Carcinoid

　　类癌病因尚未阐明。类癌瘤是一种能产生小分子多肽类或肽类激素的肿瘤，即APUD细胞瘤，它能通过靶细胞增加环腺甙单磷酸盐起作用，能分泌具有强烈生理活性的血清素（5-羟色胺），胰舒血管素和组织胺外，有的还可分泌其它肽类的激素，如促肾上腺皮质激素、儿茶酚胺、生长激素、甲状旁腺激素、降钙素、抗利尿素、促性腺激素、胰岛素、胰升血糖素、前列腺素、胃泌素、胃动素等物质。产生类癌综合征的主要物质是血清素和缓激肽，组织胺也参与一部分作用。
　　血清素对周围血管和肺血管均有直接收缩作用，对支气管也有强烈收缩作用，对胃肠道节前迷走神经和神经节细胞有刺激作用，使胃肠道蠕动增强，分泌增多。
　　缓激肽有强烈的扩血管作用，有些类癌瘤尤其是胃类癌可产生大量的缓激肽、组胺等血管活性物质而引起皮肤潮红。循环中血清素增高还可引起心内膜纤维化。
　　正常情况下，食物中摄入的色氨酸仅2％左右被用作5-羟色胺（5-HT）的合成，98％进入烟酸及蛋白合成的代谢途径。但在类癌综合征的病人，60％的色氨酸可被瘤细胞摄取，造成5-HT合成增加，烟酸合成减少。60％摄入瘤细胞的色氨酸经色氨酸羟化酶催化成5-羟色氨酸（5-HTP），再经多巴脱羧酶变成5-HT，部分储存于瘤细胞的分泌颗粒内，其余部分直接进入血液内。在血液中游离的5-HT大部分经肝、肺、脑中的单胺氧化酶（MAO）降解成5-羟吲哚乙酸（5-HIAA）自尿内排出。起源于中肠系统的类癌病人血清中5-HT水平升高，而尿内5-HIAA排出增加，此属典型的类癌综合征。此类约占类癌综合征病例的75％以上。前肠系统类癌往往缺乏多巴脱羧酶，不能使5-HTP转变成5-HT，5-HTP就直接被释放进入血液内，因此病人血清内5-HTP水平升高，而5-HT不升高。病人尿中5-HTP及5-HT排出增加，而5-HIAA增加不明显，此即不典型类癌综合征。

　　Carcinoid tumors can complicate various systemic complications, with specific manifestations varying with the site of the lesion. Appendiceal carcinoid tumors can cause luminal obstruction, often leading to appendicitis, manifested as right lower quadrant pain; intestinal obstruction symptoms Small intestinal carcinoid tumors and their metastatic masses can cause intestinal obstruction; gastrointestinal bleeding Gastric or duodenal carcinoid tumors may cause upper gastrointestinal bleeding; intestinal carcinoid tumors may also cause hematochezia or occult bleeding, and can cause anemia.

　　The symptoms of carcinoid tumors themselves are not obvious or only local symptoms, while carcinoid syndrome often has obvious systemic symptoms. Rectal carcinoid tumors are often found incidentally during screening.

　　1. Local symptoms of carcinoid tumors

　　1. Right lower quadrant pain Appendiceal carcinoid tumors can cause luminal obstruction, therefore, they often lead to appendicitis, manifested as right lower quadrant pain.

　　2. Intestinal obstruction symptoms Small intestinal carcinoid tumors and their metastatic masses can cause intestinal obstruction, with symptoms such as abdominal pain, distension, bowel sounds, nausea, and vomiting.

　　3. Abdominal mass A small number of carcinoid tumors may cause abdominal masses, and malignant carcinoid tumors that invade surrounding tissues or metastasize often present with abdominal masses.

　　4. Gastrointestinal bleeding Gastric or duodenal carcinoid tumors may cause upper gastrointestinal bleeding; intestinal carcinoid tumors may also cause hematochezia or occult bleeding, and can cause anemia.

　　5. Respiratory symptoms The most common manifestation of bronchial carcinoid is respiratory symptoms, such as cough, sputum, hemoptysis, chest pain, etc.

　　2. General symptoms of carcinoid syndrome

　　Mostly caused by liver metastasis of malignant small intestinal carcinoid tumors, or by carcinoid tumors in the bronchus, stomach, pancreas, thyroid, ovary, and other sites.

　　1. Flushing of the skin

　　63% to 94% of patients may have this symptom, which often occurs in the upper body, mainly in the face and neck, with the skin showing episodic changes to bright red. Gastric carcinoid tumors, due to the possible secretion of histamine, may cause skin rash-like red macules, and during the attack, it may be accompanied by fever, tears, palpitations, hypotension, swelling of the face and orbital area, with varying degrees and durations of attacks, most lasting about 1 to 5 minutes, and in cases with long-standing disease, it may last for several hours. Initially, attacks may occur every few days or weeks, and later may increase to several times a day, and symptoms may be triggered by emotional excitement, physical activity, alcohol consumption, eating foods high in tyramine, and injection of calcium, catecholamine drugs, etc. After many years of attacks, the skin capillaries and small veins may show chronic localized dilation, causing fixed skin cyanosis changes, which are often manifested on the face and perioral area, similar to patients with long-standing mitral stenosis.

　　2. Gastrointestinal symptoms

　　Mainly manifested as hyperperistalsis of the intestines, which can cause paroxysmal abdominal colic, bowel sounds, and diarrhea ranging from soft stools to watery stools, with a sense of urgency. Gastrointestinal symptoms are seen in 68% to 84% of patients, most of whom also have paroxysmal skin flushing, only 15% of patients without flushing symptoms, and a few patients may develop malabsorption syndrome, leading to significant nutritional status decline.

　　3. Respiratory symptoms

　　Small bronchospasm can occur, causing paroxysmal asthma, seen in 8% to 25% of patients. This symptom can sometimes appear earlier than other symptoms, leading to misdiagnosis as allergic diseases. Like skin flushing, it can also be triggered by emotional excitement, physical activity, and other factors.

　　4. Cardiovascular symptoms

　　Seen in 11% to 53% of cases, subendocardial fibrosis can occur after long-term illness, affecting the valve area, with the right heart being more obvious and the left heart being less severe. If it occurs in the left ventricle, mitral valve disease is the main manifestation, similar to rheumatic heart disease. Cardiac lesions are often the main cause of death in carcinoid patients.

　　5. Other manifestations

　　More than 90% of patients have liver metastases, often with signs of liver enlargement. In some cases, later stages can show brownish pigmentation and hyperkeratosis of the skin, presenting with a rough skin-like change. Myopathy can also occur, manifested as atrophy of type I and type II muscle fibers. Joint disease is characterized by joint stiffness and pain during movement, with erosion of interphalangeal joints visible on X-rays, multiple cystic lucency areas within the phalanges, and osteoporosis in the area near the interphalangeal and metacarpophalangeal joints.

　　The etiology of carcinoid tumors has not been elucidated, and there are currently no effective preventive measures. However, in daily life, a reasonable diet, a nutritious diet, appropriate exercise, maintaining a healthy weight, developing good habits, paying attention to cleanliness, and other measures are conducive to the prevention of the disease.

　　Carcinoid tumors lack specific signs and symptoms, making diagnosis quite difficult. Clinically, they are often overlooked or misdiagnosed as appendicitis, Crohn's disease, colorectal cancer, and other diseases. When carcinoid tumors present with carcinoid syndrome, diagnosis becomes easier. Typical symptoms include skin flushing, diarrhea, abdominal pain, asthma, right heart valve disease, and liver enlargement. An increase in serum 5-HT levels and an increase in 5-HIAA excretion in urine are significant for diagnosis. Histological examination of the tumor can obtain a definitive diagnosis. Routine laboratory tests include:

　　1. 5-HT measurement The serum 5-HT content in patients with carcinoid syndrome is often significantly elevated, usually between 83-510μmol/24h (normal range 11-51μmol/24h).

　　2. 5-HIAA measurement The excretion of 5-HIAA in the urine of patients with carcinoid syndrome is increased, often exceeding 78.5μmol/24h, usually between 156.9 and 3138μmol/24h (normal value

　　3. Provocation test for flushing ① 10ml of ethanol is added to 15ml of orange juice and taken orally. After 3-5 minutes, about 1/3 of the patients experience skin flushing. ② 15-20μg of norepinephrine and 5-10μg of epinephrine are injected intravenously. These two provocative tests are helpful for diagnosis, but caution should be exercised in patients with a history of arrhythmia, heart failure, or asthma.

　　The diet of carcinoid patients should be rich in nutrition and calories, supplemented with protein, and sufficient vitamins should be provided; avoid foods that can induce flushing and diarrhea, such as dairy products, eggs, oranges, etc.

　　Surgical resection is the best treatment for carcinoids, but the treatment method for different patients with carcinoids needs to be determined according to the specific condition and extent of the lesion after systematic examination.
　　First, surgical treatment
　　Surgical resection of the primary lesion is the most effective treatment. Early surgery has the best effect, but even if metastasis occurs, resection of the large primary lesion can alleviate and eliminate symptoms. Metastasis of appendiceal carcinoid tumors is rare, and it is generally believed that simple appendectomy is sufficient. Consider extended radical surgery only when there is obvious macroscopic metastasis and the tumor diameter exceeds 2cm. The malignancy rate of small intestinal carcinoids is high, and radical surgery should be performed actively.
　　Small asymptomatic rectal carcinoids can be locally resected. Rectal carcinoids with a diameter over 1cm are more likely to metastasize to regional lymph nodes, while those with a diameter less than 1cm generally do not extend beyond the submucosa. It is considered that radical surgery is limited to those with a diameter over 2cm, invasion of the muscular layer, or recurrence after local resection.
　　For gastric and duodenal carcinoid tumors, if the diameter is less than 1cm, local resection can be performed. For those over 1cm in diameter, partial gastric resection and omentectomy should be performed. Carcinoid tumors in the second and third segments of the duodenum may require pancreaticoduodenectomy, but this operation has a high mortality rate and should be performed with caution.
　　The best palliative treatment for liver metastases is liver lobectomy or resection of the metastatic tumor. There are reports that after resection of large solitary intrahepatic metastases, symptoms are significantly relieved, urinary 5-HIAA levels decrease significantly, and patients can survive for many years. If surgical resection is not possible, hepatic artery catheter embolization or perfusion therapy can be performed.
　　There are many complications associated with carcinoid tumor surgery, including the risk of anesthesia accidents, the potential induction of carcinoid crisis during tumor exploration, and the compression of the tumor during surgery often causing severe hypotension. Therefore, preoperative preparation is required, including the use of large doses of serotonin antagonists and the availability of vasoactive drugs to correct hypotension promptly. Avoid the use of sympathomimetic drugs and use phenobarbital cautiously for induction.
　　There have been reports that cardiac valve lesions in patients with carcinoid syndrome can be significantly improved through repair surgery.
　　Secondly, medical treatment
　　Primarily aimed at the different vasoactive substances released by carcinoid tumors, as well as symptomatic treatment and supportive therapy.
　　1. Serotonin synthesis inhibitors　Parachlorophenylanine can inhibit the activity of tyrosine hydroxylase, blocking the synthesis of serotonin. The dose is 2 to 4 g per day, taken in four divided doses. It can completely relieve diarrhea and reduce the onset of skin erythema. This drug is rarely used now and has been replaced by 5-fluorotryptophan. Its effect is similar to that of the former, but with fewer side effects. The dose is 600 mg, taken in three divided doses. At 6 to 8 weeks, the excretion of 5-HIAA in the urine is significantly reduced. Methyldopa and 4-deoxy-pyridoxine hydrochloride can inhibit the dehydroxylation of serotonin, thereby blocking the synthesis of serotonin. It has a certain effect on alleviating abdominal pain and diarrhea, especially for symptoms caused by gastrointestinal carcinoid syndrome. The dose is 250 to 500 mg per time, 3 to 4 times a day. However, it is ineffective for most carcinoids that produce serotonin, and its side effects are prone to cause hypotension.
　　2. Serotonin antagonists　There are the following three types:
　　(1) Methysergide: Oral administration at a dose of 6 to 24 mg/day. During an acute attack, a single intravenous injection of 1 to 4 mg can be given, or 10 to 20 mg can be added to 100 to 200 ml of physiological saline for intravenous infusion over 1 to 2 hours. It can effectively control erythema, asthma attacks, and diarrhea. Its effect on controlling diarrhea is stronger than that of cyproheptadine. Side effects include hypotension, fainting, fatigue, and drug resistance. Long-term use can lead to post-peritoneal, valve, and other fibrotic lesions as well as fluid retention.
　　(2) Cyproheptadine (periactin): Oral administration at a dose of 6 to 30 mg/day. To alleviate acute symptoms, 50 to 75 mg can be added to 100 to 200 ml of physiological saline for intravenous infusion. The efficacy is similar to that of methysergide, but it is superior in controlling erythema. The side effects are similar to those of methysergide, but it will not cause fibrotic lesions.
　　(3) Noznam: It can decompose 5-HT, and is commonly administered intravenously at a dose of 2.5 g.
　　3. Kallikrein inhibitors　The following drugs can be selected:
　　(1) Tranexamic acid (Trasylol): It can inhibit kallikrein, with the fastest and strongest effect, which can quickly destroy bradykinin in the blood, thereby alleviating hypotension. It is commonly administered intravenously at a dose of 20,000 to 125,000 units, and up to 2.5 million units can be used within 24 hours.
　　(2) 6-Aminocaproic acid: It can counteract kallikrein. It is initially administered intravenously at a dose of 5 g, followed by 1 g/hr to maintain the effect.
　　(3) Iniprol (Cy66): It can also inhibit kallikrein. It can be administered intravenously at a dose of 1 million units, and the dose can be increased if necessary.
　　(4) Phenoxybenzamine: administered at a dose of 10 to 30 mg/day. It can inhibit the release of kallikrein.
　　4. Application of other drugs
　　(1) Antihistamines: They can help control flushing in a few cases with increased histamine levels.
　　(2) Corticosteroids: Prednisone 15 to 40mg/d can have a significant effect on the anterior enteric type of carcinoid with carcinoid syndrome, but has no effect on other carcinoids.
　　(3) Prochlorperazine: 10mg three to four times a day, occasionally helps control flushing. Phenothiazine has a certain therapeutic effect on alleviating the endocrine symptoms of the anterior enteric type of carcinoid.
　　(4) Methyldopa (aldome): 250 to 500mg, once every 6 to 8 hours, can help relieve diarrhea.
　　(5) Somatostatin analogues Sandostatin: Recent literature reports that Sandostatin can effectively control the symptoms of carcinoid syndrome and reduce the size of the tumor. 250μg per time, subcutaneous injection, 2 to 3 times a day, can quickly control skin flushing and diarrhea in the short term, and serotonin levels decrease rapidly, with good palliative efficacy.
　　5. Chemotherapy　Adriamycin (adriamycin) or 5-Fu have an efficacy rate of about 20%. The combined use of streptozotocin and 5-Fu can achieve an efficacy rate of 33%. The median effective maintenance period is 7 months. In recent years, there have been reports that the use of α-interferon can alleviate the symptoms of carcinoid syndrome. 3 to 6 million units per day, intramuscular injection, with an efficacy rate of 47%, and a median effective maintenance period of 34 months.

　　The prognosis of carcinoid depends on the location of the primary tumor, the extent and degree of metastasis, and the effectiveness of surgical treatment. It is generally believed that carcinoid tumors grow slowly, and even if the condition is late, they should be removed as much as possible, and the efficacy is still good. Carcinoid tumors in the appendix and rectum often have no metastasis, are easy to be removed and根治, and have the best prognosis. The 5-year survival rate after surgery is 99% and 83%. The prognosis of patients with carcinoid syndrome caused by carcinoid tumors in the stomach and ileum is also good, and they can survive for 5 to 25 years after radical treatment. The prognosis of carcinoid syndrome caused by carcinoid tumors in the bronchus and colon is poor, and the survival time is only 1 to 2 years, and most die due to heart, lung, and liver failure.