Overview
A series of clinical symptoms caused by a variety of substances secreted by carcinoid cellsTypical symptoms are paroxysmal flushing of the skin, as well as abdominal pain, diarrhea, and bronchospasmTumor cells produce a variety of active substances, such as 5-hydroxytryptophanMainly treated with drugs, such as the growth-suppressor analog octreotide
Definition.
Carcinoid tumors are a specific type of tumor, also called highly differentiated neuroendocrine tumors, that occur mostly in the gastrointestinal tract and lungs, and very rarely in the genitourinary tract.
Carcinoid cells produce a variety of active substances, which, after entering the blood and reaching a certain concentration, can cause a series of symptoms such as skin flushing, abdominal pain, diarrhea, bronchospasm and cardiac valvulopathy, which is called carcinoid syndrome.
Carcinoid syndrome is commonly seen in metastatic digestive tract carcinoid tumors, especially in small intestine carcinoid tumors with liver metastasis, while carcinoid syndrome is less common in patients with stomach and lung carcinoid tumors.
Classification
Since carcinoid syndrome is seen in patients with carcinoid tumors, carcinoid tumors are mainly classified here.
Classification according to embryonic origin
Carcinoid tumors can be classified into three types according to their embryologic origin: foregut, midgut and hindgut.
Foregut carcinoid tumors include lung, esophagus, stomach, proximal duodenum and pancreas. 5-hydroxytryptophan (5-HT) secretion is low, while 5-hydroxytryptophan and histamine secretion is high, and the carcinoid syndrome is atypical.
Middle intestinal carcinoid tumors include distal duodenum, jejunum, ileum, appendix, ascending colon, transverse colon, and liver. Carcinoid tumors originated from these sites have more 5-HT secretion and may show typical carcinoid syndrome.
Carcinoid tumors of the hindgut, including descending colon, sigmoid colon and rectum carcinoid tumors, do not secrete 5-HT and generally do not present with carcinoid syndrome.
Incidence
Carcinoid tumors are relatively rare, with a study in the United States showing an incidence of approximately 4.7 per 100,000 persons per year in the general population, but the incidence is gradually increasing [1-2].
The incidence is slightly higher in men than in women.
The median age at diagnosis is 63 years.
Causes
Causes
The etiology of carcinoid syndrome is mainly due to the ability of carcinoid cells to produce biologically active amines and peptides, including 5-hydroxytryptamine, bradykinin, histamine, catecholamines, prostaglandins, and vasoactive intestinal peptide.
However, the etiology of carcinoid tumors is unclear.
5-Hydroxytryptamine (5-HT)
5-HT comes from tryptophan in food, under normal condition, only 1% of tryptophan is utilized by gastrointestinal mucosal cells, but after the occurrence of carcinoid tumors, 70% or even more tryptophan in food is transformed into 5-hydroxytryptophan in carcinoid cells.
Patients with carcinoid tumors produce too much 5-HT, which exceeds the inactivation capacity of the liver and lungs, or when carcinoid tumors metastasize to the liver, which reduces the inactivation capacity of the liver, there is a sudden and large increase in the concentration of 5-HT in the blood, and these changes can explain many of the symptoms of carcinoid syndrome.
When most of the tryptophan is used to synthesize 5-hydroxytryptophan, resulting in a niacin deficiency, patients may exhibit rough flaky skin, ligamentous inflammation of the tongue, xerostomia, and blurred consciousness [3].
5-Hydroxytryptophan stimulates intestinal secretion and peristalsis and inhibits intestinal absorption. Therefore, 5-hydroxytryptamine is the most likely cause of diarrhea in patients with carcinoid syndrome [4-5].
5-hydroxytryptamine may also stimulate fibroblast growth and fibrosis formation. These effects can lead to peritoneal fibrosis and cardiac valve fibrosis associated with carcinoid syndrome.
However, 5-hydroxytryptamine does not cause flushing of the skin. The flushing caused may be associated with bradykinin, prostaglandins, tachykinin, substance P, and histamine [6].
Bradykinin
The production and release of bradykinin is one of the main causes of paroxysmal skin flushing .
Bradykinin acts by causing small arteries to dilate, blood pressure to fall, heart rate to increase, capillaries to dilate, and skin flushing.
Histamine
Primary neuroendocrine tumors of the stomach can produce histamine, and 5-hydroxytryptophan can also promote histamine release, which can lead to atypical flushing and itching of the skin.
Prostaglandins
Prostaglandins stimulate peristalsis and fluid secretion in the gastrointestinal tract, and although elevated serum prostaglandin levels have been seen in patients with carcinoid syndrome, the specific symptoms associated with them have not been fully clarified.
Pathogenesis
Carcinoid cells can synthesize, store and secrete a variety of biologically active substances, mainly including 5-hydroxytryptamine, bradykinin, histamine and prostaglandins.
When carcinoid tumor is in advanced stage or liver metastasis occurs, the biologically active substances produced exceed the body’s degradation ability, and the biologically active substances directly affect the blood vessel wall, gastrointestinal tract, bronchial smooth muscle, and heart valves, resulting in carcinoid syndrome.
Symptoms
Main Symptoms
Flushing of the skin
Skin flushing is the main clinical manifestation of carcinoid syndrome and is seen in 85% of patients.
Typical skin flushing is often sudden, with a deep red, cyanotic or purple coloration of the skin, mainly affecting the face, neck and upper chest.
Initially, the flushing may last only 30 seconds to 30 minutes, accompanied by a mild sensation of warmth, with episodes occurring once every few weeks. As the disease progresses, they may increase to several episodes per day and last longer, up to several hours.
Severe flushing may be accompanied by a drop in blood pressure and a rapid pulse.
Flushing is usually a spontaneous attack, but can also be triggered by events such as eating, drinking, defecation, emotional events, liver palpation, and anesthesia [7-9].
Gastrointestinal symptoms
Gastrointestinal symptoms occur in about 80% of patients, which severely affect the patient’s ability to perform daily activities, and are mainly characterized by episodes of abdominal cramps, watery diarrhea, and a sense of urgency and heaviness.
Abdominal cramps may be due to intestinal obstruction caused by mesenteric fibrosis or primary tumor.
The number of diarrhea per day varies, usually watery stools without blood, up to 30 times a day, accompanied by abdominal cramps, which may be associated with increased peristalsis and enhancement of intestinal motility.
The feeling of urgency and heaviness mostly refers to the patient’s feeling of incomplete bowel movement and anal distension.
Diarrhea is often not associated with episodes of skin flushing.
Respiratory symptoms
10% to 20% of patients with carcinoid syndrome experience wheezing and dyspnea, which manifests as episodes of asthma with asthmatic sounds in the lungs.
Wheezing episodes are associated with 5-HT and histamine, among others, and often occur during flushing episodes.
Cardiovascular symptoms
Carcinoid heart disease can occur in 50% of patients with carcinoid syndrome and is the first manifestation in up to 20% of patients [10-11] and is the leading cause of complications and death in patients with carcinoid syndrome [12-13].
It is characterized by the presence of deposits in the endocardium and valves and occurs most often in the right-sided chambers of the heart, with less frequent involvement of the left heart.
Early symptoms of right heart valvular heart disease include fatigue and exertional dyspnea, i.e., symptoms are not apparent at rest and dyspnea occurs with physical exertion. As the disease progresses, right heart failure can develop, manifesting as increasing dyspnea, edema, ascites, and eventually cardiac cachexia.
Venous capillary dilatation
Occurs in the advanced stages of carcinoid syndrome.
Caused by prolonged vasodilatation, it is most common on the nose, upper lip, and zygomatic areas and is similar to rosacea acne.
Secondary symptoms
Dietary tryptophan is used to synthesize large amounts of 5-hydroxytryptophan in rare cases may trigger niacin deficiency, which manifests as rough flaky skin, tongue inflammation, xerostomia, and blurred consciousness.
Inadequate protein synthesis can cause myasthenia gravis.
It may cause extensive fibrosis in the retroperitoneum and other areas, leading to ureteral obstruction.
Excessive sweating, angioneurotic edema, and emotional abnormalities may also occur.
Variant carcinoid syndrome
Some patients with gastric carcinoid tumor or lung carcinoid tumor may have clinical manifestations different from those of classical carcinoid syndrome, which is called variant carcinoid syndrome.
Variant carcinoid syndrome of the stomach
It is mainly characterized by flushing of the skin, accompanied by a strong itching sensation, and rarely diarrhea or cardiac changes.
Variant of Carcinoid Syndrome of the Lungs
The flushing may be severe and prolonged, lasting from hours to days, and may be accompanied by disorientation, anxiety, and tremors.
Other manifestations of this variant include periorbital edema, tearing, salivation, hypotension, tachycardia, diarrhea, dyspnea, asthma, edema, and oliguria.
Carcinoid crisis
Carcinoid crisis is a life-threatening carcinoid syndrome that occurs primarily in patients with extensive tumor lesions and can be triggered by tumor management (e.g., biopsy or surgery) or anesthesia.
Symptoms include persistent skin flushing, bronchial asthma attacks, abnormally high or low blood pressure, cardiac arrhythmia, confusion or even coma, etc. It is a life-threatening condition if not treated promptly.
Consultation
Department of Medicine
Gastroenterology
Patients with symptoms such as paroxysmal skin flushing, abdominal pain, diarrhea, coughing and wheezing can consult the gastroenterology department because most carcinoid syndrome occurs in intestinal carcinoid tumors, and the primary carcinoid tumor can be treated in the gastroenterology department after diagnosis.
Respiratory medicine
If the above symptoms occur and it is clear that the primary carcinoid tumor is in the lungs, you can consult the Department of Respiratory Medicine.
Oncology
If antitumor treatment is needed after the diagnosis of carcinoid tumor, you can consult the Department of Oncology.
Preparation for medical treatment
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for Medical Treatment
Wear loose clothing that is easy to put on and take off, so that the doctor can easily do physical examination and other laboratory tests.
Try not to wear jewelry, and remove your dentures if possible to facilitate MRI examination.
It is recommended that a family member accompany you.
If you have previously taken acetaminophen, stop taking it 3 days before your appointment.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, specific presentations, etc.
Has the skin of the face, neck or upper chest suddenly turned red or purple and felt hot?
Are there purple spots or streaks on the skin of the nose, cheeks or upper lip?
Are there any symptoms of diarrhea? What is the approximate number of times per day that you have diarrhea? Is there blood in the stool?
Are there any symptoms of wheezing (breath sounds with a murmur) or difficulty breathing?
Are there any swelling of the legs, breathlessness or tiredness after activity?
Was there a trigger, such as eating a large meal or drinking alcohol, before these symptoms appeared?
How long do these symptoms last? About how often do they flare up?
Medical History Checklist
Is there a history of carcinoid or other tumors in the immediate family, such as parents, siblings, children, etc.?
Has alcohol been consumed? How long has the alcohol been consumed? How much per day?
Does he/she smoke? How long have you been smoking? How many cigarettes per day?
Checklist
Test results for the last 6 months to bring to the doctor’s office
Laboratory findings: urinary 5-hydroxyindoleacetic acid, chromogranin, tumor markers CEA, AFP, etc.
Imaging test results: Computed tomography (CT) and magnetic resonance imaging (MRI), as well as tests in which the body is imaged by injecting special substances intravenously.
Endoscopic findings: Gastroenteroscopy findings.
Heart-related findings: Electrocardiogram (ECG) and echocardiogram findings.
Diagnosis
The presence of carcinoid syndrome is usually considered when a patient has suggestive symptoms, such as chronic severe diarrhea and/or flushing of the skin that cannot be explained by other causes.
The diagnosis of carcinoid syndrome should include the localization of the carcinoid in addition to the disease itself.
Diagnosis is based on
Medical History
Carcinoid syndrome is usually not preceded by a characteristic medical history and may be associated with the following medical history:
Is there a history of smoking? How long have you been smoking? How many cigarettes per day?
Is there a history of pancreatic achalasia, gastroesophageal reflux disease (GERD), Barrett’s esophagus, etc.?
Is there a history or family history of colonic adenoma and ulcerative colitis [14-15]?
Clinical manifestations
Symptoms.
Paroxysmal skin flushing is the most typical symptom, in addition to gastrointestinal, respiratory, and cardiovascular symptoms.
Refer to the previous section on symptoms.
Physical signs
Erythema of the skin is distributed on the face, neck and upper trunk.
Abdominal pain and diarrhea may be complicated by abdominal tenderness and increased bowel sounds.
In patients with asthma, rales may be heard on auscultation of the lungs.
Patients with heart valve disease may have heart enlargement and heart murmur, etc. Patients with carcinoid heart disease may also have lower limb edema, jugular vein angulation (jugular vein is enlarged and full when standing or sitting) and other signs of heart failure.
When carcinoid tumor metastasizes to liver, jaundice, hepatomegaly on palpation or pressure pain in liver area may appear.
Laboratory examination
Carcinoid syndrome is caused by the secretion of 5-hydroxytryptamine and other biologically active substances from carcinoid tumors into the circulation; therefore, measurement of these substances in the blood and/or urine is important in the diagnosis and follow-up of patients with carcinoid syndrome.
Urinary 5-hydroxyindoleacetic acid (5-HIAA)
is the initial diagnostic test of choice for carcinoid syndrome and requires collection of a full 24-hour urine sample.
The normal reference value for 5-HIAA is <10mg/24h, and patients often have >40mg/24h.
5-HIAA is the end product of 5-hydroxytryptamine metabolism, and the test is highly sensitive and specific for carcinoid syndrome.
Ingestion of certain medications and tryptophan/5-hydroxytryptamine-rich foods may lead to false-positive results, so these medications such as p-acetamidophenol-based or foods such as bananas and kiwi should be avoided for 3 days prior to urine collection.
The 5-HIAA urinary excretion test is usually most useful in primary midgut carcinoids, which produce the highest levels of 5-hydroxytryptamine.
Blood 5-hydroxytryptamine (5-HT) concentration
This includes whole blood 5-HT, platelet-rich plasma 5-HT, and platelet-poor plasma 5-HT assays.
Blood 5-HT levels are significantly higher in patients with carcinoid syndrome than in normal subjects. Whole blood 5-HT concentration was determined to be less than 17.1 μmol/L (300 ng/L) in the peripheral blood of normal subjects, and often greater than 28.5 μmol/L (500 ng/L) in patients with carcinoid syndrome.
The blood 5-HT level test is not used as a standard diagnostic test for carcinoid syndrome because platelets in stored blood samples can release 5-HT, or because a false-positive result on the 5-HT test may occur because of the intake of tryptophan/5-hydroxytryptamine-rich foods prior to the test.
Chromogranin (CgA) Concentration
Because of its relatively low specificity, CgA is generally not screened for in the diagnosis of carcinoid syndrome or carcinoid tumor.
For patients with diagnosed advanced carcinoid tumors, CgA is an appropriate tumor biomarker to assess disease progression, treatment efficacy, etc.
Tumor Markers
These include carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP).
If CEA is elevated it can help indicate the presence of a tumor in the body due to carcinoid syndrome.
Patients with liver metastases usually have elevated AFP.
Other tests
Such as basic blood routine, liver and kidney function, etc., especially liver function may play an important role in helping the diagnosis of the disease, and patients with carcinoid syndrome often have abnormal liver function.
Energizing tests
It can be used as a method of early diagnosis, including ethanol provocation test and drug provocation test.
When carcinoid syndrome is highly suspected but urinary 5-hydroxyindoleacetic acid is not obviously elevated, provocation test can be performed.
Ethanol provocation test
Drinking 4ml of 45% white wine, the test is positive if the skin shows typical flushing after 3~4 minutes.
Drug provocation test
The test is positive if there is typical flushing of the skin, decrease in blood pressure and increase in heart rate 45～90 minutes after intravenous injection of norepinephrine.
The drug test is dangerous and should be used with caution. This reaction can be blocked by phentolamine injection.
Imaging examination
It is mainly used for localization and staging of carcinoid tumors.
Carcinoid syndrome is mainly associated with metastatic carcinoid tumors originating from the small intestine or proximal colon; therefore, imaging should focus on the abdomen and pelvis.
Commonly used localization tests mainly include magnetic resonance imaging (MRI), CT, growth inhibitor receptor scintigraphy (SRS), 18F-fluorodeoxyglucose (18F-FDG) positron emission computed tomography (PET/CT), and endoscopy.
MRI
MRI is the most sensitive method for detecting the presence of liver metastases, but the accuracy of detection is lower when the lesion size is very small and can be combined with CT and ultrasound findings.
MRI is more difficult to localize primary carcinoid tumors.
CT
Enhanced CT is recommended for all patients with carcinoid tumors.
Most of the liver metastases of carcinoid tumors have rich blood supply, which can be easily observed by CT after injection of contrast agent.
However, the ability of CT to localize the site of tumor origin is average. Carcinoid tumors originating from the jejunum, ileum, and appendix are small and usually difficult to detect on CT, and colon carcinoid tumors tend to be large, but CT cannot differentiate colon carcinoid tumors from colon adenocarcinomas.
Growth inhibitory receptor scintigraphy (SRS)
is a highly sensitive and specific method for localizing neuroendocrine tumors.
Most carcinoid tumors express high levels of growth inhibitory receptors, so the receptors can be labeled by radioisotopes, allowing whole-body imaging and also providing information about SSTR expression. Markers include 111-In pentetreotide, 68 gallium (68-Ga ), which, in combination with CT, can increase the detection rate and improve the staging of carcinoid tumors.
PET/CT
PET/CT is a non-tumor-specific imaging method for all tumors. The more 18F-FDG uptake in a lesion, the more malignant and proliferative the carcinoid tumor is.
Patients with PET/CT positive carcinoid tumors usually have active proliferation of lesions and rapid progression of disease.
Clinically, PET/CT is usually used in combination with SRS to comprehensively assess the expression of growth inhibitory receptors and the malignancy of carcinoid tumors, and to accurately stage them.
Endoscopy
In the evaluation of metastatic carcinoid tumor with unknown primary site, or the site cannot be determined by any of the above imaging methods, endoscopy of the upper and lower gastrointestinal tracts should be performed (pay attention to observe the end of the ileum).
Endoscopy can not only observe the lesion directly, but also take biopsy for pathohistologic diagnosis.
Pathologic examination
Surgical exploration and biopsy is the gold standard for diagnosis of carcinoid tumor.
Other examinations
Electrocardiogram and cardiac ultrasound
Valve lesions in patients with carcinoid heart disease can deteriorate rapidly, which is one of the common causes of death in carcinoid syndrome. Sometimes, even though the valve damage is serious, the cardiac function is still good and the patients can be asymptomatic, thus delaying the treatment of the disease. Therefore, patients with carcinoid syndrome should have ECG and cardiac ultrasound examination.
Abnormal electrocardiogram can be used for preliminary screening, and cardiac ultrasound can directly observe whether the heart is enlarged, whether the valves are diseased and whether regurgitation occurs.
Differential diagnosis
Carcinoid syndrome has a wide range of symptoms, and the differential diagnosis is not entirely consistent from one symptom to another.
Differential of skin flushing
Skin flushing needs to be differentiated from other causes of skin flushing such as systemic mastocytosis, menopausal syndrome, pheochromocytoma, and diabetic autonomic neuropathy.
Systemic mastocytosis
Systemic mastocytosis is a rare condition in which there are abnormally more mast cells in the skin and gastrointestinal tract, and the mast cells secrete histamine, causing a range of clinical symptoms including skin flushing.
Similarities: Patients with both disorders have flushing of the skin, erythema, papules, and dilated capillaries on the skin and mucous membranes, and may be accompanied by chronic diarrhea.
Differences: Unlike carcinoid syndrome, patients with mastocytosis have arthralgia, bone pain, and allergy-like symptoms, as well as gastritis and peptic ulcers secondary to histamine overload.
Diagnostic points: flushing of the skin with arthralgia and bone pain; skin biopsy confirms mast cell infiltration of the dermis; increased histamine in the blood, but normal urinary 5-hydroxyindoleacetic acid levels, and a negative catecholamine provocation test.
Menopausal syndrome
Similarity: paroxysmal flushing of the skin.
Difference: Menopausal syndrome is most common in middle-aged women, and patients have many clinical symptoms, including sweating, dizziness, emotional instability, agitation, irritability, depression, suspiciousness, and other psychiatric symptoms or emotional abnormalities in addition to skin flushing.
Diagnostic Points: Menopausal syndrome is a functional disorder, so the diagnosis of menopausal syndrome must be considered on the premise of ensuring that there are no parenchymal organ or tissue lesions.
Differentiation of diarrhea
It needs to be differentiated from other causes of endocrine diarrhea such as vasoactive intestinal peptide tumors, gastrinomas, rectal choroidal adenomas, and medullary thyroid carcinomas.
Vasoactive intestinal peptide tumor
Similarity: Because the tumor tissue can secrete vasoactive intestinal peptide, patients may present with secretory diarrhea and skin flushing, which should be distinguished from carcinoid syndrome.
Differences: Patients often show the triad of watery diarrhea, low blood potassium and gastric acid deficiency, of which diarrhea is the most obvious symptom of this disease, with large amount of watery diarrhea and long duration, accompanied by weight loss, abdominal cramps and other symptoms.
Diagnostic points: patients with vasoactive intestinal peptide tumor have no relief of diarrhea even after 72 hours of fasting; patients are usually accompanied by severe hypokalemia and gastric acid deficiency; laboratory tests can find that the serum vasoactive intestinal peptide (VIP) level is significantly elevated, more than 60 pmol/L; abdominal ultrasound, CT, selective pancreatic arteriography and other localization tests can find pancreatic space-occupying lesions.
Gastrinoma
Similarity: both can occur frequent diarrhea, both watery diarrhea.
Differences: In addition to diarrhea, gastrinomas are associated with severe and persistent peptic ulcers. The ulcers are frequent and difficult to treat.
Diagnostic key points: usually stubborn, multiple, intractable peptic ulcers and diarrhea are the two main symptoms; blood gastrin level is obviously elevated; abdominal ultrasound or CT can find pancreatic space-occupying lesions.
Rectal villous adenoma
Similarity: both have diarrhea.
Difference: It is a kind of colon polyp which is less common, preferred in young and middle-aged people, accompanied by incomplete bowel movement and blood in the stool.
Diagnostic point: patients with rectal villous adenoma have more frequent defecation, more feeling of incomplete defecation, sometimes there is mucus or blood in feces, while the diarrhea of carcinoid syndrome is usually watery stool without blood; colonoscopy can find colonic space-occupying lesions, and if it is not good to identify the feasibility of pathologic examination.
Differentiation of wheezing
Wheezing attacks in carcinoid syndrome should be differentiated from bronchial asthma and other diseases.
Bronchial asthma
Similarity: Both of them may present symptoms such as wheezing, asthmatic sound and dyspnea.
Differences: Bronchial asthma is a chronic inflammatory disease of the airways, mostly related to exposure to irritants such as cold air, pollen, etc. Asthma usually flares up and worsens at night and/or early in the morning, and can be relieved by most patients on their own or after treatment.
Diagnostic points: can be identified by bronchial provocation test, etc..
Differentiation of cardiovascular system
Tricuspid valve lesion of the heart caused by carcinoid tumor should be differentiated from rheumatic heart disease.
Similarity: both of them will have tricuspid valve lesions, corresponding heart murmur can appear in the corresponding valve area; ventricle and atrium will be enlarged, and cardiac insufficiency will appear in the later stage.
Differences: Rheumatic heart disease is a heart disease with predominantly valvular lesions left after carditis caused by acute rheumatic fever. It is often accompanied by other symptoms such as pharyngitis, fever, joint pain, redness and swelling of the joints, erythema of the skin, and hard nodules.
Diagnostic points: patients with rheumatic heart disease often have a history of isthmusitis; anti-streptococcal hemolysin O titers may be elevated.
Treatment
Treatment of carcinoid syndrome includes treatment for a range of symptoms as well as treatment for the primary carcinoid tumor, with this article focusing on the former.
Aim of treatment: control the symptoms and improve the survival quality of patients.
Treatment principle: Carcinoid syndrome is mainly treated by drugs, including initial treatment of carcinoid syndrome, treatment of refractory carcinoid syndrome, treatment of carcinoid heart disease, treatment of carcinoid crisis and general treatment.
Initial treatment of carcinoid syndrome
The initial treatment of carcinoid syndrome consists of two main points: treatment with growth inhibitor analogs and treatment of liver metastases.
Growth inhibitor analogs
Inhibition of secretion
Growth inhibitor analogs can bind to growth inhibitor receptors on the surface of most carcinoid tumors and inhibit the secretion of a variety of substances, such as 5-hydroxytryptophan, which can significantly improve skin flushing and diarrhea in more than 80% of patients with carcinoid syndrome [16].
Growth inhibitor analogs include octreotide and lanreotide.
Initial treatment of carcinoid syndrome can be done with short-acting octreotide, which can be injected at home by the patient or family members themselves, but if the patient’s symptoms are severe, long-release octreotide is needed. Lanreotide works similarly to octreotide.
If symptoms worsen or are refractory, the dose or frequency of administration of the growth inhibitor analog can be increased within safe limits.
For a few weeks after using both drugs, patients may experience nausea, abdominal discomfort, bloating, and/or steatorrhea, followed by gradual resolution of symptoms, which can be relieved by pancreatic enzyme supplementation if it persists. Additionally growth inhibitor analogs can cause gallstones, and if the patient undergoes abdominal surgery for other reasons at this time, the gallbladder may be removed prophylactically [17].
Anti-tumor effects
Some studies have shown that in addition to the ability of growth inhibitor analogs to inhibit the secretion of a variety of substances and control carcinoid syndrome, these two drugs can inhibit tumor growth and play a role in the treatment of primary carcinoid tumors [18-19].
Treatment of liver metastasis
Hepatic resection
is the treatment of choice for patients with carcinoid tumor who develop liver metastasis.
It is indicated for patients in whom at least 90% of the lesions can be successfully resected or ablated.
Patients presenting with diffuse bilobar liver metastases, hepatic impairment and extensive extrahepatic metastases are unable to undergo hepatic resection.
To prevent carcinoid crisis caused by anesthesia and/or intraoperative tumor management, preoperative and intraoperative treatment with octreotide is indicated.
Hepatic artery embolization
Often used in patients with liver-predominant metastatic lesions that cannot be surgically resected, it is effective in improving skin flushing and diarrhea.
Embolization may be performed with microspheres alone (simple embolization) or with a mixture of chemotherapeutic agents (chemoembolization).
Short-term side effects of hepatic embolization include abdominal pain, fever, nausea/vomiting, and malaise, and prophylactic octreotide therapy is also generally required before and after embolization to reduce the risk of carcinoid crisis.
Treatment of refractory carcinoid syndrome
If good therapeutic results cannot be achieved after treatment with growth inhibitor analogs as described above, primary trostan, interferon, antidiarrheal agents, and systemic therapy may be used at this time.
Trostat
Trostan reduces the production of 5-hydroxytryptamine and can be used in combination with growth inhibitor analogs to treat carcinoid syndrome-associated diarrhea that is not well treated with growth inhibitor analog monotherapy.
The drug is usually taken with food and may have adverse effects such as nausea and depression.
Interferon.
In some patients refractory to growth inhibitor analogs, small doses of interferon alone reduce symptoms such as flushing and diarrhea.
Interferon exerts its antitumor effects by stimulating immune cells and inhibiting angiogenesis.
However, interferon is often associated with adverse effects such as malaise, depression, and flu-like symptoms, so it is rarely used except in refractory carcinoid syndrome.
Antidiarrheal drugs
Antidiarrheal medications such as loperamide and/or difenocoumarol-atropine may be used to control persistent diarrhea.
Ondansetron (5-hydroxytryptamine receptor antagonist) can also reduce diarrhea.
In addition, if treatment for the cause of diarrhea caused by carcinoid syndrome is poor, the presence of other causes of diarrhea such as should be considered:
Symptomatic fat malabsorption and steatorrhea caused by long-term growth inhibitor analog therapy can be supplemented with pancreatic enzymes.
Bile malabsorption and bile salt-induced diarrhea occurring in patients undergoing distal small bowel resection can be treated with bile acid sequestrants such as colestipol or colestipol, especially in patients with persistent diarrhea after right hemicolectomy.
Systemic therapy
Includes everolimus and 177-lutetium (Lu) dotatate (peptide receptor radioligand therapy).
Everolimus is able to treat carcinoid tumors and thus carcinoid syndrome, but diarrhea is a common side effect of everolimus and may exacerbate the patient’s symptoms.
177-Lutetium (Lu) dotatate (peptide receptor radioligand therapy), 177-Lu dotatate is a drug that consists of two parts, one that binds to growth inhibitory receptors on the surface of carcinoid tumors, acting similar to octreotide, and the other part is a particle with radioactive properties that kills the cancer cells by means of physical radiation. It is capable of relieving symptoms in patients who are poorly treated with growth analogs alone.
Treatment of Carcinoid Heart Disease
Growth inhibitor analogs
Studies have shown that 5-hydroxytryptophan or one of its metabolites plays a role in the development of carcinoid heart disease. Therefore, growth inhibitor analogs and other medications that reduce circulating levels of 5-hydroxytryptophan can reduce the risk of carcinoid heart disease as well as treat carcinoid heart disease, but do not improve the condition of an already diseased valve.
Surgery
Valve surgery is currently the only effective treatment for carcinoid heart disease.
Diuretics
Diuretics may temporarily improve symptoms associated with edema, but may further reduce cardiac output, which may increase fatigue.
Trostat
Carcinoid heart disease may be associated with higher levels of 5-hydroxytryptamine in the blood. For patients with metastatic carcinoid tumors and high levels of 5-hydroxytryptamine in the blood, this medication may be considered to slow the progression of carcinoid heart disease.
Treatment of carcinoid crisis
Carcinoid crisis can be treated with medications such as octreotide and vasopressors along with intravenous rehydration.
It is important to note that carcinoid crisis should be prevented.
Prognosis
Cure
Carcinoid syndrome is mainly seen in digestive tract carcinoids, which have a better prognosis.
Metastasis depends on the size of the tumor, the probability of metastasis for tumors less than 1cm is 2%, and the probability of metastasis for tumors larger than 2cm is significantly increased. Some studies show that the 5-year survival rate of patients with carcinoid tumor with distant metastasis in small intestine is 21%~50%.
However, the prognosis of patients with carcinoid heart disease is poor, and some studies show that the median time to death of patients with carcinoid heart disease is 2.6 years, and heart valve replacement can significantly improve the survival rate and survival time of patients.
Prognostic factors
The prognosis of patients with carcinoid syndrome is related to the level of urinary 5-hydroxyindoleacetic acid; the higher the level, the shorter the patient’s survival, and the main causes of death are heart failure, liver failure, and cachexia.
In addition, carcinoid syndrome is closely related to the prognosis of carcinoid itself, which is mainly affected by the primary tumor site and histological grading. Patients with gastrointestinal carcinoid usually have a longer survival than patients with other malignant tumors, even in the advanced stage, and the overall survival of patients who have undergone radical resection is more often than not as long as 5 to 10 years.
In addition the prognosis of patients with metastatic tumors is also affected by various factors such as the patient’s physical condition, the presence of extrahepatic distant metastases, and age.
Daily
Daily Management
Dietary management
Patients with carcinoid syndrome often suffer from malnutrition due to tryptophan depletion, decreased food intake, diarrhea, and loss of appetite, and malnutrition can worsen the prognosis of patients.
Choose a variety of foods from the basic food groups and increase the daily intake of fruits and vegetables, whole grains, and skim or low-fat milk and dairy products. Fresh fruits, vegetables and cereals are rich in vitamins and minerals and may help prevent or improve symptoms such as rough skin caused by vitamin deficiencies.
Try to focus your protein intake on plant proteins, such as beans, and minimize your animal protein intake.
Minimize red meat and processed meats, such as pork, beef, ham and other foods.
Keep fat intake low and minimize high-fat foods such as fried foods. Reducing fat intake may help reduce the incidence of steatorrhea and better control diarrhea.
Patients with diarrhea should reduce their intake of fruits and vegetables, and try to choose dry foods and eat small, frequent meals.
Minimize the consumption of amine-rich foods such as alcoholic beverages, fava beans, sauerkraut and soy sauce.
Life management
Stop smoking and drinking.
Exercise every day and take proper exercise to enhance immunity.
Patients receiving radiotherapy should pay attention to avoid rubbing or washing the skin in the radiation area, so as not to irritate the skin, aggravate the discomfort or lead to infection, and pay attention to disinfection and protection against skin breakage to avoid secondary infection.
Psychological support
Patients should be actively listened to, supported, consoled and understood, eliminating the negative emotions such as nervousness and anxiety, and helping patients to build up confidence and hope to overcome the disease.
Disease monitoring
Patients who have already received treatment need to be monitored for symptoms such as the duration and intervals between episodes of skin flushing and the number of episodes of diarrhea to determine whether the condition is worsening and whether the treatment is effective. If the disease continues to progress and worsen, it means that the treatment is not effective and the treatment program needs to be adjusted promptly.
Patients with carcinoid syndrome should undergo regular cardiac ultrasound and cardiac monitoring to detect and treat carcinoid heart disease as early as possible and reduce patient mortality.
Patients should also be monitored for symptoms such as nausea and depression, which may be related to adverse drug reactions, and the dosage and frequency of medication should be adjusted according to the degree of adverse reactions.
Follow-up review
Follow-up review includes observation of symptoms such as the reappearance of skin flushing, diarrhea, blood or urine testing for hormonal markers such as urinary 5-hydroxyindoleacetic acid and imaging tests such as MRI.
Lifetime follow-up after surgery is recommended for most patients who undergo surgery, but not for those with rectal and appendiceal lesions less than 1 cm and low malignancy on pathology.
For the first 5 years, patients can be followed every 6 months; after 5 years, the follow-up interval can be extended appropriately.
Prevention
Prevention is mainly aimed at the symptoms of carcinoid syndrome to minimize the episodes of skin flushing and diarrhea, but it cannot completely prevent the symptoms from occurring and developing.
Skin flushing can be triggered by factors such as emotional excitement, eating too fast, drinking alcohol, etc. Therefore, we can pay attention to the observation of triggering factors during the onset of the disease and try to avoid these situations to prevent frequent skin flushing episodes.
Patients with diarrhea can reduce the intake of fruits, vegetables, and high-fat foods to prevent worsening of diarrhea.
Patients who have not yet developed carcinoid heart disease need to be actively treated and undergo regular ultrasound examinations of the heart to prevent or promptly treat carcinoid heart disease.