Eric Shinohara, MD, MSCI
Updated by: Lara Bonner Millar, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2011
The neuroendocrine system is comprised of cells that are spread throughout several organ systems, including the lungs and digestive system. They are called neuroendocrine cells because they have characteristics of both nerve and endocrine cells. Nerve cells use electrical impulses to transmit signals. Endocrine cells, such as the thyroid and pancreas, make up glands that secrete hormones, such as thyroid hormone and insulin, which can be used to communicate with other organs. Tumors of the neuroendocrine system account for about 2% of all cancers and can be classified as either pancreatic endocrine tumors or carcinoid tumors. Approximately 12,000 cases of carcinoid tumor are diagnosed a year. They most commonly arise in the gastrointestinal system (esophagus, stomach, intestines) and are thought to regulate digestion by controlling digestive enzyme release and intestinal motility. About 30% of carcinoid tumors arise in the lungs. Because carcinoid tumors originate from hormone producing tissues, many of the side effects of carcinoid tumors can be linked to the inappropriate release of various compounds into the blood stream, which will be discussed later.
Carcinoid tumors occur slightly more frequently in women than men with an overall rate of approximately 2.5 cases per 100,000 people. Carcinoid tumors also appear to be slightly higher in African Americans with 4.48 and 3.98 cases per 100,000 African American men and women, respectively. It is diagnosed most commonly between the ages of 50 to 70. Carcinoid tumors often do not cause symptoms and can be difficult to diagnose.
These tumors arise in three areas: the foregut, midgut and hindgut. The foregut includes the lungs and the stomach, the midgut is comprised of the small intestine, appendix, and the beginning of the large bowel (colon), and the hindgut is composed of the end of the large bowel, the rectum and the organs of the genitourinary tract (ovaries, testes). Recent data suggests that over the past 30 years the incidence of carcinoid tumors appears to be rising. Previously it was believed that these tumors were fairly benign, however, recent data suggest that they may be more aggressive than previously thought, with a 5-year survival rate of 67.2% for all carcinoid tumor sites.
Carcinoid tumors appear to be more common in women and African Americans. African Americans also tend to have a worse prognosis. There are medical conditions which are associated with carcinoid syndrome, including Multiple Endocrine Neoplasia (MEN) type I, Zollinger-Ellison Syndrome, atrophic gastritis, and ovarian teratomas. Recent studies suggest that the number of cases of carcinoid tumors diagnosed a year have been increasing by 6% per year, but it is unclear as to why this is occurring. Some studies have suggested that smoking may double the risk of carcinoid tumors in the small intestine. There does not appear to be an association between carcinoid tumors and diet.
Presently, there is no way to prevent carcinoid tumors. There may be an association between carcinoid tumors and smoking, hence not starting or quitting smoking may reduce the risk of developing carcinoid tumors.
The signs of carcinoid tumor vary with the organ from which they arise. Generally, these tumors are found incidentally during an operation or procedure for another disease, such as during an appendectomy or a colonoscopy. Studies have suggested that 1 in 300 people who undergo appendectomy will have a carcinoid tumor found in the appendix. If symptoms are present, they tend to be relatively vague, such as abdominal discomfort. Symptoms which cause people to seek medical attention are uncommon. In the small intestine, carcinoid tumors can cause obstruction or intestinal bleeding. Carcinoids of the colon can also cause intestinal bleeding. Carcinoids of the rectum (very end of the colon prior to the anus where stool is stored) can be found during rectal exam and can cause rectal pain or bleeding. Carcinoid tumors tend to be slow growing, which also contribute to the slow evolution of symptoms. This has led to long intervals between the start of symptoms and diagnosis.
The most distinctive symptom of carcinoid tumors, known as carcinoid syndrome, rarely occurs. Carcinoid syndrome is made up of a constellation of symptoms which are caused by the release of a variety of substances (serotonin, histamine, and substance P, among others) by the carcinoid tumor. These symptoms can be precipitated by certain foods, such as those high in tyramine, such as blue cheese and chocolates, and those that contain ethanol, such as wine and beer. Carcinoid syndrome most commonly affects people with carcinoid tumors of the small bowel, however these tumors do not cause the symptoms associated with carcinoid syndrome until liver metastasis develop. This occurs because excess hormones produced by carcinoid tumors in the intestine are usually broken down by the liver. Therefore 90% of people, who have carcinoid syndrome, will have metastatic disease. Carcinoids of the lung and other non-digestive tract organs can also, on occasion, cause carcinoid syndrome.
One third of tumors of the midgut cause symptoms, and 10% will be associated with carcinoid syndrome. Only 10% of carcinoid tumors of the hindgut are symptomatic and they are rarely associated with carcinoid syndrome.
Carcinoid syndrome includes:
When a person presents with one or more of the above mentioned symptoms and carcinoid syndrome is suspected by the physician, confirmatory laboratory and imaging tests are ordered to verify that the symptoms are the result of a carcinoid tumor.
Generally, carcinoid tumors are found incidentally during an operation or a procedure. However, if a person has symptoms, which are suspicious for carcinoid syndrome, tests can be ordered to confirm that these symptoms are truly from a carcinoid tumor. Generally, the first test ordered is a urine test to detect serotonin breakdown products. In particular, the compound 5-hydroxyindoleacetic acid (5-HIAA) is measured in a 24 hour collection of the person's urine. This test can correctly confirm that the person's symptoms are due to a carcinoid tumor 75% of the time. However, the person being tested must avoid a number of foods and medications during the testing period which can falsely elevate or decrease the 5-HIAA level. Normally 2 to 8 mg/day of 5-HIAA is found in urine, however, up to 30 mg/day can be found in people with malabsorptive disease or who have recently eaten tryptophan rich foods (chocolate, certain types of cheeses). Generally people with carcinoid syndrome have 5-HIAA values of greater than 100 mg/day, though not always. People with metastatic carcinoid tumors, but without carcinoid syndrome, tend to have elevated 5-HIAA levels, yet generally have lower levels than those with carcinoid syndrome. This test may not be useful for detecting carcinoid tumors of the foregut (stomach and lungs) as they often do not produce 5-HIAA. In these cases imaging studies may be useful, which will be discussed later.
If the urine test fails to produce a diagnosis, blood tests can be performed. The blood test is used to determine 5-HIAA blood levels while the person is fasting. Normal values vary from laboratory to laboratory, but are generally between 101-283 ng/ml. Other blood tests can be used including tests for chromogranin A, bradykinin, kallikrein, and substance P among others, however these tests are not available at all hospitals.
Generally, if the 5-HIAA blood test fails to produce a diagnosis, an epinephrine (adrenaline) provocation test can be performed. In this test, the physician tries to induce symptoms associated with carcinoid syndrome by giving intravenous (IV) epinephrine. This test can confirm that a carcinoid tumor is causing the person's carcinoid syndrome symptoms nearly 100% of the time. The person's blood pressure, heart rate and facial color are closely monitored as epinephrine is given IV. The physician starts with 2 micrograms and goes up by 2 micrograms every five minutes until symptoms develop or a dose of 10 micrograms is reached. People with a carcinoid tumor will experience flushing, increased heart rate and decreased blood pressure at one of these doses and these symptoms generally last for one to two minutes. The test is stopped after the person first experiences these symptoms.
A new provocation test uses pentagastrin, a polypeptide that can stimulate the secretion of gastric acid and pepsin (a digestive enzyme). IV pentagastin is given and flushing symptoms are identified. The advantage of this test is that it can be used to detect not only midgut and hindgut tumors, but also foregut tumors unlike the tests mentioned previously.
Imaging tests can be used once the diagnosis of carcinoid tumor has been established using one of the above mentioned tests to locate the tumor. Alternatively, imaging studies may be the initial studies ordered to detect the tumor, particularly in cases where carcinoid syndrome is not present. Based on the suspected location of the tumor, several tests can be used. Barium studies can be used to find tumors; they coat the digestive tract and can outline tumors which can then be seen on X-ray. Barium swallows are used to locate tumors in the upper digestive tract such as the in the esophagus, stomach and the first part of the small intestine. Barium enemas work in a similar fashion, with contrast injected into the rectum, and can be used to examine the rectum and colon for tumors. Endoscopy can also be used to directly visualize tumors using a special camera attached to a flexible tube, allowing the physician to reach the esophagus and stomach. A colonoscopy is done in a similar fashion and can be used to examine the rectum and colon directly. Bronchoscopy can be used to examine the airways of the lungs for tumors. Another special type of scope (camera) has an ultrasound probe at the end of it. The ultrasound uses sound waves to detect how deep a tumor has invaded normal tissue. Biopsies can be taken during any of these exams and examined microscopically by a pathologist to identify carcinoid tumors. Unfortunately, none of these studies are very good at examining the majority of the small intestine, which is where many carcinoid tumors arise. CT scans can also be used to detect tumors throughout the body and CT guided needle biopsies can sometimes be used to obtain a biopsy for pathological examination. When a carcinoid is biopsied or resected and examined under the microscope, it may be classified as either "typical" or "atypical" depending on certain features. Typical carcinoids tend to be less aggressive than atypical carcinoids.
Several different types of scans can also be used to identify where the tumor is located and if it has spread. These scans use a compound, which is known to associate with carcinoid tumors. This compound is then attached to a radioactive substance. This combination is then injected intravenously and is taken up by the carcinoid tumor. Special scanners then detect the radioactive substance to identify where the tumor is. An example of this is the indium-111 octreotide scan, which can be used to localize the tumor. Octreotide is similar to somatostatin, a compound which can bind to somatostatin receptors, which are found on carcinoid tumors. However, there are other types of tumors, which can express somatostatin receptors; hence this study is not 100% specific for carcinoid tumors. The indium-111 is a radioactive compound, which is attached to the somatostatin, allowing the localization of the octreotide to be determined using a special scanner. An older scan, the I-131 MIBG scan, works in a similar fashion and can be used to locate the tumor. MIBG accumulates in the carcinoid tumor and the attached I-131 can be detected using a scanner to localize the tumor. However, like the indium-111 octreotide scan, other neuroendocrine tumors can also be detected. Hence this test is also not specific for carcinoid tumors. A PET scan using 5-hydroxytryptophan, a compound which is taken up by carcinoid tumors can also be used to identify where a tumor is located and if it has spread anywhere. Results from these imaging studies can be combined with CT scan results to better locate tumors.
In the past, carcinoid tumors did not have a formal staging system. They were staged as either localized, which means that the tumor has not spread beyond the wall of the organ or place of origin; regional, which is when the tumor has spread beyond the confines of the organ to adjacent tissues or lymph nodes, or distant metastatic spread, which indicates that the tumor has spread to distant organs and tissues.
Now the American Joint Committee on Cancer Staging (AJCC) has included carcinoid in a formal staging system, which applies to carcinoids of the stomach, colon, rectum, and ampulla of vater. There is a separate staging system for carcinomas arising within the appendix. Although there is now a staging system, the classification of tumors into localized, regional, or metastatic is still relevant in terms of thinking about prognosis and appropriate treatment options.
Duodenum, Ampulla, Jejunum, or Ileum
Colon or Rectum
Regional Lymph Nodes
Stage Grouping: combines the T, N & M staging to define a stage.
Regional Lymph Nodes
Stage Grouping: combines the T, N & M staging to define a stage.
Generally, the treatment of choice for people with localized carcinoid is surgical excision of the tumor. The role of chemotherapy and radiotherapy has been debated, particularly when a complete surgical resection is performed. Treatment information about each type of carcinoid tumor will be discussed by location.
Foregut: Symptoms associated with foregut carcinoids include peptic ulcers, abdominal pain and intestinal bleeding. They are rarely associated with carcinoid syndrome.
Midgut: Symptoms associated with midgut carcinoids include vague abdominal pain (40% of the time) and obstruction of the intestinal tract (25% of the time). They are associated with carcinoid syndrome approximately 10% of the time. The gut can fold in on itself, where a portion of the gut slides into another portion of the intestine (intussusception) resulting in obstruction of the intestine. The tumor itself may grow large enough to cause obstruction of the intestine as well.
Hindgut: Symptoms associated with hindgut carcinoids are similar to other rectal cancers. Change in bowel habits, rectal bleeding and intestinal obstruction can occur. Carcinoids of the hindgut are rarely associated with carcinoid syndrome. Hindgut tumors can also arise in the genitourinary system which includes the kidneys and gonads (ovaries or testes).
Regional Spread: When tumor has spread to the lymph nodes around the primary region, surgery is usually attempted to remove all of the tumor as well as the nodes around the tumor, which have disease. If this is not possible surgery is still often done to prevent symptoms from developing, such as obstruction of the intestine.
Distant Metastasis: Surgery cannot be used to cure the disease at this stage. Surgery is still used to prevent symptoms, such as obstruction, from developing but the focus is on treatments that can slow the progression of the disease and alleviate symptoms.
Other medications: Other treatments that control the symptoms of carcinoid syndrome are commonly used. Medications which boost the immune system may also be used to slow tumor growth.
Treatment of the Heart: Damage to the heart can occur due to prolonged exposure to serotonin, causing problems with the heart valves and ultimately heart failure. Octerotide and other somatostatin analogs can be used to control serotonin levels to limit heart damage. Echocardiograms are performed using an ultrasound (sound waves) machine to determine how well the heart is functioning and can be used to monitor the heart's condition. If heart damage has occurred, medications which are commonly used in heart failure can be used. Heart failure occurs when the heart is unable to circulate blood as effectively as a normal heart. This can cause fluid to build up in the body, particularly the legs (edema) and as it progresses can cause fluid to build up in the lungs as well (pulmonary edema). Treatments for this include diuretics (water pill), which draw excess water out of the body and medications to help regulate the heart beat to make it more efficient.
Follow up testing varies widely depending on the location of the carcinoid tumor, the stage of the disease at diagnosis, and the initial treatment given. For example, carcinoid tumors confined to the wall of the appendix may require no follow up after local resection; however tumors of the rectum which are locally resected need to be followed closely. At present, a standard surveillance program for small intestine carcinoid, where carcinoids commonly arise, has not been established. Generally, your physician may have you follow up every 3-6 months to determine if symptoms of carcinoid syndrome have developed. Imaging studies such as CT or MRI scans are usually done every 6-12 months or if symptoms develop warranting an immediate imaging study. Your physician may also order an echocardiogram periodically to evaluate heart function. Other tests, such as blood tests for serotonin and other products produced by carcinoid tumors, may also be checked regularly.
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