Epidemiology
The age-adjusted incidence of carcinoid tumors worldwide is approximately 2 per 100,000 persons.[1,2] The average age at diagnosis is 61.4 years.[3] Carcinoid tumors represent about 0.5% of all newly diagnosed malignancies.[2,3]
Anatomy
Carcinoid tumors are rare, slow-growing tumors that originate in cells of the diffuse neuroendocrine system. They occur most frequently in tissues derived from the embryonic gut. Foregut tumors, which account for up to 25% of cases, arise in the lung, thymus, stomach, or proximal duodenum. Midgut tumors, which account for up to 50% of cases, arise in the small intestine, appendix, or proximal colon. Hindgut tumors, which account for approximately 15% of cases, arise in the distal colon or rectum.[4] Other sites of origin include the gallbladder, kidney, liver, pancreas, ovary, and testis.[3,4,5]
GI carcinoid tumors, especially tumors of the small intestine, are often associated with other cancers. Synchronous or metachronous cancers occur in approximately 29% of patients with small intestinal carcinoids.[3] However, it is possible that the association may be due in part to the serendipitous discovery of slow-growing carcinoid tumors, which are found while staging or investigating symptoms from other tumors.
Histology
The term carcinoid should be used for well-differentiated neuroendocrine tumors (NETs) or carcinomas of the GI tract only; the term should not be used to describe pancreatic NETs or islet cell tumors.[6] (Refer to the PDQ summary on Pancreatic Neuroendocrine Tumors [Islet Cell Tumors] Treatment for more information.) Data regarding carcinoids and other NETs, such as poorly differentiated neuroendocrine carcinomas, may be combined in some epidemiologic and clinical studies, rendering separate consideration difficult. Occurring nonrandomly throughout the GI tract are more than 14 cell types, which produce different hormones.[7] (Refer to the Cellular and Pathologic Classification of GI Carcinoid Tumors section of this summary for more information.) Although the cellular origin of NETs of the GI tract is uncertain, consistent expression of cytokeratins in NETs and the expression of the caudal-related homeodomain protein 2 (CdX2 protein), an intestinal transcription factor in endocrine tumors of the small intestine, suggests an origin from an epithelial precursor cell.[8]
Most NETs of the small and large intestines occur sporadically, while others may occur within the background of an inherited neoplasia syndrome such as multiple endocrine neoplasia type 1 (MEN1) or neurofibromatosis type 1 (NF1) (e.g., gastrin-producing G-cell tumors and somatostatin-producing D-cell tumors of the duodenum, respectively).[9] Tumor multifocality is the rule within the background of neuroendocrine cell hyperplasia, but multifocality is found in approximately one-third of patients with small enterochromaffin cell tumors in the absence of proliferative or genetic factors; clonality studies suggest that most of these neoplasms are separate primary lesions.[10,11] Gastric carcinoids may be associated with chronic atrophic gastritis.[7]
Histopathology
Individual carcinoid tumors have specific histologic and immunohistochemical features based on their anatomic location and endocrine cell type. However, all carcinoids share common pathologic features that characterize them as well-differentiated NETs.[5] In the gastric or intestinal wall, carcinoids may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules; the overlying gastric or intestinal mucosa may be intact or have focal ulceration.
Neuroendocrine cells have uniform nuclei and abundant granular or faintly staining (clear) cytoplasm, and are present as solid or small trabecular clusters, or are dispersed among other cells, which may make them difficult to recognize in sections stained with hematoxylin and eosin; immunostaining enables their exact identification.[12] At the ultrastructural level, neuroendocrine cells contain cytoplasmic membrane-bound dense-cored secretory granules (diameter >80 nm) and may also contain small clear vesicles (diameter 40–80 nm) that correspond to the synaptic vesicles of neurons.
Molecular genetics
Occasionally, GI carcinoids occur in association with inherited syndromes, such as MEN1 and NF1.[13,14,15]
MEN1 is caused by alterations of the MEN1 gene located at chromosomal region 11q13. (Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.) Most carcinoids associated with MEN1 appear to be of foregut origin.[13] NF1 is an autosomal dominant genetic disorder caused by alteration of the NF1 gene at chromosome 17q11.[16] Carcinoids in patients with NF1 appear to arise primarily in the periampullary region.[5,17,18]
In sporadic GI carcinoids, numerous chromosomal imbalances have been found by comparative genome hybridization analysis. Gains involving chromosomes 5, 14, 17 (especially 17q), and 19 and losses involving chromosomes 11 (especially 11q) and 18 appear to be the most common.[19,20]
The most frequently reported mutated gene in GI carcinoids is CTNNB1. In one study, CTNNB1 exon 3 mutations were found in 27 (37.5%) of 72 cases.[21]
However, no consistent genetic markers for GI carcinoid prognosis have yet been identified.[9] (Refer to the Cellular and Pathologic Classification of GI Carcinoid Tumors section of this summary for more information.)
Carcinoid syndrome
Carcinoid syndrome, which occurs in fewer than 20% of patients with carcinoid tumors, is caused by the release of metabolically undergraded vasoactive amines into the systemic circulation. It is associated with flushing, abdominal pain and diarrhea, bronchoconstriction, and carcinoid heart disease.[22,23] Because vasoactive amines are efficiently metabolized by the liver, carcinoid syndrome rarely occurs in the absence of hepatic metastases. Exceptions include circumstances in which venous blood draining from a tumor enters directly into the systemic circulation (e.g., primary pulmonary or ovarian carcinoids, pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoids, or extensive bone metastases).
Carcinoid heart disease develops in more than one-third of patients with carcinoid syndrome. Pathologically, the cardiac valves become thickened because of fibrosis, and the tricuspid and pulmonic valves are affected to a greater extent than the mitral and aortic valves. Symptoms include:[22]
Severe carcinoid heart disease is associated with reduced survival. (Refer to the Prognostic Factors section of this summary for more information.)
Site-Specific Clinical Features
The clinical features of GI carcinoids vary according to anatomical location and cell type.[5,12,24] Most carcinoids in the GI tract are located within 3 feet (~90 cm) of the ileocecal valve, with 50% found in the appendix.[25] They are often detected fortuitously during surgery for another GI disorder or during emergency surgery for appendicitis, GI bleeding, or perforation.[26]
Gastric carcinoids
Most gastric carcinoids are enterochromaffin-like (ECL)-cell carcinoids; rarely, other types may occur in the stomach. (Refer to Table 1 in the Cellular and Pathologic Classification of GI Carcinoid Tumors section of this summary for more information.)
Type I ECL-cell gastric carcinoids, the most common type, typically do not have clinical symptoms. They are often discovered during endoscopy for reflux, anemia, or other reasons; and are typically multifocal. Occurring most commonly in women (female-to-male ratio, 2.5:1) at a mean age of 63 years, achlorhydria may be present, and hypergastrinemia or evidence of antral G-cell hyperplasia is usually found.[5,24,27] These tumors are gastrin-driven and arise in a background of chronic atrophic gastritis of the corpus, usually because of autoimmune pernicious anemia but sometimes caused by Helicobacter pylori infection.[9]
Type II ECL-cell carcinoids, the least common type of gastric carcinoids, occur at a mean age of 50 years with no gender predilection. The hypergastrinemia associated with MEN1-Zollinger-Ellison syndrome (ZES) is thought to promote the ECL-cell hyperplasia that leads to type II tumors.[27,28]
Type I and type II ECL-cell gastric carcinoids have been reported to metastasize in fewer than 10% of cases.[27,29] Type III gastric ECL-cell carcinoids, the second most common type of gastric carcinoid, occur mostly in men (male-to-female ratio, 2.8:1) at a mean age of 55 years.[27] There are no neuroendocrine manifestations, and patients typically present with signs and symptoms related to an aggressive tumor.[5,30]
Duodenal carcinoids
Comprising only 2% to 3% of GI NETs and discovered incidentally or because of symptoms from hormonal or peptide production, duodenal carcinoids may also arise in the periampullary region, obstruct the ampulla of Vater, and produce jaundice.[3,5,31] The age at presentation varies widely (range, 19–90 years; mean age, 53 years).[15,32]
The most common duodenal carcinoids are gastrin-producing G-cell tumors (~two-thirds) followed by somatostatin-producing D-cell tumors (~one-fifth), which rarely produce systemic manifestations of somatostatin excess.[5,31,33]
Gastrin production from G-cell carcinoids (also called gastrinomas if serum gastrin levels are elevated) results in ZES in approximately one-third of the cases of duodenal G-cell tumors.[24] Although duodenal G-cell carcinoids may occur sporadically, 90% of patients with MEN1 develop them.[5] The clinical manifestations of serum gastrin elevation include:
The most common symptom is abdominal pain; the combination of abdominal pain and diarrhea is present in approximately 50% of patients. In contrast to sporadic gastrinomas, which are usually solitary lesions, gastrinomas in patients with MEN1-ZES are usually multiple and smaller than 5 mm.[5]
Somatostatin-producing D-cell tumors occur exclusively in and around the ampulla of Vater, and as many as 50% of patients with D-cell carcinoids have NF1.[34] Most of the patients with NF1 are Black women, and their tumors are exclusively located in the periampullary region.[15,32] As a result of their location, these tumors may cause local obstructive symptoms and signs such as jaundice, pancreatitis, or hemorrhage. Although D-cell carcinoids produce somatostatin, systemic manifestations of excess somatostatin such as steatorrhea, diarrhea, diabetes mellitus, hypochlorhydria and achlorhydria, anemia, and cholelithiasis are rare.[31]
Jejunal and ileal carcinoids
Most jejunal and ileal carcinoids are argentaffin-positive, substance P–containing, and serotonin-producing EC-cell tumors that generate carcinoid syndrome when hepatic or retroperitoneal nodal metastases are present. L-cell, glucagon-like polypeptide-producing, and pancreatic polypeptide- and polypeptide YY-producing tumors occur less frequently.[24] Ileal carcinoids develop preferentially in the terminal ileum.[12] Jejunal and ileal carcinoids occur equally in men and women at a mean age of 65.4 years.[3] Similar to all carcinoids, jejunal and ileal carcinoids vary in their biologic behavior and ability to metastasize. Typically, EC-cell carcinoids of the small intestine metastasize to lymph nodes and the liver.[5] Patients with these lesions may be asymptomatic. The primary tumor may cause small intestinal obstruction, ischemia, or bleeding, and some patients may complain of a long history of intermittent crampy abdominal pain, weight loss, fatigue, abdominal distention, diarrhea, or nausea and vomiting.[5,23,35]
At the time of diagnosis, ileal NETs (i.e., carcinoids plus poorly differentiated neuroendocrine carcinomas) are commonly larger than 2 cm and have metastasized to regional lymph nodes; in as many as 40% of cases, the tumors are multifocal.[12] Immunocytochemically, the cells contain serotonin, substance P, kallikrein, and catecholamine. Approximately 20% of patients with ileal NETs have regional lymph node and liver metastases. Most GI carcinoids secrete their bioactive peptides and amines into the portal circulation, and the effects of these biochemical mediators are diminished or negated by hepatic detoxification; accordingly, carcinoid syndrome (e.g., flush, diarrhea, and endocardial fibrosis) occurs only in patients with liver metastases because hepatic detoxification of serotonin is bypassed.
Appendiceal carcinoids
Most appendiceal carcinoids are serotonin-producing EC-cell tumors similar to carcinoids that occur in the jejunum and ileum; less commonly, appendiceal carcinoids are L-cell tumors similar to those in the colon.[16] The biologic behavior of both cell types is strikingly different in the appendix compared with tumors of the ileum and nonappendiceal colon. Most appendiceal carcinoids have a benign clinical course and do not metastasize, perhaps because growth in the appendix produces obstruction, appendicitis, and subsequent surgical removal.[5,36] Although appendiceal carcinoids occur in patients of all ages, patients with these tumors tend to be much younger than patients diagnosed with other appendiceal neoplasms or carcinoids at other sites. Appendiceal carcinoids are reportedly more common in female patients.[3,5] However, age and gender patterns may be spurious, reflecting the younger age range of patients who typically undergo appendectomy for inflammatory appendicitis, and the larger number of incidental appendectomies performed in women during pelvic operations.
Colorectal carcinoids
Most colorectal carcinoids occur in the rectum; fewer arise in the cecum.[5] In the cecum, argentaffin-like EC-cell carcinoids are most common, become increasingly less common in the more distal colon, and are uncommon in the rectum.[31] Rectal carcinoids account for approximately one-fourth of GI carcinoids and fewer than 1% of all rectal cancers.[3,31] Most rectal carcinoids have L-cell differentiation. The mean age of patients at diagnosis for colonic carcinoids is 66 years and for rectal carcinoids, 56.2 years. Although there is no specific gender predilection for colorectal carcinoids, rectal carcinoids are more common in the Black population.[3,37] Abdominal pain and weight loss are typical symptoms of colonic carcinoids, but more than 50% of patients with rectal carcinoids are asymptomatic, and the tumors are discovered at routine rectal examination or screening endoscopy.[24] Symptoms of rectal carcinoids include bleeding, pain, and constipation. Metastatic disease from colonic carcinoids may produce carcinoid syndrome, whereas metastatic disease from rectal carcinoids is not associated with carcinoid syndrome.[5,38]
Diagnostics: Biochemical Markers, Imaging, and Approach
Biochemical markers
Biochemical investigations in the diagnosis of GI carcinoids include the use of 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) collection, which has a specificity of approximately 88%, although the sensitivity is reported to be as low as 35%.[39,40,41] A time-consuming test, 5-HIAA requires dietary avoidance of serotonin-rich foods, such as bananas, tomatoes, and eggplant.[42] Measurement of plasma chromogranin A (CgA), first described in a study of adrenal gland secretions in 1967 as one of the soluble protein fractions (also including CgB and CgC) of chromaffin granules, is also useful.[43] Although plasma levels of CgA are very sensitive markers of carcinoids, they are nonspecific because they are also elevated in other types of NETs, such as pancreatic and small cell lung carcinomas.[44,45,46] Plasma CgA appears to be a better biochemical marker of carcinoids than does urinary 5-HIAA.[47] Numerous investigations have revealed an association between plasma CgA levels and disease severity.[26] However, false-positive plasma levels of CgA may occur in patients on proton pump inhibitors, reported to occur even with short-term, low-dose treatment.[48,49] Many other biochemical markers are associated with NETs—including substance P, neurotensin, bradykinin, human chorionic gonadotropin, neuropeptide L, and pancreatic polypeptide—but none match the specificity or predictive value of 5-HIAA or CgA.[44]
Imaging
Imaging modalities for GI carcinoids include the use of somatostatin scintigraphy with indium In 111 (111In)-octreotide; bone scintigraphy with technetium Tc 99m-methylene diphosphonate (99mTc-MDP); iodine I 123-metaiodobenzylguanidine (123I-MIBG) scintigraphy; computed tomography (CT); capsule endoscopy (CE); enteroscopy; and angiography.[26]
Somatostatin receptor scintigraphy
There are five different somatostatin receptor (SSTR) subtypes; more than 70% of NETs of both the GI tract and pancreas express multiple subtypes, with a predominance of receptor subtype 2 [sst(2)] and receptor subtype 5 [sst(5)].[50,51] The synthetic radiolabeled SSTR analog 111In-DTP-d-Phe10-{octreotide} affords an important method, somatostatin receptor scintigraphy (SRS), to localize carcinoid tumors, especially sst(2)-positive and sst(5)-positive tumors; imaging is accomplished in one session, and small primary tumors and metastases are diagnosed more readily than with conventional imaging or imaging techniques requiring multiple sessions.[26,52,53] Overall sensitivity of the octreotide scan is reported to be as high as 90%; however, failed detection may result from various technical issues, small tumor size, or inadequate expression of SSTRs.[26,54]
Bone scintigraphy
Bone scintigraphy with 99mTc-MDP is the primary imaging modality for identifying bone involvement in NETs and detection rates are reported to be 90% or higher.[26] 123I-MIBG is concentrated by carcinoid tumors in as many as 70% of cases using the same mechanism as norepinephrine and is used successfully to visualize carcinoids; however, 123I-MIBG appears to be about half as sensitive as 111In-octreotide scintigraphy in detecting tumors.[26,55]
CT/MRI
CT and magnetic resonance imaging (MRI) are important modalities used in the initial localization of carcinoid primaries and/or metastases. The median detection rate and sensitivity of CT and/or MRI have been estimated at 80%; detection rates by CT alone vary between 76% and 100%, while MRI detection rates vary between 67% and 100%.[26] CT and MRI may be used for initial localization of the tumor only because both imaging techniques may miss lesions otherwise detected by 111In-octreotide scintigraphy; one study has shown that lesions in 50% of patients were missed, especially in lymph nodes and extrahepatic locations.[26,56]
PET
A promising approach for positron emission tomography (PET) as an imaging modality to visualize GI carcinoids appears to be the use of the radioactive-labeled serotonin precursor carbon C 11-5-hydroxytryptophan (11C-5-HTP). With 11C-5-HTP, tumor detection rates have been reported to be as high as 100%, and some investigators have concluded that 11C-5-HTP PET should be used as a universal detection method for detecting NETs.[57,58,59] In one study of NETS, including 18 patients with GI carcinoids, 11C-5-HTP PET detected tumor lesions in 95% of patients. In 58% of cases, 11C-5-HTP PET detected more lesions than SRS and CT, compared with the 7% that 11C-5-HTP PET did not detect.[59] Other imaging approaches have been investigated using technetium-labeled isotopes, combining CT/MRI with fluorine F 18-fluorodopa PET, combining iodine I 131-MIBG with 111In-octreotide, and coupling the isotopes gallium Ga 68 and copper Cu 64 to octreotide.[26]
EUS
Endoscopic ultrasonography (EUS) may be a sensitive method for the detection of gastric and duodenal carcinoids and may be superior to conventional ultrasound, particularly in the detection of small tumors (2 mm–3 mm) that are localized in the bowel lumen.[60,61] In one study, the EUS was reported to have an accuracy of 90% for the localization and staging of colorectal carcinoids.[62]
CE
The development of CE in the diagnosis of GI carcinoids is nascent, although this technique may prove useful in the detection of small bowel carcinoids.[63]
Enteroscopy
Double-balloon enteroscopy is a time-consuming procedure that is being studied in the diagnosis of small bowel tumors, including carcinoids.[64,65] It is usually performed under general anesthesia, although it can be done under conscious sedation.
Angiography
MRI angiography has replaced angiography to a large extent. However, selective and supraselective angiography may be useful to:
Angiography may be useful as an adjunct to surgery, particularly in the case of large invasive lesions in proximity to the portal vein and superior mesenteric artery. Overall, this imaging technique provides a more precise topographic delineation of the tumor or tumor-related vessels and facilitates resection.[26]
General diagnostic approaches
As might be expected, diagnostic approaches to GI carcinoids vary according to anatomical location. In 2004, a consensus statement regarding the diagnosis and treatment of GI NETs was published on behalf of the European Neuroendocrine Tumor Society,[66] which details site-specific approaches to the diagnosis of GI carcinoids.
Prognostic Factors
Factors that determine the clinical course and outcome of patients with GI carcinoid tumors are complex and multifaceted and include the following:[67]
Elevated expression of the proliferation antigen Ki-67 and the tumor suppressor protein p53 have been associated with poorer prognosis; however, some investigators suggest that the Ki-67 index may be helpful in establishing prognosis of gastric lesions only and maintain that no consistent genetic markers of prognosis have yet been discovered.[9] Adverse clinical prognostic indicators include:
Follow-up and Survivorship
In general, patients with carcinoid tumors of the appendix and rectum experience longer survival than patients with tumors arising from the stomach, small intestine, and colon. Carcinoid tumors occurring in the small intestine, even those of small size, have a greater propensity to metastasize than those in the appendix, colon, and rectum.[67] Appendiceal and rectal carcinoids are usually small at the time of initial detection, and have rarely metastasized. The presence of metastases has been associated with a reduction in 5-year survival ranging from 39% to 60% in several case series and reviews.[3,68,69,70,71] However, some patients with metastatic carcinoid tumors have an indolent clinical course with survival of several years, whereas others experience an aggressively malignant course with short survival. Although metastases are associated with a shorter survival in large patient samples, the presence of metastases alone does not sufficiently predict the clinical course of the individual patient.
Approximately 35% of carcinoids of the small intestine are associated with carcinoid syndrome. The relatively common carcinoids of the appendix and rectum rarely produce this syndrome, and carcinoids from other sites have intermediate risks.[71,72] Investigations using echocardiographic criteria for carcinoid heart disease found prevalences ranging from 35% to 77% among patients with carcinoid syndrome.[73,74,75,76,77] The tricuspid valve is affected more frequently and severely than the pulmonic valve, and the presence and severity of carcinoid heart disease, particularly tricuspid valve dysfunction, is associated with shortened survival.[74,76,77,78] One study involving 64 patients with midgut carcinoid syndrome found 5-year survival rates of 30% for those with severe carcinoid heart disease versus 75% for those with no cardiac disease.[76]
In another study, statistically significantly reduced survival was observed for patients with midgut carcinoids who had urinary 5-HIAA concentrations greater than 300 μmol/24 hours compared with patients who had lower concentrations of urinary 5-HIAA.[79] Correspondingly, a study of patients with midgut carcinoid syndrome showed that urinary 5-HIAA levels greater than 500 μmol/24 hours were associated with shorter survival.[76] The degree of elevation of urinary 5-HIAA is also associated with the severity of carcinoid symptoms, with the highest levels being observed in patients with carcinoid heart failure.[76,80] In one study, vascular endothelial growth factor (VEGF) expression by low-grade tumors and surrounding stromal cells was associated with progression-free survival (PFS); median durations of PFS in patients with strong and weak VEGF expression were 29 months and 81 months, respectively.[81]
Related Summaries
Other PDQ summaries containing information related to GI carcinoid tumors include the following:
References:
A variety of neuroendocrine cells normally populate the gastrointestinal (GI) mucosa and submucosa. The type, location, and secretory products of GI neuroendocrine cells are well defined and are summarized in Table 1 below. As previously noted, individual carcinoid tumors have specific histologic and immunohistochemical features based on their anatomic location and neuroendocrine cell type. However, all carcinoids share common pathologic features that characterize them as well-differentiated neuroendocrine tumors (NETs).[1]
| CCK = cholecystokinin; D = somatostatin-producing; EC = enterochromaffin; ECL = enterochromaffin-like; G = Gastrin cell; GIP = gastric inhibitory polypeptide; L = enteroendocrine; M = motilin; N = neurotensin; PP = pancreatic polypeptide; S = secretin. | ||
| a Adapted from [1,2,3] | ||
| Cell Type | Location | Secretory Product |
| G cell | Gastric antrum and duodenum | Gastrin |
| ECL cell | Gastric fundus and body | Histamine |
| D cell | Stomach, duodenum, jejunum, colon, and rectum | Somatostatin |
| EC cell | Stomach, duodenum, jejunum, ileum, colon, and rectum | Serotonin, motilin, and substance P |
| CCK cell | Duodenum and jejunum | Cholecystokinin |
| GIP cell | Duodenum and jejunum | Gastric inhibitory polypeptide |
| M cell | Duodenum and jejunum | Motilin |
| S cell | Duodenum and jejunum | Secretin |
| PP cell | Duodenum | Pancreatic polypeptide |
| L cell | Jejunum, ileum, colon, and rectum | Polypeptide YY |
| N cell | Jejunum and ileum | Neurotensin |
Updated in 2000, the World Health Organization (WHO) classification of GI NETs is clinically and prognostically useful for patients with newly diagnosed NETs of the GI tract because it accounts for specific biological behavior according to location and tumor differentiation.[4,5]
This classification distinguishes between the following:
In this classification, the term carcinoid (or typical carcinoid) is used only for well-differentiated NETs of the GI tract, excluding the pancreas; the term malignant carcinoid (or atypical carcinoid) is used for the corresponding well-differentiated NETs at the same GI tract locations.[6,7] Despite some uncertainty surrounding the role of cell proliferation indices in the prognosis of NETs, it is clear that poorly differentiated carcinomas are highly aggressive and require a special therapeutic approach.[7,8,9] In a second step, the WHO classification subdivides GI NETs on the basis of localization and biology to achieve a prognostically relevant classification of the tumors.[5,6,7,9] In this subclassification, GI anatomical locations included the following:
(Refer to the Site-Specific Clinical Features section in the General Information About GI Carcinoid Tumors section of this summary for more information about a clinicopathologic correlation of cell types and anatomical location.)
In addition, in the WHO classification scheme, GI NETs have been grouped with pancreatic NETS (islet cell tumors) and labeled as gastroenteropancreatic NETs (GEP-NETs). However, because of differences in chromosomal alteration patterns and molecular genetics between GI NETs and pancreatic NETs, some investigators have suggested that this GEP-NET grouping requires reassessment.[7,9,10]
Because there were no proven molecular and genetic alterations with clinical and prognostic relevance, only traditional morphologic and histopathologic criteria were used in the classification. In addition to the level of differentiation, these criteria include the following:
Traditional cytologic and histopathologic assessment of growth patterns and cellular features of well-differentiated NETs are often of little help in predicting their functional behavior and degree of malignancy. In general, typical carcinoids occurring in the stomach, the appendix, or the rectum have an excellent prognosis.[6] In contrast, poorly differentiated NETs that are composed of cells displaying severe nuclear atypia, a high mitotic index, and few secretory granules are invariably high-grade malignancies.[7]
Diagnostic markers that help to identify GI NETs include the following:
Hormones that are highly specific for certain GI NETs are serotonin and substance P for ileal and appendiceal NETs, and VMAT2 for ECLomas.[7]
References:
American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define neuroendocrine tumors.[1,2,3,4,5,6]
Gastric Carcinoids
| Stage | TNM | Description |
|---|---|---|
| b The explanation for superscript b is at the end of Table 5. | ||
| I | T1, N0, M0 | T1 = Invades the lamina propria or submucosa and ≤1 cm in size.b |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| a Reprinted with permission from AJCC: Neuroendocrine Tumors: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 351–9. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 351–9. | ||
| b The explanation for superscript b is at the end of Table 5. | ||
| II | T2 or T3, N0, M0 | T2 = Invades the muscularis propria or >1 cm in size.b |
| T3 = Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa.b | ||
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 351–9. | ||
| b The explanation for superscript b is at the end of Table 5. | ||
| III | T1, T2, T3, or T4; N1; M0 | T1, T2, T3, or T4 = See Stage IV Neuroendocrine Tumors of the Stomach below in Table 5. |
| N1 = Regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| T4, N0, M0 | T4 = Invades visceral peritoneum (serosal) or other organs or adjacent structures.b | |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 351–9. | ||
| b For any T, add (m) for multiple tumors [TX(#), where X = 1−4 and # = number of primary tumors identified]; for multiple tumors with different Ts, use the highest. | ||
| IV | TX, T0, T1, T2, T3, or T4; NX, N0, N1; M1 | TX = Primary tumor cannot be assessed. |
| T0 = No evidence of primary tumor. | ||
| T1 = Invades the lamina propria or submucosa and ≤1 cm in size.b | ||
| T2 = Invades the muscularis propria or >1 cm in size.b | ||
| T3 = Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa.b | ||
| T4 = Invades visceral peritoneum (serosal) or other organs or adjacent structures.b | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis. | ||
| N1 = Regional lymph node metastasis. | ||
| M1 = Distant metastasis. | ||
Duodenal Carcinoids
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Duodenum and Ampulla of Vater. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 361–73. | ||
| I | T1, N0, M0 | T1 = Tumor invades the mucosa or submucosa only and is ≤1 cm (duodenal tumors); tumor ≤1 cm and confined within the sphincter of Oddi (ampullary tumors). |
| N0 = No regional lymph node involvement. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Duodenum and Ampulla of Vater. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 361–73. | ||
| II | T2 or T3; N0, M0 | T2 = Tumor invades the muscularis propria or is >1 cm (duodenal); tumor invades through sphincter into duodenal submucosa or muscularis propria, or is >1 cm (ampullary). |
| T3 = Tumor invades the pancreas or peripancreatic adipose tissue. | ||
| N0 = No regional lymph node involvement. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Duodenum and Ampulla of Vater. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 361–73. | ||
| III | T4, N0, M0 | T4 = Tumor invades the visceral peritoneum (serosa) or other organs. |
| N0 = No regional lymph node involvement. | ||
| M0 = No distant metastasis. | ||
| Any T, N1, M0 | Any T = See Stage IV Neuroendocrine Tumors of the Duodenum and Ampulla of Vater below in Table 9. | |
| N1 = Regional lymph node involvement. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Duodenum and Ampulla of Vater. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 361–73. | ||
| IV | Any T, Any N, M1 | TX = Primary tumor cannot be assessed. |
| T1 = Tumor invades the mucosa or submucosa only and is ≤1 cm (duodenal tumors); tumor ≤1 cm and confined within the sphincter of Oddi (ampullary tumors). | ||
| T2 = Tumor invades the muscularis propria or is >1 cm (duodenal); tumor invades through sphincter into duodenal submucosa or muscularis propria, or is >1 cm (ampullary). | ||
| T3 = Tumor invades the pancreas or peripancreatic adipose tissue. | ||
| T4 = Tumor invades the visceral peritoneum (serosa) or other organs. | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node involvement. | ||
| N1 = Regional lymph node involvement. | ||
| M1 = Distant metastases. | ||
Jejunal and Ileal Carcinoids
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Jejunum and Ileum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 375–87. | ||
| b The explanation for superscript b is at the end of Table 13. | ||
| I | T1, N0, M0 | T1 = Invades lamina propria or submucosa and ≤1 cm in size. |
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Jejunum and Ileum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 375–87. | ||
| b The explanation for superscript b is at the end of Table 13. | ||
| II | T2 or T3; N0, M0 | T2 = Invades muscularis propria or >1 cm in size. |
| T3 = Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa. | ||
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Jejunum and Ileum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 375–87. | ||
| b The explanation for superscript b is at the end of Table 13. | ||
| III | T1, T2, T3, or T4; N1, N2; M0 | T1, T2, T3, or T4 = See Stage IV Neuroendocrine Tumors of the Jejunum and Ileum below in Table 13. |
| N1 = Regional lymph node metastasis <12 nodes. | ||
| N2 = Large mesenteric masses (>2 cm) and/or extensive nodal deposits (≥12), especially those that encase the superior mesenteric vessels. | ||
| M0 = No distant metastasis. | ||
| T4, N0, M0 | T4 = Invades visceral peritoneum (serosal) or other organs or adjacent structures. | |
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Jejunum and Ileum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 375–87. | ||
| b For any T, add (m) for multiple tumors [TX(#) or TX(m), where X = 1−4, and # = number of primary tumors identifiedc]; for multiple tumors with different T, use the highest. | ||
| c Example: If there are two primary tumors, only one of which invades through the muscularis propria into subserosal tissue without penetration of overlying serosa (jejunal or ileal), we define the primary tumor as either T3(2) or T3(m). | ||
| IV | TX, T0, T1, T2, T3, or T4; NX, N0, N1, N2; M1 | TX = Primary tumor cannot be assessed. |
| T0 = No evidence of primary tumor. | ||
| T1 = Invades lamina propria or submucosa and ≤1 cm in size. | ||
| T2 = Invades muscularis propria or >1 cm in size. | ||
| T3 = Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa. | ||
| T4 = Invades visceral peritoneum (serosal) or other organs or adjacent structures. | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis has occurred. | ||
| N1 = Regional lymph node metastasis <12 nodes. | ||
| N2 = Large mesenteric masses (>2 cm) and/or extensive nodal deposits (≥12), especially those that encase the superior mesenteric vessels. | ||
| M1 = Distant metastasis. | ||
Appendiceal Carcinoids
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Appendix. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 389–94. | ||
| I | T1, N0 M0 | T1 = Tumor ≤2 cm in greatest dimension. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Appendix. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 389–94. | ||
| II | T2 or T3; N0, M0 | T2 = Tumor >2 cm but ≤4 cm. |
| T3 = Tumor >4 cm or with subserosal invasion or involvement of the mesoappendix. | ||
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Appendix. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 389–94. | ||
| III | T1, T2, T3, or T4; N1; M0 | T1, T2, T3, or T4 = See Stage IV Neuroendocrine Tumors of the Appendix below in Table 17. |
| N1 = Regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| T4, N0, M0 | T4 = Tumor perforates the peritoneum or directly invades other adjacent organs or structures (excluding direct mural extension to adjacent subserosa of adjacent bowel), e.g., abdominal wall and skeletal muscle. | |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Appendix. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 389–94. | ||
| IV | TX, T0, T1, T2, T3, or T4; NX, N0, N1; M1 | TX = Primary tumor cannot be assessed. |
| T0 = No evidence of primary tumor. | ||
| T1 = Tumor ≤2 cm in greatest dimension. | ||
| T2 = Tumor >2 cm but ≤4 cm. | ||
| T3 = Tumor >4 cm or with subserosal invasion or involvement of the mesoappendix. | ||
| T4 = Tumor perforates the peritoneum or directly invades other adjacent organs or structures (excluding direct mural extension to adjacent subserosa of adjacent bowel), e.g., abdominal wall and skeletal muscle. | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis. | ||
| N1 = Regional lymph node metastasis. | ||
| M1 = Distant metastasis. | ||
Colonic and Rectal Carcinoids
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 395–406. | ||
| b The explanation for superscript b is at the end of Table 21. | ||
| I | T1, N0, M0 | T1 = Tumor invades the lamina propria or submucosa and is ≤2 cm. |
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 395–406. | ||
| b The explanation for superscript b is at the end of Table 21. | ||
| IIA | T2, N0, M0 | T2 = Tumor invades the muscularis propria or is >2 cm with invasion of the lamina propria or submucosa. |
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| IIB | T3, N0, M0 | T3 = Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa. |
| N0 = No regional lymph node metastasis has occurred. | ||
| M0 = No distant metastasis. | ||
| Stage | Tb NM | Description | |
|---|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 395–406. | |||
| b The explanation for superscript b is at the end of Table 21. | |||
| IIIA | T4, N0, M0 | T4 = Tumor invades the visceral peritoneum (serosa) or other organs or adjacent structures. | |
| N0 = No regional lymph node metastasis has occurred. | |||
| M0 = No distant metastasis. | |||
| IIIB | T1, T2, T3, or T4; N1; M0 | T1 = Tumor invades the lamina propria or submucosa and is ≤2 cm. | |
| T2 = Tumor invades the muscularis propria or is >2 cm with invasion of the lamina propria or submucosa. | |||
| T3 = Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa. | |||
| T4 = Tumor invades the visceral peritoneum (serosa) or other organs or adjacent structures. | |||
| N1 = Regional lymph node metastasis. | |||
| M0 = No distant metastasis. | |||
| Stage | Tb NM | Description |
|---|---|---|
| a Reprinted with permission from AJCC: Neuroendocrine Tumors of the Colon and Rectum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 395–406. | ||
| b For any T, add (m) for multiple tumors [TX(#) or TX(m), where X = 1−4 and # = number of primary tumors identifiedc]; for multiple tumors with different T, use the highest. | ||
| c Example: If there are two primary tumors, only one of which invades through the muscularis propria into the subserosal tissue without penetration of the overlying serosa, we define the primary tumor as either T3(2) or T3(m). | ||
| IV | TX, T0, T1, T2, T3, or T4; Any N; M1 | TX = Primary tumor cannot be assessed. |
| T0 = No evidence of primary tumor. | ||
| T1 = Tumor invades the lamina propria or submucosa and is ≤2 cm. | ||
| T2 = Tumor invades the muscularis propria or is >2 cm with invasion of the lamina propria or submucosa. | ||
| T3 = Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa. | ||
| T4 = Tumor invades the visceral peritoneum (serosa) or other organs or adjacent structures. | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis has occurred. | ||
| N1 = Regional lymph node metastasis. | ||
| M1 = Distant metastasis. | ||
References:
Standard treatments for patients with gastrointestinal (GI) carcinoid tumors include the following:
Treatments being tested in clinical trials include the following:
Surgery
The only potential curative therapy for GI carcinoids, which may be possible in as many as 20% of patients, is resection of the primary tumor and local lymph nodes.[2,3,4] Endoscopic surgery may be suitable for some tumors depending on the location, number, size, and degree of malignancy.[4] Resection of nonhepatic tumor primaries is associated with increased median survival ranging from 69 to 139 months.[5,6] However, the extent of resection depends on the site of origin of a given tumor, the involvement of surrounding structures, and the extent of metastases.[1]
Somatostatin Analogs
The development of long-acting and depot formulations of somatostatin analogs has been important in the amelioration of symptoms of carcinoid syndrome. The result has been a substantial improvement in quality of life with relatively mild adverse effects.[1,7] The inhibitory effects of somatostatin on neurotransmission, motor and cognitive functions, smooth muscle contractility, glandular and exocrine secretions, intestinal motility, and absorption of nutrients and ions are mediated by cyclic adenosine monophosphate inhibition.[8,9] Experimentally, somatostatin has been shown to have a cytostatic effect on tumor cells. This effect involves hyperphosphorylation of the retinoblastoma gene product and G1 cell cycle arrest, in addition to somatostatin receptor (SSTR) subtype 3 [sst(3)]-mediated (and to a lesser extent, SSTR subtype [sst(2)]-mediated) apoptosis.[10,11,12] Somatostatin also appears to have some antiangiogenic properties.[1] However, only a small number of patients treated with somatostatin analog therapy experience partial tumor regression.[1,4]
Currently available somatostatin analogs display high affinity for sst(2) and SSTR subtype 5, low affinity for SSTR subtype 1 and SSTR subtype 4, and medium affinity for sst(3). (Refer to the Somatostatin receptor scintigraphy section in the General Information About GI Carcinoid Tumors section of this summary for more information.) Octreotide, a short-acting somatostatin analog and the first biotherapeutic agent used in the management of carcinoid tumors, exhibits beneficial effects that are limited to symptom relief, with about 70% of patients experiencing resolution of diarrhea or flushing. [1,4]
In the treatment of carcinoids, lanreotide, a long-acting somatostatin analog administered every 10 to 14 days, has an efficacy similar to that of octreotide and an agreeable formulation for patient use.[13] The effects of lanreotide on symptom relief are comparable to those of octreotide, with 75% to 80% of patients reporting decreased diarrhea and flushing; however, there appears to be little improvement in tumor responses over shorter-acting octreotide.[1] Depot formulations include long-acting repeatable (LAR) octreotide and a slow-release depot preparation of lanreotide. One study comparing subcutaneous short-acting octreotide with monthly LAR octreotide reported an increased median survival from the time of metastatic disease diagnosis (143 months vs. 229 months in favor of the LAR form), representing a 66% lower risk for death among patients treated with the LAR formulation.[14] A randomized, controlled study in metastatic midgut neuroendocrine tumors showed improved time to tumor progression with monthly LAR octreotide compared with placebo. (Refer to the Jejunal and Ileal Carcinoids section in the Treatment Option Overview for GI Carcinoid Tumors section of this summary.)
The typical duration of treatment with somatostatin analogs is approximately 12 months because of the development of tachyphylaxis (reported less frequently with long-acting formulations) and/or disease progression.[15,16,17] In the management of carcinoid crises, intravenous somatostatin analogs are effective; crises are usually precipitated by anesthesia, surgical interventions, or radiologic interventions.[18] Adverse effects of somatostatin analog administration include:[19,20]
Biliary sludge and cholelithiasis occur in as many as 50% of the patients, but few patients (1%–3%) develop acute symptoms requiring cholecystectomy.[21]
Interferons
The most researched interferon in the treatment of carcinoid disease is interferon-alpha (IFN-alpha); comparable to somatostatin analogs, the most pronounced effects of IFN-alpha are inhibition of disease progression and symptom relief, with approximately 75% of patients reporting the resolution of diarrhea or flushing.[1] IFN-alpha, similar to other IFNs studied in the treatment of carcinoids (e.g., IFN-gamma and human leukocyte interferon), has substantial adverse effects, including alopecia, anorexia, fatigue, weight loss, fever, a flu-like syndrome, and myelosuppression; however, IFN-alpha may show greater antitumor activity than somatostatin analogs.[13] Both single-agent and multiagent chemotherapeutics appear to have little role in the management of these essentially chemoresistant tumors; no protocol has shown objective tumor response rates greater than 15%.[1]
Treatment of Hepatic Metastases
The management of hepatic metastases may include surgical resection; hepatic artery embolization; cryoablation and radiofrequency ablation (RFA); and orthotopic liver transplantation.[1] In one large review of 120 carcinoid patients, a biochemical response rate of 96% and a 5-year survival rate of 61% were reported for patients whose hepatic metastases were resected surgically.[22] The 5-year survival rate without surgical therapy is approximately 30%.[4] For hepatic artery embolization, the most frequently used single agent is gelatin powder; and, in more than 60 patients with carcinoid tumors, the use of gelatin powder resulted in 34% and 42% of patients achieving biochemical and tumor-diminution responses, respectively.[23,24,25] Trials using transcatheter arterial occlusion with chemoembolization have also been performed, with the most thoroughly researched combination involving hepatic artery ligation with gelatin foam and doxorubicin (4 trials and 66 patients), resulting in biochemical responses in 71% of patients and tumor regression in approximately 50% of patients.[1] However, the duration of response can be short lived after embolization, and embolization may be associated with adverse effects that range from transient symptoms (e.g., pain, nausea, fever, and fatigue), which occur in 30% to 70% of patients, to liver enzyme abnormalities, which occur in as many as 100% of patients (i.e., transaminitis and postembolization syndrome), to florid and potentially lethal carcinoid crisis with massive release of vasoactive substances.[4]
In one prospective trial, 80 RFA sessions were performed in 63 patients with neuroendocrine hepatic metastases (including 36 carcinoids), and 92% of the patients reported at least partial symptom relief. In the same 63 patients, 70% had significant or complete relief at 1 week postoperatively, with a perioperative morbidity of 5%; duration of symptom control was 11 ± 2.3 months, and median survival time was 3.9 years after the first RFA.[26] There are few trials of cryoablation of hepatic metastases, and the results of liver transplantation for metastatic disease are disappointing, reflecting the typically advanced disease states of transplant recipients.[1]
Information about ongoing clinical trials is available from the NCI website.
Radionuclides
The four radionuclide conjugates most commonly used in the treatment of carcinoid disease are iodine I 131-metaiodobenzylguanidine (131I-MIBG), indium In 111 (111In), yttrium Y 90, and lutetium Lu 177 (177Lu), with the latter three bound to a variety of somatostatin analogs. However, the median tumor response rate for the patients treated with 131I-MIBG is less than 5%, although the modality appears somewhat more effective in achieving biochemical stability (~50%) or tumor stability (~70%).[1] Although 111In-labeled somatostatin analogs are the most commonly studied radiopeptides to date, largely reflecting their availability, and with therapeutic benefits similar to 131I-MIBG, the most promising advance in radiopeptide therapeutics has been the development of 177Lu-octreotate, which emits both beta and gamma radiation.[1] In the largest patient series treated to date with lutetium-labeled somatostatin analogs (n = 131; 65 with GI carcinoids), remission rates were correlated positively with high pretherapy octreotide scintigraphy uptake and limited hepatic tumor load.[27] In patients with extensive liver involvement, median time to progression was shorter (26 months) compared with patients who had either stable disease or tumor regression (>36 months).
Management of Carcinoid-Related Fibrosis
Bowel obstruction secondary to peritoneal fibrosis is the most common presenting symptom of small intestinal carcinoids. Heart failure secondary to right-sided valvular fibrosis represents a serious extraintestinal manifestation of carcinoid fibrosis and occurs in 20% to 70% of patients with metastatic disease; it accounts for as much as 50% of carcinoid mortality.[28,29] Currently, there is no effective pharmacologic therapy for either clinical problem. In the instance of bowel obstruction, surgical lysis of the adhesions often is technically demanding because of the cocoon-like effects of extensive fibrosis stimulated by the various tumor-derived growth factors.[30] Valvular replacement usually is required to manage carcinoid heart disease.[1]
Symptomatic Therapy
In addition to the use of long-acting depot formulations of somatostatin analogs as the principal agents in the amelioration of carcinoid symptoms, the nonspecific supportive care of patients includes:
Carcinoid crisis is manifested by profound flushing, extreme blood pressure fluctuations, bronchoconstriction, dysrhythmias, and confusion or stupor lasting hours or days and may be provoked by induction of anesthesia or an invasive radiologic procedure.[18,31] This potentially fatal condition can occur after manipulation of tumor masses (including bedside palpation), administration of chemotherapy, or hepatic arterial embolization.[32] In contrast with the treatment of other causes of acute hypotension, the use of calcium and catecholamines should be avoided in carcinoid crisis because these agents provoke the release of bioactive tumor mediators that may perpetuate or worsen the situation. Plasma infusion and octreotide are used for hemodynamic support. For the most part, the use of somatostatin analogs has replaced other pharmacologic maneuvers in the treatment of crises, and their use has been associated with increased survival rates. Prophylactic use of subcutaneous octreotide or the administration of a depot somatostatin analog in a timely fashion before any procedures are undertaken is mandatory to prevent the development of a crisis.[1]
Molecular-Targeted Therapies
Various therapies targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor, and mammalian target of rapamycin (mTOR) are in development.[1,33] Therapeutic agents under investigation include the VEGF monoclonal antibody, bevacizumab; VEGF tyrosine kinase inhibitors, sunitinib, vatalanib, and sorafenib; and the mTOR inhibitor, everolimus (RAD001).
General Therapeutic Approaches
As might be expected, therapeutic approaches to GI carcinoids vary according to anatomical location. In 2004, a consensus statement regarding the diagnosis and treatment of GI neuroendocrine tumors was published on behalf of the European Neuroendocrine Tumor Society,[4] which details site-specific approaches to the treatment of GI carcinoids.
References:
Type I gastric carcinoids smaller than 1 cm are indolent with minimal risk for invasion and can be removed with endoscopic mucosal resection.[1,2,3] Local surgical excision may be performed for rare larger or invasive tumors, but exceptional cases with large multifocal lesions may require gastric resection. Follow-up with yearly endoscopic surveillance and repeated gastroscopy with multiple gastric biopsies is required, and treatment with somatostatin analogs may prevent recurrence.[4]
For type II carcinoids, surgery is focused on removing the source of hypergastrinemia, typically by excision of duodenal gastrinomas in patients with multiple endocrine neoplasia type I via duodenotomy with resection of lymph node metastases.[5,6,7] Because of their generally benign course similar to type I tumors, type II tumors can usually be managed with endoscopic resection (particularly for tumors <1 cm) followed by close endoscopic surveillance.[1,3] Liberal surgical excision or gastric resection with regional lymphadenectomy is performed for larger and multifocal tumors or for those with deep wall invasion or angioinvasion.[3] In patients with multiple tumors, somatostatin analog treatment may be used to reduce tumor growth, particularly if hypergastrinemia has not been reversed by surgery.[4]
Sporadic type III gastric carcinoids, which behave more aggressively than type I and type II tumors, are treated with gastric resection and regional lymphadenectomy.[3] Tumors larger than 2 cm or those with atypical histology or gastric wall invasion are most appropriately dealt with by gastrectomy or radical gastrectomy.[1,8,9] Most of these tumors are metastatic at the time of presentation.[8] The 5-year survival rate may approach 50%, but, in patients with distant metastases, it is only 10%.[10,11]
Subtyping gastric carcinoids is helpful in the prediction of malignant potential and long-term survival and is a guide to management.[12] Based on a combined population from 24 Swedish hospitals, one study of 65 patients with gastric carcinoids (51 type I, 1 type II, 4 type III, and 9 poorly differentiated [designated as type IV in the study]), management varied according to tumor type. Among all of the patients, 3 received no specific treatment, 40 underwent endoscopic or surgical excision (in 10 cases combined with antrectomy), 7 underwent total gastrectomy, and 1 underwent proximal gastric resection; radical tumor removal could not be performed in 2 of 4 patients with type III and 7 of 9 patients with poorly differentiated tumors. (Refer to the Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors section of this summary for more information.) Five- and 10-year crude survival rates were 96.1% and 73.9%, respectively, for type I tumors (not different from the general population) but only 33.3% and 22.2% for poorly differentiated gastric neuroendocrine tumors.[12][Level of evidence: 3iiD]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Duodenal carcinoids are rare, and there is no consensus on the optimal extent of surgical treatment.[1] In a retrospective review of 24 patients with a pathologic diagnosis of duodenal carcinoid tumor, most tumors (89%) measured smaller than 2 cm in diameter, and most (85%) were limited to the mucosa or submucosa. Lymph node metastases were identified in surgical specimens in 7 (54%) of 13 patients in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm, which were limited to the submucosa. At a mean follow-up of 46 months, the disease-specific survival rate was 100%, and only 2 patients had recurrences in regional lymph nodes. No patient was reported to have distant metastases or the carcinoid syndrome.[1][Level of evidence: 3iiB] The authors of this study concluded that, although duodenal carcinoids are indolent, the presence of regional lymph node metastases cannot be predicted reliably on the basis of tumor size or depth of invasion, and their impact on survival is unclear.
In general, endoscopic excision of primary duodenal carcinoids appears to be most appropriate for tumors smaller than 1 cm.[1] Duodenal carcinoids smaller than 2 cm may be excised locally; for tumors between 1 cm and 2 cm, complete resection is ensured by operative full-thickness excision.[1,2] Follow-up endoscopy is indicated. Tumors larger than 1 cm may be difficult to remove completely endoscopically and should be evaluated with endoscopic ultrasonography before endoscopic resection is attempted because of their potential to invade beyond the submucosa.[3]
Appropriate management of tumors larger than 2 cm can be problematic.[2] However, in general, these tumors can be treated with operative full-thickness excision and regional lymphadenectomy. Lymphadenectomy is performed even in the face of negative preoperative imaging because of the high rate of lymph node metastasis for these tumors.[1]
In addition, some authors recommend that for tumors larger than 2 cm, a regional lymphadenectomy includes the lymph nodes in the following locations:
Regardless of the size of the primary tumor, abnormal lymph nodes detected on pretreatment imaging studies or at the time of surgery should be resected. Because little is known about the natural history of unresected, grossly evident lymph node metastases, nonoperative management might otherwise be supported. Node-positive patients should undergo continued radiographic surveillance regardless of the size of the primary tumor.[1]
Ampullary and periampullary duodenal carcinoids deserve special consideration because they differ clinically, histologically, and immunohistochemically from carcinoid tumors that occur elsewhere in the duodenum.[5] Although their rarity precludes the establishment of any definitive natural history, these tumors appear to behave unpredictably and might be viewed as a distinct category of carcinoid tumor when treatment options are being considered.[2] Compared with tumors in other duodenal sites, even small (<1 cm) ampullary and periampullary carcinoid tumors exhibit distinctly different aggressive behavior, and they may metastasize early.[5,6]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
At the time of diagnosis, 58% to 64% of patients with carcinoids of the small intestine have metastatic disease in the regional lymph nodes or the liver.[1] Early surgical treatment should include removal of the mesentery by wedge resection and resection of lymph node metastases surrounding the mesenteric artery and vein to preserve intestinal vascular supply and to limit the intestinal resection.[2] With grossly radical tumor resections, patients may remain symptom free for extended periods of time; however, because of the tenacity of carcinoid tumors, patients should undergo lifelong surveillance.
Surgical treatment for advanced carcinoids involves prophylactic removal of mesenteric metastases early on because later the disease may become impossible to manage surgically.[3] Repeat surgery may be necessary if mesenteric metastases are left during primary surgery or have progressed after primary surgery.[2] These operations are difficult because of fibrosis between regions of the intestine, and surgery may result in fistulation, intestinal devascularization, or creation of a short bowel.[3] In patients with inoperable metastatic disease, the 5-year survival rate is approximately 50% for those with inoperable liver metastases and approximately 40% for those with inoperable liver and mesenteric metastases.[4,5]
The effect of octreotide (long-acting repeatable, 30 mg intramuscularly every 28 days) on time to tumor progression in patients with metastatic midgut neuroendocrine tumors has been tested in a randomized, placebo-controlled clinical trial.[6] Although the planned study accrual was 162 patients, because of slow accrual, it was stopped after 85 evaluable patients were enrolled. At an interim analysis, the median time to tumor progression was 14.3 months in the octreotide group versus 6 months in the placebo group (hazard ratio, 0.34; 95% confidence interval, 0.20–0.59; P < .0001). Quality of life was similar in both treatment groups. There was no difference in overall survival, but about three-quarters of the control group received octreotide at disease progression.[6][Level of evidence: 1iDiii]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Approximately 90% of appendiceal carcinoids measure smaller than 1 cm and are not located in the appendiceal base; these tumors can be consistently cured by appendectomy.[1]
Appendiceal carcinoids larger than 2 cm require right-sided hemicolectomy and ileocecal lymphadenectomy because of the significant risk of metastasis.[1] For tumors measuring 1 to 2 cm, treatment is controversial, but hemicolectomy may be appropriate if there is invasion in the mesoappendix, if there is residual tumor in the resection margins, or in the presence of lymph node metastases. For same-size lesions confined to the appendiceal wall, appendectomy alone may carry a low risk for metastases. Acceptable indications for hemicolectomy may include operative specimens that show high proliferative activity (high Ki67 index), high mitotic index, or signs of angioinvasion, but evidence is limited and histologic parameters for risk evaluation in appendiceal carcinoids measuring 1 cm to 2 cm requires definition.[1,2,3] Follow-up should be considered in patients for whom elevated serum chromogranin A may indicate the need for extended operation. Although survival is excellent with locoregional tumor, 10-year survival is approximately 30% with distant metastases.[1]
Goblet cell carcinoid or adenocarcinoid is a rare variant of appendiceal carcinoid with mixed endocrine and exocrine features.[1] Often presenting with a diffusely inflamed appendix and occurring in patients at a later age (~50 years), these tumors are aggressive, often with peritoneal and ovarian metastases, and occasionally appearing as mucinous adenocarcinoma.[2,3,4] They do not express somatostatin receptors and cannot be visualized by indium In 111-octreotide scintigraphy. Goblet cell carcinoids are treated with right-sided hemicolectomy and lymphadenectomy in combination with chemotherapy. For disseminated tumors, aggressive surgical reduction including peritonectomy and oophorectomy may be required.[1] Goblet cell carcinoids have a 10-year survival rate of approximately 60%.[2]
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Colonic carcinoids are often exophytic and large (>5 cm), but they rarely bleed. Only occasional right-sided lesions are positive with indium In 111-octreotide scintigraphy. Many of these tumors are aggressive with a high proliferation rate, and they often present with more liver metastases than regional lymph node metastases.[1] These tumors of the colon are treated similarly to adenocarcinoma of the colon.[2] Attempts to achieve radical resection by hemicolectomy or subtotal colectomy with lymphadenectomy should be made, but frequently only debulking is possible. The overall 5-year survival rate is approximately 40% and is slightly worse than the survival rate for colon adenocarcinoma.[1]
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In general, rectal carcinoids often present as very small, isolated lesions.[1] The TNM system is used for rectal carcinoids, but size appears to be one of the best estimates of recurrence. Rectal carcinoids should be evaluated by endoscopic ultrasound (EUS) or rectal magnetic resonance imaging (MRI). Tumors smaller than 1 cm can be safely removed by endoscopic excision.[2,3,4,5] Excised specimens should be examined histologically to exclude muscularis invasion.[2,6,7,8]. A report about the rectal carcinoid patients in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated that the 5-year survival rate for patients with stage I carcinoid was 97%.[9]
For patients with tumors that are greater than 2 cm or that have invasion of the muscularis as seen by EUS or MRI, surgical resection with abdominoperineal resection (APR) or low anterior resection (LAR) is recommended because of the high rate of nodal metastases and risk of distant metastatic disease. In the report from the SEER database, patients with stage II or III rectal carcinoids had 5-year survival rates of 84% and 20%, respectively.[9] In a report from the National Cancer Database, among 3,287 patients with rectal carcinoids, the 5-year survival rates for patients with stage II or III disease was 87.3% and 35.5%, respectively.[10]
There is considerable debate about whether local excision or rectal resection (i.e., APR or LAR) is needed for tumors that are 1 cm to 2 cm. Although it may be possible to recognize tumors with particular atypia and high mitotic index before embarking on the more radical surgery, the presence of muscularis invasion or regional metastases generally supports rectal resection. In a multicenter series of 100 patients who underwent anterior resection for rectal carcinoids, the rate of nodal metastases for patients with tumors between 1 cm and 2 cm was 31%.[11] In this series, tumor size greater than 1 cm and lymphovascular invasion were the two strongest predictors of lymph node metastases. In patients with distant metastases, prognosis is generally poor, with an overall 5-year survival rate of approximately 30%.[12]
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Although the definitive role of surgery in metastatic disease has not been established, conservative resections of the intestine, mesenteric tumors, and fibrotic areas may improve symptoms and quality of life substantially in patients with metastatic hepatic, mesenteric, and peritoneal carcinoids. If the condition of the patient is such that surgery is not a greater risk than the disease, the primary tumor should be resected to prevent an emergency presentation with obstruction, perforation, or bleeding.[1] Despite common acceptance that resection of at least 90% of the tumor burden is required to achieve palliation, approximately 60% of patients with surgery alone will experience symptom recurrence; the 5-year survival rate is between 35% and 80%, depending on the experience of the surgical center.[2,3] Because treatment with somatostatin analogs can achieve similar rates of symptom relief with fewer adverse effects, in each patient the benefits of surgical treatment of gastrointestinal (GI) carcinoid tumors should be weighed carefully against the potential risks of an open exploration. Tumor debulking, however, may potentiate pharmacologic therapy by decreasing the secretion of bioactive substances.[4]
Management of hepatic metastases may include surgical resection; hepatic artery embolization; cryoablation and radiofrequency ablation; and orthotopic liver transplantation. (Refer to the Treatment of Hepatic Metastases section of the Treatment Option Overview for GI Carcinoid Tumors section of this summary for more information.) Cytoreductive surgery for hepatic metastases from GI carcinoids can be performed safely with minimal morbidity and mortality resulting in regression of symptoms and prolonged survival in most patients.[5] In one large review that included 120 carcinoid patients, a biochemical response rate of 96% and a 5-year survival rate of 61% were reported for patients whose hepatic metastases were resected surgically.[6][Level of evidence: 3iiDii]
In the case of liver metastases, localization and resection of the primary tumor may be considered, even among patients in whom the primary neoplasm is asymptomatic. In a retrospective study involving 84 patients, 60 of whom had their primary neoplasm resected, the resected group had a greater median progression-free survival (PFS) of 56 months, compared with 25 months of PFS for the primary nonresected group (P < .001). Median survival time for the resected group was longer at 159 months when compared with 47 months for the nonresected group (P < .001).[7][Level of evidence: 3iiDii ]
Although the response of carcinoid tumors to external-beam radiation therapy is very limited, palliative radiation therapy has some efficacy for bone and brain metastases and in the management of spinal cord metastases.[4]
Treatment with single-agent chemotherapy or multiple-agent chemotherapy appears to be of little benefit in the management of GI carcinoids because no regimen has shown objective tumor response rates greater than 15%.[4]
Treatment with radionuclides such as iodine I 131-metaiodobenzylguanidine and lutetium Lu 177-octreotate may be of benefit. (Refer to the Radionuclides section of the Treatment Option Overview for GI Carcinoid Tumors section of this summary for more information.)
Somatostatin analogs and interferon-alpha are the primary agents used in the treatment of carcinoid syndrome. (Refer to the Somatostatin Analogs section and Interferons section of the Treatment Option Overview for GI Carcinoid Tumors section of this summary for more information.) Management of the symptoms of carcinoid syndrome may also include dietary modification and the use of various antidiarrheal agents, antihistaminics for skin rashes, and theophylline or beta-2 adrenergic receptor agonists for bronchospasm. (Refer to the Symptomatic Therapy section of the Treatment Option Overview for GI Carcinoid Tumors section of this summary for more information.)
Information about ongoing clinical trials is available from the NCI website.
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The prognosis for any treated carcinoid patient with progressive or recurrent disease is poor. Deciding on further treatment depends on many factors, including previous treatment, site of recurrence, and individual patient considerations. Attempts at re-resecting slow-growing tumors (e.g., repeat or multiple liver resections) are worthy of consideration after extensive evaluation, because successful further reduction of tumor volume may provide long-term palliation. Recurrence at any single site may also be potentially resectable. Clinical trials are appropriate and should be considered when possible.
Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult gastrointestinal carcinoid tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Adult Treatment Editorial Board. PDQ Gastrointestinal Carcinoid Tumors Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389233]
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Last Revised: 2021-06-17
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