Carcinoid syndrome refers to a group of symptoms that occur when NETs secrete large amounts of various humoral substances into the systemic circulation. The most common features are cutaneous flushing (85%–90%), secretory diarrhea (75%–80%), bronchospasm (10%–20%), and fibrotic growths involving the endocardium and right heart valves (33%) and sometimes pleural, peritoneal, or retroperitoneal fibrosis. Carcinoid syndrome does not cause hypertension but may cause hypotension, especially during prolonged flushing spells. Carcinoid syndrome most often results from midgut NETs (jejunum, ileum, appendix, cecum, ascending colon) that have metastasized to the liver. Carcinoid syndrome is only rarely associated with foregut and hindgut NETs.
Carcinoid syndrome results from the production and release of biologically active amines and peptides (e.g., serotonin, histamine, or tachykinins) from neuroendocrine tumors. Approximately 8% to 28% of these tumors result in carcinoid syndrome. The liver metabolizes serotonin to inactive products and, therefore, most patients do not develop carcinoid syndrome until they have significant liver metastases, which permit serotonin to directly enter the systemic circulation. Because serotonin is rapidly metabolized, it cannot be measured. However, 5-hydroxyindoleacetic acid (5-HIAA) is the main serotonin metabolite and can be measured in 24-hour urine samples.
Carcinoid syndrome most commonly results from small bowel primary tumors. Classic symptoms include intermittent flushing, diarrhea, wheezing (from bronchoconstriction), and right-sided heart failure (from valvular fibrosis of the right-sided valves). Carcinoid crisis is a life-threatening exacerbation of carcinoid syndrome, which manifests as profound flushing, bronchospasm, tachycardia, and volatile swings of blood pressure. Patients with foregut or midgut carcinoid tumors (with or without having carcinoid syndrome) are at risk for carcinoid crisis during manipulation, whether that be surgery or radiologic intervention.
Symptoms of carcinoid syndrome
Flushing in carcinoid syndrome
The classic carcinoid flush that occurs with midgut NETS is characterized by sudden episodes of reddish-to-purplish flushing of the face, neck, and chest associated with cutaneous burning, lasting anywhere from 30 seconds to 30 minutes. More severe or prolonged flushing episodes may be associated with hypotension and tachycardia. Telangiectasias eventually develop on the malar areas, nose, and upper lip as a result of prolonged vasodilation in the cutaneous vasculature.
Gastric NET flushing is more often patchy, serpiginous, bright red, and intensely pruritic. Pulmonary NET flushing can be prolonged (hours to days) and more severe, and may be associated with hypotension, tachycardia, anxiety, disorientation, periorbital edema, lacrimation, salivation, dyspnea, wheezing, and diarrhea.
Why does niacin deficiency and pellagra often accompany carcinoid syndrome?
Niacin deficiency occurs in carcinoid syndrome because large amounts of tryptophan are diverted from niacin synthesis to produce serotonin. This can result in the classic features of pellagra—glossitis, angular stomatitis, rough scaly skin, mental confusion, and hypoproteinemia.
Once carcinoid syndrome is diagnosed, what is the next step?
The tumor must be localized. This may be difficult because of the small size of many carcinoid tumors. Multiphasic CT or MRI and somatostatin receptor scintigraphy are generally recommended to localize any carcinoid tumor. Luminal evaluation by endoscopy with consideration for endoscopic ultrasonography is also recommended for ileal, rectal, large intestine, and gastric carcinoids. Echocardiography should be performed if right-sided heart disease is suspected in cases of carcinoid syndrome.
How is the diagnosis of carcinoid syndrome usually made?
Carcinoid syndrome caused by midgut NETs (jejunum, ileum, appendix, cecum, ascending colon) is diagnosed by demonstrating markedly elevated 24-hour urinary 5-HIAA excretion; 5-HIAA is a breakdown product of serotonin.
Normal urinary 5-HIAA excretion is < 8 mg/24 hr. Other causes of mild-to-moderate 5-HIAA elevations are shown in ; excretion of 5-HIAA is usually < 30 mg/24 hr in these situations.
Carcinoid syndrome is most often associated with urinary 5-HIAA excretion > 100 mg/24 hr, although only mild or normal values may be seen in some patients.
Patients should avoid foods that are rich in tryptophan and/or serotonin and medications, which can produce false positive or false negative 5-HIAA results, for 3 days prior to and on the day of collection of the 24-hour urine specimen.
Causes of Abnormal 5-Hydroxyindoleacetic Acid (5-HIAA) Excretion Other than Carcinoid Syndrome.
|Diseases —malabsorption disorders|
|Food (tryptophan rich) —bananas, pineapples, kiwi, plums, avocados, eggplant, pecans, walnuts, hickory nuts|
|Medications that increase 5-HIAA —acetaminophen, ephedrine, guaifenesin, mephenesin, methocarbamol, phenacetin, caffeine, nicotine, methamphetamine, phenobarbital, acetanilid, reserpine, phentolamine, phenmetrazine, coumaric acid, melphalan, fluorouracil|
How is carcinoid syndrome diagnosed if urinary 5-HIAA is normal?
Foregut carcinoid tumors usually lack the enzyme L-amino acid decarboxylase and, therefore, do not convert 5-hydroxytryptophan to serotonin; serotonin and 5-HIAA values are, therefore, usually normal. Assays for 5-hydroxytryptophan are not available. Whole-blood serotonin, platelet-rich plasma serotonin, and urinary serotonin assays are available, but their performance characteristics have not yet been established. Accordingly, they are not recommended as routine screening tools; nonetheless, these measurements may be useful in select patients. Similarly, a plasma 5-HIAA assay has been developed, but its usefulness for diagnosing carcinoid syndrome has not been well evaluated, and the test itself is not widely available.
Chromogranins A, B, and C are secreted by multiple types of NETs. Chromogranin A is often significantly elevated in carcinoid syndrome, but there are numerous other conditions and medications (especially proton pump inhibitors) that can elevate serum chromogranin A levels. Because elevations are nonspecific, serum chromogranin A is not recommended as a routine screening test for carcinoid syndrome. Proceeding directly to imaging of the abdomen, pelvis, and chest is often the best option.
What procedures are the best to localize the source of carcinoid syndrome?
Cross-sectional imaging with multiphasic contrast-enhanced CT scanning of the areas of suspected tumor location (usually starting with the abdomen and pelvis) is the best initial imaging study. Some authorities prefer MRI because of its superior detection of hepatic metastases. Somatostatin-based functional imaging with 68-Ga DOTATATE or In-111 pentetreotide (octreoscan) is an imaging technique that is particularly useful when a tumor is not detected with cross-sectional imaging. When available, 68-Ga DOTATATE is the preferred functional imaging agent because of demonstrated superior performance.
What is the treatment for carcinoid syndrome?
Surgery can be curative when carcinoid syndrome results from a carcinoid tumor that has not metastasized. However, approximately 90% of patients with carcinoid syndrome have extensive metastases at the time of diagnosis. The goal of therapy, therefore, is most often to provide palliation and to prolong survival.