Carcinoid Syndrome

　　How is carcinoid syndrome caused? Briefly described as follows:

　　1. Etiology

　　Oberndorfer first proposed in 1907 that carcinoid is a slow-growing intestinal adenocarcinoma and proposed the name 'carcinoid'. Masson proved in 1928 that carcinoid originates from argentaffin cells in the intestinal mucosa, named after the cells show argentaffin staining. Lembeck first discovered 5-HT in carcinoid tissue in 1953 and confirmed it as the biologically active substance that causes carcinoid syndrome. In 1954, Thorson and Lsler reported independently on cases of carcinoid syndrome. Carcinoid is not rare in clinical practice, but only a few cases develop carcinoid syndrome. Carcinoids of different embryonic origins have different biochemical, pathological, and clinical characteristics. Williams divided carcinoids into three types: foregut, midgut, and hindgut. In short, carcinoids from the foregut (gastroduodenal, bronchial) are nonargentaffin, due to the lack of aromatic amino acid decarboxylase, 5-HT production is less, while 5-HTP content is higher, and they can also produce histamine and various peptides; carcinoids from the midgut (small intestine, ileocecal junction, ascending colon, pancreas, part of transverse colon) are argentaffin and argyrophilic, and can produce more 5-HT. Foregut carcinoids secrete 5-HT and 5-hydroxytryptophan, pancreas vasodilator, vasoactive amines, and polypeptide hormones, producing endocrine tumor syndrome; midgut carcinoids secrete 5-HT and show typical carcinoid syndrome. Hindgut carcinoids are mostly without function and are often in a static state in clinical practice. Pancreatic carcinoids are a variant of midgut carcinoids and can produce typical carcinoid syndrome, but they are often already multicentric and have metastasized at the time of diagnosis, and it is rarely possible to perform radical resection.

　　Carcinoid syndrome patients have fibrous tissue hyperplasia in various parts such as the endocardium, pleura, peritoneum, and posterior abdominal wall, which may be caused by excessive metabolites such as 5-HT.

　　2. Pathogenesis

　　The clinical manifestations of carcinoid and their location and origin are closely related, and also depend on the peptide and amine mediators they produce. Carcinoids can produce a variety of chemical mediators, such as 5-HT, bradykinin, adrenaline, prostaglandins, and various gastrointestinal peptides and neuropeptides, including active intestinal peptide, substance P, neurokinin A, B, K, gastrin, cholecystokinin, secretin, glucagon, intestinal glucagon, gastrin-releasing peptide, somatostatin, pancreatic polypeptide, tyrosine neuropeptide, insulin, vasoactive intestinal peptide, motilin, calcitonin, methionine enkephalin, endorphin, parathyroid hormone, ACTH, and chorionic gonadotropin, etc. Many carcinoids can secrete two or more hormones, and the hormones contained and secreted in primary and metastatic carcinoids can be different, which has been confirmed in the immunohistochemical study of carcinoids.

　　What diseases can carcinoid syndrome trigger? Briefly described as follows:

　　1. Pulmonary symptoms are asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma.

　　2. Gastrointestinal symptoms include abdominal pain, abdominal distension, and tenesmus, with diarrhea similar to urine, occurring up to 10-20 times a day. Abdominal pain or colic may occur before diarrhea.

　　3. The heart may show a rapid heartbeat, low blood pressure, or shock. In the late stage, there may be congestive right heart failure, with symptoms such as sitting respiration and lower limb edema.

　　What are the symptoms of carcinoid syndrome? Briefly described as follows:

　　1. Intermittent flushing of the skin.It mainly occurs on exposed parts such as the face, neck, and anterior chest, and can also spread throughout the body. It is intermittent and can occur suddenly, presenting as bright red or purple, lasting from several minutes to 1-2 days. If skin flushing occurs for several years, fixed skin changes may appear at the site of frequent attacks, presenting as multiple dilated capillaries and slight purplish redness, on the cheeks, nose, upper lip, and lower jaw. Attacks are often accompanied by other symptoms: such as tachycardia, low blood pressure, and gastrointestinal and pulmonary symptoms. Triggers include alcohol consumption and certain foods, pain, emotional fluctuations, and physical activity. Adrenaline, norepinephrine, and catecholamines can induce attacks.

　　2. Pulmonary symptoms.The main manifestations are asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma. Asthma may occur simultaneously with skin flushing. Anesthesia or adrenaline can induce asthma or exacerbate it. The cause of asthma is due to smooth muscle spasm caused by substances such as 5-HT.

　　3. Gastrointestinal symptoms.Abdominal pain, abdominal distension, and tenesmus are common, with varying degrees. Diarrhea is similar to urine, occurring up to 10-20 times a day. Abdominal pain or colic may occur before diarrhea, and skin flushing is not necessarily simultaneous with diarrhea, caused by 5-HT. 5-HT antagonists, such as methysergide, can be used. Methysergide (Methysergide and Parachlorophenylamine) can stop diarrhea, but may also cause nausea, vomiting, and malabsorption. When there is a large liver metastasis in carcinoid tumors, there may be persistent or intermittent upper right abdominal pain, radiating to the right shoulder and back, as well as fever. This is related to the large tumor volume, involvement of the liver capsule, relative ischemia, necrosis, or hemorrhage.

　　4. Cardiac symptoms.At the same time as the appearance of skin flushing, the patient may experience a rapid heartbeat, decreased blood pressure, or shock; in the late stage, there may be congestive right heart failure, manifested as orthopnea, lower limb edema, and auscultation of pulmonary valve stenosis murmur and tricuspid valve stenosis and insufficiency murmur.

　　5. Carcinoid crisis.Carcinoid crisis is a serious complication of carcinoid syndrome, usually occurring in foregut carcinoids. The urine 5-HIAA can suddenly increase, and the clinical manifestations include severe and widespread skin flushing, marked worsening of diarrhea with abdominal pain, and symptoms of central nervous system dysfunction such as dizziness, somnolence, and coma, as well as cardiovascular abnormalities such as tachycardia, arrhythmia, hypertension, and severe hypotension.

　　6. Other manifestations.Due to the catabolic effects of tumors and severe diarrhea, there may be weight loss, even cachexia, and hypoproteinemia. There may be some hyperfunction of hormones such as insulin, growth hormone, parathyroid hormone, gonadotropin, and adrenocorticotropic hormone, with corresponding symptoms. The level of 5-hydroxyindoleacetic acid (5-HIAA) in the urine of patients with carcinoid syndrome is increased, exceeding 50mg/24h urine (normal range is 2-9mg/24h urine).

　　How to prevent carcinoid syndrome? Briefly described as follows:

　　1. Strengthen physical exercise, enhance physical fitness, and exercise more in the sun. Sweating can help excrete acidic substances from the body through sweat, avoiding the formation of an acidic constitution.

　　2. Develop good living habits, quit smoking, and limit alcohol intake. The World Health Organization predicts that if people stop smoking, the world's cancer rate will decrease by one-third in 5 years. Cigarettes and alcohol are highly acidic substances, and long-term smokers and drinkers are prone to develop an acidic constitution.

　　3. Do not eat too much salty and spicy food, and do not eat overheated, cold, expired, or deteriorated food. The elderly, the weak, or those with certain genetic diseases can eat some cancer-preventive foods and alkaline foods with high alkaline content to prevent brain tumors and maintain a good mental state.

　　6. Maintain a good attitude towards stress, combine work and rest, and do not overwork. Traditional Chinese medicine believes that stress leads to overwork and physical weakness, thereby causing a decrease in immune function, endocrine disorders, and internal metabolic disorders, leading to the deposition of acidic substances in the body. Stress can also lead to mental tension, causing blood stasis, internal heat, and other symptoms.

　　What examinations should be done for carcinoid syndrome? Briefly described as follows:

　　1. Determination of 5-HIAA in urine.The level of this test in patients with carcinoid syndrome is increased, as 99% of 5-HT is converted into 5-HIAA in the body and excreted through urine. Therefore, the determination of increased 5-HIAA in 24-hour urine has diagnostic value. Most of these patients have blood concentrations greater than 120μg/L, and the level of 5-HIAA in urine exceeding 30mg/24h urine or 50mg/24h urine has diagnostic value.

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

　　3, Determination of 5-HT in carcinoid tumor tissue.5-HT in tumor tissue is significantly elevated, which is more sensitive than the determination of 5-HIAA in urine.

　　4, Pentagastrin stimulation test.The pentagastrin stimulation test is helpful for the diagnosis of carcinoid syndrome. After intravenous injection of 0.6μg/kg of pentagastrin, blood is taken at 1, 3, 5, 10, and 15 minutes to measure 5-HT. The increase in blood 5-HT in all cases is greater than 40% or greater than 50μg/L.

　　5, Rough screening test.Drop a drop of the patient's urine on filter paper, then sprinkle azo P-dinitrobenzamide. If red, it is positive, indicating an increase in 5-HIAA in the urine; if purple, it indicates pheochromocytoma. This test helps to differentiate between the two.

　　6, Measure the whole blood.5-HT in plasma or platelets is helpful for diagnosis, but the method is complicated and difficult to popularize.

　　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 chromogranin is mainly used as a circulating marker. Chromogranin is a secretory protein widely distributed in the neuroendocrine granules of normal neuroendocrine cells or tumor cells. Three types of chromogranin proteins have been identified, namely chromogranin A, B, and C, which have different amino acid structures but many common biochemical characteristics. Immunohistochemistry or radioimmunoassay shows that the level of carcinoid chromogranin can reach 90% to 100%.

　　8, Provocation test.During the non-attack phase of redness, provocation tests can be used to induce an attack, common methods include:

　　(1) Ask the patient to drink 10ml of alcohol, about 1/3 of the patients will appear skin redness 3 to 5 minutes later.

　　(2) One to two minutes after injecting 5-10μg of adrenaline or 15-20μg of norepinephrine, patients with carcinoid syndrome may experience facial and neck skin redness, along with conjunctival hemorrhage, tears, and increased respiratory rate. This method may cause hypotension and shock symptoms, so it should be used with caution.

　　The dietary therapy methods for carcinoid syndrome are briefly described as follows:

　　1, 60g of cuttlefish meat, 10 whitebark seeds, with appropriate seasonings. Wash and place in a pot, add an appropriate amount of water, and cook until the meat is tender. Add seasonings and serve with the soup. Take it once a day, and drink the soup together.

　　2, 50g of Catharanthus roseus, 200g of pork, with appropriate amounts of oil, salt, soy sauce, scallion, pepper, and monosodium glutamate. Boil the Catharanthus roseus in a cloth bag and extract the juice, then stir-fry the pork and add the juice of Catharanthus roseus for stewing until the pork is cooked. Add salt and monosodium glutamate when the meat is done, and take it once a day.

　　3. Shanglu porridge formula: 10g of Shanglu (Ophiopogon japonicus), 100g of粳米 (short-grain rice), 5 dates, appropriate amount of clear water. Preparation: First, decoct Shanglu in water to make a decoction, strain, then add short-grain rice and dates to cook porridge. Eat on an empty stomach, with a slight diuresis as a measure, do not overdo it. Benefits: Promote the function of the bowels and urination, promote diuresis and reduce swelling. Suitable for ascites caused by urinary difficulty in ovarian cancer.

　　4. Chenxiang niurou (Cinnamon Beef): 30g of Chenpi (dried tangerine peel), 15g of Xiangfuzi (cyperus rotundus), 500g of beef, appropriate amounts of scallion, ginger, and salt. Preparation: Boil Chenpi and Xiangfuzi in 2000 grams of water for half an hour, strain, then add beef and seasonings such as scallion, ginger, and salt, stew over low heat until tender, cool, slice, and eat. Benefits: Relieve liver qi, invigorate the spleen and nourish the Qi.

　　The treatment methods of carcinoid syndrome are briefly described as follows:

　　First, treatment

　　1. Surgical treatment

　　Take pancreatic carcinoids as an example to illustrate.

　　(1) The basic goal of surgical treatment for pancreatic carcinoids: Surgery is the only cure for this type of tumor, and early diagnosis and early surgical resection of the tumor are the best treatment method. Even if metastasis occurs, the resection of the functional primary carcinoid can alleviate and eliminate symptoms. However, pancreatic carcinoids are often multi-centric and metastatic at the time of diagnosis, and cannot be treated with radical surgery. Palliative lobectomy or resection of metastatic tumors can be performed. The basic goals of surgical treatment are two: one is to cure the tumor or control the development of malignant tumors; the other is to eliminate or alleviate the endocrine symptoms caused by the tumor.

　　(2) The principles of extensive radical resection for surgical treatment of pancreatic endocrine tumors: Extensive radical resection refers to the complete or at least 90% above complete resection of the primary and metastatic tumors, including the removal of intrapulmonary metastases, including partial hepatectomy or lobectomy, and the resection of metastatic lymph nodes. The main reasons for adopting the extensive radical surgery policy are:

　　① Such tumors have a relatively good prognosis, and the long-term survival rate after surgical resection is high.

　　② Extensive radical surgery can more effectively alleviate the endocrine symptoms caused by tumors and improve the quality of life.

　　③ Extensive radical resection is very beneficial to improve the effectiveness of future treatment.

　　The National Institutes of Health reported 42 consecutive cases of metastatic pancreatic endocrine tumors, of which 17 were considered resectable, and a total of 20 operations were performed (including partial hepatectomy), resulting in a 5-year survival rate of 79% in the extensive radical surgery group, with a 5-year survival rate of up to 100% in patients with limited metastatic lesions who underwent complete resection, while the 5-year survival rate of patients who did not undergo extensive radical surgery was only 28%.

　　2. Non-surgical treatment

　　The purpose is symptomatic treatment, to reduce the production of 5-HT and kinin-releasing enzymes or to counteract their effects; antitumor treatment, to control the development of tumors; supportive therapy, to improve the general condition of patients.

　　(1) Many drugs can increase the release of 5-HT, and should be avoided or used sparingly. For example, morphine, halothane, dextran, polymyxin, tyramine, and guanithidine, etc.

　　(2) 5-HT Agonists: Chlorophenylalanine, 1g each time, 3 to 4 times a day, can effectively alleviate or reduce nausea, vomiting, and diarrhea, and can also reduce the severity of facial and neck skin flushing attacks, but cannot reduce the frequency of attacks;

　　(3) 5-HT antagonists: Methylsergol butyrate, during an acute attack, 1-4mg is given intravenously once; or 10-20mg is added to 100-200ml of normal saline and infused intravenously within 1-2 hours, which can control flushing, asthma, and diarrhea. Sedgentan 4-8mg, once every 6 hours, and nozinam 2.5g intravenous injection can alleviate symptoms and have a role in controlling diarrhea and urgency.

　　(4) Other drugs: Corticosteroids such as prednisone 15-40mg/d can achieve varying degrees of efficacy. Codeine and Compound Camphor Lotion can also be used to control diarrhea.

　　(5) Chemotherapy and radiotherapy: Patients with metastasis that cannot be surgically cleared should be given chemotherapy. Commonly used chemotherapy drugs include 5-FU, cyclophosphamide, levamisole, doxorubicin, streptozocin, VP-16, thiotepa, etc., which can alleviate symptoms, but the efficacy is poor, with an average effective rate of 30% to 50%. Combined chemotherapy is better than single drug use, and commonly used combined chemotherapy regimens include STZ + ADM or 5-FU, VP-16 + cisplatin, etc. Radiotherapy can alleviate pain caused by bone metastasis.

　　(6) Hepatic artery embolization of liver metastasis: The application of hepatic artery embolization and (or) chemotherapy for the liver metastasis of neuroendocrine tumors can alleviate symptoms in 80% to 90% of patients. If hepatic artery embolization and chemotherapy are used sequentially, more than half of the patients can have complete symptom relief, and some patients may have varying degrees of symptom relief.

　　II. Prognosis

　　Pancreatic neuroendocrine tumors are a type of rare and characteristic symptom tumors. Early detection depends on the doctor's understanding and vigilance of the disease, and diagnosis relies on the detection of specific plasma hormones under basic or induced tests. The application of various imaging diagnostic and interventional diagnostic methods for tumor localization plays an important role in the diagnosis of this disease. Pancreatic neuroendocrine tumors all have the potential for malignancy, but the degree of malignancy is generally low, and the prognosis is good. Therefore, the treatment of this disease should adopt a relatively active attitude, including extensive radical surgery, active systemic or interventional chemotherapy, and symptomatic supportive therapy, which can achieve relatively satisfactory efficacy.