction. It is caused by endogenous secretion of mainly serotonin and kallikrein.

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. Interestingly, if the primary tumor is from the GI 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 of the skin, usually of the head and the upper part of thorax.

Diarrhea: When the diarrhea is intense and explosive, it may lead to electrolyte disturbance and dehydration.
Abdominal pain: Due to desmoplastic reaction of the mesentery or hepatic metastases.
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 (fibrosis of tricuspid and pulmonary valves).
Nausea and Vomiting

Diagnosis
With a certain degree of clinical suspicion, the most useful initial test is the 24-hour urine 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 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 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 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 tumor. Capsule video endoscopy has recently been used to localize the tumor. Often laparotomy 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 (a somatostatin analogue which decreases the secretion of serotonin by the tumor and, secondarily, decreases the breakdown product of serotonin (5-HIAA))
Telotristat ethyl (Xermelo) along with a somatostatin analogue in patients not responding to somatostatin analogue monotherapy. It is a tryptophan hydroxylase inhibitor and reduces the production of serotonin.
Peptide receptor radionuclide therapy (PRRT) with lutetium-177, yttrium-90 or indium-111 labeled to octreotate is highly effective
Methysergide maleate (antiserotonin agent but not used because of the serious side effect of retroperitoneal fibrosis)
Cyproheptadine (an antihistamine drug with antiserotonergic effects)
Alternative treatment for qualifying candidates:

Surgical resection of tumor and chemotherapy (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), used for patients with liver metastases.
Uncertainties
Disease progression is difficult to ascertain because the disease can metastasize 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 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.

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