Carcinoid Syndrome

Carcinoid syndrome develops only in some patients with carcinoid tumors and is characterized by a kind of reddening of the skin ("hot flashes"), abdominal colic, spasms and diarrhea. In a few years, the valvular apparatus of the right heart may develop. The syndrome develops as a result of the action of vasoactive substances secreted by tumor cells (including serotonin, bradykinin, histamine, prostaglandins, polypeptide hormones); a tumor, as a rule, is metastatic.

[1], [2], [3], [4], [5], [6]

Causes of the carcinoid syndrome

Endocrinologically active tumors from diffuse peripheral endocrine or paracrine systems produce various amines and polypeptides, whose action is manifested by certain clinical symptoms and signs that together constitute a carcinoid syndrome.

Carcinoid syndrome is usually a consequence of endocrinologically active tumors that develop from neuroendocrine cells (mostly in the ileum) and produce serotonin. And nevertheless these tumors can develop and in other places GASTROINTESTINAL TRACT (especially often in an appendix and a rectum), a pancreas, bronchuses or less often in gonads. Occasionally, some neoplasms with a high degree of malignancy (for example, small cell lung carcinoma, pancreatic islet carcinoma, medullary thyroid carcinoma) are responsible for the development of this syndrome. Carcinoid tumors localized in the intestine usually do not give clinical signs of carcinoid syndrome until liver metastases develop, because the products of the tumor metabolism are rapidly destroyed in the blood and liver by hepatic enzymes, in the portal circulation system (for example, serotonin is destroyed by the hepatic monoamine oxidase). 

Metastasis in the liver  leads to the release of products of tumor metabolism through the hepatic veins directly into the systemic circulation. Metabolic products released by carcinoid tumors, primarily localized in the lungs and ovaries, bypass the portal vein system and therefore can induce the development of such clinical symptoms. Occasionally, carcinoid tumors of intestinal localization, only with intra-abdominal proliferation, can directly release active substances into the general bloodstream or lymphatic system, causing the development of clinical symptoms.

The action of serotonin on smooth muscle results in the development of diarrhea syndrome, intestinal colic and malabsorption. Histamine and bradykinin because of their vasodilating effects cause flushing of the facial skin and development of characteristic "tides". The role of prostaglandins and various polypeptide hormones produced by paracrine cells is not known to this day; these questions await further research. Sometimes the development of carcinoid tumors may accompany elevated levels of human chorionic gonadotropin and pancreatic polypeptides.

Many patients develop right-sided endocardial fibrosis, leading to pulmonary artery stenosis and regurgitation of blood through the tricuspid valve. Lesions of the left ventricle, which can be diagnosed with carcinomas of bronchial localization, are quite rare, since serotonin is destroyed during passage through the lungs.

[7], [8], [9], [10], [11]

Symptoms of the carcinoid syndrome

The most frequent (and often the earliest) symptom of carcinoid syndrome is discomfort associated with the development of characteristic "hot flushes" appearing in typical places (head and neck), often preceded by emotional stress or heavy intake of food, hot drinks or alcohol. There may be striking changes in skin color, ranging from mild pallor or erythema to a violet hue. Gastrointestinal spasms with the development of recurrent diarrheal syndrome occur quite often and form the main complaints of patients. Malabsorption syndrome may occur. Patients who develop valvular heart disease may experience cardiac murmurs. Some patients may experience asthmatic breathing, decreased libido and erectile dysfunction; Pellagra develops rarely.

[12], [13], [14]

Diagnostics of the carcinoid syndrome

Diagnosis of serotonin secreting carcinomas is carried out on the basis of the presence of a classical clinical symptom complex. A diagnosis is confirmed when an increase in urinary excretion of the tumor metabolism product - 5-hydroxyindoleacetic acid (5-HIAA) is detected. To avoid false positive results in a laboratory study, the analysis is performed provided that the patient is excluded from the diet 3 days before the study of serotonin-containing products (such as bananas, tomatoes, plums, avocados, pineapples, eggplants, walnuts). Some drugs containing guaifenesin, metacarbamol, phenothiazides, can also distort the results of the test, so they should be canceled in advance before the study. On the third day, a 24-hour portion of urine is collected for the test. Normally urinary excretion of 5-HIAA is less than 10 mg / day (<52 μmol / day); In patients with carcinoid syndrome, excretion is usually more than 50 mg / day (> 250 μmol / day).

Provocative tests with calcium gluconate, catecholamines, pentagastrin or alcohol are used to provoke the occurrence of "hot flashes". These samples can be used diagnostically when the diagnosis is questionable, but they must be carried out with great care. In order to determine the location of tumors, a suitable non-invasive modern technique is used, which makes it possible to establish precise localization of non-functioning carcinomas, although invasive diagnostic intervention, sometimes including laparotomy, may be required. Scanning using radioluclide-labeled ligands of the somatostatin receptor 1111-p-pentetreotide or using 123-meta-iodo-benzyl guanidine can reveal metastases.

It is necessary to exclude other conditions, which are based on a typical clinical picture of "hot flashes", but which nevertheless may not have any connection with the carcinoid syndrome. In patients who do not have urinary excretion of 5-HIAA, the development of a similar clinical syndrome can be caused by disorders involving systemic activation of mast cells (eg, systemic mastocytosis with increased urinary histidine metabolites and increased serum tryptase), and idiopathic anaphylaxis. Additional causes of tidal development include menopausal syndrome and the use of ethanol-containing foods and medications such as niacin, certain tumors (eg, vipoma, renal cell carcinoma, medullary thyroid carcinoma).

[15], [16]

Treatment of the carcinoid syndrome

Some symptoms, including "hot flashes", decrease with somatostatin therapy (which inhibits the secretion of most hormones), but without reducing the excretion of 5HIAA or gastrin. Numerous clinical studies have shown good results in the treatment of carcinoid syndrome with the use of octreotide, a long-acting somatostatin analogue. Octreotide is the drug of choice in the treatment of symptoms such as diarrhea and "hot flashes". Judging by clinical estimates, the effectiveness of tamoxifen is not always observed; reduces the clinical manifestations of leukocyte interferon (IFN).

Tides can also be successfully treated with phenothiazines (for example, prochlorperazine from 5 to 10 mg or chlorpromazine 25-50 mg orally every 6 hours). Histamine receptor blockers can also be used in therapy. The administration of phentolamine 5-10 mg intravenously prevented the development of experimentally induced "hot flushes". The appointment of glucocorticoids (for example, prednisolone 5 mg orally every 6 hours) can be useful in the case of pronounced "hot flashes" caused by carcinoma of bronchial localization.

Syndrome of diarrhea can be successfully treated by administration of codeine phosphate (15 mg orally every 6 hours), opium tincture (0.6 ml orally every 6 hours), loperamide (4 mg orally as a saturation dose and 2 mg after each bowel movement , up to a maximum of 16 mg per day). Diphenoxylate 5 mg orally every other day or peripheral serotonin antagonists such as cyproheptadine 4-8 mg orally every 6 hours or methyl ester 1 to 2 mg orally 4 times a day.

Niacin and sufficient intake of protein foods are prescribed to prevent the development of pellagra, as food tryptophan is a competitive inhibitor of serotonin secreted by the tumor (reduces its effect). Assign inhibitors of enzymes that prevent the conversion of 5-hydroxytryptophan to serotonin, such as methyldopa (250-500 mg orally every 6 hours) and phenoxybenzamine (10 mg per day).

Forecast

Despite the obvious metastasis of this category of tumors, they nevertheless grow slowly, and the survival time of such patients who have carcinoid syndrome - 10-15 years - is not unusual. Repeated surgical treatment of primary pulmonary carcinoid tumors is often successful. In patients with liver metastases, surgical intervention is indicated only for diagnostic purposes or only as a palliative. There is no (according to the literature) efficacy and from chemotherapeutic treatment, although streptozocin therapy with 5-fluorouracil and sometimes doxorubicin has found wide application in clinical practice.

[17], [18], [19]