Carcinoid syndrome

Introduction to carcinoid syndrome Carcinoidsyndrome (carcinoidsyndrome), in addition to the esophagus, can occur in any part of the digestive tract carcinoid, located in the appendix accounted for 1/3, more common in women, rarely metastasized. 2% in the stomach, the rest in the duodenum, colon (more common in men), gallbladder and Meckel's diverticulum, can also occur in the bronchi and ovary, but less common. Occurred in the small intestine, the degree of malignancy is large, and can be transferred to the lungs, bones and other intra-abdominal organs. Bronchial carcinoids with carcinoid syndrome have a poor prognosis. Carcinoids can occur at any age. The onset age of carcinoids in the appendix is 30 to 40 years old, and carcinoids in other parts occur mostly in 50 to 60 years old. basic knowledge The proportion of illness: 0.003% - 0.008% Susceptible people: no special people Mode of infection: non-infectious Complications: Asthma, abdominal pain, bloating, diarrhea, shock, edema

Causes of carcinoid syndrome

Causes

Biochemical abnormalities:

Carcinoid syndrome has a greater chance of carcinogenesis and extensive liver metastasis. The most characteristic biochemical abnormality of carcinoid is serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid ( Overproduction of 5-HIAA), normally 99% of the tryptophan in the diet is used to synthesize niacin and protein, while more than half of the tryptophan intake in carcinoid patients is converted to 5 by tryptophan decarboxylase. -hydroxytryptophan (5-HTP), which in turn produces 5-HT, and is metabolized to 5-HIAA. Recent studies have confirmed that carcinoids not only produce amines but also produce peptides, PP substances, motilin and prostaglandins, and carcinoid volumes. Small, when the diameter does not exceed 3.5cm, generally does not cause symptoms and signs, when the carcinoid volume is large, a large amount of secretions are produced to convert all the tryptophan in the food into 5-HT, etc., due to liver metastasis of the liver Can not effectively metabolize, inactivate the products of primary cancer, the secretion products of carcinoids enter the systemic circulation through the hepatic vein, the volume of liver metastases is larger than that of the primary carcinoid, and a large amount of secreted products enter the systemic circulation and cause a series of changes, 5 - After HT is formed, it enters the bloodstream and is taken up by the platelets and distributed in the tissue. In, it acts on target cells.

Intestinal mucosa argyrophil cells:

Oberndorfer first proposed carcinoid carcinoma as a slow-growing intestinal adenocarcinoma in 1907 and proposed the name carcinoid. Masson proved in 1928 that carcinoid cells originated from the intestinal lining of argyrophil cells because the cells showed pro-silver staining. As the name suggests, Lembeck first discovered 5-HT in carcinoid tissue in 1953 and confirmed it to be a bioactive substance that causes carcinoid syndrome. In 1954, Thorson and Lsler independently reported cases of carcinoid syndrome, clinically. It is not uncommon, but only a few cases have carcinoid syndrome. Carcinoids of different embryo origin have different biochemical, pathological and clinical features. Williams divides carcinoid into three types: foregut, midgut and hindgut. It is said that carcinoids from the foregut (gastric duodenum, bronchus) are not silver-affinitive. Due to the lack of aryl acid decarboxylase, 5-HT production is less, and 5-HTP content is higher, they can also Produces histamine and various peptides; carcinoids from the midgut (small intestine, ileocecal, ascending colon, pancreas, partial transverse colon) are pro-silver and argyrophilic, producing more 5-HT, foregut Cancer secretes 5-HT and 5-hydroxytryptophan, vasopressin, blood vessel activity Amphetamine and peptide hormones produce endocrine neoplasia syndrome; midgut carcinoid secretion of 5-HT, showing typical carcinoid syndrome, post-intestinal carcinoid multi-function is clinically more quiescent, pancreatic carcinoid is midgut A variant of cancer can produce a typical carcinoid syndrome, but in the diagnosis, it is often a multi-centered disease, and metastasis has occurred, and radical resection is rarely performed.

5-HT metabolites:

Patients with carcinoid syndrome have fibrous tissue hyperplasia in the endocardium, pleura, peritoneum, and posterior wall of the abdomen, which may be caused by excessive metabolites such as 5-HT.

Pathogenesis

The clinical manifestations of carcinoids are closely related to its location and origin, and also depend on the peptides and amine mediators it produces. Carcinoids produce a variety of chemical mediators such as 5-HT, bradykinin, adrenaline, prostate. A class of gastrointestinal peptides and neuropeptides, including active intestinal peptide, substance P, neurokinin A, B, K, gastrin, cholecystokinin, secretin, glucagon, glucagon , gastrin-releasing peptide, somatostatin, pancreatic polypeptide, casein neuropeptide, insulin, neurotensin, motilin, calcitonin, methotrexate, beta-endorphin, parathyroid hormone, ACTH As well as chorionic gonadotropin, many carcinoids can secrete two or more hormones, and the hormones contained and secreted in primary carcinoid and metastatic carcinoids can be different, which is in the immunohistochemical study of carcinoid It was confirmed.

Gastrointestinal peptide hormones and chemical mediators secreted by carcinoid tumors can produce corresponding pathophysiological and clinical manifestations. In a group of 353 carcinoid reports, 58% of patients have 2 or more hormones, and 9% of patients Clinically, there are 2 or more hormones, and 0.6% of patients may show different endocrine symptoms at different times; many carcinoids are typical endocrine tumor syndromes, such as Zhuo Ai syndrome, acromegaly. Disease, Cushing's syndrome and high parathyroidism, etc., tyrosin (PYY) secreted by carcinoids in ovarian teratoma may be the cause of severe constipation in patients, but in many cases, carcinoid The various peptide hormones produced do not produce corresponding clinical symptoms.

The pathophysiology of carcinoid syndrome has not been fully understood so far. A large number of studies have shown that 5-HT and its metabolic abnormalities are the most prominent biochemical manifestations of the syndrome, and blood lipids 5-HT in about 84% of patients with carcinoid syndrome Urine 5-HIAA increased, 5-HT may be associated with diarrhea of carcinoid syndrome, gastrointestinal motility changes can be observed by injecting 5-HT into volunteers or by inducing 5-HT in vitro, such as enhancement of intestinal motility And by accelerating, gastric and colonic motility inhibition; administration of 5-HT blockers can reduce diarrhea, which is considered to be one of the mediators of skin flushing, in the flushing of spontaneous or drug-induced carcinoid syndrome patients The level of bradykinin in hepatic venous blood is elevated. Intravenous bradykinin can cause typical skin flushing in these patients. Other possible mediators are tachykinins, including substance P, neuropeptide K (NPK). , neurokinin A (NPA), etc., used to think that carcinogenic valvular heart disease is caused by 5-HT, but recently found that valvular heart disease after the decline of 5-HIAA in urine is still developing, there is evidence that by tumor cells The resulting multiple transforming growth factors (TGF) may be in the heart Forming a film fibrosis play a role, in short, it is the result of the occurrence of carcinoid syndrome synergy various media and peptide hormones.

Carcinoid syndrome prevention

1, regular inspection, timely discovery, surgery.

2. Follow up after treatment.

3, because the cause of this disease has not been fully elucidated, mainly pay attention to some of the dietary and environmental risk factors that cause cancer.

Carcinoid syndrome complications Complications asthma abdominal pain bloating diarrhea shock edema

1. The lungs are characterized by asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma.

2. Gastrointestinal abdominal pain, abdominal distension and urgency are more common, diarrhea is urinary, up to 10 to 20 times a day, may be accompanied by abdominal pain or cramps before diarrhea.

3. The heart may have a rapid heartbeat, lower blood pressure or shock, and may have congestive right heart failure in the late stage, showing side breathing and lower extremity edema.

Carcinoid syndrome symptoms Common symptoms Abdominal diarrhea, hypotension, gastrointestinal symptoms, abdominal pain, ascites, weight loss, abdominal mass, vertigo, carcinoid red

1. Intermittent flushing of the skin mainly occurs in exposed parts such as the face, neck and front chest, but also throughout the body. It is intermittent and can occur suddenly, in bright red or purple, and the duration can be from several minutes to 1-2 days. If the skin flushes for several years, there will be fixed skin changes in the often-exposed areas, with many vasodilatation and slight purplish redness, cheeks, nose, upper lip and lower jaw, often accompanied by other symptoms: Tachycardia, low blood pressure and gastrointestinal, lung symptoms, predisposing factors such as drinking and certain foods, pain, mood swings and physical activity, etc., adrenaline, norepinephrine and catecholamines can cause seizures.

2. Pulmonary symptoms mainly manifest as asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma, asthma can occur simultaneously with skin flushing, anesthesia or adrenaline can induce asthma or exacerbate asthma, The cause of asthma is caused by smooth muscle spasm caused by substances such as 5-HT.

3. Gastrointestinal symptoms abdominal pain, abdominal distension and urgency are more common, varying degrees, diarrhea is urinary, up to 10 to 20 times a day, may be accompanied by abdominal pain or cramps before diarrhea, diarrhea and skin flushing do not necessarily occur at the same time, It is caused by 5-HT, using 5-HT antagonist drugs such as methyl ergometrine, methyl ergometrine (Methysergide and Parachlorphenylain can prevent diarrhea, nausea and vomiting and malabsorption, when carcinoid has huge liver metastasis There may be persistent or paroxysmal right upper abdominal pain, radiation to the right shoulder and back and fever, which is related to the large tumor volume, liver capsule involvement and relative ischemia, necrosis or hemorrhage.

4. Cardiac symptoms In the presence of flushing of the skin, patients may have rapid heartbeat, decreased blood pressure or shock, and may have congestive right heart failure in the late stage, manifested in sitting breathing, lower extremity edema, auscultation with pulmonary stenosis murmur and tricuspid stenosis. And turn off the murmur.

5. Carcinoid crisis The carcinoid crisis is a serious complication of carcinoid syndrome, which usually occurs in the foregut carcinoid. The urine 5-HIAA can suddenly increase. The clinical manifestations are severe and widespread skin flushing, and the diarrhea is obviously aggravated. With abdominal pain, there may be central nervous system symptoms such as dizziness, lethargy, coma, and cardiovascular abnormalities such as tachycardia, heart rhythm disorder, hypertension and severe hypotension.

6. Other manifestations due to the catabolism of the tumor, and severe diarrhea, loss of weight and even cachexia, hypoproteinemia, may have some hyperactive hormones, such as insulin, growth hormone, parathyroid hormone, gonadotropin, promote Corticosteroids, etc., the corresponding symptoms, patients with carcinoid syndrome increased urinary 5-hydroxyindole acetic acid (5-HIAA), more than 50mg/24h urine (normally 2 ~ 9mg / 24h urine).

Examination of carcinoid syndrome

1. Determination of 5-HIAA in urine: The value of this type of examination is increased in patients with carcinoid syndrome. Because 99% of 5-HT is converted into 5-HIAA in the body and discharged through the urine, it is determined that the increase of 5-HIAA in the urine for 24 hours is Diagnostic value, the majority of patients with blood concentration >120g / L, urine 5-HIAA more than 30mg / 24h urine, more than 50mg / 24h urine has a diagnostic value.

2. Determination of 5-HT or 5-HTP (5-hydroxytryptophan) in urine: If 5-HIAA excretion in urine is found to be low, paper chromatography should be further used to determine whether 5-HT or 5-HTP is increased. .

3. 5-HT assay in carcinoid tumor tissue: 5-HT is significantly elevated in tumor tissue, which is more sensitive than 5-HIAA assay in urine.

5. Pentagastrin gastrin challenge test: The pentapeptide gastrin challenge test is helpful for the diagnosis of carcinoid syndrome. It is taken at 1, 3, 5, 10, 15 min after intravenous injection of pentagastrin at 0.6 g/kg. Blood 5-HT was measured, and the increase of 5-HT in all cases was >40% or >50 g/L.

5. Rough screening test: Drop a drop of the patient's urine on the filter paper, and then spray azo P-dinitrobenzylamine. If it is red, it is positive, indicating that 5-HIAA in the urine is increased. Chromoblastoma, this test helps to identify the two.

6. Determination of 5-HT in whole blood, plasma or platelets, which is helpful for diagnosis, but the method is cumbersome and difficult to promote.

7. Chromogranin: Currently known neuroendocrine cell markers include neuron-specific enolase, chromogranin, synaptophysin, etc. These markers are mostly used for immunohistochemical identification of tumors and can be used for The main marker of circulating markers is chrome granule, a secreted protein widely distributed in the neuroendocrine granules of normal neuroendocrine cells or tumor cells. Three chromosomal proteins, namely chrome granules, have been identified. A, B, C, their amino acid structure is different, but there are many common biochemical characteristics, using immunohistochemistry or radioimmunoassay to show that the level of carcinoid chrome granules is up to 90% to 100%, there is a group of reports suggesting Of 44 cases of carcinoid, 17 cases of sporadic pancreatic endocrine tumors and 11 cases of pancreatic endocrine tumors with familial multiple endocrine tumors, plasma chromogranin A increased by 99%, chromogranin B and C levels increased At 88% and 6%, respectively, chromogranin A or B is a valuable indicator for the diagnosis of pancreatic endocrine tumors.

8. Induction test: In the non-onset period of flushing, the induced stimulation test can be used to make it. Common methods are as follows:

(1) The patient is allowed to drink 10 ml, and about 1/3 of the patients develop skin flushing after 3 to 5 minutes.

(2) After injection of epinephrine 5 ~ 10g or norepinephrine 15 ~ 20g 1 ~ 2min, patients with carcinoid syndrome may appear facial and neck skin flushing, at the same time there may be combined membrane bleeding, tearing, breathing faster, this method Blood pressure can be reduced and shock symptoms, so should be used with caution.

Localization diagnosis is an indispensable part of the diagnosis of pancreatic endocrine tumors, because only if the tumor is determined to be single or multiple, located in the pancreas or outside the pancreas, and whether there is liver or lymph node metastasis, the correct treatment plan can be formulated.

1. Conventional non-invasive imaging examination: There are many methods for image examination at present, and the equipment is also very advanced. However, in general, the diagnosis of pancreatic endocrine tumors, especially the detection of small tumors, is still not satisfactory, CT, ultrasound. And MRI can detect 10% of tumors <1cm in diameter, 30% to 40% of tumors with a diameter of 1 to 3cm and 50% of tumors with a diameter of 3cm. Angiography can detect 20% to 30% of diameter <1cm For tumors, the detection rate of ultrasound for liver metastases is 20%, CT is 35% to 74%, the detection rate of angiography is 33% to 86%, and the detection rate of MRI is 4l% to 83%. This suggests that current imaging diagnostic methods can miss a significant proportion of smaller primary pancreatic endocrine tumors.

2. Interventional localization of pancreatic endocrine tumors: Because the current imaging diagnostic methods are not satisfactory for the localization of pancreatic endocrine tumors, under the conditions of equipment and technical level, interventional diagnostic methods should be used as much as possible. A variety of new diagnostic methods, interventional positioning tests include interventional blood sample collection and interventional stimulation tests, which are both biochemical and localized.

(1) Percutaneous transhepatic portal vein catheterization (PEPVC): The percutaneous transhepatic portal vein is inserted into the splenic vein from the portal vein to the spleen, and the blood is taken for segmentation under fluoroscopy. The assay was positive when the hormone concentration gradient was >50%.

The formula for calculating the hormone concentration gradient is

Gradient%=[(selective vascular hormone concentration-peripheral vascular hormone concentration) ÷ peripheral blood hormone concentration]×100%

(2) Selective arterial injection of secretin/calcium (SAIS/SAIC): In recent years, injection of drugs such as secretin or calcium by selective arterial intubation stimulates tumor hormone secretion. The blood is collected through the drainage vein of the tumor and the concentration is measured. The advantage of this method is that it can be performed simultaneously with angiography, and the calculation method of the SAIS/SAIC positive standard is not required to be the same as the PTPC.

Principles of interventional localization diagnosis for pancreatic endocrine tumors: 1 First, routine imaging diagnosis should be performed. If the tumor has metastasis, PTPC or SAIS/SAIC are unnecessary; 3 pairs of VIP tumors, somatostatin, glucagon Tumor, ACTH tumor, etc. may consider PTPC preferred; 3 insulinoma may be the first choice for SAIC; 4 gastrinoma may be preferred SAIS.

3. Hormone receptor radionuclide imaging of pancreatic endocrine tumors

(1) Somatostatin (SS) receptor radionuclide imaging: It has been demonstrated that many tumors in humans contain SS receptors, such as pancreatic endocrine tumors, pituitary tumors, and the like, using classical receptor binding assays and in vitro autoradiography techniques. Cancer, small cell lung cancer, medullary thyroid carcinoma, ganglionoma, pheochromocytoma, neuroblastoma, astrocytoma, etc., recently applied 123I-octreotide, 111In-somatostatin pentapeptide, 125I-Tyr3 - Octreotide and (111In-DTPA-D-Phe1)-octreotide for localization of pancreatic endocrine tumors. The advantage of the latter is that it is excreted by the kidneys rather than by bile, and does not affect the examination of the liver and its abdominal lesions. ~100% of gastrinoma and 80% to 90% of pancreatic endocrine tumors other than insulinoma, in addition, octreotide radionuclide scan can also detect 92% of intrahepatic metastases, for the identification of small intrahepatic metastases Focal and intrahepatic vascular lesions are particularly helpful.

(2) VIP receptor radionuclide imaging: In vitro experiments show that almost all VIP receptors are expressed in well-differentiated gastrointestinal pancreatic endocrine tumors, and about half of the undifferentiated tumors have VIP receptors. Expression, according to this observation, VIP receptor imaging has been applied to the clinic, preliminary results show that in the same group of carcinoid and insulinoma patients, the positive rate of VIP receptor radionuclide imaging is 92.9% (13/14 For example, the positive rate of imaging with octreotide nuclide is very close to 90.9%.

4. Endoscopic diagnosis and localization of pancreatic endocrine tumors Endoscopic ultrasonography (EUS) diagnosis of pancreatic tumors is a new development in the diagnosis of pancreatic diseases in recent years. Under the operation of experienced endoscopists, EUS is the detection of primary tumors. One of the most effective means, through the duodenal cavity and the corpus of the stomach, allows for a more satisfactory observation of the head of the pancreas and the tail of the pancreas than for CT and surface ultrasound (US), therefore, EUS For pancreatic endocrine tumors, there is a great diagnostic value. According to the comprehensive literature, 61 cases of EUS were found in 75 cases of pancreatic endocrine tumors, and the sensitivity was 81.3%; 39 cases were simultaneously EUS, CT and US, positive rate 84.6%, 17.9%, and 10.3%, respectively. In the pancreatic endocrine tumors that were negative by CT and detected by EUS, the tumor diameter was mostly <15 mm (5-21 mm), indicating that EUS has its uniqueness in the diagnosis of pancreatic endocrine tumors. At the office.

Diagnosis and diagnosis of carcinoid syndrome

Diagnostic criteria

Early asymptomatic or non-specific symptoms, the diagnosis depends on the vigilance of the clinician, the following conditions should consider the possibility of carcinoid:

1. Intermittent skin flushing and unexplained diarrhea history for many years.

2. Have abdominal pain, diarrhea and weight loss.

3. There are cough, asthma and dyspnea accompanied by pulmonary valve, tricuspid murmur.

4. Late stage, liver metastases, liver and liver pain and heart failure such as ascites, lower extremity edema, jugular vein engorgement, pulsation, etc., or abdominal masses and lung masses, etc., are highly suggestive of pancreatic carcinoids. Further laboratory and other auxiliary inspections.

Differential diagnosis

Bronchial asthma

(1) recurrent wheezing, difficulty breathing, chest tightness or cough, mostly related to contact with allergens, cold air, physicochemical stimulation, viral upper respiratory tract infection, exercise, etc. When asking about medical history, you should pay attention to whether the symptoms occur. In: special seasons and climatic conditions; when visiting a particular location, such as at home, school or work location; doing certain things, such as making beds, caring for small animals or cooking.

(2) When the attack occurs, the lungs can be smelled and scattered or diffuse, and the wheezing sound mainly in the expiratory phase, and the expiratory phase is prolonged.

(3) The above symptoms can be relieved by treatment or relieved by themselves.

2. Functional dyspepsia Functional dyspepsia has pain or pain in the upper abdomen. A few patients have burning pain, fullness or early satiety, hernia, nausea and vomiting, acid reflux, heartburn, anorexia, etc. Some patients with FD have Lower gastrointestinal symptoms, manifested as diarrhea, constipation or diarrhea alternate with stool, the stool is not exhaustive, some patients have mental symptoms, such as depression, anxiety, doubt, fear and so on.

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