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The carcinoid syndrome is characterized by
- are the most common endocrine consequences of these tumors.
The metastatic tumors associated with carcinoid syndrome usually arise from primary tumors in the ileum.
Death usually is caused by cardiac or hepatic failure and by complications associated with tumor growth.
When all of its clinical features are present, carcinoid syndrome is easily recognized. The diagnosis also must be considered when any one of its clinical manifestations is present.
The diagnostic hallmark consists of overproduction of 5-hydroxyindoles accompanied by increased excretion of urinary 5-HIAA. Normally, excretion of 5-HIAA does not exceed 9 mg daily. Ingestion of foods containing serotonin may complicate the biochemical diagnosis of carcinoid syndrome; both bananas and walnuts contain enough serotonin to produce abnormally elevated urinary excretion of 5-HIAA after their ingestion. When dietary 5-hydroxyindoles are excluded, urinary excretion of 25 mg of 5-HIAA daily is diagnostic of carcinoid. Elevation in the range of 9 to 25 mg may be seen with carcinoid syndrome, nontropical sprue, or acute intestinal obstruction. Measurement of serotonin in blood or platelets is of interest but has less diagnostic value than assay of the major metabolite of serotonin in the urine.
The sensitivity and specificity of plasma chromogranin A elevations in the diagnosis of peptide-producing endocrine neoplasms were 81 and 100 percent, respectively.percent, respectively. (N Engl J Med 1986 May 1;314(18):1145-51)
Cecil Textbook of Medicine 20th Ed. 1996
CARCINOID SYNDROME. This is a rare disease.
The following clinical manifestations (if present) would support this disease:
The following lab data (if present) would be useful in establishing the presence of the disease:
REF: UpToDate 2006
The carcinoid syndrome
Shanthi V Sitaraman, MD, PhD, FRCP
Stephen E Goldfinger, MD
INTRODUCTION Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors. These tumors synthesize, store, and release a variety of polypeptides, biogenic amines, and prostaglandins. Some of these tumor products are responsible for the carcinoid syndrome, but the relative contributions of each and specificity of any for particular components of the syndrome are uncertain.
Carcinoid tumors may arise anywhere in the gastrointestinal tract, in the bronchi, and occasionally elsewhere. The liver inactivates the bioactive products of carcinoid tumors. This may explain why patients who have gastrointestinal carcinoid tumors have the carcinoid syndrome only if they have hepatic metastases, resulting in the secretion of tumor products into the hepatic veins.
CLINICAL FEATURES OF THE CARCINOID SYNDROME Seventy-five to eighty percent of patients with the carcinoid syndrome have small bowel carcinoids; however, the expression is variable in individual patients. Among carcinoid tumors, approximately 10 percent of those in the small intestine, less than one percent of those in the appendix, and virtually none in the rectum are associated with the syndrome. Gastric and bronchial carcinoids are associated with atypical carcinoid syndromes. As noted above, among patients with intestinal carcinoid tumors, the carcinoid syndrome does not occur in the absence of liver metastases. In contrast, bronchial and other extraintestinal carcinoids, whose bioactive products are not immediately cleared by the liver, can rarely cause the syndrome in the absence of metastatic disease because of their direct access to the systemic circulation.
Cutaneous flushing Episodic flushing is the clinical hallmark of the carcinoid syndrome, and occurs in 85 percent of patients. The typical flush associated with midgut carcinoids (jejunum, ileum, appendix) begins suddenly and lasts 20 to 30 seconds. It primarily involves the face, neck and upper chest, which become red to violaceous or purple, and is associated with a mild burning sensation (show picture 1). Severe flushes are accompanied by a fall in blood pressure and rise in pulse rate. As the disease progresses, the episodes may last longer and the flushing may be more diffuse and cyanotic. The differential diagnosis of flushing is listed in Table 4 (show table 4)
Most flushing episodes occur spontaneously, but they can be provoked by eating, drinking alcohol, defecation, emotional events, palpation of the liver, and anesthesia [16-18]. Episodes induced by anesthesia may last hours and be accompanied by severe hypotension ("carcinoid crisis"). This problem can be prevented by pretreatment with octreotide . (See "Treatment of carcinoid tumors and the carcinoid syndrome").
Venous telangiectasia These purplish vascular lesions, similar to those seen in acne rosacea, appear late in the course of the carcinoid syndrome. They are due to prolonged vasodilatation, and most often occur on the nose, upper lip, and malar areas.
Diarrhea Secretory diarrhea occurs in 80 percent of patients and is often the most debilitating component of the syndrome. Stools may vary from few to more than 30 per day, are typically watery and nonbloody, and can be explosive and accompanied by abdominal cramping. The abdominal cramps may be a consequence of mesenteric fibrosis.
The diarrhea is usually unrelated to flushing episodes. Transit time through the intestine may be extremely short ; as a result, opacification of the entire small bowel and even the colon may be evident fluoroscopically at a time when a patient is completing an initial barium drink .
Bronchospasm Ten to twenty percent of patients with the carcinoid syndrome have wheezing and dyspnea, often during flushing episodes. Carcinoid wheezing should not be mistaken for bronchial asthma because treatment with beta agonists can trigger intense, prolonged vasodilation .
Cardiac valvular lesions Carcinoid heart disease is characterized by pathognomonic plaque-like deposits of fibrous tissue. These deposits occur most commonly on the endocardium of valvular cusps, the cardiac chambers, and occasionally on the intima of the pulmonary arteries or aorta (show figure 2). The valves and endocardium of the right side of the heart are most often affected, because inactivation of humoral substances by the lung protect the left heart. The clinical manifestations and treatment of carcinoid heart disease are discussed separately. (See "Carcinoid heart disease").
Minor manifestations There are a number of minor manifestations associated with carcinoid tumors:
There are four other potential manifestations of bronchial carcinoids:
Seventy-five to eighty percent of patients with the carcinoid syndrome have small bowel carcinoids; however, the expression is variable in individual patients . Among carcinoid tumors, approximately 10 percent of those in the small intestine, less than one percent of those in the appendix, and virtually none in the rectum are associated with the syndrome (show table 3). Gastric and bronchial carcinoids are associated with atypical carcinoid syndromes (see below).
Among patients with intestinal carcinoid tumors, the carcinoid syndrome does not occur in the absence of liver metastases. In contrast, bronchial and other extraintestinal carcinoids, whose bioactive products are not immediately cleared by the liver, can rarely cause the syndrome in the absence of metastatic disease because of their direct access to the systemic circulation.
Episodic flushing is the clinical hallmark of the carcinoid syndrome, and occurs in 85 percent of patients. The typical flush associated with midgut carcinoids (jejunum, ileum, appendix) begins suddenly and lasts 20 to 30 seconds. It primarily involves the face, neck and upper chest, which become red to violaceous or purple, and is associated with a mild burning sensation (show picture 1). Severe flushes are accompanied by a fall in blood pressure and rise in pulse rate. As the disease progresses, the episodes may last longer and the flushing may be more diffuse and cyanotic. The differential diagnosis of flushing is listed in Table of Flushing.
Some patients with functioning gastric or bronchial carcinoids have clinical and biochemical variations from the classic syndrome.
Diagnosis of the carcinoid syndrome
Shanthi V Sitaraman, MD, PhD, FRCP
Stephen E Goldfinger, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.1 is current through December 2005; this topic was last changed on April 21, 2005. The next version of UpToDate (14.2) will be released in June 2006.
INTRODUCTION Many carcinoid tumors are discovered incidentally during endoscopic or radiographic procedures planned for other purposes; this is especially true of carcinoids of the stomach and rectum (show table 1). When carcinoid tumors cause symptoms, the initial evaluation is directed toward two goals:
Verification that symptoms suggestive of the presence of the carcinoid syndrome are due to an actively secreting tumor
Localization of the tumor
The issues of documenting and localizing functioning carcinoid tumors will be reviewed here. The clinical manifestations, and treatment of the carcinoid syndrome are discussed separately. (See "The carcinoid syndrome" and see "Treatment of carcinoid tumors and the carcinoid syndrome" and see "Management of metastatic neuroendocrine tumors").
BIOCHEMICAL TESTING FOR THE CARCINOID SYNDROME The presence of the carcinoid syndrome is usually considered when the patient has suggestive symptoms such as otherwise unexplained diarrhea or flushing. The differential diagnosis of flushing, for example, includes physiologic events, drugs, and a number of diseases other than the carcinoid syndrome (show figure 1). (See "The carcinoid syndrome").
Urinary excretion of 5-HIAA The most useful initial diagnostic test for the carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid (HIAA), which is the end product of serotonin metabolism (show figure 2). This test has a sensitivity of 75 percent and specificity of up to 100 percent , but is fraught with errors that may be induced by the ingestion of certain drugs and foods (show table 2).
The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/day (10 to 42 µmol/day). Values of up to 30 mg/day (157 µmol/day) may be found in patients with malabsorption syndromes such as celiac and Whipple's disease, as well as after the ingestion of large amounts of tryptophan-rich foods. Although some patients with the carcinoid syndrome have similar modest elevations, most have values for urinary 5-HIAA excretion above 100 mg/day (523 µmol/day). In one study, for example, urinary 5-HIAA excretion in patients with the carcinoid syndrome ranged from 99 to 2070 mg/day (518 to 10826 µmol/day) . Lower, but still elevated values were seen in patients with metastatic carcinoid tumors but not the carcinoid syndrome (50 to 260 mg/day [262 to 1360 µmol/day]).
Measurement of urinary 5-HIAA excretion may not be useful in foregut carcinoids (bronchial, gastric) which often lack aromatic amino acid decarboxylase. Many patients with these tumors have minimal or no elevations in urinary 5-HIAA excretion. Instead, the tumors produce 5-hydroxytryptophan (show table 1). Unfortunately, assays for 5-hydroxytryptophan are not available in clinical laboratories in the United States. Thus, if a foregut carcinoid is suspected, other studies directed to tumor localization should be considered (see "Tumor localization" below).
Chromogranin concentration Chromogranins (designated as A, B, and C) are proteins that are stored and released with peptides and amines in a variety of neuroendocrine tissues. Neuroendocrine tumors have been associated with increased concentrations of chromogranins . As a general rule, the chromogranin concentration parallels 5-HIAA excretion.
Although the chromogranin concentration appears to be a sensitive marker of neuroendocrine tumors, their specificity has not been well-established. Thus, they are not generally used for the diagnosis of the carcinoid syndrome.
However, the concentration of chromogranin A may be an independent predictor of prognosis. This was illustrated in a study in which predictors of survival were evaluated in 301 patients with carcinoid tumors . On multivariate analysis, advanced age and a plasma chromogranin A concentration of >5000 µg/L were independent predictors of poor overall survival.
Blood serotonin concentration Determination of the whole blood serotonin concentration is often helpful when urinary 5-HIAA testing yields equivocal results. The mean fasting blood serotonin concentration in normal subjects ranged, in one report, from 71 to 310 ng/mL (0.4 to 1.8 µmol/L). Ten patients with the carcinoid syndrome had markedly elevated values (790 to 4500 ng/mL (4.5 to 25.5 µmol/L); of these, two had normal urinary 5-HIAA excretion . However, the specificity of this test is undetermined; patients have been referred to one of us (SEG) because of modest serotonin elevations, but without any other suggestive evidence of a carcinoid or any other type of neuroendocrine tumor. (Serotonin levels are known to be elevated in the paraganglioma syndrome, which includes extra-adrenal pheochromocytomas.)
Other substances elaborated by the carcinoid and released into the peripheral circulation include chromogranin A, bradykinin, kallikrein, neuropeptide K, neurokinins A and B, and substance P. Measurements of these compounds are only available in selected laboratories.
Provocation tests Provocation of flushing using epinephrine or pentagastrin are useful in evaluating patients who describe flushing, but have normal or only marginally elevated biochemical markers.
Epinephrine provocation test With the epinephrine provocation test, a slow intravenous infusion of 5 percent dextrose in water is started and baseline blood pressure and pulse are recorded with the patient in the supine position. Epinephrine is administered as a bolus dose, starting at 2 µg and increasing the dose by that amount every five minutes to a maximum of 10 µg. The patient is observed for flushing, hypotension, and tachycardia, which appear between 45 to 120 seconds after an injection and last for at least one minute in a positive test. The test is stopped after the first positive response. The hypotension is usually not profound and is transient; if it persists or the patient is symptomatic, 5 mg of phentolamine can be given intravenously. This test has a sensitivity of nearly 100 percent [7,8].
Pentagastrin provocation test The pentagastrin provocation test is performed by administration pentagastrin (0.06 mg/kg body weight intravenously). This test is relatively new, but has an advantage over the epinephrine provocation test in that it induces flushing in patients with either foregut or midgut tumors [6,9].
TUMOR LOCALIZATION Once the biochemical diagnosis of the carcinoid syndrome is confirmed, usually by an elevated 24-hour excretion of 5 HIAA, the tumor must be localized. Two techniques, abdominal computed tomography (CT) and pentetreotide imaging (indium-111 octreotide imaging) have a complementary role in this pursuit. (See "Localization of pancreatic endocrine tumors (islet-cell tumors)").
Other tests Barium and endoscopic studies (mainly for patients with symptomatic gastric or colonic carcinoids; show picture 1), video capsule endoscopy, abdominal magnetic resonance (MR) imaging, and angiography are reserved for selected patients with suspected carcinoid tumors that have not been localized by the above methods.
Chest x-ray and CT scan can be used to localize bronchial carcinoid tumors. These tumors tend to be centrally located endobronchial lesions; however, approximately 20 percent arise peripherally and present as a well circumscribed solitary pulmonary nodule (show radiograph 2) . Bronchial carcinoids can present with severe and prolonged flushes, hemoptysis, or rarely signs of left-sided heart failure due to valve disease. (See "The carcinoid syndrome", section on Bronchial carcinoid variant syndrome).
SUMMARY ARE RECOMMENDATIONS
The presence of the carcinoid syndrome is usually considered when the patient has suggestive symptoms such as otherwise unexplained diarrhea or flushing. The differential diagnosis of flushing, for example, includes physiologic events, drugs, and a number of diseases other than the carcinoid syndrome (show figure 1). (See "The carcinoid syndrome").
The most useful initial diagnostic test for the carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid (HIAA), which is the end product of serotonin metabolism (show figure 2). This test has a sensitivity of 75 percent and specificity of up to 100 percent , but is fraught with errors that may be induced by the ingestion of certain drugs and foods (show table 2).
Determination of the whole blood serotonin concentration is often helpful when urinary 5-HIAA testing yields equivocal results.
Provocation of flushing using epinephrine or pentagastrin are useful in evaluating patients who describe flushing, but have normal or only marginally elevated biochemical markers.
Once the biochemical diagnosis of the carcinoid syndrome is confirmed, usually by an elevated 24-hour excretion of 5 HIAA, the tumor must be localized. Two techniques, abdominal computed tomography (CT) and indium-111 octreotide imaging) have a complementary role in this pursuit.
Abdominal CT with intravenous and oral administration of radiographic contrast agents has a sensitivity of 87 percent for identifying at least one of four manifestations of a carcinoid tumor.
Clinical characteristics of carcinoid tumors
Shanthi V Sitaraman, MD, PhD, FRCP
Stephen E Goldfinger, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.1 is current through December 2005; this topic was last changed on April 27, 2005. The next version of UpToDate (14.2) will be released in June 2006.
INTRODUCTION Carcinoid tumors are rare, but are the most common gastrointestinal neuroendocrine tumors [1-4]. Symptoms of the carcinoid syndrome (eg, flushing and diarrhea) are infrequent (show table 1), occurring in approximately 10 percent of patients with small bowel carcinoid. (See "The carcinoid syndrome"). The age distribution of carcinoid tumors ranges from the second to the ninth decade, with the peak incidence occurring between the ages of 50 and 70.
In a series of 13,715 carcinoids reported to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rates for Caucasian men and women over the last decade were 2.47 and 2.58 per 100,000, while they were somewhat higher for black men and women (4.48 and 3.98 per 100,000 population per year) . In a separate report from the SEER database of 11,427 carcinoid cases treated between 1973 and 1997, the majority of carcinoids were located in the gastrointestinal tract (55 percent) and bronchopulmonary system (30 percent) . Within the gastrointestinal tract, most carcinoids arose in the small intestine (45 percent, most commonly in the ileum), followed by rectum (20 percent), appendix (16 percent), colon (11 percent), and stomach (7 percent).
Similar incidence rates were found in a database study from a Swedish registry that included 5,184 carcinoid tumors seen between 1958 and 1998 . A regression analysis suggested a family history of carcinoid in a first-degree relative (relative risk 3.6), a well-educated social background (relative risk 2.8), and birth in a large city (relative risk 1.39).
PATHOLOGY Carcinoid tumors were so named because they seemed morphologically different and clinically less aggressive than the more common intestinal adenocarcinoma . Carcinoids arise from enterochromaffin cells of the gastrointestinal tract. The term enterochromaffin refers to the ability to stain with potassium chromate (chromaffin), a feature of cells that contain serotonin. On gross appearance, carcinoid tumors are well circumscribed round submucosal lesions; the cut surface appears yellow due to their high lipid content (show picture 1).
Carcinoid tumors have traditionally been classified based upon their origin from the embryonic divisions of the alimentary tract . The classification includes tumors of the foregut (including the lungs, bronchi and stomach), the midgut (including the small intestine, appendix, and proximal colon), and the hindgut (including the distal colon, rectum, and genitourinary tract). The different types of tumors correlate with their morphologic pattern, silver affinity, and clinical behavior (show table 2).
Cells of foregut tumors take up silver only after being treated with a reducing agent and are termed argyrophil cells.
Cells of midgut carcinoids take up silver and are termed argentaffin cells.
Cells of hindgut tumors exhibit variable affinity to silver using modified techniques: 60 to 70 percent of hindgut tumors contain argyrophilic cells, 8 to 16 percent contain argentaffin cells, and the remainder do not stain with silver.
One-third of midgut carcinoids are symptomatic and one-tenth are associated with carcinoid syndrome. In comparison, hindgut carcinoids are usually asymptomatic and rarely cause carcinoid syndrome, even when metastatic.
In addition to these embryologically based divisions, carcinoid tumors have been classified based upon histologic characteristics as "typical" or "atypical" (anaplastic) (show table 3) . Typical tumors are well differentiated, containing small regular cells with rounded nuclei (show histology 1). Five distinct histologic patterns have been recognized :
Trabecular (ribbon like)
A variety of special stains can be used to demonstrate the neuroendocrine components of the tumor (show histology 2).
Compared to typical tumors, atypical carcinoids have increased nuclear atypia, greater mitotic activity, and contain areas of necrosis (show histology 3A-3B). Despite these histologic distinctions, the biologic behavior of carcinoid tumors does not always correspond to their histologic characteristics. The distinction between benign and malignant carcinoid is based upon the presence or absence of metastasis rather than histology alone, because even malignant tumors show little or no cellular pleomorphism, hyperchromasia, or increased mitotic activity. The metastatic potential of carcinoids correlates with the size and the site of the primary tumor.
ORGAN-RELATED FEATURES The clinical characteristics of carcinoid tumors vary with the location of the tumor. In the SEER database described above, the highest percentage of metastatic disease at diagnosis was found with small intestinal and colonic carcinoids, while those of rectal, bronchopulmonary, or gastric origin were more likely to be localized .
Appendix Carcinoid tumors are the most common neoplasms in the appendix. Approximately 1 in 300 appendixes contain a carcinoid tumor, almost always as an incidental finding . Appendiceal carcinoids are felt to arise from endocrine cells in the lamina propria and submucosa .
Appendiceal carcinoids are detected most commonly in the patients in their 40s or 50s, which most likely reflects the younger age of patients who undergo appendectomy. They are probably more common in women, although this association has in part been attributed to the greater frequency of incidental appendectomies in women who undergo pelvic surgery. However, among children, appendiceal carcinoids are more common in girls supporting the female gender association since incidental appendectomies are unusual in this age group. (See "Cancer of the appendix and pseudomyxoma peritonei", section on Carcinoid tumors).
Most patients with appendiceal carcinoids are asymptomatic. Symptoms are more likely with large tumors, those located at the base of the appendix, and with metastatic disease. The majority of tumors are located in the distal one-third of the appendix where they are unlikely to cause obstruction. In approximately 10 percent of patients, tumors are located at the base, where they can cause obstruction, leading to appendicitis . Features of the carcinoid syndrome may be present in patients with tumors that have metastasized to the liver. (See "The carcinoid syndrome").
The prognosis of appendiceal carcinoids is best predicted by the size of the tumor. Tumors less than 2 cm in size (found in approximately 95 percent of patients) are unlikely to have metastasized when diagnosed (show table 4). In contrast, up to 30 percent of larger tumors have already metastasized at diagnosis. Five-year survival rate overall is approximately 71 percent, and for patients with distant metastasis, ranges from 10 to 30 percent. (See "Cancer of the appendix and pseudomyxoma peritonei", section on Carcinoid tumors).
Because of the association of tumor size with prognosis, tumors less than 2 cm can usually be treated by simple appendectomy. In contrast, it is appropriate to perform right hemicolectomy to patients with larger appendiceal carcinoids since tumors may recur locally following simple appendectomy. Although some authorities have also advised right hemicolectomy in patients who have mesoappendiceal invasion regardless of tumor size, recurrence is unlikely for small tumors with this feature that are treated by simple appendectomy. (See "Cancer of the appendix and pseudomyxoma peritonei", section on Carcinoid tumors and see "Treatment of carcinoid tumors and the carcinoid syndrome").
Small intestine Carcinoid tumors of the small intestine represent approximately one-third of small intestine neoplasms . The tumors are felt to arise from intraepithelial endocrine cells, in contrast to appendiceal carcinoids, which arise from subepithelial endocrine cells . Small intestinal carcinoid tumors are most commonly located in the ileum within 60 cm of ileocecal valve .
Patients usually present in their 60s or 70s with abdominal pain or small bowel obstruction, and often have metastases to lymph nodes or the liver, even if the primary tumor is small (show table 4) [15,16]. Bowel obstruction or abdominal pain may be due to intussusception, the mechanical effect of the tumor, or mesenteric ischemia due to local fibrosis or angiopathy (show radiograph 1A-1B) . The carcinoid syndrome is present in approximately 5 to 7 percent of these patients [16,18].
Multiple tumors are present in up to 30 percent of patients . Compared with those with solitary ileal carcinoids, such patients tend to be younger, are more likely to have the carcinoid syndrome, and have a worse prognosis .
Patients with small bowel carcinoid tumors should be treated with resection of the involved segment and small bowel mesentery. Resection may be required for palliation even in those with known metastatic disease. The prognosis depends upon the stage of disease. Five year survival in patients with distant metastasis is approximately 36 percent . (See "Treatment of carcinoid tumors and the carcinoid syndrome").
Colon Colonic carcinoids are usually detected in patients who are in their 70s during evaluation for abdominal pain, anorexia, or weight loss . Features of the carcinoid syndrome are uncommon. The majority of tumors are located in the right colon, particularly the cecum [21,22]. Because of the high capacitance of the right colon, most patients do not become symptomatic until the tumors are large. In two series, the average size of tumors was approximately 5 cm at diagnosis [21,22], and approximately two-thirds of patients had local nodal or distant metastasis. The relationship between tumor size and metastatic propensity is depicted in Table 4 (show table 4).
Small localized tumors are most likely to be cured by resection [5,15]. In the SEER database, the five-year survival for patients with local, regional, or distant disease was approximately 76, 72, and 30 percent, respectively .
Rectum The vast majority of rectal carcinoids are found incidentally by rectal examination or endoscopy. They are most commonly diagnosed in patients in their 60s . Uncommon manifestations include rectal bleeding or pain; the carcinoid syndrome is rare.
The size of rectal carcinoids correlates closely with the likelihood of metastases. Tumors smaller than 1 cm are rarely metastatic , while approximately 10 percent of tumors between 1 and 1.9 cm, and more than 70 percent of those over 2 cm metastasize, most often to local lymph nodes or the liver [5,24].
Optimal treatment of rectal carcinoid tumors depends upon the size. Tumors that are less than 1 cm may be excised locally. Treatment of tumors larger than 1 cm but smaller than 2 cm has been controversial. Although local excision may suffice, some authorities recommend more extensive resection in patients who have muscular invasion or symptoms, which may be associated with a worse prognosis .
Tumors larger than 2 cm have usually been treated by low anterior or abdominoperineal resection, similar to treatment for rectal adenocarcinomas . However, this aggressive approach has been questioned since improved survival has not been consistently demonstrated compared to local excision [26,27].
Thus, the treatment of carcinoid tumors larger than 1 cm should be considered on an individual basis, including comorbid illnesses and the patient's age in the decision. In the SEER database, the five-year survival rates for localized, regional, or distant disease involving the rectum or rectosigmoid junction over the last decade were 90, 49, and 26 percent, respectively .
Stomach Gastric carcinoids are grouped into three categories [28,29]:
Type 1 Type 1 gastric carcinoids are associated with chronic atrophic gastritis and often pernicious anemia [30,31]; they account for 70 to 80 percent of all gastric carcinoids. (See "Metaplastic (chronic) atrophic gastritis").
The tumors are derived from enterochromaffin-like (ECL) cells. The prevailing hypothesis is that ECL cells develop into carcinoids after chronic stimulation by the high gastrin levels that occur in patients with atrophic gastritis. The mechanism of hyperproliferation may be related to mutations in the Regl alpha gene, which may normally function as an autocrine or paracrine suppressor of gastrin stimulation of ECL proliferation .
The importance of gastrin in ECL transformation is supported by the observation that carcinoid tumors develop in certain animals treated with high doses of proton pump inhibitors, which are associated with hypergastrinemia . However, carcinoid tumors have not been observed in humans treated with proton pump inhibitors, suggesting that other factors may be important. The relationship between ECL cells and carcinoid tumors is further supported by the finding of ECL hyperplasia surrounding carcinoid tumors in the majority of patients .
Patients with gastric carcinoids related to chronic atrophic gastritis are usually diagnosed in their 60s or 70s during endoscopic evaluation for abdominal pain or anemia. The disease is more common in women [34,35]. The carcinoid syndrome does not occur. Endoscopically, the tumors are usually smaller than 1 cm, often multiple, and may appear as polypoid lesions with a small central ulceration (show endoscopy 1 and show endoscopy 2) and (show picture 1, and show histology 4A-4C).
Gastric carcinoid tumors developing in the setting of atrophic gastritis are usually indolent. Metastases occur in less than 10 percent of tumors 2 cm, but approximately 20 percent of larger tumors . Tumors less than 1 cm can be resected endoscopically with close follow-up . Large or recurrent tumors may require surgical resection. Antrectomy reduces hypergastrinemia and can lead to regression of tumors . However the long term benefit of antrectomy is uncertain given the indolent nature of the tumors and the relatively advanced age at which patients are diagnosed.
Type 2 Type 2 gastric carcinoids occur in association with gastrinomas (Zollinger-Ellison syndrome) or multiple endocrine neoplasia (MEN) type 1. They account for less than 5 percent of gastric carcinoids. Similar to carcinoids in atrophic gastritis, the tumors are thought to arise from ECL cells. However, in contrast to the other forms of carcinoid, the MEN1 gene locus (a tumor suppressor gene located on chromosome 11q13) appears to be involved in the pathogenesis of many of these tumors. In one report, inactivation of the MEN1 gene was detected in 15 of 20 type 2 gastric carcinoids compared to only one to six type 1 carcinoids, and none of nine intestinal or rectal carcinoids . (See "Definition and genetics of multiple endocrine neoplasia type 1").
Type 2 gastric carcinoids behavior similarly to type 1 tumors and are usually indolent . (See "Approach to therapy in multiple endocrine neoplasia type 1" and see "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)").
Type 3 Type 3 gastric carcinoids are known as sporadic carcinoids because they occur in the absence of atrophic gastritis or the Zollinger-Ellison or MEN1 syndromes. They account for 20 percent of gastric carcinoids, and are the most aggressive; local or hepatic metastases are present in up to 65 percent of patients who come to resection [28,37]. The tumors do not respond to antrectomy.
Type 3 gastric carcinoids often contain a variety of endocrine cells and may be associated with carcinoid syndrome (show table 1). They often produce 5-hydroxytryptophan in contrast to type 1 and 2 tumors, which more often produce serotonin. (See "The carcinoid syndrome").
Although the biologic behavior of gastric carcinoids correlates with the three types described above, overlap can occur. A number of independent markers of malignancy have been evaluated (such as cellular proliferation and angioinvasion) but their ability to predict the biologic behavior of these tumors has been insufficiently validated for routine use. Multivariate models that incorporate these predictors have also been developed. In one report, 15 clinicopathologic variables and tumor markers were analyzed in 102 patients with gastric carcinoids who were followed for 5 to 60 months . On multivariate analysis, the best model of tumor behavior included a combination of angioinvasion, clinicopathologic type, mitotic index, Ki67 grade (a proliferation assay) and tumor size.
Lung Pulmonary carcinoids are classified among other pulmonary neuroendocrine tumors such as small cell lung cancer. The tumors are thought to arise from Kulchitsky's cells within the bronchial mucosa [39,40]. Most tumors are perihilar.
Patients usually present in their 50s with recurrent pneumonia, cough, hemoptysis or chest pain [41-43]. The tumors are capable of secreting several different hormones, which can produce a number of paraneoplastic syndromes including Cushing's syndrome, acromegaly, and the carcinoid syndrome, which occurs in less than 5 percent of patients [44-46]. Carcinoid syndrome can occur without liver metastases. When cardiac involvement is present, it is usually left sided. (See "The carcinoid syndrome", section on Bronchial carcinoid variant syndrome).
The prognosis of bronchial carcinoids depends upon their histologic features. Tumors that are well-differentiated are usually indolent, with metastases occurring in fewer than 15 percent of patients [47-49]. When present, metastases are usually in lymph nodes, liver, bone or skin. Survival following local or segmental resection for well-differentiated localized tumors exceeds 90 percent . In the SEER database, the five-year survival rates for localized, regional, and distant bronchopulmonary carcinoids were 81, 77, and 26 percent, respectively .
In contrast to the indolent course observed in well differentiated tumors, patients with pulmonary carcinoids that have atypical histologic features (such as increased nuclear and mitotic rate and areas of necrosis) have a worse prognosis (show histology 5) [47,48]. These tumors tend to occur in the peripheral lung fields, are larger at diagnosis then well-differentiated tumors, and are metastatic in approximately 30 to 50 percent of patients [50,51]. As a result, more extensive resection may be required than for well-differentiated tumors [46,51]. Because of their aggressive behavior, some authorities have classified them as well-differentiated pulmonary neuroendocrine carcinomas rather than carcinoid tumors [43,47].
Ovary Ovarian carcinoids are noteworthy because they can produce the carcinoid syndrome without hepatic metastases due to their direct drainage into the systemic circulation. They often arise within an cystic teratoma or dermoid tumor, and the coexistence of an ovarian germ cell tumor may have prognostic implications. (See "Overview of ovarian germ cell tumors"). In one report,189 of 329 ovarian carcinoids (57 percent) coexisted with cystic teratomas/dermoid tumors . When compared to carcinoids without associated germ cell tumors, these carcinoids were significantly smaller (45 versus 90 cm), less likely to have liver metastases (2 versus 15 percent) or the carcinoid syndrome (14 versus 23 percent), and the five-year survival rates were modestly better (94 versus 84 percent) .
CLINICAL FEATURES The majority of patients with carcinoid tumors are asymptomatic, and the tumor is diagnosed incidentally at endoscopy, surgery, or autopsy . The initial symptoms of carcinoid may be nonspecific. When present, symptoms correlate with the location and extent of the tumor (show table 1).
Foregut tumors The symptoms associated with foregut carcinoid tumors vary with the site. Gastric carcinoids may present with peptic ulcer disease, abdominal pain or bleeding, and occasionally with atypical carcinoid syndrome. In comparison, duodenal carcinoids may produce duodenal or biliary obstruction or duodenal ulcer, while patients with the bronchial carcinoid variant may have flushes that are severe and prolonged, lasting hours to days. These flushes may be associated with disorientation, anxiety, and tremor. (See "The carcinoid syndrome").
Midgut tumors The most common initial symptom of small intestinal carcinoids is abdominal pain, occurring in approximately 40 percent of patients . The pain is usually vague and nonspecific. Intermittent obstruction is seen in 25 percent of all small intestinal carcinoids [54,55].
As discussed above, obstruction may be caused by intraluminal tumor, but often results from mesenteric kinking and distortion brought on by tumor invasion and a secondary desmoplastic response. The latter produces a characteristic radiographic abnormality: a combination of abrupt angulation with a filling defect in the small bowel (show radiograph 1A-1B).
Pain may also arise from vascular compromise secondary to large bulky mesenteric nodal metastasis, mesenteric vascular invasion, and/or microvascular metastasis . Possibly contributing to the ischemic process is the vasospastic effect of serotonin produced by the tumor. Approximately 5 to 7 percent of patients with midgut carcinoids present with one or more symptoms of the carcinoid syndrome, typically when metastatic disease is present [16,18].
Hindgut tumors The hindgut carcinoids (transverse and descending colon, and rectum) are usually nonsecretory. When symptoms do occur, they are the same as those of adenocarcinoma: changes in bowel habit, obstruction, or bleeding.
Hindgut carcinoids can also arise in the genitourinary system. At least 20 have been described in the kidney  and more than 50 in the testes . These lesions commonly present as abdominal or testicular masses.
Treatment of carcinoid tumors and the carcinoid syndrome
Shanthi V Sitaraman, MD, PhD, FRCP
Stephen E Goldfinger, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.1 is current through December 2005; this topic was last changed on May 2, 2005. The next version of UpToDate (14.2) will be released in June 2006.
INTRODUCTION Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors (show table 1) . Two of the most common manifestations are flushing and diarrhea (show table 2). (See "The carcinoid syndrome").
Management of patients with these tumors should include:
Localization of the tumor and possible metastases by CT scan and somatostatin receptor scintigraphy [2,3]. (See "Diagnosis of the carcinoid syndrome").
Removal of the tumor if metastases have not occurred
Control of carcinoid symptoms if present
More than 90 percent of patients with the carcinoid syndrome have metastatic disease. Exceptions are bronchial and ovarian tumors that can produce symptoms without metastasis (show table 3).
LOCALIZED CARCINOID TUMORS The treatment of choice for a patient who has a localized carcinoid tumor is surgery. The extent of the surgical resection depends on the site of origin and size of the primary tumor. (See "Clinical characteristics of carcinoid tumors" for a detailed discussion on carcinoid tumors arising in specific organs).
Appendix The prognosis of appendiceal carcinoids is best predicted by the size of the tumor. Tumors less than 2 cm in size (found in approximately 95 percent of patients) are unlikely to have metastasized when diagnosed (show table 4). In contrast, up to 30 percent of larger tumors have already metastasized at diagnosis. (See "Clinical characteristics of carcinoid tumors").
Because of the association of tumor size with prognosis, tumors less than 2 cm can usually be treated by simple appendectomy. In contrast, it is appropriate to perform right hemicolectomy to patients with larger appendiceal carcinoids because the tumors may recur locally after appendectomy. Although some authorities have also advised right hemicolectomy in patients who have mesoappendiceal invasion regardless of tumor size, small tumors with this feature that are removed by simple appendectomy are unlikely to recur. Treatment of appendiceal carcinoid tumors is addressed in detail elsewhere. (See "Cancer of the appendix and pseudomyxoma peritonei", section on CArcinoid tumors).
Small intestine Small intestinal carcinoids have the potential to metastasize, irrespective of size (show table 4). They should be removed by segmental resection and mesenteric lymph node excision [4,5]. The surgeon should also perform a complete inspection of the bowel since such patients may be at increased risk for synchronous neoplasms (see below). (See "Diagnosis and management of small bowel neoplasms").
Rectum Radical excision is recommended for patients with tumors larger than 2 cm and for 1 to 2 cm tumors that are invading the muscularis propria. Rectal carcinoids smaller than 1 cm can be treated by local excision .
Stomach Type 1 and type 2 gastric carcinoids smaller than 2 cm are treated by local excision and follow-up endoscopic surveillance every 6 to 12 months. Larger tumors are treated by partial gastrectomy [7,8]. In type 1 tumors associated with chronic atrophic gastritis and secondary hypergastrinemia, antrectomy, with resultant loss of G-cell mass and normalization of serum gastrin concentrations, can lead to reversal of endocrine hyperplasia and a reduction in tumor size [9,10]. However, this approach has not been validated by long-term follow-up, and is not considered standard therapy at this time. Sporadic (type 3) gastric carcinoids are treated by partial or total gastrectomy with local lymph node resection . (See "Clinical characteristics of carcinoid tumors" for a definition and characteristics of the different types of gastric carcinoids).
Colon Patients with colonic carcinoids should be treated with radical colectomy, although local resection has been reported to be effective for early stage disease.
Bronchial Bronchial carcinoids may present as a mass (which may be obstructive) or rarely, as the carcinoid syndrome. The preferred treatment is surgical resection. Overall survival at four or five years is 89 to 92 percent when these tumors show typical histology and are unassociated with carcinoid syndrome even when local lymph node metastases are present [11,12].
METASTATIC CARCINOID TUMORS AND CARCINOID SYNDROME Patients with the carcinoid syndrome may benefit from therapies for the different components of the syndrome.
The patient should be advised to avoid factors that induce flushing episodes, such as alcohol ingestion or specific forms of physical activity that involve pressure or trauma to the right upper quadrant.
Mild diarrhea may respond to codeine phosphate, and cholestyramine may ameliorate the diarrhea if the patient has had a distal ileal resection to remove the primary tumor.
Asthma can be treated with theophylline or the beta-2 adrenergic agonist albuterol (which does not precipitate flushing attacks).
Surgery plays a limited role in the treatment of patients with the carcinoid syndrome because almost all have extensive metastatic disease. Curative surgery can be offered only to the rare patient with resectable nodal, hepatic, or isolated brain metastasis, or to patients with extraintestinal primary tumors such as bronchial and ovarian carcinoids that cause the carcinoid syndrome without metastasis (see "Surgery" below). Resection is also recommended for small intestinal carcinoids, even in the presence of metastases, to prevent the development of fibrosing mesenteritis.
Surgical procedures in patients with carcinoid syndrome are potentially hazardous due to the precipitation of carcinoid crisis during induction of anesthesia or surgical manipulation of tumors. This complication can be prevented by pretreatment with octreotide, which should be used prophylactically.
Treatment of symptoms A large number of drugs have some efficacy for patients with flushing or more severe diarrhea (show table 5). In patients with severe symptoms, the only drug that is likely to be effective with acceptable toxicity is the somatostatin analog octreotide. Flushing and diarrhea are initially relieved in 75 to 80 percent of patients treated with 50 µg of octreotide three times daily subcutaneously [13,14]. Increasing doses are often required over time; up to 500 µg three times daily can be given.
Octreotide is usually well tolerated, but has some side effects (show table 6) [15,16]. About one-third of patients have nausea, abdominal discomfort, bloating, loose stools and fat malabsorption during the first several weeks of therapy, after which the symptoms subside. Although symptoms are usually mild, some patients do not tolerate them. More importantly, octreotide reduces postprandial gallbladder contractility and delays gallbladder emptying, and up to 25 percent of patients develop asymptomatic cholesterol gallstones or sludge during the first 18 months of therapy . Prophylactic treatment with ursodeoxycholic acid may be beneficial . (See "Nonsurgical treatment of gallstone disease").
Two long-acting preparations of octreotide are available; octreotide, 20 mg given by intramuscular injection once a month , and lanreotide SR, 20 to 30 mg IM every 10 days. A randomized crossover study of lanreotide (20 mg IM every 10 days) versus octreotide (200 µg SQ two or three times daily) in 33 patients with the carcinoid syndrome demonstrated equivalent efficacy for symptom control and reduction in tumor cell markers .
In patients who do not respond to or cannot tolerate octreotide or lanreotide, therapy varies with the primary symptom and site of the tumor. Patients with diarrhea can be treated with cyproheptadine, a serotonin antagonist, while those with gastric carcinoids that elaborate histamine can be treated a histamine blocker. Cyproheptadine also may be of benefit in patients with malignant carcinoid syndrome who develop anorexia or cachexia .
Treatment of metastatic disease
Surgery Surgery is most often considered for patients with hepatic metastases, although it should also be considered for the rare patient with a solitary cerebral metastasis [21,22].
The liver is the predominant site of metastatic disease. Resection of hepatic metastases can effectively palliate symptoms of hormonal hypersecretion and, in selected patients, may result in long-term survival. In general, resection is only undertaken in patients with a limited number of hepatic metastases, and is most successful when undertaken with curative intent. There is some risk to noncurative surgery since it appears to be associated with an increased incidence of local surgical complications, possibly due to poor wound healing related to the continued catabolic state
Other approaches to the treatment of hepatic metastases include the use of radiofrequency ablation and cryoablation, either alone or in conjunction with surgical debulking. Orthotopic liver transplantation has been performed in a few patients. (See Management of metastatic neuroendocrine tumors", section on Surgical management). Valve surgery can be performed in those with symptomatic carcinoid heart disease . (See "Carcinoid heart disease").
Octreotide and interferon alfa Long-acting somatostatin analogs such as octreotide LAR may benefit patients with metastatic carcinoid not only by decreasing symptoms from functionally active tumors, but also by slowing tumor growth [24-27]. However, radiographic regression of disease during treatment with somatostatin analogs is rare. (See "Management of metastatic neuroendocrine tumors", section on Somatostatin analogs).
Interferon alfa has been reported to result in biochemical responses, and to induce tumor stabilization in 20 to 40 percent of patients with gastrointestinal neuroendocrine tumors. In one series of 130 patients with metastatic carcinoid tumors, interferon therapy resulted in decreased urinary 5-hydroxyindolactic acid excretion in 42 percent, and tumor regression in 15 percent . The widespread use of interferon in these patients has been limited by side effects, which may include flu-like symptoms, fatigue, and depression. The addition of interferon to octreotide has also been effective in controlling symptoms in patients who are resistant or refractory to octreotide alone. (See "Management of metastatic neuroendocrine tumors", section on Interferon alfa).
Chemotherapy Although many cytotoxic drugs (including fluorouracil, dacarbazine, streptozocin, cyclophosphamide, and doxorubicin) have been tried in various combinations, randomized trials have revealed only minor activity in patients with metastatic carcinoid tumors. The potential benefits of traditional chemotherapy in patients with metastatic carcinoid must therefore be weighed against the possibility of side effects, which may include nausea and myelosuppression. (See "Management of metastatic neuroendocrine tumors", section on Cytotoxic chemotherapy).
Embolization and chemoembolization Liver metastases rely primarily on the hepatic artery for their blood supply. This provides the rationale for embolization of the hepatic artery, with the goal of inducing necrosis of the metastases with minimal damage to normal liver parenchyma. In uncontrolled trials, hepatic artery embolization can induce marked symptomatic improvement in patients with hepatic metastases from carcinoid, with reductions in flushing and diarrhea occurring in up to 75 percent. These responses last for 1 to 18 months, but eventually all patients progress [29,30].
Transarterial chemoembolization can be associated with substantial mortality (up to 2 percent) and morbidity, including fever, leukocytosis, severe abdominal pain, rise in serum aminotransferase values, and infection. Although these symptoms are transient, a more serious immediate complication is carcinoid crisis which can be prevented with prophylactic administration of octreotide . This topic is discussed in detail elsewhere. (See "Management of metastatic neuroendocrine tumors", section on Hepatic artery chemoembolization).
CARCINOID CRISIS Profound flushing, extreme changes in blood pressure, bronchoconstriction, arrhythmias, and confusion or stupor lasting many hours or even days can occur in patients with carcinoid tumors. This syndrome, called carcinoid crisis, can occur spontaneously, after palpation of tumor masses (at the bedside or during surgery), during induction of anesthesia, after administration of chemotherapy, or after hepatic arterial embolization, particularly in patients with extensive disease [31,32]. The crisis may be fatal.
Treatment for carcinoid crisis differs from other causes of acute hypotension, because calcium and catecholamines provoke release of mediators from the carcinoid tumor and may worsen the syndrome. The blood pressure should be supported by infusion of plasma and octreotide should be given . Octreotide should be given before general anesthesia and hepatic artery embolization to prevent carcinoid crisis [30,33,34].
SYNCHRONOUS OR METACHRONOUS NEOPLASIA Several series have described a higher than expected rate of synchronous or metachronous noncarcinoid cancers in patients diagnosed with carcinoid tumors [35-38]. Many of these tumors are adenocarcinomas involving the gastrointestinal tract while others arise in the lung, prostate, cervix, and other diverse sites. One of the largest series to evaluate this issue included 13,715 carcinoid tumors that were studied in surveillance programs from the National Cancer Institute . Overall, 22 percent of carcinoid tumors were associated with other noncarcinoid neoplasms. The highest percentage occurred in association with small intestinal carcinoids (29 percent) compared with carcinoids found in the rectum, gallbladder, appendix, or pancreas (range 13 to 19 percent).
The biologic basis for these observations is unclear. Some authors have hypothesized that the tumors may result from prolonged exposure to growth factors secreted by the carcinoid tumors . However, direct evidence for such an association has not been demonstrated.
Whether patients diagnosed with a carcinoid tumor should undergo screening and then regular surveillance for these noncarcinoid tumors is unclear. Some authors suggest that surveillance of the colon, rectum, small intestine, lung, cervix, and ovaries is appropriate for patients with carcinoid tumors, particularly those involving the small intestine, appendix, or colon . However, such a program has several implications, including the exposure of patients to unnecessary invasive testing and its associated morbidity, costs, and effects on quality of life. Furthermore, the yield and benefits of such a surveillance program have yet to be defined.
PROGNOSIS Carcinoid tumors, both primary and secondary, are characterized by slow growth. Even when metastases are present, survival is measured in terms of years rather than months. The prognosis of carcinoids is largely based upon the size, invasiveness, and histology of the primary tumor; those that are judged to have a typical (versus atypical) histology have a better prognosis . Other predictors of decreased survival include the presence of severe structural and functional abnormalities of the tricuspid valve , and molecular markers of tumor proliferation such as Ki67 .
Data derived from the United States National Carcinoid Register revealed a median five-year survival for all patients of 82 percent . Five-year survival varied with the extent of disease:
Localized tumors 94 percent
Regional lymph node metastases 64 percent
Widely metastatic tumors ranged from 0 to 27 percent, with some variation based upon the site of origin; median survival in these patients was less than two years
In another group of 204 patients, the likelihood of metastasis was 85 percent in those whose primary tumor exceeded 2.5 cm in diameter and invaded at least one-half way through the organ wall . Subjects with smaller and less invasive tumors had an excellent prognosis; only 1 of 120 such patients had a fatal outcome.
The presence of the carcinoid syndrome confers a poorer median survival, ranging from less than one year to 38 months [42,43]. These data were collected in studies performed before the availability of newer treatments. Thus, the current prognosis might be somewhat better.