Clinical picture of neuroendocrine tumors. Carcinoid syndrome and other syndromes

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Carcinoid syndrome- a symptom complex associated with the growth and hormone production of tumors originating from enterochromaffin cells. Carcinoid refers to a tumor that causes carcinoid syndrome (Table 1).

Table 1

Carcinoid syndrome

Etiology	Tumor of enterochromaffin cells of the gastrointestinal tract, less commonly of the bronchi
Pathogenesis	Hypersecretion of serotonin, kinins, histamine, catecholamines and prostaglandins in combination with invasive tumor growth and metastasis
Epidemiology	Incidence of new cases 1 in 100,000 per year
Main clinical manifestations	1. Diarrhea, abdominal pain, belching 2. Hot flashes, telangiectasia, cyanosis 3. Bronchospasm, dyspnea, generalized itching 4. Fibrosis of heart valves 5. Tumor growth and metastasis
Diagnostics	1. Excretion of 5-hydroxyindoleacetic acid, serotonin, histamine 2. Topical diagnosis of tumor
Differential diagnosis	1. Clinical syndromes accompanied by hot flashes (postmenopausal syndrome, liver cirrhosis, idiopathic hot flashes)
	2. Pheochromocytoma 3. Metastases to the liver of a tumor of unknown primary location
	1. Surgical treatment, chemoembolization and alcohol ablation of liver metastases 2. Antiproliferative and symptomatic therapy: octreotide, α-interferon, polychemotherapy
	5-year survival rate about 50%

Etiology

According to the histological structure, the set of hormones produced and the degree of malignancy, carcinoid tumors vary significantly depending on the location. Carcinoid tumors are divided into those originating from the anterior, middle and posterior parts of the primary embryonic gut (Table 2). Intestinal carcinoids account for 90% of all carcinoid tumors. Most often, intestinal carcinoid is localized in the terminal ileum, appendix, and rectum.

table 2

Classification of carcinoid tumors

Division of the primary intestine	Tumor localization	Hormones produced	Symptoms
Prointestinal carcinoid	Respiratory tract	5-hydroxytryptophan, adenopituitary hormones, neuropeptides	Carcinoid syndrome, Cushing's syndrome
Prointestinal carcinoid	Stomach, duodenum	Gastrointestinal peptides, serotonin, histamine	Carcinoid syndrome, hypersecretion of hydrochloric acid, diarrhea, diabetes, Cushing's syndrome
Mid-intestinal carcinoid	Small intestine, appendix, right colon	Serotonin, tachykinin group peptides	Carcinoid syndrome, hormonally inactive tumors
Postintestinal carcinoid	Left side of the colon, rectum	Gastrointestinal peptides	Hormonally inactive tumors

Pathogenesis

Most of the symptoms of carcinoid syndrome are caused by hypersecretion by the tumor of substances such as serotonin, kinins, histamine, catecholamines and prostaglandins. The main biochemical marker of carcinoid syndrome is serotonin. Tumors originating from the foregut (bronchi, stomach) mainly produce 5-hydroxytryptophan rather than serotonin. The main metabolite of biogenic amines is 5-Hydroxyindoleacetic acid(5-GIUK). The pathogenesis of individual clinical manifestations of carcinoid syndrome is presented in Table. 3.

Table 3

Pathogenesis of individual clinical manifestations of carcinoid syndrome

The extensive symptoms of carcinoid syndrome in intestinal carcinoid correspond to a late stage of the tumor process and metastatic liver damage. The primary tumor, as a rule, is small in size, and the products secreted by it, entering the liver, are completely inactivated. When the liver ceases to cope with massive tumor secretion, its products begin to enter the systemic circulation, and only then do the symptoms of carcinoid syndrome appear. In the same way, mechanically, the predominant damage to the endocardium of the right parts of the heart in intestinal carcinoid is explained, where blood from the affected liver enters through the inferior vena cava. The difference between extraintestinal carcinoid and intestinal forms is that tumor secretion products enter directly into the systemic circulation and not into the portal system. Thus, in these cases, the symptoms of carcinoid syndrome can develop even in the early stages of the tumor process, when radical surgery is still possible.

Epidemiology

The incidence of new cases of carcinoid tumors is 1 in 100,000 per year. The average age of manifestation of small intestinal carcinoids is 50-60 years; occurs with equal frequency in men and women.

Clinical manifestations

Diarrhea, abdominal pain, belching.
Hot flashes, telangiectasia, cyanosis. Hot flashes can be triggered by physical activity, alcohol, or foods such as cheese, smoked meats, and coffee. They can be repeated throughout the day, usually lasting several minutes, accompanied by severe sweating. Patients complain of a feeling of heat, palpitations and trembling. Some may experience excessive tearing and drooling. Against this background, severe arterial hypotension, difficulty breathing, and diarrhea may occur. The skin of the face and upper half of the body gradually acquires a persistent red-bluish tint, and telangiectasia appears (Fig. 1). With carcinoid of the stomach and bronchi, hot flashes appear as bright red spots on the face and upper half of the body with a clear border.
Bronchospasm (10-15%), dyspnea, generalized itching.
Fibrosis of the heart valves (2/3 of patients) with the development of right ventricular failure, rarely - mesenteric and retroperitoneal fibrosis (with symptoms of intestinal obstruction and ureteral obstruction).
Tumor growth and metastasis (intestinal obstruction, obstructive jaundice, etc.).

Rice. 1. Change in patient's complexion during hot flashes with carcinoid syndrome

Diagnostics

1. The main marker of carcinoid tumors is the serotonin metabolite - 5-HIAA, determined in 24-hour urine. Decisive in the diagnosis of bronchial and gastric carcinoid is the determination of serotonin and histamine in the urine.

2. Topical diagnosis of a tumor. Scintigraphy of somatostatin receptors is highly informative for carcinoid tumors.

Differential diagnosis

1. Clinical syndromes accompanied by hot flashes (postmenopausal syndrome, liver cirrhosis, idiopathic hot flashes).

2. If there is a pronounced sympathoadrenal component in the clinical picture, a differential diagnosis with pheochromocytoma is necessary.

3. Metastases to the liver of a tumor of unknown primary location.

Treatment

Surgical intervention may make sense even if distant, especially solitary, slowly growing metastases are detected.

Chemoembolization and alcohol ablation of liver metastases.

Antiproliferative and symptomatic therapy: the drug of choice is octreotide. In addition, α-interferon drugs and polychemotherapy (streptozotocin, 5-fluorouracil and adriamycin) are effective.

Forecast

The malignancy of carcinoid tumors varies greatly, with a 5-year survival rate of approximately 50%. Cases of a fulminant course have been described, but more often the life expectancy of patients, even with a widespread metastatic process, is more than 5 years (cases of survival up to 20 years and many cases up to 10 years are described) and can be significantly extended against the background of modern antiproliferative therapy. The prognosis is most favorable for carcinoid of the appendix, the worst - for bronchial carcinoid.

Dedov I.I., Melnichenko G.A., Fadeev V.F.

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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%.

Pathophysiology of carcinoid syndrome.

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.

Clinical picture.

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.

Methods for diagnosing carcinoid syndrome.

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.

Positron emission tomography (PET).

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.

Treatment of carcinoid syndrome.

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 analogues.

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.

Alpha interferon.

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.

Other treatments for carcinoid syndrome.

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.

10. Oberg K, Kvols L, Caplin M et al 2004 Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastropancreatic system. Ann Oncol 15 966-973

11. Pape UF, Wiedenmann B 2003 Adding interferon-alfa to octreotide slows tumor progression compared with octreotide alone in people with disseminated midgut carcinoid tumors. Cancer Treat Rev 29 565-5569

12. Saslow SB, Camilleri M et al. 1996 Relation between fat malabsorption and transit abnormalities in human carcinoid diarrhea. Gastroenterology 110 405-410

13. Service FJ 1995 Hypoglycemic disorders. N Engl J Med 332 1144-1152

14. Soga J., Yakuwa Y Somatostatinoma/inhibitory syndrome: a statistical evaluation of 241 reported cases. Syndrome: a statistical evaluation of 173 report cases J Exp Clin Cancer Res.-1999.-Vol. 18.- P. 13-22

15. Soga J., Yakuwa Y. Vipoma/diarrheogenic// J Exp Clin Cancer Res.-1998.-Vol. 17.- P. 389-400

16. Woodart P. K., Feldman J. M., Paine S. S. & Baker M. E. Midgaut carcinoid tumors: CT findings and biochemical profiles. J. Comput Assist. Tomogr. 19, 400-405.1995

17. Egorov A.V., Kuzin N.M. Issues in the diagnosis of neuroendocrine tumors of the pancreas Practical Oncology Vol. 6, No. 4 – 2005, pp. 208-210

18. Paltsev M. A., Kvetnoy I. M. Guide to neuroimmunoendocrinology Moscow “Medicine”. - 2008. - p. 79, p. 434

19. Simonenko V.B., Dulin P.A., Makanin M.A. Neuroendocrine tumors // Moscow "Gaeotar-Media". - 2010. - pp. 94-95, 97, 102,107

Dizziness
Nausea
Abdominal pain
Fever
Red spots on hands
Cardiopalmus
Vomit
Diarrhea
Red spots on the neck
Facial redness
Tearing
Redness of the neck
Hot flashes
Swelling of the limbs
Redness of the nose
Wheezing in the chest
Accumulation of fluid in the abdominal cavity
Swelling of the nose
Bluishness of facial skin
The appearance of deep wrinkles on the face

There is a certain type of neuroendocrine tumors - carcinoids, which release certain hormones into the blood (most often serotonin, prostaglandin, histamine and others). Due to the entry of these hormones into the blood, a person develops carcinoid syndrome, which is characterized by certain symptoms.

It turns out that the root cause of the development of such a pathological condition is a tumor in any of the organs. In this case, the hormone-producing tumor may be located:

in the appendix;
in the small or large intestine;
in the stomach.

Causes

As is already clear from the definition of pathology, the reasons for the development of carcinoid syndrome lie in the presence of a neuroendocrine tumor in the patient’s body. Fortunately, these tumors grow very slowly, so if the pathology is detected at an early stage, a complete cure or prolongation of a person’s life by 10 years or more is possible. Therefore, it is so important to undergo regular examinations and pay attention to any suspicious symptoms that may indicate carcinoid syndrome - a sign of cancer in the body.

Predisposing factors for the development of this pathological condition may be:

hereditary predisposition (in particular multiple endocrine neoplasia);
gender – pathology is more often observed in men;
excessive drinking and smoking;
certain types of neurofibromatosis;
history of stomach disease.

In addition, different forms of carcinomas occur in people of different races. Thus, African Americans are more likely to experience stomach tumors, while Europeans are more likely to experience lung carcinomas.

Symptoms

With tumors of different localization, the symptoms of carcinoid syndrome appear with a certain degree of probability. For example, tumors of the small intestine of all neuroendocrine tumors occur in 10% of cases. In this case, the signs of carcinoid syndrome with such an oncological disease will be as follows:

diarrhea;
paroxysmal abdominal pain;
nausea and vomiting.

Tumors of the appendix are even less common and the prognosis for removal of the appendix is often favorable in cases where the tumor is small and does not metastasize.

The most common neuroendocrine carcinoma is gastric, which comes in three types and has a high probability of metastasis:

Type I is a tumor less than 1 cm in size. It is often benign, so the prognosis for treating the pathology is favorable;
Type II – a neoplasm up to 2 cm in size, which extremely rarely degenerates into a malignant tumor;
Type III is the most common - these are tumors up to 3 cm in size, which are malignant and often grow into surrounding tissues. The prognosis, even with timely diagnosis, is unfavorable. But, if you detect a tumor at an early stage during a preventive examination and treat it comprehensively, then you can provide a person with 10–15 years of a full life, which is already a lot considering the serious diagnosis.

In other places where tumors are localized, carcinoid syndrome develops almost immediately after the tumor appears, so timely consultation with a doctor and treatment of the underlying pathology can save a person’s life. If we talk about the symptoms of carcinoid syndrome, they are typical, but they are not diagnostically important, since individually they can manifest themselves in many other pathologies of internal organs.

So, the main symptoms of a condition such as carcinoid syndrome are:

diarrhea;
hyperemia;
abdominal pain;
wheezing;
CVS pathology;
tides.

In addition, some people may develop carcinoid crisis, a life-threatening condition with serious consequences.

Diarrhea occurs in most patients with carcinoid syndrome. It occurs for two reasons - either due to the effect of the hormone serotonin, or due to the location of the tumor in the intestine. Hyperemia is typical in a condition such as carcinoid syndrome. A person’s face turns red in the cheeks and neck, body temperature rises, dizziness appears and heart rate increases, although blood pressure is within normal limits.

Other symptoms, such as abdominal pain, wheezing in the lungs and swelling of the extremities or fluid accumulation in the abdominal cavity (which occurs with heart pathologies) are not characteristic - they can occur with any disease, so they are of no diagnostic value. But hot flashes, similar to those that women experience during menopause, can characterize carcinoid syndrome, since they do not occur with other diseases. Unlike menopausal hot flashes, they come in four types:

with the first type, redness occurs in the face and neck, which lasts for several minutes;
with the second, the face acquires a cyanotic tint, which lasts for 5–10 minutes, while the nose swells and becomes purple-red;
with the third type, the duration of the hot flash can be from several hours to several days - the condition is characterized by lacrimation, the appearance of deep wrinkles on the face, dilation of the blood vessels of the face and eyes;
with the fourth type of hot flashes, red spots of irregular shape appear on the neck and arms of a person.

Diagnosis and treatment

Diagnosis of a condition such as carcinoid syndrome is difficult, since all the symptoms of the pathology are common, and if there is no characteristic facial hyperemia or hot flashes, it is difficult to determine the disorder that caused these symptoms, so patients are prescribed a comprehensive examination, which includes:

taking biochemistry tests;
immunofluorescence studies;
instrumental research methods.

The most informative instrumental methods are CT and magnetic resonance imaging, which make it possible to detect tumors in organs even at an early stage of development, which increases the patient’s chances of recovery. But other instrumental methods that diagnostics has at its disposal are also prescribed: radiography, scintigraphy, endoscopy, phlebo- and arteriography.

Treatment of a pathological condition such as carcinoid syndrome includes treatment of the underlying cause, that is, the tumor. The treatment method can be determined by diagnosis, since it shows the location of the tumor, its stage of development and other criteria important for developing a treatment plan.

The main methods of treating oncology today are:

surgical excision of the tumor;
chemotherapy;
radiation therapy;
symptomatic treatment.

The main method is surgical removal of the tumor, which can be radical, palliative and minimally invasive. Radical excision involves removing the area affected by the tumor, adjacent tissues and lymph nodes, as well as metastases present in the body.

Palliative surgery involves removing only the primary tumor and the largest metastases. The minimally invasive surgery involves ligating the hepatic vein to relieve symptoms such as hot flashes and diarrhea. After surgical excision, a complex of chemotherapy drugs is prescribed to destroy metastases in the body and tumor remnants (if any). The combined use of surgical methods and chemotherapy allows the patient to prolong life, and in some cases (when the tumor is detected at an early stage) to be completely cured.

As for symptomatic treatment, it is necessary to alleviate the patient’s condition. For this purpose, serotonin antagonists, H1 and H2 receptor blockers, antidepressants, alpha-interferon and other drugs according to indications are prescribed.

This is a combination of symptoms caused by the presence of a neuroendocrine tumor (carcinoid) in the body and the release of large amounts of hormones into the blood. Carcinoids produce about forty biologically active substances, but the most important among them are serotonin, histamine, tachykinin, kalikrein and prostaglandin. Neuroendocrine tumors can occur in any organ of the digestive system (usually in the small intestine), as well as in the bronchi.

Signs of carcinoid syndrome

Sudden redness of the skin of the face, neck, and chest caused by a rush of blood to these areas of the body is the hallmark of carcinoid syndrome. This symptom occurs in approximately 85% of people with neuroendocrine tumors.

The course of such an attack differs in patients with different tumor locations. Thus, in patients with intestinal carcinoid, such flushes of blood to the face and torso occur suddenly and last from thirty seconds to half an hour. At this time, a person is overtaken by a feeling of heat. Severe attacks are accompanied by a drop in blood pressure and increased heart rate. As the disease progresses, attacks may become more frequent and prolonged, and the skin may become bluish.

The syndrome can occur spontaneously, or be provoked by food intake, alcohol, stress, bowel movements, anesthesia and other factors. Attacks triggered by anesthesia can last for hours and be accompanied by a pronounced drop in blood pressure. This phenomenon in medicine is called carcinoid crisis.

Another sign of carcinoid syndrome is the appearance of venous telangiectasias on the skin. This is the dilation of small blood vessels, which appears in the form of spider veins or networks on the skin. Telangiectasia in carcinoid syndrome often occurs in the area of the upper lip, nose, and cheekbones.

An equally significant symptom is diarrhea, which is reported in approximately 80% of patients with neuroendocrine tumors. The frequency of stool can vary from several times to thirty per day. The stool is usually watery, without blood. Diarrhea may be accompanied by abdominal pain.

Approximately 10-20% of patients complain of shortness of breath and wheezing, most often occurring during attacks of redness of the skin of the face and torso.

Carcinoid syndrome is characterized by the deposition of fibrin plaques on the heart valves, chamber walls, as well as on the inner walls of the pulmonary artery and aorta. The right side of the heart is most often affected. Such changes lead to valvular insufficiency. This symptom occurs in 40% of patients.

If the carcinoid tumor is localized in the stomach or bronchi, the course of an attack of carcinoid syndrome may vary. When the tumor is localized in the stomach, the skin may turn red in spots, and the person is bothered by severe itching. Diarrhea and heart damage are rare. Symptoms of carcinoid syndrome with this tumor localization are caused by the biologically active substance histamine.

In patients with a carcinoid tumor localized in the bronchi, hot flashes are more severe and prolonged, sometimes lasting several days. These attacks may be accompanied by disorientation, anxiety, and tremor (shaking of body parts). In addition, such patients experience symptoms such as:

Swelling of the skin around the eyes;
lacrimation;
Increased salivation;
Hypotension (low blood pressure);
Cardiopalmus;
Diarrhea;
Dyspnea;
Oliguria (decreased urine volume).

It is believed that these symptoms in bronchial carcinoid tumors are caused by the influence of histamine secreted by the tumor itself.

Symptoms

There are also less significant symptoms that occur with carcinoid tumors. Thus, a violation of tryptophan metabolism with excessive formation of serotonin can lead to vitamin PP deficiency, which manifests itself in the form of pellagra. This disease is characterized by symptoms such as diarrhea, dermatitis (inflammation of the skin) and dementia (dementia).

Carcinoid tumors can also affect protein metabolism. As a result of impaired protein synthesis, muscle weakness and even atrophy develop.

Patients with severe bouts of redness may experience persistent swelling in the face and, less commonly, in the extremities.

Diagnostics

Symptoms of carcinoid syndrome are not specific, that is, they can also appear in other diseases, for example, IBS (irritable bowel syndrome) or colitis, so it is extremely important to determine that the change in the patient’s condition is caused precisely by the presence of tumors in the body.

To test for carcinoid syndrome caused by serotonin-secreting tumors, a test is performed to test for the presence of a tumor waste product, 5-hydroxyindoleacetic acid (5-HIAA), in the urine. To exclude a false positive result, three days before the test, the patient is prohibited from taking foods that contain serotonin (tomatoes, pineapples, bananas, avocados, plums, walnuts, eggplants, etc.) as well as medications that contain it.

Treatment

For treatment, medications are prescribed that suppress the production of hormones by the neuroendocrine tumor or reduce their effect. Some symptoms, particularly hot flashes, can be relieved with somatostatin medications (octreotide). In addition, hot flashes can be combated with the help of phenothiazines (chlorpromazine), phentolamines.

Loperamide and diphenoxylate can be prescribed to treat diarrhea. To prevent pellagra, a meal rich in vitamin PP is prescribed, as well as a synthetic analogue of the vitamin.

To prevent the conversion of 5-hydroxytryptophan to serotonin, patients are prescribed methyldopa or phenoxybenzamine.

Information about octreotide, loperamide and other drugs can be found in the electronic reference book

ICD-10 code

Carcinoid (carcinoid syndrome) is a rare, potentially malignant, hormonally active tumor originating from argentophilic cells. Most often, carcinoid tumors are localized in the gastrointestinal tract, less often they occur in the bronchi, gall bladder, pancreas and ovaries. The size of tumors is usually not large and varies from 0.1 to 3 cm.

Carcinoid syndrome is a disease caused by the circulation of mediators, which is manifested by redness of the skin (90%), diarrhea (75%), noisy breathing (20%), endocardial fibrosis (33%), damage to the valves of the right heart; sometimes pleural, peritoneal or retroperitoneal fibrosis occurs.

Causes

The etiology of carcinoid, like other tumors, is still unclear. The origin of many symptoms of the disease is due to the hormonal activity of the tumor. A significant release of serotonin, lysylbradykinin and bradykinin, histamine, and prostaglandins by tumor cells has been proven.

The development of carcinoid syndrome is caused by a hormonally active tumor arising from enterochromaffin (argentaffin) cells of the intestine (Kulchitsky cells). In this case, increasing intestinal disorders are accompanied by hypertensive syndrome.

Classification

One of the most appropriate approaches to the classification of carcinoid tumors of the gastrointestinal tract is their division according to embryogenesis into anterior, middle and posterior. In accordance with this, they distinguish:

Carcinoid tumors of the anterior part of the digestive tube (bronchi, stomach, duodenum, pancreas); these neoplasms are argentaffin-negative, contain a small amount of serotonin, sometimes secrete 5-hydroxytryptophan and ACTH, and are capable of metastasizing to the bones;
Carcinoids of the middle part of the digestive tube (jejunum, ileum, right colon) are Argentaffin-positive, contain a lot of serotonin, rarely secrete serotonin or ACTH, rarely metastasize;
Carcinoid tumors of the posterior part of the digestive tube (transverse colon, descending colon and rectum) are Argentaffin-negative, rarely contain serotonin and ACTH, and can metastasize to bone. Sometimes they are also found in the gonads, prostate, kidneys, mammary glands, thymus gland or skin.

Symptoms

Symptoms and the course of carcinoid consist of local symptoms caused by the tumor itself and the so-called carcinoid syndrome caused by its hormonal activity. Local manifestations are local soreness; Often there are signs reminiscent of acute or chronic appendicitis (with the most common localization of the tumor in the appendix) or symptoms of intestinal obstruction, intestinal bleeding (if localized in the small or large intestine), pain during defecation and discharge of scarlet blood with feces (with rectal carcinoid ), weight loss, anemia. Carcinoid syndrome includes peculiar vasomotor reactions, attacks of bronchospasm, hyperperistalsis of the gastrointestinal tract, characteristic skin changes, lesions of the heart and pulmonary artery. It is not observed in a pronounced form in all patients, but more often with tumor metastases to the liver and other organs, especially multiple ones.

Typical symptoms are:

Hyperemia
Diarrhea
Abdominal pain
Wheezing due to bronchospasm (narrowing of the airways)
Heart valve disease
Surgery can cause a complication known as carcinoid crisis.

Flushing is the most common symptom of carcinoid syndrome. In 90% of patients, hyperemia occurs during the disease. Flushing is characterized by redness or discoloration of the face and neck (or upper body), as well as an increase in temperature. Flushing attacks usually occur suddenly and spontaneously, but they can also be caused by emotional stress, physical stress or alcohol consumption.

Attacks of hyperemia can last from a minute to several hours. Congestion may be accompanied by a rapid heart rate, low blood pressure, or dizziness if blood pressure drops too much and blood is not getting to the brain. Rarely, hyperemia is accompanied by high blood pressure. The hormones that are responsible for hyperemia are not fully recognized.

Diarrhea is the second important symptom of carcinoid syndrome. About 75% of patients with carcinoid syndrome experience diarrhea. Diarrhea often occurs along with flushing, but can also occur without it. In carcinoid syndrome, diarrhea is most often caused by serotonin.

Heart disease occurs in 50% of patients with carcinoid syndrome. Carcinoid syndrome usually results in scarring and stiffness of the pulmonary valve on the right side of the heart. Stiffness of these two valves reduces the heart's ability to pump blood from the right ventricle to the lungs and other parts of the body, which can lead to heart failure.

Typical symptoms of heart failure include an enlarged liver (due to the supply of blood to the heart in heart failure when it is unable to pump all the incoming blood), swelling of the legs and ankles (dropsy), and swelling of the abdomen due to fluid buildup (abdominal hydrops). The cause of damage to the tricuspid and pulmonary valves of the heart in carcinoid syndrome, in most cases, is the intense long-term effect of serotonin on the blood.

Carcinoid attack is a dangerous condition that can occur during surgery. It is characterized by a sudden drop in blood pressure that causes shock, sometimes accompanied by an excessively rapid heart rate, increased blood glucose, and severe bronchospasm.

A carcinoid attack can be fatal. The best way to prevent a carcinoid attack is surgery.

Wheezing occurs in approximately 10% of patients with carcinoid syndrome. Wheezing is a consequence of bronchospasm (spasm of the airways), which occurs as a result of the release of hormones by a carcinoid tumor.

Abdominal pain is a common symptom in patients with carcinoid syndrome. Pain may occur due to metastases in the liver, due to the fact that the tumor affects neighboring tissues and organs, or intestinal obstruction.

Diagnostics

The diagnosis is confirmed by a high level of sorotonin in the blood plasma, increased urinary excretion of 5-hydroxyindoleacetic acid, as well as the detection of intestinal, liver, and lung tumors during instrumental research. Biochemical parameters can be distorted when consuming foods containing large amounts of serotonin (bananas, walnuts, citrus fruits, kiwi, pineapples), taking rauwolfia preparations, phenothiazines, salicylates, as well as in pathological conditions complicated by intestinal obstruction, when the excretion of 5-hydroxyindoleacetic acid may increase to 9–25 mg/day.

Immunofluorescence studies confirm the presence of neuropeptides (serotonin, substance P and neurotensin) in carcinoid tumors. The determination of carcinoembryonic antigen (CEA) in the diagnosis of carcinoid tumors also has a certain meaning: its level is usually normal or minimal. If the CEA concentration is elevated, another tumor should be suspected.

Comprehensive topical diagnosis of carcinoids involves X-ray examination, computed tomography, ultrasound scanning, the use of immunoautoradiographic methods for determining hormones in the blood, selective arterio- and venography, scintigraphy with indium-111-octreotide and morphological examination of the biopsy specimen. The use of the entire complex of modern research methods (fluoroscopy, endoscopy, selective arterio- and phlebography, ultrasound, computed tomography, radionuclide studies, determination of hormones in the blood, immunohistochemical study of tumor biopsies) ensures the correct diagnosis in 76.9% of cases.

Treatment

Considering the general principles of therapy for carcinoid syndrome, it should be noted that the earliest possible removal of the tumor is advisable. However, it must be remembered that clinical manifestations of carcinoid syndrome very often occur in cases where there are already functionally active metastases in the liver. In this case, radical surgical treatment is not feasible. However, mitigation of the clinical picture of carcinoid syndrome can be achieved by excision of as much of the metastases as possible, thus reducing the total amount of serotonin-producing tissue. If surgery is not possible for any reason, radiotherapy can be used, the effectiveness of which, however, is low due to the resistance of carcinoid tumors to radiation exposure. After radiation therapy, no reliable data on an increase in life expectancy have been obtained.

Among the medications used in the treatment of carcinoid tumors, cyclophosphamide should be highlighted, the effectiveness of which, according to a number of authors, is about 50%. There are also reports that a good therapeutic effect is observed when prescribing serotonin antagonists, of which cyproheptadine and deseryl are the most widely used. Cyproheptadine has not only an antiserotonin, but also an antihistamine effect. It is prescribed intravenously in a dose of 6 to 40 mg. Deseryl is used orally at a dose of 6 to 24 mg and intravenously over 1–2 hours at a dose of 10–20 mg.

Some antidepressants - fluoxetine, sertraline, fluvoxamine, paroxetine can be used for symptomatic therapy.

Histamine H1 and H2 receptor blockers (cimetidine, ranitidine, diphenhydramine/diphenhydramine) are effective for carcinoids that produce predominantly histamine. Loperamide (Imodium) is used to relieve diarrhea.

Synthetic analogues of somatostatin - octreotide (Sandostatin) and lanreotide (Somatulin) - are widely used to treat carcinoid syndrome. Sandostatin, interacting with somatostatin receptors, suppresses the production of active substances by the tumor. The recommended regimen for the use of sandostatin (octreotide) in the treatment of carcinoid and neuroendocrine syndromes is 150–500 mcg subcutaneously 3 times a day. The drug increases the survival rate of patients with carcinoid tumors and the presence of metastases, improves the quality of life of patients, relieving or eliminating hot flashes, intestinal motor dysfunction, and diarrhea.

Numerous studies have been conducted on the use of interferon α in patients with carcinoid tumors. To treat patients, doses of α-interferon 3–9 IU were used subcutaneously 3–7 times a week. The use of higher doses of the drug does not improve treatment rates, but significantly increases the percentage of toxic reactions. When treated with α-interferon, improvement is observed in 30–75% of cases.

Treatment of arterial hypertension is carried out according to general rules. In some cases, treatment should be aimed at combating complications of carcinoid syndrome, such as cardiovascular failure, gastrointestinal bleeding, etc. It should be noted that the duration of the disease (10 years or more), significant exhaustion of patients with carcinoid syndrome requires the appointment of restorative therapy.

Thus, the main type of treatment for patients with carcinoid and neuroendocrine tumors is surgery. Their drug treatment is based on chemotherapy, the use of somatostatin analogues and α-interferons.