Signs of carcinoid. Carcinoid syndrome - causes, signs, symptoms and treatment. Carcinoid syndrome: symptoms, photos

The complex of symptoms that arise as a result of the growth and release of hormones by a carcinoid tumor is called carcinoid syndrome. It occurs more often at the age of 50–60 years. The frequency of development is the same in men and women. Although the lesions are infrequently identified clinically, difficulties in detecting them suggest that they are in fact more common.

The tumor arises from enterochromaffin cells. These cells are located in the mucous membrane of the gastrointestinal tract from the esophagus to the anus (less commonly, the tumor occurs in the bronchi). They produce various hormones, including serotonin.

Development mechanism

Depending on the location, a carcinoid tumor produces different hormones and exhibits different malignant activity. Almost 90% of formations are located in the gastrointestinal tract. They are most often located in the ileum, appendix and rectum.

Depending on the location, a carcinoid tumor produces different hormones and exhibits different malignant activity.

Depending on in which part of the primary intestine carcinoids develop during embryogenesis, they are divided into foregut, mid-intestine, and hind intestine. Foregol tumors are located in the lungs, stomach and duodenum. Those located in the respiratory department produce 5-hydroxytryptophan, neuropeptides and adenohypophysis hormones. Lead to carcionoid syndrome, Cushing's syndrome.

Tumors that are located in the stomach and duodenum produce serotonin, histamine and gastrointestinal peptides. It also causes carcinoid syndrome and Cushing's syndrome, and also leads to diarrhea, diabetes and increased secretion of hydrochloric acid.

Midintestinal carcinoids are located in the small intestine, appendix, and right colon. Produce serotonin and tachykinins. They are the cause of carcinoid syndrome. Hindintestinal structures grow in the rectum and colon and secrete gastrointestinal peptides.

Thus, the external signs of the syndrome are caused by increased secretion by the tumor and the release into the blood of substances such as serotonin, histamine, prostaglandins, catecholamines and kinins.

Symptoms

Carcinoid syndrome manifests itself in the body by the following reactions:

• diarrhea;
• belching;
• stomach ache;
• tides;
• whistling when breathing;
• generalized itching;
• heartbeat;
• red face;
• intestinal obstruction;
• jaundice;
• dyspnea;
• cyanosis;
• dyspnea;
• dilation of small vessels (mesh or asterisks).

Symptoms appear most fully when the tumor is at a late stage of development and metastasizes to organs. At the initial stage, the formation is small in size. Therefore, the substances that it produces are neutralized when they enter the liver.

When the liver can no longer cope with a large volume of secreted products, they enter the general bloodstream and cause carcinoid syndrome. This explains the damage to the heart in the intestinal form of the tumor, since blood from the affected liver enters there through the vena cava. With extraintestinal carcinoids, substances produced by the blood enter directly into the bloodstream, so carcinoid syndrome appears in the early stages of the disease, when surgery is possible.

Hot flashes are characterized by a feeling of heat, trembling, and palpitations. They can be provoked by the intake of alcohol, cheese, coffee, and smoked products. Attacks may occur several times during the day. Their duration is usually several minutes. At these moments, a decrease in pressure and difficulty breathing may occur. A carcinoid crisis may occur, leading to the development of shock.

Gradually, the skin of the face and upper half of the body becomes red and blue, with nets and stars of small vessels.

Gradually, the skin of the face and upper half of the body becomes red-blue, with nets and stars of small vessels

In the case of bronchial and gastric carcinoid, the face and upper body are covered with red spots with a clear border. Among the changes, 4 forms can be distinguished.

1. Changes occur only in the face and neck area.
2. The nose becomes very red (purple in color). Facial cyanosis persists for a long time.
3. The capillaries are constantly dilated, lacrimation occurs, and the attack can last up to several hours.
4. There are red spots of various shapes on the neck and arms.

Diagnostics

To make a diagnosis, a urine test is taken and a topical diagnosis of the tumor is performed. An important marker of carcinoid tumors is the breakdown product of serotonin - 5-hydroxyindoleacetic acid. The decisive factor in determining gastric and bronchial carcinoid is the presence of serotonin and histamine in the urine.

Topical diagnosis involves ultrasound, x-ray, computed tomography, venography and other methods. The small size of the tumor makes it difficult to detect. It happens that it is even impossible to roughly guess the place where it is located.

Sometimes pronounced symptoms help determine the location of the tumor. Thus, the location of the formation in the intestine causes an uncertain picture of the disease: upset stool, vague abdominal pain, increased gas formation. Carcinoid can be detected by laparoscopy. Lung masses are detected using bronchoscopy.

Carcinoids have receptors for somatostatin on the cell membrane. Moreover, such receptors in 90% of tumors are contained not only in the carcinoids themselves, but also in their metastases. Therefore, in conjunction with other studies, it makes sense to use radionuclides. A comprehensive examination helps to identify and establish an accurate diagnosis in 80% of cases.

When making a diagnosis, it is necessary to differentiate with liver cirrhosis, idiopathic hot flashes, postmenopausal syndrome, fetochromocytoma, as well as liver metastases of a tumor of unknown location.

Drug therapy

The basis of drug treatment is chemotherapy, α-interferons and somatostatin analogues.

Chemotherapy treatment

There is no definite opinion about the timing of chemotherapy. Some authors believe that it should be used after surgery if there is an unfavorable prognosis. For example, damage to the liver or heart. In any case, given the difficulties in finding the location of the tumor and its excision, the use of chemotherapy treatment is very important.

There are no methods of chemical therapy that would completely get rid of the disease. Cytostatics are most often used. These are: etoposide, dacarbazine, dactinomycin, streptozocin and other drugs. Their effectiveness does not even reach 30%.

A slightly better treatment result (40%) is shown by combination treatment. The remission period reaches approximately six months.

Due to its low effectiveness, chemotherapy is tried to be used in extreme cases, when other methods do not produce results, and the disease develops quickly. At the beginning of treatment, minimal dosages of drugs are used to prevent a sudden release of large amounts of hormones into the blood. This can lead to a carcinoid crisis.

Symptomatic treatment

To eliminate the symptoms of carcinoid syndrome, serotonin antagonists (methylsergide) are used. Sometimes antidepressants are used: paroxetine, sertraline and others. For carcinoids that secrete histamine, the use of histamine receptor blockers is effective. In case of diarrhea, Imodium helps.

Synthetic analogues of somatostatin have also found use in carcinoid syndrome. These are: sandostatin and somatulin. Thus, sandostatin, by inhibiting the release of active substances, reduces the appearance of symptoms of the syndrome in almost 90% of patients with carcinoid tumor. It inhibits the production of compounds such as:

• serotonin;
• insulin;
• thyrotropin;
• gastrin;
• glucagon;
• cholecystokinin;
• pepsin;
• growth hormone and others.

Sandostatin significantly increases not only the survival rate among patients, but also eliminates/facilitates the occurrence of hot flashes, improves intestinal health, and significantly improves people’s quality of life. In addition, large doses of the drug lead to the death of cells of formations of a neuroendocrine nature. Currently, studies are being conducted to study the cytotoxic effect of the drug when it interacts with tumor cell receptors.

The use of α-interferon in carcinoid syndrome is also widely used. In this case, the improvement can reach 75%. Although the effect of the drug has not been studied in detail, the effectiveness of its use has been clinically proven. The combined effect of α-interferon and synthetic analogues of somatostatin on carcinoids is currently being studied. Results have already been obtained that indicate increased survival in the majority of patients.

Surgical treatment

Surgical methods are mainly used to treat carcinoid syndrome. It could be:

• tumor removal;
• resection of metastases;
• ligation of the hepatic arteries.

Surgical methods are mainly used to treat carcinoid syndrome.

The choice of direction is influenced by the location of the formation and the presence/absence of metastasis. In case of damage to the colon and mesenteric lymph nodes, removal of part of the intestine (about half of the colon) is indicated. If the tumor is localized in the appendix, it must be removed. The recovery rate during radical surgery on the small intestine can reach 100. When removing the appendix and in the case of the colon - up to 25%.

If radical treatment is impossible for some reason, palliative (life-sustaining) surgery is performed. In such cases, large metastases, and sometimes the tumor (if possible), are excised and chemotherapy is prescribed.

In severe cases of carcinoid syndrome and lack of effect from drug treatment, hepatic artery embolization is used. Symptoms such as hot flashes and upset stools disappear almost immediately after the intervention. In 40 patients they reappeared after 12 months.

Forecast

The malignancy of carcinoid tumors varies greatly. In addition to cases with very rapid, lightning-fast development, there are known cases of 10-year and even 20-year survival. Most often, the life expectancy of patients after treatment is 5–10 years. The worst prognosis is for carcinoids located in the lungs. And the most favorable one is in the appendix.

Those who are already going through hard times, a special syndrome arises, inherent only to such pathologies. It is characteristic of carcinoids - tumors consisting of neuroendocrine cells.

Due to the slow progression of the disease, some people may experience a complete recovery, but only with early diagnosis and surgery.

Carcinoids and carcinoid syndrome

Carcinoids are so named because of their morphological similarity to carcinomas, but they differ from the latter in a lower degree of malignancy.

Currently, they account for up to 9% of gastrointestinal cancers, but can form in any part of the body (approximately 0.2% of the total).

Tumors are formed from cells of the nervous system and are hormonally dependent, since they themselves produce serotonin and some other biologically active proteins. The age of patients diagnosed with such diseases is usually at least 50-60 years.

Carcinoids grow slowly over many years. Their sizes are often small, so until recently they were considered almost . Often they were revealed only after an autopsy, and were not the cause of death.

But it has now been proven that in 80% of cases, without treatment, these neoplasms spread into the intestines, abdominal organs, etc.

Carcinoid syndrome is a set of clinical manifestations that are entirely caused by the presence of carcinoid in a person. Since these tumors secrete hormones, the latter enter the blood and contribute to the development of the entire pathological symptom complex.

This phenomenon does not occur in every patient, but it can last for several years and include various symptoms from the skin, abdomen, heart, etc.

Photo of a patient with carcinoid syndrome

The development of carcinoid syndrome is more likely in the presence of a tumor of the small intestine and bronchi, since it is such neoplasms that produce a significant amount of hormones.

Since other tumors of the gastrointestinal tract and other parts of the body produce less such substances, their symptoms may be absent until the last stage. Only the presence of metastatic processes changes the picture, reflected in the appearance of the clinical picture.

Types of carcinoids

Up to 40% of tumors that cause a characteristic syndrome are located in the small intestine, up to 25% in the appendix, 15% near the anus. Less common are neoplasms of the described type in the stomach, bronchi, and reproductive system.

The main characteristics of carcinoids, depending on location, are as follows:

1. . It develops on the bottom or fornix of the organ; when gastric juice is released, it provokes the release of histamine, a mediator of allergy. As a result, hydrochloric acid is produced in increased quantities. Women get sick more often. The symptoms resemble those of an ulcer - pain, heartburn, and sometimes bleeding. There are three types of formations - those arising from atrophic gastritis, from Zollinger-Ellison syndrome, without connection with any diseases.
2. . They are often diagnosed by chance, as they rarely cause symptoms. With large sizes, clinical hemorrhoids may be observed, as well as constipation and rectal bleeding. Even if metastases form, carcinoid syndrome is unlikely.
3. Bronchial tumor. They occur infrequently, up to 2% of neoplasms in the lower respiratory tract. Many patients are heavy smokers, and in the latter, usually slowly progressing tumors take on an aggressive course and often spread to the diaphragm.
4. . The most common type of localization. Almost always in the later stages it gives a complex of characteristic symptoms, and also manifests itself as metastases and obstruction. Can lead to intestinal ischemia (oxygen starvation due to poor circulation), kinks and deformation. These tumors are very difficult to diagnose.
5. Tumor of the appendix (appendix). They are observed more often in young people, in the vast majority of cases they are discovered when the cecum is removed due to its inflammation. They are small in size, almost do not metastasize, and therefore are often considered benign.
6. . Accounts for up to 2% of the total number of cancerous lesions of the lung parenchyma. Smoking is often cited as the cause. Mostly, cancer is detected in people over 60 years of age and males. There are several types of such carcinoids - highly differentiated, poorly differentiated, atypical. The prognosis of the last two types is poor, the degree of malignancy is high.

Causes of the disease

The etiology of carcinoids has not yet been clarified. However, predisposing factors are considered:

• Heredity
• Bad ecology
• Working in hazardous industries
• Excessive consumption of fried foods and smoked foods
• Atrophic gastritis and other precancerous diseases

The immediate cause of the development of the entire symptom complex is the production of hormones, hormone-like substances and allergy mediators by the emerging tumor.

Since this complication does not occur in every patient, the following conclusion was made: the syndrome is typical only for metastatic tumors, or for large tumors that have crossed the liver barrier. This is important because all tumor products enter the systemic circulation and are not “extinguished” by the liver.

Typically, the following substances are found in the bloodstream of a sick person:

• Histamine
• Prostaglandins
• Serotonin
• Bradykinin
• Enteramine
• Chromogranine

An excess of such components, of which the most irritating is serotonin, leads to the development of symptoms of carcinoid syndrome. In particular, hormones can constrict blood vessels, which causes an increase in blood pressure.

The interaction of a pathologically large amount of secreted substances and other normal hormones in the body also causes heart damage with the development of valvular insufficiency and other severe disorders.

Symptoms

Signs carcinoid syndrome are varied and will largely depend on what specific substances were produced by the neoplasm.

In the vast majority of cases, severe redness of the skin occurs, which is most noticeable on the front of the head, on the front of the neck, and on the décolleté. The body temperature of many patients also does not remain normal - it increases.

Not everyone has skin hyperemia all the time. Some suffer from sudden hot flashes in the upper body and head only after overload, nervous strain, drinking alcohol, or spicy food. Paroxysmal redness of the skin and heat can go away spontaneously after a couple of minutes or after 2-5 hours.

If you measure the pulse at such a moment, it will be increased, and the pressure, on the contrary, will be reduced. Hypertension rarely occurs during attacks.

Another symptom that occurs in almost 90% of cases is frequent diarrhea. Diarrhea occurs without a combination with hot flashes, or develops along with them. If at the moment of diarrhea you take drugs that inhibit serotonin, then this unpleasant symptom ends.

Sometimes, instead of diarrhea, intestinal obstruction develops with severe pain in the peritoneum, if the neoplasm is already so large that it blocks the intestinal lumen.

Other possible symptoms associated with carcinoid syndrome:

• Swelling, dropsy of the abdomen, enlarged liver, its pain, severe shortness of breath, including in a lying position - signs of heart failure.
• Bronchospasm, wheezing in the chest, breathing problems as a result of bronchial compression or the influence of tumor hormones.
• Dizziness and fainting as a result of oxygen starvation of brain tissue.

Over time, the intensity of symptoms increases, as does the frequency of acute manifestations. A complication can be a crisis state with severe hypotension up to shock, with suffocation due to bronchial spasm. The immediate cause of this consequence is surgery on the tumor.

Diagnosis of the syndrome

The main indicator that reflects the occurrence of carcinoid syndrome is an increase in serotonin in the blood.

In addition, the patient has very high levels of 5-hydroxyindoleacetic acid in his urine.

In order for the tests to be accurate and objective, a few days before they are performed, a person is prohibited from eating foods with a high presence of serotonin.

If all the symptoms are too obvious, and the analysis does not give a positive result, a test with provocation (for example, drinking alcohol) is necessary.

After identifying markers of carcinoid syndrome, it is urgent to do a detailed examination and find the area where the tumor is localized.

The following methods may be needed to search:

• X-ray
• , MRI
• Endoscopic and standard ultrasound
• Capsule endoscopy of the intestine
• Fibrogastroduodenoscopy
• Fibervideocolonoscopy
• Bronchoscopy
• Laparoscopic examinations

Since the syndrome develops only in 15-20% of patients, it must be distinguished from the manifestations of menopause, hypertension, and side effects of taking medications.

Treatment of the disease

The best option for effective treatment is to remove the tumor at an early stage or as it is detected. This is the only way to completely eliminate carcinoid syndrome.

But sometimes surgery is impossible, since tumor metastases already exist in the liver or in a number of other organs. However, attempts are always made to remove at least some of the new tumors, which will reduce the overall volume of abnormal hormone-producing tissue.

Use for this type of cancer does not make sense. has a weak therapeutic effect, but in the complete absence of the opportunity to operate, it is still prescribed. A cytostatic is more often recommended, which works in half of the clinical cases.

As for the symptomatic treatment of the syndrome, it is advisable to carry it out by taking drugs that inhibit serotonin (for example, Deseril).

Other means to reduce discomfort are:

• Antihypertensive drugs
• Opioid analgesics
• Astringents
• Antidiarrheal drugs
• Glucocorticosteroids
• Antidepressants
• Antihistamines
• Interferons

Patients should avoid eating foods rich in serotonin (bananas, nuts, etc.). This will help reduce intoxication with this hormone.

Forecast

The average survival time with the syndrome is 5-15 years due to the slow growth of tumors (50% of people live more than 5 years). If the operation is successfully performed, the prognosis is favorable.

Very rarely there is a fulminant course of the disease with a fatal outcome. The most unfavorable prognosis is for bronchial carcinoid.

Video about modern diagnosis and treatment of carcinoid syndrome:

Carcinoid syndrome is a complex of symptoms that occurs due to the release of hormones by carcinoid tumors (the most common neoplasms of neuroendocrine cells) and their entry into the bloodstream. Carcinoid tumors are slowly progressing neoplasms that are relatively rare. Carcinoid syndrome occurs in 15-20% of patients with carcinoids. All age categories of the population are susceptible to the development of the pathological process.

A characteristic sign of carcinoid syndrome is sudden flushing of the skin of the face, neck and chest.

Causes and risk factors

Carcinoid syndrome usually occurs against the background of endocrinologically active neoplasms in the ileum and rectum, appendix or other parts of the gastrointestinal tract, as well as in the pancreas, bronchi, etc.

Forms of the disease

Depending on the clinical manifestations, the following forms of pathology are distinguished:

• latent carcinoid syndrome (in the absence of clinical manifestations, but altered biochemical parameters of blood and urine);
• carcinoid syndrome without identifying the primary tumor site and its metastases;
• carcinoid syndrome with identification of the primary focus of the tumor and its metastases or only metastases to the liver.

Depending on the location, carcinoid syndrome is distinguished with a tumor of the anterior, middle or posterior part of the digestive tube.

Symptoms

Symptoms depend on the hormones secreted by the tumor. The clinical picture of carcinoid syndrome in intestinal neoplasms, as a rule, appears only when they metastasize to the liver.

A characteristic sign of the pathology is sudden hyperemia of the skin of the face, neck and chest, caused by a rush of blood. Often, skin hyperemia occurs due to eating, drinking alcohol, or distress. The nature of hyperemia differs depending on the location of the carcinoid tumor. In patients with intestinal neoplasms, hyperemia may be accompanied by a feeling of heat, and as the disease progresses, the skin may acquire a cyanotic hue during attacks.

When the tumor is localized in the stomach, hyperemic spots may appear on the skin, accompanied by severe itching. If the carcinoid tumor is localized in the bronchi, the attacks are more severe and prolonged (up to several days) and may be accompanied by tremor and disorientation in space.

In addition to hyperemia, spider veins or vascular networks appear on the skin (mainly in the nasolabial triangle, on the cheekbones).

Another typical manifestation of carcinoid syndrome is diarrhea. The frequency of bowel movements can vary from several to several dozen times a day. Diarrhea is often accompanied by abdominal pain and gastrointestinal cramps.

In patients with developed valvular heart lesions, heart murmurs occur.

In addition, with carcinoid syndrome, the following may be observed:

• wheezing;
• dyspnea;
• lacrimation;
• swelling around the eyes;
• increased salivation;
• decreased libido;
• hypotension;
• tachycardia;
• oliguria, etc.

Diagnostics

To make a diagnosis of carcinoid syndrome:

• taking anamnesis;
• determination of excretion of 5-hydroxyindoleacetic acid (a metabolic product of carcinoid neoplasm) in daily urine;
• biochemical examination of blood and urine;
• Ultrasound of internal organs;
• computed or magnetic resonance imaging;
• positron emission tomography;
• venography, selective arteriography;
• endoscopic examination;
• biopsy with morphological, histological and immunohistochemical examination of the biopsy sample.

To avoid false-positive results in a laboratory urine test, three days before the test, foods that contain serotonin, as well as medications that can distort the test results, are excluded from the patient’s diet.

Carcinoid syndrome occurs in 15-20% of patients with carcinoids.

Electrocardiography and echocardiography are performed to detect cardiac damage.

If the diagnosis is in doubt, in order to provoke specific attacks (“hot flashes”), tests are carried out with pentagastrin, catecholamines, alcohol, etc.

It is necessary to carry out differential diagnosis with idiopathic anaphylaxis, side effects from taking medications, manifestations of menopause, irritable bowel syndrome, etc.

Treatment

Radical surgical treatment of a carcinoid tumor and its metastases eliminates the clinical manifestations of carcinoid syndrome. If the tumor is unresectable, surgical intervention is not possible due to the patient’s general condition or for other reasons, as well as to eliminate signs of carcinoid syndrome with an undetected tumor, conservative treatment is indicated.

Symptomatic treatment of manifestations of carcinoid syndrome is carried out using drugs that inhibit the production of hormones by a carcinoid tumor, as well as glucocorticoids, antidepressants, etc.

Possible complications and consequences

Carcinoid syndrome in some cases is complicated by carcinoid crisis, which can occur against the background of:

• major surgery;
• stress;
• instrumental diagnostic examination;
• chemotherapy;
• anesthesia during surgery.

Signs of carcinoid crisis:

• sudden change in blood pressure (hypertension or hypotension);
• deterioration of general condition;
• frequent noisy breathing;
• tachycardia, thready pulse;
• disorders of the central nervous system, etc.

A carcinoid crisis occurs acutely and, in the absence of an urgent set of intensive care measures, can progress to shock and coma.

Forecast

The prognosis for carcinoid syndrome depends on the extent of the cancer process. In the presence of only a primary tumor and its successful treatment, the average five-year survival rate is 95%; in patients with multiple distant metastases, this figure does not exceed 20%. If regional lymph nodes are involved in the pathological process, the five-year survival rate is reduced to 60-70%.

With successful surgical intervention, the prognosis is favorable.

The prognostic factor for carcinoid syndrome is the proliferative activity of the cells of the primary neoplasm. Carcinoid tumors with a low proliferation index have a more favorable prognosis.

Prevention

Specific measures to prevent carcinoid syndrome have not been developed. Nonspecific preventive measures include:

• healthy lifestyle;
• sufficient physical activity;
• rejection of bad habits;
• balanced balanced diet;
• avoiding the influence of oncogenic substances on the body (including occupational hazards);
• timely diagnosis and treatment of internal diseases, etc.

Video from YouTube on the topic of the article:

The occurrence of carcinoid syndrome is determined by several reasons. Of significant importance are: slow growth of the primary tumor, massive metastasis and the size of metastases. However, the extraportal location of the latter plays a decisive role. All of these factors cause hypersecretion of serotonin and other biologically active substances, which periodically enter the bloodstream and have a pathological effect on various organs and systems.

The most characteristic group of vasomotor disorders includes the so-called “flushing syndrome,” described in detail by Waldenstrom and Thorson. First of all, periodic “redness” of the face, shoulders, and upper half of the body occurs, accompanied by a burning sensation, heat, palpitations, tachycardia, a feeling of weakness, and sometimes profuse sweating. The skin color suddenly turns bright red, and then quickly changes to pink and returns to a normal shade. Often spots of cyanosis (“spotted cyanosis”) remain on the skin against a background of general pallor. This attack lasts from 30 seconds to 10 minutes. During the day, the patient has from 5 to 30 such attacks.

Provoking factors for “redness syndrome” are: emotional and physical stress, rich, hot food, alcohol intake, defecation.

Over time, hyperemia of the skin can become permanent, cyanosis progresses, and patients resemble in their appearance patients with polycythemia (plethoric habitus). Telangiectasia sometimes occurs.

Some researchers try to explain the cyanotic phase of the flushing attack by a possible synergistic effect on the vascular system of serotonin and bradykinin, when simultaneously administered to rats, a spasm of the venules and a retrograde spasm of the blood in the capillaries occurred (Weiner and Altura, 1967).

Attacks of redness with gastric carcinoids begin with bright red focal erythema with clearly defined boundaries. Apparently, in such patients, in addition to serotonin, significant amounts of histamine and 5-hydroxytryptophan, a precursor of serotonin, periodically enter the blood. The predominant formation of the latter by tumor tissue is due to a deficiency of decarboxylase, which ensures the synthesis of serotonin (Jones et al., 1968).

Carcinoid syndrome, which occurs with bronchial tumors, has specific features; attacks of redness are distinguished by the severity of their appearance, often accompanied by fever, lacrimation, runny nose, nausea and vomiting, hypotension and oliguria (Sandler, 1968). Such “carcinoid crises” (Kahil et al., 1964) can be caused by direct rapid entry of humoral agents into the arterial system, bypassing the portal circulation. “Rush syndrome” is sometimes accompanied by hypertension, as well as diarrhea and asthma attacks.

Diarrhea in some cases is combined with cramping pain in the abdomen, pronounced rumbling. This symptom is due to intestinal hyperperistalsis caused by increased secretion of serotonin, and possibly bradykinin. Both of these agents increase the tone of the smooth muscles of the bronchi, spasm them, which often leads to atypical attacks of bronchial asthma.

In addition to the “redness syndrome,” with a functioning carcinoid, changes of a different nature may be observed on the skin.

Some patients experience “pellagra-like lesions” associated with endogenous hypovitaminosis PP, caused by a relative lack of tryptophan for the synthesis of nicotinic acid in the intestine. Hyperkeratosis occurs, the skin becomes dry, peels, grayish-black areas of pigmentation form on the forearms and lower extremities, and glossitis is noted.

Along with “pellagra-like lesions,” focal hyperpigmentation of a diffuse nature may be observed, caused by excessive deposition of serotonin destruction products in the skin. Skin metastases from carcinoid are sometimes painful.

In patients with carcinoid syndrome, in 40-50% of cases, tricuspid valve insufficiency and stenosis of the pulmonary artery are determined (Sjoerdsma, 1956). The pathogenesis of these lesions remains unclear, but most researchers are proponents of the “biochemical theory” of their occurrence. The latter considers endocardial damage (mainly proliferative rather than inflammatory in nature) in carcinoid syndrome as a consequence of hypersecretion of serotonin and other biologically active substances that primarily affect the endocardium and contribute to excessive growth of connective tissue.

Serotonin clearly increases the tone of the arterial vessels of the lungs (Page, 1958), which creates additional stress on the right ventricle. The latter hypertrophies early, and then quickly begins its myogenic dilatation with phenomena of stagnation in the systemic circulation.

In addition to hemodynamic factors, the origin of edema in carcinoid syndrome involves hypoalbuminemia due to a lack of tryptophan for protein synthesis, as well as a systematic increase in venous pressure at the height of “redness” attacks. The antidiuretic effect of serotonin also plays a certain role, and in some patients, an increased concentration of antidiuretic hormone.

Patients suffering from carcinoid syndrome for a long time become exhausted, and in some cases the weight remains.

Sometimes severe dizziness and transient visual disturbances caused by cerebral hypoxia occur.

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Introduction Carcinoid syndrome was first described in 1954. The syndrome usually develops in patients with intestinal carcinoid with metastases to the liver, less often in patients with lung carcinoid and other localizations. The clinical picture of the syndrome is caused by the release of specific hormones produced by the tumor into the blood. Often the symptoms can be so severe that they lead to the development of a life-threatening condition - carcinoid crisis.

Epidemiology

The incidence of this pathology is 1-2 cases per 100,000 population. However, with autopsy this figure is higher and equal to 8.4 per 100,000 population. The incidence ratio between men and women is the same - 1:1, the average age of patients is 60 years. An analysis of clinical cases of 13,000 patients in the United States from 1950 to 1999 showed that 2/3 of the patients had carcinoid of the gastrointestinal tract (GIT) and 1/3 of the bronchopulmonary region. Among patients with gastrointestinal carcinoid, 42% had small intestinal tumors and 58% had ileal tumors. In 60% of patients, liver metastases are detected at the time of initial diagnosis of the disease. The 5-year survival rate is 60%.

The pathophysiology of the tumor and the pathogenesis of the disease are largely associated with the entry of hormonally active substances into the blood and changes in the sensitivity of specialized receptors to them. The most consistent characteristics of carcinoid syndrome include the activity of 5-hydroxytryptophan decarboxylase, which catalyzes the formation of serotonin from tryptophan. Once released, serotonin is rapidly inactivated by monoamine oxidase to 5-hydroxyindolealdehyde, which is converted to 5-hydroxyindoleacetic acid (5-OHIAA). This acid is quickly and almost completely excreted in the urine, so the content of serotonin circulating in the blood can be measured by the amount of 5-OHIAA excreted per day.

With carcinoid syndrome, the picture is somewhat different: an increased content of serotonin is detected in the tissue of the tumor and metastases. Impaired tryptophan metabolism leads to a significant increase in the proportion of tryptophan, which is metabolized through the formation of hydroxyindole. Normally, only 1% of tryptophan is converted into serotonin, in patients with carcinoid - 60%. As a result, the amount of nicotinic acid decreases and symptoms of pellagra and other phenomena of negative nitrogen balance are observed. 5-hydroxyindolurate is also found in the urine of patients with carcinoid. The mechanism of paroxysmal vasodilation in patients with carcinoid syndrome is not clear enough. It is associated with the action of serotonin and histamine, as well as various indoles and vascular-active peptides.

Another monoamine produced by carcinoids, dopamine, plays an equally important role in the pathophysiology of the syndrome. It is a precursor of norepinephrine and adrenaline, performing an independent function in the central nervous system. The activity of this neurotransmitter mainly determines autonomic dysfunction in patients with carcinoid.

Thus, hormone-like substances produced by the tumor affect all body systems. This circumstance allows us to talk about carcinoid syndrome as a disease with its own mechanisms for maintaining pathological processes that involve all organs and systems.

The main manifestations of carcinoid syndrome are diarrhea and hot flashes. In 95% of cases, classic carcinoid syndrome manifests as hot flashes (90%), diarrhea (70%), abdominal pain (40%), heart valve damage (40-45%), telangiectasias (25%), shortness of breath (15%) and pellagra (5%).

Proposed mediators of symptoms in carcinoid syndrome are presented in Table 1.

Table No. 1.

Often patients with manifestations of a hormonally active tumor are observed by a neurologist or psychiatrist. The basis for this is the abundance of difficult to objectify complaints, indicating obvious dysfunction of the central nervous system. Often skin changes are the most consistent manifestation of carcinoid. Flushing of the facial skin is the most common symptom of the disease.

The typical flush of classic carcinoid syndrome (midgut tumor) begins suddenly and is a pink or red discoloration of the skin of the face and upper torso that lasts several minutes. The attack can occur several times a day, accompanied by lacrimation and is provoked by the intake of alcohol or food containing tyramine (chocolate, nuts, bananas). Unlike menopausal hot flashes, attacks with carcinoid syndrome are “dry” and are not accompanied by sweating. It is possible that this typical hot flush does not have a direct connection with serotonin, but is associated with the effects of tachykinins, neuropeptide K and substance P.

There are several types of tides:

. the first type is erythematous, usually limited to the face and neck, lasting only 1-2 minutes;

the second type of hot flashes is longer lasting, while a constant cyanotic tint remains on the patient’s face, and during an attack the nose becomes purple-red;

a flush of the third type lasts for hours and days and can be accompanied by the formation of deep wrinkles on the forehead, remaining even after the attack has stopped, the vessels of the conjunctiva are constantly dilated, patients complain of lacrimation, hypotension and diarrhea are possible;

Type 4 hot flashes are characterized by the formation of irregularly shaped bright red spots, often located around the base of the neck and on the arms.

This effect is caused by histamine produced by NETs. Antihistamines can reduce the frequency and intensity of hot flashes.

Distinguishing different types of hot flashes has a certain clinical significance. Hot flushes of the first and second types are usually associated with carcinoid tumors originating from the midgut, but are also possible in patients with carcinoid tumors of the bronchi and pancreas.

Abdominal syndrome is caused by the influence of serotonin on gastrointestinal motility and secretion. Usually these are abdominal pains of a cramping nature, simulating an attack of cholecystitis, appendicitis, peptic ulcer and other manifestations of an “acute abdomen”. As a rule, pain is accompanied by certain dyspeptic disorders (nausea, vomiting, diarrhea). Diarrhea with carcinoid syndrome is very difficult to distinguish from similar disorders of other origins. In rare cases, diarrhea is accompanied by steatorrhea.

Sometimes cardiovascular symptoms come to the fore. Under the influence of high concentrations of serotonin, endothelial fibroelastosis and narrowing of the arteries develop. Signs such as severe tachycardia, pain in the heart, increased blood pressure in combination with ECG changes of an ischemic and metabolic nature and signs of circulatory failure suggest a disease of the cardiovascular system. The nature of metabolic disorders in patients with carcinoid leads to secondary changes in the heart (fibroelastosis of the right parts, tricuspid valve, pulmonary valves), creating a corresponding physical and echographic picture.

The development of bronchospasm is also associated with excessive release of serotonin, bradykinin and histamine by the tumor. Often, attacks of difficulty breathing force a differential diagnosis with bronchial asthma.

Atypical syndrome (5%) is a purplish discoloration of the skin that lasts several hours, after which telangiectasias and hypertrophy of the skin of the face and upper neck remain, in addition, acrocyanosis of the upper extremities is possible. Sometimes headache, lacrimation, hypotension, skin edema and bronchospasm may occur. These symptoms are commonly seen in foregut carcinoids and are thought to be due to exposure to serotonin, histamine, and other biogenic amines. In rare cases, patients with chronic atrophic gastritis and ECL cell hyperplasia may experience other histamine-induced hot flashes with bright red, mottled skin discoloration. Diarrhea in carcinoid syndrome has no specific differences and initially has a periodic nature associated with disorders of gastrointestinal secretion and motility, but subsequently, due to intestinal lymphangiectasia and bacterial overgrowth, it can become permanent. Diarrhea is often accompanied by cramping abdominal pain, which may be caused by the influence of various humoral factors, including serotonin, tachykinins, histamine, kallikrein and prostaglandins, which stimulate intestinal peristalsis and secretion. Diarrhea in carcinoid syndrome, unlike diarrhea due to other causes, is not relieved by abstaining from food. Although true asthma attacks are rare in carcinoid syndrome, bronchospasm occurs, which may be mediated by tachykinins and bradykinins, which cause contraction of bronchial smooth muscle and local edema.

A specific feature that unites all NETs is the ability to synthesize, store and secrete biologically active substances (peptides, hormones, neurotransmitters) and express neuroendocrine markers.

Moreover, each type of NET has a unique set of biochemical characteristics that determine their functional characteristics and differences in clinical course, even within the same group of embryological origin.

Clinical manifestations of the disease are associated primarily with the corresponding endocrine hyperfunctional syndromes caused by the so-called functioning tumors.

These are gastrinomas - gastrin-producing tumors of the pancreas and duodenum with the development of Zollinger-Ellison syndrome. It is characterized by hyperchlorhydria, hypertrophy of the folds of the gastric mucosa due to excess gastrin, the presence of recurrent complicated peptic ulcers that are not amenable to standard antiulcer therapy, and in half of the cases the presence of diarrhea, which in 7-35% of patients is the only clinical symptom of the disease.

Insulinomas- insulin-producing tumors of the pancreas and, in rare cases, with extrapancreatic lesions of aberrant tissue in the duodenum, jejunum, ileum, lungs and cervix.

Clinically manifested by symptoms of hypoglycemia: headache, lethargy, dizziness, blurred or blurred vision, decreased concentration, amnesia and, less commonly, convulsions or persistent neurological deficit with the development of paralysis and coma; catecholamine reaction in the form of tremor, rapid heartbeat, cold sweat, hunger, anxiety and fear. Sometimes hypoglycemic states are manifested by attacks of psychomotor agitation, ending in a deep disorder of consciousness. The clinical picture of insulinoma is characterized by the so-called Whipple triad:
- the occurrence of attacks of spontaneous glypoglycemia on an empty stomach or after exercise;
- manifestation of symptoms of hypoglycemia: decrease in blood sugar (below 40 mg% -2.22 mmol/l) during an attack; stopping an attack by intravenously administering glucose or taking sugar orally.

VIPomas (Werner-Morrison syndrome)- these tumors are so named because of the secretion of vasoactive intestinal peptide (V1P). The syndrome was first described in 1958. It occurs mainly in the adult population with a frequency of 0.05–0.2 per 1,000,000 people with a male to female ratio of 1:3. Vipomas in 70–80% of cases arise in the pancreas (in 75% of cases in its tail), in 10–20% – in the adrenal glands, nerve ganglia, small intestine, mediastinum, and lungs. Pancreatic vipomas are almost always malignant (80% metastasize to the liver), extrapancreatic vipomas are benign. MEN 1 syndrome is diagnosed in only 6% of patients.

VIP-secreting formations have also been described in the adrenal glands, small intestine, mediastinum and lungs. The main symptom of VIP is constant or intermittent diarrhea, abdominal pain, weight loss, hypokalemia, acidosis, dehydration - the combination of these symptoms is called “Werner-Morrison syndrome” or pancreatic cholera. A characteristic sign of secretory diarrhea is the lack of improvement when abstaining from eating. In most cases, more than 3 liters of liquid stool are released per day. Sometimes severe watery secretory diarrhea reaches up to 30 liters per day, which leads to severe loss of fluid and electrolytes with the development of asthenia, convulsions, cardiac arrhythmias and even sudden death.

Glucagonomas- in 100% of cases they occur in the pancreas, in the tail (50–80% of cases), in the head (in 22%), and in the body (in 14%). In terms of incidence, glucagonomas are extremely rare tumors - from 0.01 to 0.1 per 1,000,000 people. MEN-1 syndrome is associated with 5–17% of cases.

Glucagonomas are malignant in 80% of cases, metastasize to the liver in 90% of cases, to lymph nodes in 30%, metastases to the spine, ovaries, and peritoneum are rarely described. The connection between glucagon symptoms and glucagon production was established in 1974. The level of glucagon in the patient’s blood is 10 times higher than normal. Glucagon stimulates the breakdown of glycogen, gluconeogenesis, ketogenesis, insulin secretion, lipolysis, and inhibits gastric and pancreatic secretions.

Glucagonomas are rare tumors of pancreatic α-cells, usually accompanied by a typical syndrome that develops as a result of excess glucagon: weight loss, chronic skin rashes, carbohydrate metabolism disorders, stomatitis, cheilitis and glossitis, alopecia, anemia, venous thrombosis, gastrointestinal tract -intestinal symptoms including diarrhea, abdominal pain, colic, anorexia. Pathognomonic symptoms for glucagonoma are a rash and necrolytic migratory erythema, which is most often localized in the groin with spread to the genitals, perineum, anus and thighs; quite often erythema is observed in the perioral area and is accompanied by the appearance of ulcers in the corners of the mouth. Typically, patients report severe itching and pain in the affected areas. Neurological symptoms such as ataxia, dementia and muscle weakness may occur, and psychiatric disorders often develop. There is an increase in the frequency of thromboembolism, manifested by deep vein thrombosis and pulmonary embolism. More than half of deaths from glucagonoma are associated with thromboembolic complications.

Clinical manifestations of the syndrome are: weight loss (70–80%), diabetes (75%), dermatitis (65–80%), stomatitis (30–40%), diarrhea (15–30%). Frequent manifestations of the disease are mental disorders, thrombosis and thromboembolism. Primary tumors at the time of diagnosis reach large sizes - from 5 to 10 cm, in 80% of cases there are distant metastases to the liver.

Somatostatinomas- rare tumors of pancreatic D-cells. They are also found in the biliary tract, small intestine (mainly in the duodenum), colon and rectum, bronchi; cases of somatostatin secretion by small ketosis lung cancer, medullary thyroid cancer and pheochromocytoma have been described.

They manifest themselves as the so-called inhibitory syndrome associated with excess production of somatostatin, which inhibits the secretion of almost all pancreatic and intestinal hormones, reduces gastric and intestinal motility, and impairs the absorption of fats and calcium. Typically, patients present with hyperglycemia, cholelithiasis, diarrhea and steatorrhea, hyperchlorhydria, dyspeptic syndrome, anemia and weight loss. However, in patients with extrapancreatic somatostatinomas, this symptom complex is practically not observed, and the clinical manifestations of the disease are associated with the local effect of the tumor, and not with the general effect of somatostatin.

There are a number of tumors that secrete ectopic hormones, such as ACTH, releasing hormone, parathyroid hormone-related peptide and calcitonin, somatotropin, pancreatic polypeptide, luteinizing hormone, etc. The clinical symptoms of these NETs are due to corresponding hormonal manifestations. Ectopic secretion of ACTH can lead to the development of Cushing's syndrome, ectopic secretion of parathyroid hormone in parathyrenomas is associated with hypercalcemia and calcareous deposits, somatoliberinomas can be combined with acromegaly. The diagnosis of such tumors is confirmed by an increase in plasma levels of the corresponding hormones. During immunohistochemical examination of these tumors, most of the cells usually have a positive reaction to the ectopic hormone that causes clinical symptoms.

The term non-functioning primarily means NETs with morphological signs of hormonal production, but not manifesting clinical hyperfunctional syndromes. The asymptomatic course may be due to the synthesis of inactive hormones, parallel secretion of peptide inhibitors, or downregulation of peripheral receptors.

Clinical symptoms are often caused by the presence of a space-occupying lesion and the local effect of the tumor on surrounding organs and tissues, as well as manifestations of metastatic disease.

Neuroendocrine tumors originate from neuroendocrine cells, which, when specifically stimulated, secrete proteins and biogenic amines. These products can act as markers, as they are specific for each type of tumor. NET can be diagnosed by determining available biological markers in serum and urine in patients with vague abdominal symptoms.

The most informative immunological test for diagnosis is measuring the level of chromogranin A. An increase in the content of this marker is a reliable sign of the disease. Up to 90% of NETs, ​​regardless of symptoms, secrete chromogranin A. It should be remembered that the level of this marker also increases in patients with renal failure, chronic atrophic gastritis A, and taking H+,K+ -ATPase inhibitors. The test for determining the level of chromogranin A has high specificity (86%) and sensitivity (96%). Chromogranin A is used to monitor therapeutic response because there is a correlation between tumor burden and serum marker levels. Thus, this indicator is the most sensitive for assessing disease progression.

Another equally important marker of carcinoid syndrome is 5-hydroxyindoleacetic acid (5-OHIAA), the content of which is determined in the urine. 5-OHIAA is the main metabolite of serotonin. Increased urinary excretion of 5-OHIAA is observed in patients with carcinoid syndrome. Chronic elevation of 5-HIAA is associated with life-threatening carcinoid cardiac disease.

One of the leaders among signaling molecules involved in neuroimmunoendocrine regulation is serotonin (5-hydroxytryptamine, 5-HT). It is formed from tryptophan and breaks down to 5-hydroxy-3 indolylacetic acid (5-HIAA). In the human body, about 90% of endogenous serotonin is contained in the gastrointestinal tract, where it is mainly synthesized and accumulated in enterochromaffin cells, taking part in the regulation of motility and mucus secretion. Mast cells are also capable of secreting serotonin; 5% of serotonin is synthesized in 5-HT neurons. Almost all (95%) of plasma 5-HT is bound to platelets.

Serotonin is known as a neurotransmitter and has a variety of receptors acting through G proteins and ion channels. There are seven main types of serotonin receptors, some of which have subtypes: 5-GT1 (subtypes A,B,D,E,F), 5-GT2 (subtypes A,B,C), 5-GT3 - 5-GT7. Receptors are tissue specific and each type mediates a different set of functions.

Serotonin has a direct effect on smooth muscle, including in the vascular wall, causing contraction or relaxation under different conditions and depending on the type of receptor. In addition, it may suppress or potentiate responses induced by other vasoactive agents.

Serotonin is responsible for the symptoms associated with carcinoid syndrome, which occurs in more than 60% of midgut tumors. Serotonin increases the secretion of fluid in the intestines and the speed of passage of food masses, which creates the preconditions for the development of diarrhea. It is part of a cascade of factors leading to the appearance of tumor-associated fibrosis. Heart valve leaflets from carcinoid patients secrete large amounts of TGF-β and TGF-latent binding protein. It is serotonin that causes an increase in the production of TGF-β and stimulates the synthesis of collagen in the interstitial cells of the valves of patients with carcinoid cardiopathy; the presence of its echographic signs correlates with the level of serotonin and tachykin.

Moreover, in carcinoid syndrome, progression of valvular disease is associated with high peak levels of urinary 5-HIAA. Serotonin also plays a key role in the development of peritoneal fibrosis. One study showed the dependence of the presence of tissue formations in the mesentery of the intestine and connective tissue cords of the abdominal cavity and pelvis depending on the level of platelet-bound serotonin and 5-HIAA in the urine.

As already mentioned above, an increase in the level of serotonin in plasma or the product of its metabolism in daily urine is a factor that allows us to first suspect the presence of a tumor from midgut derivatives. Tumors from the foregut (thymus, lung, esophagus, stomach, duodenum) also produce serotonin, but to a lesser extent, whereas tumors from the hindgut (distal colon and rectum) rarely produce serotonin.

Other biochemical parameters include: 5-hydroxytryptophan, neuron-specific enolase, adrenocorticotropic hormone, growth hormone, human chorionic gonadotropin. In the diagnosis of carcinoid syndrome, an increase in the level of adrenocorticotropic hormone in the blood serum is important.

Topical diagnosis of NETs consists of sequentially alternating two stages: preoperative and intraoperative diagnostics. For this purpose, in most cases, traditional and widely used medical techniques are used. The first and simplest of them is transcutaneous ultrasound (US). Ultrasound has undoubted advantages over other diagnostic methods, since the equipment necessary for its implementation is available in almost all medical institutions, and this method is devoid of radiation exposure to the patient. However, the diagnostic capabilities of ultrasound are significantly limited by the need in most cases to detect the main lesion and its metastases measuring less than 2 cm, and often up to 5–10 mm. As a result, the sensitivity of the method, depending on the size of the tumor and the qualifications of the specialist conducting the study, ranges from 30% to 70%.

The worst results were obtained in the diagnosis of gastrinoma - all lesions are detected in only 10–35% of patients. Despite this, with some experience of an ultrasound diagnostic specialist, it is possible to identify the primary tumor and its small metastases in 40–60% of patients, even without special sampling.

The next ultrasound diagnostic method is endoscopic ultrasound (EUS). The technique has become widespread relatively recently - no more than 10 years. However, this diagnostic method has now become one of the leading ones throughout the world, allowing to detect up to 80–95% of NETs, ​​and is often the only technique that allows identifying the localization of formations up to 5–6 mm, as well as gastrinomas in the duodenum. Currently, in our clinic, 23 patients were examined using EUS and in 87.5% of cases it was possible to detect all tumors, including multiple ones.

Non-invasive diagnostic methods that carry radiation exposure primarily include computed tomography (CT). Currently, only CT with intravenous enhancement is used to detect focal formations of the pancreas. This diagnostic method makes it possible to localize up to 45–70% of all NETs in the hepatopancreatoduodenal region and their metastases. We used all CT options, ranging from conventional (without intravenous enhancement) to multislice CT. The greatest diagnostic capabilities were observed with multislice CT (sensitivity depending on the type of NET - 58–82%).

Magnetic resonance imaging (MRI) has been used for the purpose of diagnosing NETs for quite a long time, but it has not received widespread use for this purpose. This is due to the high cost of the method and its diagnostic capabilities, which are not superior to those of ultrasound and CT. Most authors who examined all patients without conducting a special sample provide data on the sensitivity of MRI - 55–90%. It should be noted that the diagnostic capabilities of both CT and MRI are significantly reduced when it is necessary to identify the localization of multiple gastrinomas and insulinomas.

Scintigraphy with In111-labeled somatostatin analogues (SCP), For the diagnosis of NET, it has been used for more than 30 years and is currently mandatory when conducting a diagnostic search in most countries of the world. The essence of the method is that NETs, ​​to varying degrees, contain different types of somatostatin receptors, and when somatostatin analogues labeled with indium 111 are administered, they accumulate in the tumor. The sensitivity of the method is quite high and averages 60–85% and does not depend on the size of the lesion, allowing the detection of NETs up to 5 mm in diameter and their distant metastases.

The diagnostic capabilities of SRS depend on the number of somatostatin receptors in the tumor: for example, with glucagonoma and VIPoma, it is possible to determine the primary tumor in almost 90% of cases. In the case of gastrinoma, distant metastases are almost always detected and in 50–60% of cases multiple tumors of extrapancreatic localization are not detected by other research methods; however, even in this situation, up to 30% of gastrinomas are subsequently determined only at surgery.

The lowest sensitivity of SRR, not exceeding 50%, was obtained with topical diagnostics using insulin. In addition to the topical diagnosis of NET and its metastases, SRR can be used for differential diagnosis with adenocarcinoma metastases, replacing percutaneous transhepatic biopsy. For this purpose, it is also possible to study the level of nonspecific NET markers in peripheral blood. Percutaneous transhepatic biopsy under ultrasound guidance is probably more appropriate not for differential diagnosis, but for monitoring the implementation of systemic and selective biological and chemotherapy

Among the invasive methods of topical diagnosis of NETs in the hepatopancreatoduodenal region, the most widespread angiography (superselective celiacography and upper mesentericography). This technique makes it possible to make a correct diagnosis in 70–85%. The sensitivity of angiography decreases by 1.5–2 times when the size of insulinoma is less than 1.0 cm. The negative aspects of angiography are the relatively high number of false positive results and the discrepancy between data on tumor location based on pre- and intraoperative studies, sometimes reaching 5–30%.

There are a number of diagnostic methods based on determining the hormonal activity of NETs. Technique percutaneous transhepatic portal vein catheterization (PTTC) was developed and first described in 1971 by Wiechel, and from about that time, superselective catheterization of pancreatic veins with blood sampling and determination of the level of hormone produced by the tumor began to be used for topical diagnosis of hormonally active NETs. The sensitivity of the method reaches 85–100% and is not affected by the size or location of the tumor.

Despite all its advantages, the technique of conducting PCI requires complex technical equipment and highly qualified specialists performing this study. In addition, during this procedure, severe complications may develop, such as bile secretion and bleeding from puncture holes in the liver, thrombosis of the mesenteric vein (2–4%), which requires emergency surgical intervention and can be fatal.

Endocrine tumor cells take up hormone precursors, express receptors, and store and secrete synthesized hormones. The use of radiolabeled drugs is aimed at visualizing neuroendocrine tumor cells. The spatial resolution of PET is 5-10mm. To increase sensitivity, PVT is performed in conjunction with CT. This provides a continuous image, i.e. a combination of anatomical CT images and functional PET images. This combination of methods provides better diagnosis and determination of the location of the tumor.

The expression of somatostatin receptors in neuroendocrine tumors is used not only in scintigraphy, but also for PET with octreotide. Imaging techniques have been developed based on the specific uptake of amine precursors, their decarboxylation, and storage for each type of neuroendocrine tumor. Hydroxytryptophan is taken up by the carcinoid cell, decarboxylated and stored in vesicles in the form of serotonin. This method allows the visualization of tumors with little expression of somatostatin type II receptors and negative scintigraphy. PET is more effective for diagnosing carcinoid tumors than CT or MRI. PET can detect tumors up to 3 mm in diameter, sensitivity reaches 90%.

Poorly differentiated tumors that do not produce hormones or produce them in small quantities (neuroendocrine malignant tumors) give a false negative result with scintigraphy. These tumors are characterized by high proliferative capacity and uptake of fluorodeoxyglucose.

Thus, isotope studies significantly increase the accuracy of diagnosis of localization and staging of neuroendocrine tumors. In addition to information about anatomical location, they also provide information about metabolism, receptor expression, and drug distribution. PET is used to diagnose tumor location and monitor treatment for all types of endocrine tumors.

Neuroendocrine tumors can synthesize one or more peptide hormones that enter the bloodstream and act on various target organs. This excess synthesis of hormones is manifested by a specific clinical syndrome – carcinoid syndrome. The main approach to the treatment of patients with endocrine tumors involves mandatory correction of excessive secretion of hormones and their effects. Currently, symptomatic therapeutic treatment includes biological therapy using somatostatin analogues and/or interferons and the use of other methods aimed at correcting hormonal deficiency.

Somatostatin is a peptide hormone that exists in the human body in two molecular forms. It affects each organ differently. Local synthesis of somatostatin in the pancreas may have endocrine and paracrine effects that are mediated by specific somatostatin receptors. Recetoptors are also located in the mucous membrane of the gastrointestinal tract. The effect of somatostatin increases the passage time of food through the gastrointestinal tract, inhibits the secretion of intestinal hormones by endocrine cells, and inhibits the secretion and absorption of intestinal fluid.

Structural analogues of somatostatin have been synthesized for therapeutic purposes.

Octreotide is prescribed subcutaneously or intravenously in the form of one or more injections 2-3 times a day. There is also octreotide depot for intramuscular administration, used once a month.

Another synthetic analogue is lantreotide, which exists as a depot drug for intramuscular administration every 10-15 days and as a depot form for deep subcutaneous administration (Somatulin), prescribed every 4 weeks.

Carcinoid syndrome is treated with somatostatin analogues according to the following regimens:
1. Octreotide 300-1500 mcg subcutaneously.
2. Sandostatin Lar 20-60 mg intramuscularly every 4 weeks.
3. Lantreotide 30 mg intramuscularly every 2 weeks or 90-120 mg subcutaneously once a month.

It has been shown that therapy with somatostatin analogs leads to the complete disappearance of hot flashes in 60% of patients, with a simultaneous reduction in their frequency and/or severity by 2 times in more than 85% of cases, which leads to a significant improvement in the quality of life. The disappearance of diarrhea is noted in more than 30% of cases, and in more than 75% of patients an improvement in general condition is observed. More than half of the patients showed a decrease in urinary excretion of the breakdown product of serotonin - 5OIAA. In addition, objective short-term antitumor effects were observed with this treatment. However, over time, insensitivity to somatostatin analogues may develop.

To check the effectiveness and safety of treatment in each case, it should be started with short-acting drugs, for example Octreotide 100 mcg 2-3 times a day.

The main side effects are abdominal pain, flatulence, and rarely steatorrhea. These symptoms usually disappear within a few weeks. Late side effects include gallstone formation and persistent steatorrhea leading to vitamin D deficiency, calcium malabsorption syndrome, and vitamin B12 deficiency.

Interferon is an antitumor and antiviral drug. There are 5 classes of interferons. The action of interferon is realized through type I interferon receptors. Antitumor effects include: antiproliferative, apoptotic, effects on differentiation and immunomodeling of antiangiogenesis. Another effect of interferon alpha is the induction of fibrosis in liver metastases.

The effectiveness of interferon alpha is comparable to somatostatin analogues. Therefore, this drug can be used as symptomatic treatment of carcinoid syndrome in the 2nd line. A symptomatic response and a noticeable improvement in quality of life is observed in 40% of patients. The most commonly used are recombinant alpha interferon 2a (Roferon) and 2b (Intron-A). There is no significant difference in the clinical response to both drugs.

It is necessary to individually select the dose of the drug depending on the age, gender and weight of the patient. The biochemical response rate is 15-45%. The combination of somatostatin analogues with interferon alpha does not increase therapeutic efficacy. The treatment is also accompanied by pronounced side effects, which are eliminated by individual dose selection. Minor side effects: flu-like (disappears when taking paracetamol), anorexia, weight loss in 60% of cases, asthenia in half of the patients. The main side effects include: bone marrow toxicity (31%), hepatotoxicity (31%), autoimmune disorders, depression and other mental disorders. Pegylated interferon preparations are less toxic and easier to use. They are administered once a week, and low toxicity allows the use of higher doses.

The treatment of choice for carcinoid syndrome remains biological therapy with somatostatin analogues and interferon. Blockade of serotonin receptors reduces the symptoms of diarrhea, which is not always a consequence of excess hormone secretion. It may intensify and even begin after small bowel resection for primary ileal carcinoid. In such cases, the cause of diarrhea may be short bowel syndrome and/or bacterial overgrowth that increases bile acid deconjugation. The goal of treatment is to reduce the amount of bile acids in the large intestine (bile acid sequestrants - cholestyramine), improve fat absorption by adding pancreatic enzymes, and suppress bacterial overgrowth using antibiotics. Loperamide is also used to inhibit peristalsis and increase food passage time.

Cyproheptadine is sometimes used to reduce the number of hot flashes. For pellagra, niacin replacement therapy is prescribed. Hot flashes and diarrhea can be triggered by certain factors, so lifestyle changes are necessary; patients should avoid alcohol, spicy foods and intense physical activity.

To prevent the development of the so-called carcinoid crisis during surgery, embolization, endoscopic procedures and other interventions, patients with midgut carcinoids are pretreated with short-acting or long-acting somatostatin analogues. Carcinoid tumors may express adrenergic receptors. Spinal anesthesia causes a decrease in blood pressure and secondary release of catecholamines by the adrenal glands, therefore it is contraindicated in carcinoid syndrome, for the same reason it is necessary to avoid the use of adrenergic drugs.

When a carcinoid crisis develops, surgical and non-surgical procedures are temporarily stopped, fluid volume is corrected under the control of hemodynamic parameters and additional intravenous administration of octreotide in combination with glucocorticoids is carried out. For postoperative pain relief, it is preferable to use epidural anesthesia.

In case of multiple carcinoids from gastric ECL cells with atrophic gastritis, gastrinomas or MEN I syndrome, the use of somatostatin analogues causes regression of gastric tumors of types 1 and 2. For disseminated gastric tumors of types 2 and 3, interferon alpha can be prescribed, but experience with this use is limited.

Treatment of gastrinoma always begins with suppression of hypersecretion of hydrochloric acid with high doses of H+/K+-ATPase inhibitors or frequent administration of large doses of histamine H2 receptor blockers. Prescribing octreotide and lantreotide to patients with gastrinomas in the same doses as for carcinoid syndrome helps control hypersecretion of hydrochloric acid and has a beneficial effect on prognosis and survival.

In the conservative treatment of insulinoma, there should be no long periods of fasting, so patients need to eat frequently. An alternative is to administer a continuous glucose infusion at night or throughout the day. Treatment with somatostatin analogues is carried out with caution, since inhibition of the synthesis of growth hormones and glucagon can cause hypoglycemia much more profound than the effect of insulin synthesized by the tumor. Diazoxide is the most effective drug for controlling hypoglycemia, reducing insulin secretion (at a daily dose of 50-3 mg). Side effects include edema, kidney damage and hirsutism. Verapamil and glucocorticoids have also been used with varying success.

Insulin or oral hypoglycemic agents can be used to control hyperglycemia in glucagonoma. In case of malignant or benign course of the disease, octreotide or lantreotide are good for treating necrolytic migratory erythema, are less effective for the treatment of weight loss and diabetes mellitus, and do not affect the incidence of venous thrombosis. To prevent thrombosis, aspirin or low doses of heparin are prescribed. Topical or oral administration of drugs relieves the symptoms of erythema migrans. Correction of hypoaminoacidemia and mineral deficiency is also necessary. Hyperglycemia in somatostatinomas is eliminated by prescribing insulin, hypoglycemic agents or somatostatin analogues.

For other types of hypersecretion, for example, in Cushing's syndrome due to ectopic production of ACTH, combination treatment with somatostatin analogues, ketoconazole, metyrapone, etomidate is prescribed, or laparoscopic biadrenalectomy is performed. Acromegaly with ectopic production of somatotropin somatotropin-releasing hormone is treated with somatostatin analogues, growth hormone receptor blockers, or a combination of these drugs.

For hypercalcemia in patients with paraneoplastic production of parathyroid hormone-related peptide, somatostatin analogues and bisphosphonates are indicated.

In severe cases with VIPoma (Werner-Morrison syndrome), intensive intravenous replacement of fluid losses (often up to 10 l/day) and careful correction of water-electrolyte disorders are necessary. Somatostatin analogs in this case reduce the secretion of VIP by the tumor by 50% and inhibit the secretion of water and electrolytes into the intestine. This makes it possible to control secretory diarrhea in half of the patients and achieve a pronounced improvement in the condition. Diarrhea is also reduced by the administration of glucocorticoids, which also inhibit VIP synthesis and increase sodium synthesis in the intestine. You can also use loperamide, opiates, indomethacin, lithium.

Thus, NET therapy is a complex multidisciplinary process that requires close cooperation of specialists from different fields, which facilitates not only the diagnosis, but also determines the effectiveness of NET treatment. None of the existing methods of systemic therapy leads to a cure, so the development of new regimens is necessary. The results of treatment with somatostain analogues can be improved in several ways. New chemotherapy drugs are being developed for more aggressive tumors. New discoveries in biology have led to the creation of targeted drugs that improve treatment outcomes, both when used alone and in combination with other agents. Adequate patient selection is necessary because, in some cases, tumors must have overexpression or mutation of molecular targets for effective treatment. The development of new targeted drugs allows us to maximize the quality of life of patients and survival rate.

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