19. Basic principles of evaluation and
management of patients with
carcinoid tumours
Radiographic Staging and Localisation
Pathologic assessment of tumour differentiation
and/or grade
Removal of Tumour
Control of carcinoid symptoms
INTRODUCTION — The term “carcinoid” is generally applied to neuroendocrine tumors originating in the digestive tract, lungs, or rare primary sites such as kidneys or ovaries. Use of the term carcinoid usually implies well-differentiated histology, but the term can be applied to the rare high-grade or poorly differentiated neuroendocrine tumors. In the digestive system, well-differentiated neuroendocrine tumors of the luminal gastrointestinal tract have been designated carcinoid tumors while those arising in the pancreas (and rarely in the duodenum) have been referred to as pancreatic neuroendocrine (islet cell) tumours
“Carcinoid syndrome” is the term applied to a constellation of symptoms mediated by various humoral factors that are elaborated by some carcinoid tumors. The typical carcinoid syndrome, consisting primarily of flushing and diarrhea (table 3), occurs predominantly in patients with metastatic carcinoid tumors originating in the small intestine.
Carcinoids are relatively rare tumors. In a series of 35,618 neuroendocrine tumors (which included pancreatic neuroendocrine tumors as well as carcinoids at all sites) reported to the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence for non-pancreatic primaries was 4.7 per 100,000 [2]. The annual incidence rate for African Americans was higher than for Caucasians (6.46 versus 4.60/100,000), and the incidence for males was slightly higher than for females (4.97 versus 4.49/100,000). The median age at diagnosis for all patients with neuroendocrine tumors was 63 years.
The increase is probably partly due to increased detection on radiographic imaging and endoscopy.
Distribution — In a report from the SEER database of 11,427 carcinoid cases treated between 1973 and 1997, the majority were located in the gastrointestinal (GI) tract (55 percent) and bronchopulmonary system (30 percent) [5]. Within the GI 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).
Distribution may differ in other geographic areas. As an example, colorectal carcinoids may be more frequent in the Asia/Pacific region as compared to Europe, where carcinoids are more commonly found in the stomach and ileum [6,7]. An important point is that the SEER database may be inconsistent in recording tumors that are not considered “malignant” (ie, trivial gastric carcinoids that are encountered at endoscopy in patients with chronic atrophic gastritis).
Small intestinal carcinoid tumors are most commonly located in the ileum within 60 cm of ileocecal valve; they may arise from a Meckel’s diverticulum
Approximately 25 percent of patients will have more than one small bowel carcinoid at the time of discovery.
—Carcinoid tumors are the most common neoplasms in the appendix. In approximately 1 in 300 appendectomies, carcinoid tumors are discovered incidentally, most often in the tip of the appendix
Approximately 10 percent of appendiceal carcinoids are located at the base of the appendix, where they can cause obstruction, leading to appendicitis.
Carcinoid tumors were so named because they seemed morphologically different and clinically less aggressive than the more common GI tract adenocarcinomas [8]. Carcinoids arise from enterochromaffin (neuroendocrine) cells of the aerodigestive tract. The term enterochromaffin refers to the ability to stain with potassium chromate (chromaffin), a feature of cells that contain serotonin.
While most carcinoid tumors are relatively slow-growing neoplasms, some behave aggressively. Histologic grade and differentiation correlate closely with clinical behavior.
Grade refers to the proliferative activity of tumors, commonly measured by the mitotic rate (number of mitotic figures per 10 high-powered fields) or the Ki-67 index.
In contrast, differentiation refers to the extent to which neoplastic cells resemble their non-neoplastic counterparts [9].
The most recent nomenclature for neuroendocrine tumors of the digestive system from the World Health Organization (WHO) distinguishes two broad subgroups (table 1) [10]:
•Well-differentiated neuroendocrine tumors, which are further subdivided into low-grade and intermediate grade according to proliferative rate. Intermediate grade carcinoid tumors arising in the lung (but not elsewhere) are referred to as atypical carcinoids. In general, clinical behavior is relatively indolent. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)
•Poorly differentiated carcinoids are high-grade carcinomas that resemble small cell or large cell neuroendocrine carcinoma of the lung (picture 1) [11]. They generally behave in a biologically aggressive fashion.
(foregut, midgut, or hindgut) of the alimentary tract. In general, midgut carcinoid tumors (small intestine, appendix, cecum) produce serotonin and other vasoactive substances that give rise to the typical carcinoid syndrome.
In contrast, hindgut tumors (distal colon, rectum) are rarely, if ever, associated with a hormonal syndrome.
While this classification has some utility as a means of grouping together carcinoid tumor sites according to their likelihood of producing a hormonal syndrome, it is increasingly evident that each specific primary site possesses its own unique clinical characteristics.
FOREGUT TUMORS — The symptoms associated with foregut carcinoid tumors vary with the site.
Patients with bronchial carcinoids rarely develop carcinoid syndrome in the absence of liver metastases.
MIDGUT TUMORS
Small intestine — Small bowel carcinoids have increased in frequency in the last several decades, in part due to increased detection on endoscopy and imaging studies [23].
Small bowel carcinoids are thought to arise from intraepithelial endocrine cells, in contrast to appendiceal carcinoids, which arise from subepithelial endocrine cells [25].
.
Many small bowel carcinoids are asymptomatic at presentation and found incidentally.
Among symptomatic patients, abdominal pain is the most common initial symptom, occurring in approximately 40 percent .
The pain is usually vague and nonspecific, and may be incorrectly assumed to represent irritable bowel syndrome for years before the diagnosis is made. Intermittent obstruction occurs in 25 percent of small intestinal carcinoids
. Duodenal carcinoids may produce duodenal or biliary obstruction.
Abdominal pain may be due to intussusception, the mechanical effect of the tumor, or mesenteric ischemia.
Obstruction may be caused by intussusception or by intraluminal tumor bulk, but often results from mesenteric kinking and distortion brought on by tumor invasion and a secondary desmoplastic response (picture 3). The latter produces a characteristic radiographic abnormality: a combination of abrupt angulation with a filling defect in the small bowel (picture 4).
Pain may also arise from ischemia that is due to local fibrosis or angiopathy [30]. Vascular compromise may be secondary to large bulky mesenteric nodal metastasis, mesenteric vascular invasion, and/or microvascular metastasis [30]. Possibly contributing to the ischemic process is the vasospastic effect of serotonin produced by the tumor.
Patients often have metastases to lymph nodes or the liver, even if the primary tumor is small (table 5) [31,32]. The carcinoid syndrome is present in the majority of patients who have a small bowel primary carcinoid and liver metastases [31,33-35]. Staging, treatment, and prognosis of small bowel carcinoid tumors are addressed elsewhere. (See "Treatment and surveillance of non-metastatic carcinoid tumors", section on 'Small intestine'.)
Appendix —
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.
The likelihood of regional and distant metastases is related to tumor size, but generally lower than for small intestinal carcinoids (table 5). Features of the carcinoid syndrome may be present in patients with tumors that have metastasized to the liver. (See "Clinical features of the carcinoid syndrome".)
A rare type of appendiceal tumor, sometimes referred to as an adenocarcinoid (also termed ”goblet cell” or “mucous” carcinoid) contains chromogranin A and is composed largely of goblet cells. These tumors are discussed in detail elsewhere. (See "Cancer of the appendix and pseudomyxoma peritonei", section on 'Goblet cell carcinomas'.)
Staging, prognosis and treatment of appendiceal carcinoids are discussed separately. (See "Cancer of the appendix and pseudomyxoma peritonei", section on 'Staging and prognosis' and "Cancer of the appendix and pseudomyxoma peritonei", section on 'Treatment'.)
HINDGUT TUMORS — The hindgut carcinoids (transverse and descending colon and rectum) are usually nonsecretory and not associated with the carcinoid syndrome, even when metastatic (table 4) . When symptoms do occur, they are the same as those of a colorectal adenocarcinoma: changes in bowel habits, obstruction, or bleeding. (See "Clinical manifestations, diagnosis, and staging of colorectal cancer", section on 'Clinical manifestations'.)
Genitourinary — Hindgut carcinoids rarely arise in the genitourinary system; however, both renal and testicular primary carcinoid tumors have been described in case reports and case series [45-48]. I
METASTATIC CARCINOID TUMORS — Regardless of primary site, carcinoid tumors are characterized by a strong propensity to metastasize to the liver [34]. Patients with liver metastases may experience symptoms related to tumor burden (eg, pain, jaundice, early satiety) or hormonal symptoms (eg, flushing and diarrhea). Even when extensive, metastatic well-differentiated carcinoid tumors can often cause significant hepatomegaly without any abnormalities of liver function.
2010 WHO classification — In 2006 and 2007, the European Neuroendocrine Tumour Society (ENETS) proposed a staging scheme, similar to most other types of epithelial neoplasms, for NETs of the digestive tract that was accompanied by a histologic grading system that could be applied to all stages of NETs [19,20]. This grading proposal was later endorsed by the American Joint Committee on Cancer (AJCC) (table 2) [21]. The 2010 WHO classification of tumors of the GI tract, liver, and pancreas endorsed the ENETS grading scheme for NETs of the digestive tract, separating well-differentiated tumors into low-grade (G1) and intermediate grade (G2) categories. All poorly differentiated neuroendocrine tumors are high-grade (G3) neuroendocrine carcinomas according to this classification scheme.
Although some previous proposals for grading pancreatic NETs included the presence of necrosis (which paralleled the grading system used for bronchial carcinoid tumors) ,the ENETS/WHO grade for NETs is based solely on proliferative rate, using mitotic activity and/or Ki67 labeling index. The WHO guidelines specify that mitotic counting is to be performed on 40 to 50 high power fields, and 2000 cells should be counted to determine the Ki67 index. The regions with the highest rates (“hot spots”) should be counted, and if there is disparity between the mitotic rate and the Ki67 index, the higher grade should be assigned.
Notable differences between the ENETS proposal and AJCC manual include the following:
•The ENETS proposal stages poorly differentiated neuroendocrine carcinoma in the same way as well differentiated NETs; while AJCC stages poorly differentiated neuroendocrine carcinomas as adenocarcinomas.
•AJCC applies the adenocarcinoma staging scheme to all pancreatic neoplasms (including both well differentiated NETs and poorly differentiated neuroendocrine carcinoma).
It is unclear which staging system provides better separation of the prognostically different groups, and further study is needed to reconcile these differences.
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 (table 1). 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 (table 2).
Carcinoid tumors may arise anywhere in the gastrointestinal tract, in the bronchi, and occasionally elsewhere (table 3). The liver inactivates bioactive products secreted into the portal circulation. This may explain why patients with gastrointestinal carcinoid tumors only develop the carcinoid syndrome if they have hepatic metastases, resulting in the secretion of tumor products into the systemic circulation [1]. (See "Clinical characteristics of carcinoid tumors".)
The pathophysiology and clinical manifestations of the carcinoid syndrome will be reviewed here. The diagnosis and treatment of this disorder are discussed separately. (See "Diagnosis of the carcinoid syndrome and tumor localization" and "Treatment and surveillance of non-metastatic carcinoid tumors" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)
PATHOPHYSIOLOGY — As many as 40 secretory products have been identified in various carcinoid tumors [1]. The most prominent of these are serotonin, histamine, tachykinins, kallikrein and prostaglandins.
Tryptophan metabolism — Altered metabolism of tryptophan occurs in almost all patients with the carcinoid syndrome. In normal subjects, approximately one percent of dietary tryptophan is converted to serotonin; however, this value may increase to 70 percent or more in patients with the carcinoid syndrome [2]. Serotonin is then metabolized to 5-hydroxyindoleacetic acid (HIAA) (figure 1).
However, some foregut carcinoids (gastric, bronchial) lack the aromatic amino acid decarboxylase that converts 5-hydroxytryptophan to serotonin [3]; these tumors produce 5-hydroxytryptophan (and histamine) instead of serotonin. Hindgut carcinoids (distal colon and rectum) rarely secrete serotonin or any other bioactive hormones and are therefore unassociated with hormonal syndromes even when metastatic (table 3) [3].
These alterations in tryptophan metabolism can explain many of the findings in the carcinoid syndrome.
•The diversion of tryptophan to the synthesis of serotonin in patients with widely metastatic tumors may result in tryptophan deficiency. This disorder may be characterized by decreased protein synthesis, hypoalbuminemia, and nicotinic acid deficiency with or without the clinical manifestations of pellagra (rough scaly skin, glossitis, angular stomatitis, and mental confusion) [4].
•Tumor production of serotonin is the most likely cause of the diarrhea in carcinoid syndrome. Serotonin stimulates intestinal secretion and motility and inhibits intestinal absorption [5,6].
•Serotonin may also stimulate fibroblast growth and fibrogenesis. These effects can lead to the peritoneal and cardiac valvular fibrosis associated with the carcinoid syndrome [7]. (See 'Cardiac valvular lesions' below.) Serotonin does not cause flushing [8].
Histamine — Primary gastric carcinoids can produce histamine, which may be responsible for the atypical flushing and pruritus associated with these tumors. (See 'Gastric carcinoid variant syndrome' below.) The observation that flushing can be ameliorated by combined H1 and H2 antagonism is compatible with this hypothesis [9].
Kallikrein — Some carcinoids produce kallikrein, a protein that cleaves kinin from plasma kininogens. Bradykinin, a short-lived product of this cleavage, is a potent vasodilator and may be responsible for flushing in some carcinoid patients [10]. Kinins also stimulate intestinal motility and increase vascular permeability [11].
Prostaglandins — Prostaglandins E and F stimulate intestinal motility and fluid secretion in the normal gastrointestinal tract [12]. Although elevated serum prostaglandin concentrations are found in patients with the carcinoid syndrome, their role in the symptomatology of this disorder is uncertain [13].
Tachykinins — Some tumors secrete tachykinins (substance P, neurokinin A, neuropeptide K). Elevations in the serum concentrations of these latter polypeptides may contribute to flushing and diarrhea [14-16].
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 [3]. Gastric and bronchial carcinoids are associated with atypical carcinoid syndromes. (See 'Variant syndromes' below.)
As noted above, among patients with intestinal carcinoid tumors, the carcinoid syndrome rarely occurs in the absence of liver metastases. In contrast, bronchial and other extraintestinal carcinoids, whose bioactive products are not immediately cleared by the liver, can occasionally cause the syndrome in the absence of metastatic disease because of their direct access to the systemic circulation [17].
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, cecum, appendix) begins suddenly and lasts from 30 seconds to as long as 30 minutes. It primarily involves the face, neck and upper chest, which become red to violaceous or purple, and is associated with a mild burning sensation (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 the table (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 [18-20]. Episodes induced by anesthesia may last hours and be accompanied by severe hypotension ("carcinoid crisis"). This problem can be prevented by pretreatment with octreotide.
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 or intestinal blockage by the primary tumor. The diarrhea is usually unrelated to flushing episodes. Transit time through the intestine may be extremely short [6].
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 (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 protects 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:
•As noted above, diversion of dietary tryptophan for synthesis of large amounts of serotonin can very rarely result in the development of pellagra [4], manifested by rough scaly skin, glossitis, angular stomatitis, and mental confusion. Poor dietary intake and diarrhea or malabsorption can augment this process.
•Muscle wasting may occur as a result of poor protein synthesis.
•In addition to the mesenteric fibrosis associated with carcinoid tumors, extensive fibrosis can occur in the retroperitoneal area and other sites, causing ureteral obstruction or Peyronie's disease [22,23].
•Persistent brawny edema of the face and to a lesser degree of the extremities may be an advanced manifestation of the syndrome in some patients with severe flushing attacks. This is particularly true for those with foregut carcinoids [24].
VARIANT SYNDROMES — Some patients with functioning gastric or bronchial carcinoids have clinical and biochemical variations from the classic syndrome.
Gastric carcinoid variant syndrome — In patients with the gastric carcinoid variant, the flushes may be patchy, sharply demarcated, serpiginous, and cherry red; they are also intensely pruritic. Diarrhea or cardiac lesions are unusual. The tumors that cause this variant syndrome secrete histamine [25,26].
Bronchial carcinoid variant syndrome — In patients with the bronchial carcinoid variant, the flushes can be very severe and prolonged, lasting hours to days [24]. They may be associated with disorientation, anxiety, and tremor. Periorbital edema, lacrimation, salivation, hypotension, tachycardia, diarrhea, dyspnea, asthma, edema, and oliguria are other components of this variant. (See "Bronchial carcinoid tumors".)
SUMMARY
•Seventy-five to eighty percent of patients with the carcinoid syndrome have small bowel carcinoids; however, the expression is variable in individual patients [3]. Gastric and bronchial carcinoids are sometimes associated with atypical carcinoid syndromes (see below).
•Among patients with intestinal carcinoid tumors, the carcinoid syndrome rarely occurs in the absence of liver metastases. In contrast, bronchial and other extraintestinal carcinoids, whose bioactive products are not immediately cleared by the liver, can occasionally cause the syndrome in the absence of metastatic disease because of their direct access to the systemic circulation [17].
•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, cecum, 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 (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 (table 4).
•Some patients with functioning gastric or bronchial carcinoids have clinical and biochemical variations from the classic syndrome.
Urinary excretion of 5-HIAA — A 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 (figure 1). This test has a sensitivity of about 75 percent but high specificity for the carcinoid syndrome [1]. False positive results may be induced by the ingestion of certain drugs and tryptophan/serotonin-rich foods (table 3).
Urinary excretion of HIAA is generally most useful in patients with primary midgut (jejunoileal, appendiceal, ascending colon) carcinoid tumors. Foregut (gastroduodenal, bronchus) and hindgut (transverse, descending and sigmoid colon, rectum, genitourinary) carcinoids only rarely secrete serotonin; they lack the enzyme DOPA decarboxylase and cannot convert 5-hydroxytryptophan (5-HT) to serotonin, and therefore, to 5-HIAA (figure 1) [2]; these tumors produce 5-hydroxytryptophan (and histamine) instead of serotonin.
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 (table 3). Although many patients with the carcinoid syndrome have similar modest elevations, some 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) [3].
Urinary excretion of serotonin — Measurement of urinary 5-HIAA excretion is generally not useful in foregut (gastroduodenal, bronchial) carcinoids, which often lack aromatic amino acid decarboxylase (table 1). Very rarely, these patients can present with an atypical hormonal syndrome associated with secretion of 5-hydroxytryptophan; however, assays for this metabolite are not available in clinical laboratories in the United States.
Measurement of urinary serotonin may be of value in the rare patient with a foregut carcinoid in whom carcinoid syndrome is suspected, since DOPA decarboxylase in the renal parenchyma may convert the 5-hydroxytryptophan to serotonin, leading to high levels of urinary serotonin [4].
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. Well-differentiated neuroendocrine tumors, including carcinoids, are associated with elevated blood concentrations of chromogranins, which increase with larger tumor burden [5-8]. Chromogranins B and C are less sensitive indicators of neuroendocrine tumors as compared to chromogranin A (CgA) [9].
The sensitivity and specificity of CgA depends on the cutoff value. This was illustrated in a series that compared plasma CgA levels in 238 patients with well-differentiated neuroendocrine tumors, 42 with chronic atrophic gastritis, and 48 healthy individuals [6]. Using the DAKO ELISA kit, the best cutoff range between participants without neoplasia and those with neuroendocrine tumors was 31 to 32 U/L (sensitivity and specificity of 75 and 84 percent, respectively). When specificity was set at 95 percent, with a cutoff of 84 to 87 U/L, sensitivity was only 55 percent. This assay, which measures CgA concentration in U/L, is not usually used in the United States; there is a lack of international standardization that makes it difficult to extrapolate these values to other CgA assays [10].
False positive elevations of CgA can be present in a number of other conditions (table 4). They are especially common in patients who are taking a proton pump inhibitor [11].
Due to its relatively low specificity, we do not recommend the use of CgA as a screening test for diagnosis of the carcinoid syndrome. It is more appropriately used as a tumor marker in patients with an established diagnosis in order to assess disease progression, response to therapy or recurrence after surgical resection. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Chromogranin A'.)
Blood serotonin concentration — Various serotonin assays have been described in the literature including whole blood serotonin, platelet-rich plasma serotonin and platelet poor plasma serotonin assays. However, the sensitivities and specificities of these assays have not been well established. In one report, the mean fasting blood serotonin concentration in normal subjects ranged from 71 to 310 ng/mL (0.4 to 1.8 µmol/L). Ten patients with the carcinoid syndrome had markedly elevated values, from 790 to 4500 ng/mL (4.5 to 25.5 µmol/L); of these, two had normal urinary 5-HIAA excretion [12]. However, false positive serotonin tests may occur due release of platelet serotonin as well as by ingestion of tryptophan/serotonin-rich foods [13]. Consequently, we do not recommend measurement of blood serotonin levels as a standard diagnostic test for the carcinoid syndrome.
TUMOR LOCALIZATION AND STAGING — The carcinoid syndrome is primarily associated with metastatic carcinoid tumors that originate in the small intestine or proximal colon. Vasoactive peptides that are produced by localized intestinal carcinoid tumors are inactivated in the portal circulation and thus do not result in the carcinoid syndrome. Imaging studies should therefore focus on the abdomen and pelvis. CT, MRI, and somatostatin receptor scintigraphy (SRS, OctreoScans) are the primary imaging modalities used to identify metastatic carcinoid tumors.
Computed tomography — CT scans are noninvasive and readily available. Helical (spiral) multiphasic contrast-enhanced CT is recommended for evaluation of patients with carcinoid tumors. (See "Computed tomography of the hepatobiliary tract", section on 'Contrast material' and "Computed tomography of the hepatobiliary tract", section on 'Helical (spiral) CT'.)
Most carcinoid tumors are highly vascular, and liver metastases may appear isodense with the liver on a noncontrasted study. Following the injection of intravenous (IV) contrast, carcinoids often enhance with iodinated contrast during the early arterial phase (approximately 20 seconds after contrast injection), with washout during the portal venous imaging phase (approximately 70 seconds after contrast injection) [14]. In addition, arterial phase and portal venous phase sequences can be used to maximize the conspicuity of liver metastases compared to the surrounding normal liver parenchyma (picture 1).
Carcinoid tumors originating in the small intestine often produce mesenteric masses with dense desmoplastic fibrosis, either due to direct extension of primary tumors into the mesentery, or due to mesenteric lymph node metastases (picture 2). CT scans are ideal for identification of these tumors, which are often located in the root of the mesentery and are characterized by a circumferential pattern of fibrosis which tethers surrounding small bowel.
Magnetic resonance imaging — MRI may represent the most sensitive method for detection of liver metastases. In one study of 64 patients with metastatic gastrointestinal neuroendocrine tumors, multiphasic MRI detected more hepatic lesions than either CT or somatostatin receptor scintigraphy [15]. As a result of this greater sensitivity for liver metastases, some physicians prefer MRI over CT for assessing the status of the liver in patients with carcinoid tumor [16]. This subject is discussed in detail elsewhere. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Cross-sectional imaging'.)
As with CT scans, early arterial phase imaging following the injection of contrast is critical for the detection of small hypervascular liver metastases (picture 1). In a study of 37 patients with liver metastases from gastroenteropancreatic NETs, the most sensitive sequences for detection of liver metastases were hepatic arterial phase and fast spin-echo T2-weighed images [17].
Somatostatin-receptor scintigraphy (OctreoScan) — Many carcinoid tumors express high levels of somatostatin receptors and can therefore be imaged with a radiolabeled form of the somatostatin analog octreotide (111-indium pentetreotide) using somatostatin receptor scintigraphy (SRS, OctreoScan). This technique has the advantage of instantaneous whole body scanning, which also allows detection of metastases outside of the abdominal region. Poorly differentiated neuroendocrine tumors express low somatostatin-receptor levels and are unlikely to be detected on OctreoScan imaging [18].
The accuracy of SRS has improved with the addition of single photon emission computed tomography (SPECT) to planar imaging, since SPECT permits more accurate differentiation between areas of pathologic and physiologic uptake in the abdomen (picture 3 and picture 4 and picture 5) [19,20]. In a report describing 72 patients with gastroenteropancreatic neuroendocrine tumors (ie, carcinoid, pancreatic neuroendocrine (islet cell) tumor, or other) who were examined with SPECT/CT hybrid imaging, localization was improved in 23 of 44 SRS-positive studies, and the test affected clinical management in 10 patients [20].
In older studies, the sensitivity of SRS compared favorably with other imaging modalities [21]. However, technological advancements in CT and MRI scans over the past several decades have led some to question whether SRS is still a necessary component of the staging workup for carcinoid and other neuroendocrine tumors:
•In a series of 121 patients with a gastroenteropancreatic neuroendocrine tumor, 107 of whom had metastatic disease, multiphase contrast-enhanced CT or MRI detected more pathologic lesions than did SPECT-SRS [22]. Of the 107 patients with metastatic disease that was demonstrated by CT or MRI, only 85 (79 percent) had abnormal findings on SRS that correlated with the abnormalities on cross-sectional imaging. Furthermore, none of the 107 patients had soft tissue abnormalities or primary tumors identified by SPECT-SRS that were not also seen on cross-sectional imaging. SPECT-SRS did identify clinically unsuspected bone metastases that were not identified on CT or MRI.The authors concluded that the routine use of octreotide scanning as an adjunct for tumor staging was not justified unless the finding of asymptomatic bone lesions would change patient management and the treatment plan.
•In another study of 37 patients with a neuroendocrine tumor, MRI, and CT were substantially superior to SRS for detection of liver metastases [17]. The sensitivity of OctreoScans was found to be particularly poor (<35 percent) for lesions smaller than 1.5 cm in diameter.
However, in our view, SRS is complementary to cross sectional imaging in the evaluation of a patient with carcinoid syndrome. In addition to localization of extraabdominal disease sites, SRS offers functional information on levels of somatostatin-receptor expression; this can aid in the selection of appropriate candidates with advanced disease for somatostatin-based therapies:
•In centers that perform peptide receptor radioligand therapy with radiolabeled somatostatin analogs such as 90-Y-DOTA tyr3-octreotide (90Y-edotreotide) or 177-Lu-DOTA, Tyr3-octreotate (177-Lu-DOTATOC), SRS is an essential component of workup since levels of radiotracer uptake predict response to treatment [23]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)
•It is less clear whether the level of radiotracer uptake predicts response to the conventional, non-radiolabeled somatostatin analogs octreotide and lanreotide. Some physicians advocate baseline SRS prior to treatment with a somatostatin analog; however, patients with hormonal syndromes and a negative SRS may respond to therapy with a somatostatin receptor analog. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Options to control tumor growth", section on 'Octreotide and other somatostatin analogs'.)
Functional PET imaging techniques — Although not yet clinically available, several positron emission tomography (PET) tracers for functional imaging have emerged (18-F-dihydroxy-phenyl-alanine [18F-DOPA], 11-C-5-hydroxytryptophan [11-C-5-HTP]), and 68-Ga-DOTA- D-Phe1-Tyr3-Octreotide (68-Ga-DOTATOC), which, in combination with high resolution PET integrated with CT, hold promise for improved detection and staging of NETs in the future. These novel PET modalities offer higher spatial resolution than conventional somatostatin receptor scintigraphy (SRS) and are associated with improved sensitivity for detection of small lesions (picture 3). This subject is discussed in detail elsewhere. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Other functional imaging methods'.)
Endoscopy — Upper and lower endoscopy (with attention to the terminal ileum) should be performed for the evaluation of metastatic carcinoid with an unknown primary site.
Bronchial carcinoids — (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Cross-sectional imaging'.)
CT scans and SRS 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 (picture 6). Bronchial carcinoids can present with atypical carcinoid syndrome, characterized by severe and prolonged flushes, hemoptysis, or rarely signs of left-sided heart failure due to valve disease, even in the absence of hepatic metastases. (See "Bronchial carcinoid tumors".)
SUMMARY AND RECOMMENDATIONS
•The presence of the carcinoid syndrome may be suspected when a patient has suggestive symptoms such as otherwise unexplained diarrhea or flushing. However other diagnoses must be considered. The differential diagnosis of flushing, for example, includes physiologic events, drugs, and a number of diseases other than the carcinoid syndrome (table 2). (See "Clinical features of the carcinoid syndrome".) Moreover, other neuroendocrine tumor types can cause severe chronic diarrhea. (See 'Indications' above.)
•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 (figure 1). This test has a sensitivity of 75 percent [4], but requires strict avoidance of foods containing serotonin and tryptophan as well as certain drugs during the urine collection (table 3). (See 'Urinary excretion of 5-HIAA' above.)Measurement of urinary 5-HIAA excretion is generally not useful in foregut (gastroduodenal, bronchial) carcinoids, which often lack aromatic amino acid decarboxylase. Due to its relatively low specificity, we do not recommend the use of serum chromogranin A (CgA) as a screening test for diagnosis of the carcinoid syndrome. (See 'Chromogranin concentration' above.)
•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 somatostatin receptor scintigraphy (SRS), have a complementary role in tumor localization. For diagnostic workup of carcinoid syndrome, we generally perform helical, contrast enhanced, triple-phase CT scans of the abdomen and pelvis. (See 'Computed tomography' above.)Contrast-enhanced MRIs of the abdomen and pelvis are an acceptable alternative and are preferred by some physicians because of their greater sensitivity for liver metastases. (See 'Magnetic resonance imaging' above.)
•Somatostatin-receptor-scintigraphy (SRS, OctreoScan) has a complementary role in the diagnosis and localization of carcinoid tumors. SRS offers whole-body imaging and functional information regarding tumoral expression of somatostatin receptors. (See 'Somatostatin-receptor scintigraphy (OctreoScan)' above.)
•Radiographic staging and tumor localization – Common imaging modalities include CT or MRI scans as well as somatostatin-receptor scintigraphy (SRS; OctreoScan®). Upper and lower endoscopy (with attention to the terminal ileum) should be performed for the evaluation of metastatic carcinoid with an unknown primary site. While video capsule endoscopy allows for evaluation of the entire small intestine, routine use of capsule endoscopy cannot be recommended due to the risk of bowel obstruction from retention of the capsule at the site of an intestinal carcinoid. Mesenteric masses are usually indicative of a primary tumor located in the small intestine. Radiographic staging and tumor localization of carcinoid tumors is addressed in detail elsewhere. (See "Diagnosis of the carcinoid syndrome and tumor localization".)
•Pathologic assessment of tumor differentiation and/or grade (assessment of mitotic rate and/or Ki-67 index, presence/absence of necrosis and pleomorphism). This subject is addressed in detail elsewhere. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature'.)
•Removal of the tumor if all disease is surgically resectable, even if liver metastases are present. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Options to control tumor growth", section on 'Surgical options for metastatic disease'.)
•Control of carcinoid symptoms, if present. •Somatostatin analogs such as octreotide are highly effective in controlling the symptoms associated with carcinoid tumors. For patients who are symptomatic from carcinoid syndrome, we recommend initiating treatment with a somatostatin analog (Grade 1A). (See 'Somatostatin-analog therapy' above.) We usually begin therapy with octreotide LAR 20 to 30 mg every four weeks. Depot lanreotide is another alternative to octreotide LAR.
•For patients with liver metastases, hepatic resection can provide long-term symptomatic relief of the carcinoid syndrome. While resection is widely accepted for symptomatic patients with completely resectable disease, the value of cytoreductive or debulking surgery in symptomatic patients with more advanced unresectable liver metastases is more controversial, and decisions must be individualized.
Appendix — The prognosis of appendiceal carcinoids is best predicted by tumor size. In many series, tumors less than 2 cm in diameter (found in approximately 95 percent of patients) have a low likelihood of metastases at diagnosis
In contrast, up to 30 percent of larger tumors have already metastasized at diagnosis, mostly to regional nodes.
Optimal surgical management for appendiceal carcinoids is subject to some debate.
Because most are discovered incidentally in an appendectomy specimen done for other reasons, a decision must be made whether or not to return the patient to the operating room for a right colectomy.
- Unlike simple appendectomy, colectomy removes the draining lymph nodes of the appendix and any residual disease that might remain at the base of the appendix or in the mesoappendix.
Because of the association of tumor size with prognosis,
***right colectomy for tumors larger than 2 cm and for tumors 1 to 1.9 cm with mesoappendiceal invasion
***Simple appendectomy alone is sufficient for tumors <1.0 cm in the absence of mesoappendiceal invasion and for tumors 1 to 1.9 cm that lack mesoappendiceal invasion
Carcinoid tumors of the small intestine are most commonly found in the ileum, within 60 cm of the ileocecal valve. Small intestinal carcinoids have the potential to metastasize, irrespective of size (table 4). The TNM staging system for small bowel carcinoids, which is distinct from that used for appendiceal carcinoids, is presented in the table (table 6). (See "Epidemiology, clinical features, and types of small bowel neoplasms", section on 'Carcinoid tumors'.)
Patients with nonmetastatic tumors should be treated with resection of the involved segment and small bowel mesentery. Because multiple carcinoids are present in nearly 26 percent of cases, the remainder of the small bowel should be examined at the time of surgery [3].
Although this is a controversial area, resection of the primary tumor may be advised even in patients with known distant metastases in order to reduce the potential for bowel obstruction, bleeding, or to palliate abdominal pain related to the primary tumor.
The prognosis depends upon disease stage. However, even among patients with distant metastasis, five year survival rates range from 40 to 85 percent; ten year survival rates of 60 percent are reported [4-6]. (See 'Stage and site of origin' below.)
Most rectal carcinoid tumors are small, localized, and mucosal or submucosal in location
— As with rectal adenocarcinomas, transrectal endoscopic ultrasound (TEUS) is often useful for assessment of tumor size, depth of invasion and lymph node involvement in rectal carcinoids
.Tumors that are smaller than 1 cm and confined to the mucosa or submucosa (T1) can be treated by local endoscopic excision
Multiple techniques have been described for endoscopic resection of submucosal tumors, including endoscopic submucosal dissection , band snare , band ligation , and aspiration lumpectomy.
—- The risk of recurrence is exceptionally small for stage I tumors (although not zero ); the reported five-year survival rate was 97 percent
The optimal treatment for tumors that are larger than 1 cm but smaller than 2 cm is controversial . Transanal excision can be performed in patients with intermediate sized tumors (1 to 2 cm) that are confined to the submucosa (ie, T1 (table 7).
— Patients whose tumors invade the muscularis propria (T2) in whom lymph node metastases are excluded by TEUS can also be managed with transanal excision . Transanal endoscopic microsurgery (TEM) is another option for tumors of intermediate size and invasiveness, particularly in the proximal rectum. It can be used to resect tumors that are difficult to excise using conventional techniques or as a salvage option in patients with residual positive margins [23,24].
Tumors larger than 2 cm and those that invade into or beyond the muscularis propria (ie, T3/4 tumors) or have regional lymph node metastases have usually been treated by low anterior resection or abdominoperineal resection (APR) depending on the distance from the anal verge, similar to treatment for rectal adenocarcinomas. APR is generally required for very distal rectal tumors [25].
——Prognosis is mainly dependent on tumor size and depth of invasion, as reflected by the T-stage classification [6]. The relationship between size and metastatic propensity is depicted in the table (table 4).
—- 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 .
— Carcinoid tumors of the colon tend to be more aggressive than those arising in the rectum;
— five-year survival rates were only 62 percent across all stages (compared to 88 percent for rectal carcinoids)
— Most patients with nonmetastatic carcinoid tumors of the colon should be managed with formal partial colectomy and regional lymphadenectomy, similar to treatment of colonic adenocarcinomas.
— Prognosis is dependent on stage. The TNM staging system that includes carcinoid tumors of the colon is outlined in the table
Gastric carcinoids are subdivided into three categories, with differing biologic behavior and prognoses:
•Type 1, which represent 70 to 80 percent of all gastric carcinoids, are associated with chronic atrophic gastritis. In this condition, serum gastrin rises in response to gastric achlorhydria. The elevated gastrin, in turn, simulates neuroendocrine cell hyperplasia in the stomach and development of multifocal polypoid carcinoid tumors. The clinical behavior of these tumors is usually indolent.
•Type 2, which represent approximately 5 percent of gastric carcinoid tumors, also occur as a result of elevated serum gastrin levels stimulating multifocal gastric carcinoid tumors. The underlying cause of type 2 gastric carcinoids is a pancreatic or duodenal gastrinoma (Zollinger-Ellison syndrome). The clinical behavior is usually indolent.
•Type 3 gastric carcinoids (sporadic carcinoids) occur in the absence of atrophic gastritis or the Zollinger-Ellison syndrome. 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.
Management depends on the type of gastric carcinoid:
•Type 3 (sporadic) gastric carcinoids are treated by partial or total gastrectomy with local lymph node resection [28].
•For type 1 and 2 gastric carcinoids smaller than 1 to 2 cm, endoscopic resection represents adequate therapy. Subsequent endoscopic surveillance is needed every 6 to 12 months since these patients continue to exhibit mucosal changes and hyperplasia of enterochromaffin-like cells (ECL) due to sustained hypergastrinemia.Progression to a malignant phenotype or disease-related death is rare with small tumors [31]. Metastases occur in less than 10 percent of tumors ≤2 cm . Antrectomy is a reasonable option for type 1 gastric carcinoids if there are numerous progressive tumors. Antrectomy reduces hypergastrinemia by reducing the gastrin-producing cell mass in the antrum of the stomach; in most cases, this leads to tumor regression .
— antrectomy remained tumor-free for an average of 65 months.
•More aggressive surgical therapy is rarely needed for type 1 gastric carcinoids, unless there is extensive tumor involvement of the gastric wall (which increases the risk for a coexisting adenocarcinoma , tumor size >2 cm (which increases the risk for metastases ), or for emergent bleeding .
The role of medical rather than surgical therapy (anti-gastrin maneuvers such as acidification by diet or dilute oral hydrochloric acid, or somatostatin analog therapy) for type 1 tumors is debated . Gastrin levels may or may not decrease, and continued endoscopic surveillance is necessary. Such therapy is best restricted to patients who are not suitable for surgical treatment
Stage and site of origin — As a general principle, well-differentiated tumors originating in the midgut (small intestine, proximal colon) are more prone to metastasize than are well-differentiated tumors of the foregut (lung, stomach) or hindgut (distal colon, rectum).
However, they also progress more slowly once they do metastasize, and as a result, median survival durations are longer among patients with metastatic (stage IV) carcinoid tumors of the small intestine compared to metastatic carcinoid tumors originating in other sites.
Poorly differentiated neuroendocrine carcinomas are often associated with a rapid clinical course. Well-differentiated NETs, on the other hand, generally have a much better prognosis, even if metastatic. Issues of tumor classification are discussed in detail elsewhere.
Posttreatment followup — :
•After treatment of all resected small intestinal and colonic carcinoid tumors, and for rectal, gastric, and appendiceal carcinoids >2 cm :
•3 to 12 months postresection: History and physical examination, consider abdominal/pelvic CT or MRI, consider urine 5-HIAA, consider assay of serum chromogranin A (CGA).
•>1 year postresection: History and physical examination, consider urine 5-HIAA, consider assay of serum CGA, imaging studies as clinically indicated.
•Posttreatment surveillance is not recommended for appendiceal tumors <2 cm and rectal tumors <1 cm in size. For rectal tumors 1 to 2 cm in size, the only surveillance recommended is proctoscopy at 6 and 12 months.
•For gastric carcinoids ≤2 cm, surveillance recommendations include history and physical examination with esophagogastroduodenoscopy (EGD) every 6 to 12 months for three years and annually thereafter; imaging studies only as clinically indicated.
•We generally agree with these guidelines. However, given the long-natural history and the propensity for small bowel carcinoids to metastasize, we recommend surveillance with triple-phase CT scans or MRI of the abdomen and pelvis, urine 5-HIAA and CGA every six months for the first one to two years after surgery; annually for the next four years; and then every two years until approximately 10 years after surgery for all resected small intestinal and colonic carcinoid tumors, and for rectal, gastric, and appendiceal carcinoids >2 cm.
