Progress in diagnosis and treatment of carcinoid syndrome

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[definition]Carcinoid syndrome (carcinoid syndrome [1]) is due to a variety of peptide and amine hormone secreted by the functional neuroend



Carcinoid syndrome (carcinoid syndrome [1]) is due to a variety of peptide and amine hormone secreted by the functional neuroendocrine tumors such as histamine, bradykinin, serotonin and prostaglandin 5- enter the systemic circulation, caused by syndrome of clinical manifestations of paroxysmal abdominal pain, diarrhea, skin flushing, valvular heart disease, dilated capillaries, wheezing, pellagra, cancer and life-threatening crisis class (carcinoid crisis) can be serious. Neuroendocrine tumor carcinoid syndrome occurs in foregut and midgut, especially in tumor occurrence of liver metastasis, hormone secreted by the liver is not inactivated and enter the systemic circulation and thus lead to various hormone related symptoms.

Pathogenesis and clinical symptoms

Neuroendocrine tumor cells can produce many kinds of bioactive substances, resulting in carcinoid syndrome is the main 5- serotonin, bradykinin, histamine and prostaglandin [1,2].

5- serotonin derived from tryptophan in food. Under normal circumstances, tryptophan 99% is utilized by body, formation of niacin or Niacinamide, only 1% were generated using 5- ht. After the occurrence of neuroendocrine tumors, 60% of tryptophan in food is converted to 5- HT in neuroendocrine tumor cells, so 5- serotonin in the blood of patients with neuroendocrine tumors increased significantly. The formation process of 5- serotonin from tryptophan as follows: tryptophan hydroxylase in 5- under the action of the formation of 5- hydroxytryptophan, followed by aromatic acid decarboxylase, generate 5- serotonin; 5- serotonin in monoamine oxidase under the effect of changes to 5- hydroxyindole in acetaldehyde, aldehyde dehydrogenase were used. Change 5- hydroxyindoleacetic acid (5-HIAA), this is no bioactive substances from the urine excreted. In normal human blood, the 5- HT was 0.1 ~ 0.2 g/ml, and the content of 5- was less than 10mg in the urine of 24 hours. In patients with carcinoid syndrome, the blood 5- serotonin up to 0.8 mu g/ml, the urine of 5- in the urine can be as high as 100 to 3000mg of. The main function of 5- serotonin is to dilate blood vessels, bronchial smooth muscle spasm, gastrointestinal motility increased. Thus 5 HT increased can cause skin flushing, wheezing, abdominal pain, diarrhea. In addition, 5- can stimulate the proliferation of fibroblast cells, causing cardiac (mainly right heart) intimal fibrosis [1,2].

Bradykinin is caused by another major bioactive substances of carcinoid syndrome. In neuroendocrine tumors in a large number of kallikrein, this is a proteolytic enzyme acting on the kininogen generating lysylbradykinin (kallidin), the aminopeptidase under the effect of lysine and converted to bradykinin bradykinin. Bradykinin is the role of the arteriolar relaxation, blood pressure, heart rate, diastolic blood capillary, erubescence. 5- and serotonin caused by skin flushing warmer, bradykinin induced skin flushing, skin temperature is not high, cold type. In addition, bradykinin can also increased vascular permeability, plasma extravasation, skin edema (particularly in the eyelids and lips), can also make the bronchial spasm and wheezing [1].

There is no carcinoid syndrome in the functional neuroendocrine tumors of the gastrointestinal tract. Because the liver has a large number of monoamine oxidase, when 5- serotonin into the liver through the portal vein, that is converted to 5- hydroxy indole acetic acid, and its loss of activity. If there is a liver metastasis, because inactivated ability to produce 5- serotonin too much than the liver, on the other hand can be directly 5- HT via hepatic vein into the systemic circulation, therefore the carcinoid syndrome often occurs in liver metastasis after [1].

The foregut (mainly the stomach and bronchial) neuroendocrine tumors due to lack of aromatic acid decarboxylase, 5- cannot be hydroxytryptophan into 5- serotonin, therefore these tumors mainly produce 5- hydroxytryptophan, histamine and some peptide hormones, atypical carcinoid clinical syndrome. Histamine also can make the skin moist and wheezing, and increase gastric acid and peptic ulcer. Midgut neuroendocrine tumors often produce typical carcinoid syndrome, resulting in a large number of 5- HT, in all the carcinoid syndrome, caused by midgut neuroendocrine tumors accounted for 75%-90%. Intestinal neuroendocrine tumors due to the lack of tryptophan into serotonin 5- enzyme, so even if the occurrence of liver metastasis is rare carcinoid syndrome [1].

The following table summarizes various clinical symptoms of carcinoid syndrome and the corresponding hormones that mediate these symptoms [1]:



incidence rate

Mediated hormone











Niacin deficiency due to excessive consumption of tryptophan

gastrointestinal tract



5- serotonin, bradykinin, histamine, prostaglandins, etc.

Spastic abdominal pain


cardiovascular system

Right heart damage


5- serotonin metabolites

Left heart damage


Respiratory system



Tachykinin and bradykinin

Carcinoid cancer class comprehensive life-threatening crisis can be serious when the syndrome (carcinoid crisis [1]). Carcinoid crisis mainly occurs in the foregut and midgut neuroendocrine tumors, the clinical manifestations of hypotension, tachycardia, bronchospasm, flushing and dysfunction of the central nervous system. Carcinoid crisis can occur spontaneously, also can be in after anesthesia or chemotherapy, radiotherapy and chemotherapy in tumor lysis to release large amounts of amine hormone after entering the circulatory system.

60-80% like disease (carcinoid heart) may occur in patients with carcinoid syndrome ([1,3]). The main pathological manifestations of carcinoid heart disease and valvular endocardial fibrous thickening, occurred in the right cardiac cavities, clinically with three tricuspid insufficiency and stenosis as close as the main clinical manifestations of heart disease and dysfunction, pulmonary valve stenosis. But about 10% of all cases of carcinoid heart disease also involve the left heart.


The diagnosis of carcinoid syndrome includes the following aspects:

There are episodes of skin flushing, abdominal pain, diarrhea and other symptoms of 1 patients;

2 detection of biomarkers. Elevated biomarkers in patients with carcinoid syndrome include 5- serotonin in blood and 5-HIAA[2] in urine. In foregut neuroendocrine tumors, due to lack of aromatic acid decarboxylase 5- in blood serotonin concentration so often is not high. The 5-HIAA of 24 hours urine in patients with carcinoid syndrome was greater than 30mg. 24 hour urine 5-HIAA excretion fluctuated greatly, but also influenced by food, such as potatoes, bananas, pineapple, urinary 5-HIAA excretion increased, so repeated urinalysis (at least 2 to 24 hours), and the fasting food after 24 hours of the results is more reliable. In addition, A (Chromogranin, CgA), a common biomarker for the diagnosis of neuroendocrine tumors, can also be used in the diagnosis of carcinoid syndrome. Chromogranin A exists in most neuroendocrine tumor cells with large secretory granules in the matrix, and the CO release of peptide and amine hormone precursor or angiogenesis inhibitor, pancreastatin several peptides, is currently recognized as the most valuable neuroendocrine tumors (either functional or non functional). The "universal" tumor markers. The sensitivity and specificity of elevated serum or plasma CgA levels in neuroendocrine tumors were between 70%-100% and [4].

3 localization diagnosis of neuroendocrine tumors leading to carcinoid syndrome. A variety of imaging examinations including endoscopy, endoscopic ultrasonography, ultrasound, CT, MRI, somatostatin receptor imaging (Somatostatin receptor scinigraphy, SRS), PET-CT can be used for the diagnosis of tumor location [5]. Endoscopy is mainly used for the examination of neuroendocrine tumors of esophagus and gastrointestinal tract. Ultrasound, CT, MRI can be found in diameter greater than 25px lesions, the positive rate of 60%-90%. It is worth noting that endoscopic ultrasonography has a unique advantage in the localization of neuroendocrine tumors of the pancreas, duodenum and stomach, and can even detect lesions with a diameter less than 25px, which has a diagnostic sensitivity of 80%-90%. SRS is a highly sensitive and specific diagnostic technique for neuroendocrine tumors. The neuroendocrine tumor cell surface 55%-95% expression of somatostatin receptor (Somatostatin receptor, SSTR), especially SSTR2 and SSTR5, and somatostatin (Somatostatin, SST) analogs such as octreotide (Octreotide) specific binding, SRS is the analogue of SST radiolabeled appropriate into the body, combined with the specific receptor the surface of the tumor to tumor imaging, and tumor lesion and metastasis diagnosis technology, in addition, SRS can also be used to predict the sensitivity of cancer drugs such as somatostatin or radionuclide therapy. The diagnostic sensitivity of SRS to neuroendocrine tumors was between 60%-100%. PET-CT is a functional imaging technique that can reflect the metabolic status of tumors. The commonly used tracer 18F- fluorodeoxyglucose (18F-FDG) only sensitive to poorly differentiated neuroendocrine tumor with high proliferation; the use of special tracers, such as 11C-5- (11C-5-hydroxytryptophan, 11C-5HTP), serotonin can significantly improve PET-CT of neuroendocrine tumor specificity and sensitivity, especially for tumor diameter less than 25px.

Diagnosis of 4 types of cancer heart disease [1,3]. The two key tests for the diagnosis of carcinoid heart disease on the basis of carcinoid syndrome are serum biomarkers N terminal brain natriuretic peptide (NT-pro-BNP) and transthoracic echocardiography. Carcinoid heart disease in patients with NT-pro-BNP was higher than that of non carcinoid heart disease. It has a high negative predictive value for the diagnosis of carcinoid heart disease and can be used as a screening test for carcinoid heart disease. Echocardiography can have a clear assessment of heart valve damage, the typical sonographic findings is thickening in three tricuspid valve leaves, pulmonary valve leaflets and corresponding flap, flap drift reduced, finally flap retraction, fixed and combined, causing the valve remains open position in half, function can the combination of valvular regurgitation and stenosis. Three the tricuspid valve and pulmonary valve were combined to aggravate the disorder of hemodynamics. Right atrial and right ventricular enlargement. Right ventricular volume overload, interventricular septum showed paradoxical movement, right ventricular function to the late onset of the disease. 10% of patients with carcinoid heart disease may involve the left heart valve.

In conclusion, the typical clinical symptoms, serum 5- and urinary 5-HIAA increased serum serotonin, chromogranin A increased in diagnosis of carcinoid syndrome, on the basis of elevated serum NT-pro-BNP and echocardiography typical right heart valvular lesions can be diagnosed carcinoid heart disease, finally through the imaging position lead to neuroendocrine tumor carcinoid syndrome.


The treatment of the carcinoid syndrome is the first as far as possible by surgery lead to neuroendocrine tumors of the carcinoid syndrome, if radical resection is not necessary, cytoreductive surgery or interventional surgical cytoreduction also helps relieve symptoms of the carcinoid syndrome. For patients who cannot be operated on, PRRT (Peptide Radio Receptor Therapy) or drug therapy can be used to control the symptoms of [6]. The main therapeutic agents for carcinoid syndrome include somatostatin analogues and interferon [7].

Somatostatin analogue combined with somatostatin receptor neuroendocrine tumors on the surface of tumor cells, inhibit the secretion of hormones, can better control of carcinoid syndrome, flushing, diarrhea and other symptoms, and have a certain anti-tumor effects of [7]. Somatostatin analogues are also used for the treatment of carcinoid crisis and carcinoid heart disease. 5-HIAA levels were significantly decreased after treatment with somatostatin analogues. Currently available for treatment include somatostatin analogue octreotide carcinoid syndrome (octreotide, trade name Sandostatin) and Lan Ruitai (lanreotide, trade name Somatuline), all two have strong affinity for SSTR2 and SSTR5, no affinity for SSTR1 and SSTR4, on SSTR3 and weak pro. Long-acting formulations of octreotide and lanreotide called Sandostatin-LAR, there are two kinds of sustained-release preparations, a method called Somatuline-PR, another called Somatuline Autogel. The somatostatin analogue treatment dose and usage of the carcinoid syndrome are as follows: octreotide 300-1500 g/, Sandostatin-LAR 20-60mg, subcutaneous injection; intramuscular injection once every 2-4 weeks; Somatuline-PR 30 mg, intramuscular injection every 2 weeks at a time; Somatuline Autogel 90-120mg, intramuscular injection every 4 weeks at a time. For treatment with long-acting somatostatin analogues in patients during treatment if symptoms break or symptom control is not satisfied, can be combined with octreotide for the treatment of [7] to "save".

Interferon can bind to the interferon receptor on the surface of neuroendocrine tumor, through the activation of a series of signal pathway, inhibit the synthesis of hormone or cause the degradation of hormone. Interferon is effective to about 40% of the patients with carcinoid, the symptoms of diarrhea is better than flushing. But interferon can not be used for carcinoid crisis and carcinoid heart disease treatment. Therefore, interferon is used as second-line therapy in the treatment of carcinoid syndrome ([7]).

The latest research for the carcinoid syndrome drugs including new somatostatin analogue pasireotide (Pasireotide), SSTR1, 2, of pasireotide 3 and SSTR5 have a strong affinity, phase II clinical trial results showed that the small intestine cancer drug resistance of pasireotide recurrence or standard dose of octreotide syndrome patients the effective control of the symptoms of diarrhea and flushing [7]. Telotristat etiprate is a new drug for oral 5- serotonin synthesis inhibitor, phase II clinical trial results showed that the recurrence or long-acting octreotide resistant patients with carcinoid syndrome telotristat etiprate can effectively improve the symptoms of diarrhea and urinary 5-HIAA levels were significantly lower in [8].

For carcinoid heart disease, somatostatin analogue therapy can alleviate the clinical symptoms, but can not reverse the heart valve damage caused by 5- serotonin, it is necessary to improve the heart function of patients by surgical valve replacement, prolong the survival period of [3].

Surgery can be due to the surgery itself or preoperative anesthesia in carcinoid crisis. Perioperative administration of octreotide reduces 5- serotonin release, method of operation is the most effective prevention of carcinoid crisis. At least 2 h before operation was started (50 ~ 100 g/h octreotide infusion), until 48 h after operation. Patients may need after subcutaneous injection of octreotide, the dose depends on the previous requirement and carcinoid syndrome control. In addition to avoid or minimize the use of drugs to promote the comprehensive media release of the carcinoid syndrome, such as opioids, nerve muscle relaxants, dopamine and epinephrine drugs to reduce the risk of triggering carcinoid crisis [3].

(this is the author of the 2014 CSCO annual meeting of the contributing writer, please indicate the source)


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2 O 'Toole D, Grossman A, Gross et ENETS Guidelines for Standards of in Neuroendocrine Tumors: Markers. Biochemical Neuroendocrinology; 90:194 - - 202 - the - Care Consensus D al.

3 Patel C, Mathur M, Escarcega RO, et al. heart Current understanding future directions. Heart and J.; disease:; 167:789-795.; Carcinoid (Am)

4 Singh S and Law C. Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev. Gastroenterol. Hepatol.2012 6: 313 - 334;

5 Minhu Chen, Chen Jie. Advances in diagnosis and treatment of gastrointestinal neuroendocrine tumors. Chinese Journal of Gastroenterology, 2011, (8): 505-508 (in Chinese).

6 Pavel M, Kidd M, Modlin Systemic therapeutic for carcinoid. Oncol. Semin Feb; 40 (1): 84-99. (I.): Options

7 Caplin M, Yao JC. of and Neuroendocrine Tumours. Chapter 7, Page 118-121. Published August, by Handbook, BioScientifica., Gastroenteropancreatic, Thoracic

8 Kulke M, Dorisio T, Phan A O, et al. Efficacy of Telotristat Etiprate in Refractory Carcinoid Syndrome: Preliminary Results of a Randomized, Placebo-controlled Multicenter, Study. Presented at the European Neuroendocrine Tumor Society (ENETS) Meeting - Copenhagen, Denmark - March 7-9, 2012

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