Version May 2024
INTRODUCTION — Well-differentiated neuroendocrine tumors (NETs) most commonly originate in the gastrointestinal tract and lung and rarely arise in the genitourinary tract. The term "carcinoid" is still used to describe these tumors; however, preferred terms include NET or neuroendocrine neoplasm (NEN). Well-differentiated NETs that arise in the pancreas, while histologically similar to those arising in the tubular portion of the gastrointestinal tract, are not referred to as "carcinoids" but instead as pancreatic NETs (older term: islet cell tumors). (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature'.)
"Carcinoid syndrome" is the term applied to a constellation of symptoms mediated by various humoral factors that are elaborated by some well-differentiated NETs arising in the gastrointestinal tract (table 1) [1]. Typical carcinoid syndrome, consisting primarily of flushing and diarrhea (table 2), occurs predominantly in patients with metastatic NETs originating in the small intestine. Carcinoid syndrome is rare with lung or genitourinary well-differentiated NETs. (See "Clinical features of carcinoid syndrome".)
Well-differentiated NETs are rare overall, but their age-adjusted incidence in the United States has increased significantly, partly due to increased detection on radiographic imaging and endoscopy.
This topic will cover the epidemiology, classification, and clinical features of primary well-differentiated NETs (carcinoid tumors) arising in the gastrointestinal and genitourinary systems. The pathology and nomenclature of digestive tract NETs; clinical features and diagnosis of carcinoid syndrome; issues related to tumor localization in well-differentiated NETs arising in the gastrointestinal tract; features and management of high-grade gastroenteropancreatic neuroendocrine carcinoma, bronchial NETs, and thymic NETs; and the management of patients with non-metastatic and metastatic well-differentiated NETs arising in the gastrointestinal tract are discussed separately.
●(See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
●(See "Clinical features of carcinoid syndrome".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Thymic neuroendocrine (carcinoid) tumors".)
EPIDEMIOLOGY — Well-differentiated NETs are relatively rare tumors. In a series of 35,618 NETs (which included pancreatic NETs as well as gastrointestinal NETs [GINETs] at all sites) reported to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI), the age-adjusted incidence for nonpancreatic primaries was 4.7 per 100,000 [2]. The annual incidence rate for African Americans was higher than for White Americans (6.46 versus 4.6 per 100,000), and the incidence for males was slightly higher than for females (4.97 versus 4.49 per 100,000). The median age at diagnosis for all patients with NETs was 63 years.
Roughly similar incidence rates were found in a database study from a Swedish registry that focused on 5184 GINETs tumors seen between 1958 and 1998 [3]. Incidence rates for males and females were 2.0 and 2.4 per 100,000, respectively. Although clear risk factors have not been identified, a regression analysis of this database suggested that risk was increased in the setting of a family history of a GINET in a first-degree relative (relative risk 3.6).
The incidence of well-differentiated NETs has been rising over time in the United States and elsewhere [4-7]. As an example, in an analysis of 64,971 NETs reported to the SEER registry, the age-adjusted incidence rate for all NETs rose from 1.09 to 6.98 per 100,000 between 1973 and 2012 [7]. The increase is probably partly due to increased detection on radiographic imaging and endoscopy.
Distribution — The distribution of NETs has shifted over time in the United States. In a report from the SEER database of 11,427 cases treated between 1973 and 1997, the majority were located in the gastrointestinal tract (55 percent) and bronchopulmonary system (30 percent) [8]. Within the gastrointestinal tract, most NETs arose in the small intestine (45 percent, most commonly in the ileum), followed by the rectum (20 percent), appendix (16 percent), colon (11 percent), and stomach (7 percent). However, since the implementation of screening colonoscopy (approximately in the year 2000), the proportion of patients diagnosed with rectal NETs has been greater than the proportion of those diagnosed with small intestinal NETs in 12 of 13 SEER registry reporting agencies [9]. The rising incidence of rectal NETs over time, and in all age groups, including 20 to 29 year olds, has been noted by others [10].
Distribution may differ in other geographic areas. As an example, colorectal NETs may be more frequent in the Asia/Pacific region as compared with Europe, where GINETs are more commonly found in the stomach and ileum [11,12]. An important point is that the SEER database may be inconsistent in recording tumors that are not considered "malignant" (ie, small gastric NETs that are encountered at endoscopy in patients with chronic atrophic gastritis). (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)
PATHOLOGY AND GRADING — Well-differentiated NETs arising in the tubular gastrointestinal tract, lung, and genitourinary tract were initially referred to as "carcinoids" because they seemed morphologically different and clinically less aggressive than the more common gastrointestinal tract adenocarcinomas [13]. NETs 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 NETs 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 [14].
The World Health Organization (WHO) distinguishes two broad subgroups of neuroendocrine neoplasms affecting the digestive tract (table 3) [15]:
●Well-differentiated NETs, which are further subdivided into low grade (G1), intermediate grade (G2), and high grade (G3) according to proliferative rate (table 3). In general, clinical behavior of low/intermediate grade tumors is relatively indolent. However, it is important to note that metastatic tumors can transform over time to become much more aggressive. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
Intermediate-grade NETs arising in the lung (but not elsewhere) are referred to as atypical carcinoids. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)
●Poorly differentiated neuroendocrine carcinomas, which are high-grade carcinomas that resemble small cell or large cell neuroendocrine carcinoma of the lung (picture 1) [16]. They generally behave in a biologically aggressive fashion. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
●It is important to distinguish between well-differentiated G3 NET (which are biologically similar to low and intermediate grade tumors), and poorly differentiated NEC. A more detailed discussion of the pathology and classification of NETs arising in the digestive tract is presented elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
EMBRYONIC CLASSIFICATION — NETs arising in the tubular gastrointestinal tract, lung, and genitourinary tract have traditionally been classified based on their origin from the embryonic divisions (foregut, midgut, or hindgut) of the alimentary tract (figure 1) [17]. In general, midgut gastrointestinal tract NETs (distal small intestine and proximal colon) produce serotonin and other vasoactive substances that give rise to the typical carcinoid syndrome (table 4). In contrast, tumors derived from the embryonic hindgut are rarely associated with a hormonal syndrome. (See "Clinical features of carcinoid syndrome", section on 'Pathophysiology'.)
While this classification has some utility as a means of grouping together 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 tumors vary with the site.
Stomach — Gastric NETs are subdivided into three categories that have differing biologic behavior and prognoses [18,19].
Type 1 — Type 1 tumors account for 70 to 80 percent of all gastric NETs [19-21]. They are associated with chronic atrophic gastritis and often pernicious anemia (65 percent in one series) [19]. The disease is more common in females [22-24]. (See "Metaplastic (chronic) atrophic gastritis".)
Endoscopically, the tumors are usually smaller than 1 cm, are often multiple, and may appear as polypoid lesions with a small central ulceration (picture 2A-C). The tumors are derived from enterochromaffin-like (ECL) cells.
The prevailing hypothesis is that ECL cells develop into NETs after chronic stimulation by the high gastrin levels that occur in patients with atrophic gastritis. This is supported by the observation that regression of gastric NETs can be achieved by antrectomy, which is occasionally recommended. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
Patients with gastric NETs related to chronic atrophic gastritis are usually diagnosed in their 60s or 70s during endoscopic evaluation for abdominal pain or anemia [19]. They are usually nonfunctioning tumors. These tumors are usually indolent and generally represent a benign condition. Metastases occur in less than 10 percent of tumors ≤2 cm but approximately 20 percent of larger tumors [25].
Type 2 — Type 2 gastric NETs occur in association with gastrinomas (Zollinger-Ellison syndrome), often in the setting of multiple endocrine neoplasia type 1 (MEN1). They account for approximately 5 percent of gastric NETs. Similar to the NETs that arise in the setting of atrophic gastritis, the tumors are thought to arise from ECL cells stimulated by elevated serum gastrin levels. The hypergastrinemia is produced by a gastrinoma in the pancreas or duodenum. (See "Multiple endocrine neoplasia type 1: Management" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)
Type 2 tumors behave similarly to type 1 tumors; they are frequently multifocal and usually indolent [26]. Management is addressed elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
Type 3 — Type 3 gastric NETs are known as sporadic NETs because they occur in the absence of atrophic gastritis, Zollinger-Ellison syndrome, or MEN1 syndrome. They account for 20 percent of gastric NETs and are the most aggressive; local or hepatic metastases are present in up to 65 percent of patients who come to resection [18,26]. Unlike type 1 and 2 tumors, the fasting serum gastrin is usually normal in patients with type 3 gastric NETs.
Type 3 tumors often contain a variety of endocrine cells, and they may be associated with atypical carcinoid syndrome (table 4). (See "Clinical features of carcinoid syndrome", section on 'Gastric NET variant syndrome'.)
Patients receiving PPI therapy — A fourth type of gastric NET has been recently described as arising in the setting of chronic proton pump inhibitor (PPI) use, which is associated with elevated serum gastrin levels [27]. These tumors are often, but not always, solitary. Pathologically, there tends to be evidence of parietal and enterochromaffin cell hyperplasia without evidence of atrophic gastritis. Although these mucosal changes are suggestive of hypergastrinemia, there is no underlying gastrinoma.
Tumors arising in the setting of chronic PPI use appear to behave in a less malignant fashion than true-sporadic tumors [27].
Lung — Well-differentiated lung NETs are classified among other pulmonary neuroendocrine neoplasms, such as small cell and large cell neuroendocrine lung cancer. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)
Patients with lung NETs rarely develop carcinoid syndrome, even in the presence of liver metastases. They may have a variant carcinoid syndrome with flushes or sweats that are severe and prolonged, lasting hours to days. These flushes may be associated with disorientation, anxiety, and tremor. The clinical features of lung NETs are discussed separately. (See "Clinical features of carcinoid syndrome", section on 'Lung NET variant syndrome' and "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Clinical features'.)
MIDGUT TUMORS
Jejunoileal small bowel tumors — Small bowel NETs have increased in frequency in the last several decades, in part due to increased detection on endoscopy and imaging studies [28]. In the year 2000, NETs surpassed adenocarcinomas as the most common small bowel tumor reported to the National Cancer Database [29]. Patients usually present in their 60s or 70s. (See "Epidemiology, clinical features, and types of small bowel neoplasms", section on 'Malignant tumors'.)
Small bowel NETs are thought to arise from intraepithelial endocrine cells, in contrast to appendiceal NETs, which arise from subepithelial endocrine cells [30]. Small intestinal NETs are most commonly located in the ileum within 60 cm of the ileocecal valve; they may arise from a Meckel's diverticulum [28,31-33]. Approximately 25 percent of patients will have more than one small bowel NET at the time of discovery.
Some small bowel NETs are asymptomatic at presentation and are found incidentally [34]. Among symptomatic patients, abdominal pain is the most common initial symptom, occurring in approximately 40 percent [35]. 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 NETs [35,36]. Duodenal NETs 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 intraluminal tumor bulk, but it often results from mesenteric kinking and distortion brought on by tumor invasion, lymph node metastases, and/or a secondary desmoplastic response (image 1) [37]. The last produces a characteristic radiographic abnormality: a combination of abrupt angulation and a filling defect in the small bowel (image 2).
Pain may also arise from ischemia that is due to local fibrosis or vascular compromise [36]. Vascular compromise may be secondary to large, bulky mesenteric nodal metastasis, mesenteric vascular invasion, and/or microvascular metastasis [36]. Possibly contributing to the ischemic process is the vasospastic effect of serotonin produced by the tumor.
Metastases to lymph nodes or the liver are common, even if the primary tumor is <2 cm in size (table 5) [38,39]. Carcinoid syndrome is present in the majority of patients who have a small bowel primary NET and liver metastases [38,40-42]. Staging, treatment, and prognosis of small bowel carcinoid NETs are addressed elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Small intestine'.)
Appendix — Well-differentiated NETs are the most common neoplasms in the appendix. In approximately 1 in 300 appendectomies, a NET is discovered incidentally, most often in the tip of the appendix. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Terminology and classification'.)
Appendiceal NETs 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 females, although this association has in part been attributed to the greater frequency of incidental appendectomies in females who undergo pelvic surgery. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Terminology and classification'.)
The majority are submucosal and located in the distal one-third of the appendix, where they are unlikely to cause obstruction (picture 3A-B). As a result, most patients are asymptomatic. Symptoms are more likely with large tumors and in the rare patient with metastases beyond the regional lymph nodes. Approximately 10 percent of appendiceal NETs are located at the base of the appendix, where they can cause obstruction leading to appendicitis.
The likelihood of regional and distant metastases is related to tumor size but is much lower than for small intestinal NETs (table 5). Features of carcinoid syndrome may be present in patients with tumors that have metastasized to the liver. (See "Clinical features of carcinoid syndrome".)
A rare type of appendiceal tumor, formerly referred to as "adenocarcinoid" or "goblet cell carcinoid," is now more appropriately termed "goblet cell adenocarcinoma" [43]. These cancers are staged and treated as epithelial tumors of the appendix and are discussed in detail elsewhere. (See "Epithelial tumors of the appendix", section on 'Goblet cell adenocarcinoma'.)
The staging, prognosis, and treatment of appendiceal NETs are discussed separately. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Staging and prognosis' and "Well-differentiated neuroendocrine tumors of the appendix", section on 'Treatment of localized disease'.)
HINDGUT TUMORS — Hindgut NETs (transverse and descending colon, rectum) are usually nonsecretory and not associated with 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 presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation'.)
Colon — Colonic NETs are usually detected in patients who are in their 70s during evaluation for diarrhea, abdominal pain, anorexia, or weight loss [44,45]. The incidence of functioning tumors is very low. Features of carcinoid syndrome were present in only 1 of 36 patients in one series from the Alberta Cancer Registry [46].
The majority of colonic NETs are located in the right colon, particularly in the cecum [44,46,47]. Most patients do not become symptomatic until the tumors are large. In two series, the average size of the tumors was approximately 5 cm at diagnosis [44,47], and approximately two-thirds were associated with local nodal, or distant metastasis (table 5).
Staging, treatment, and prognosis are discussed elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Colon'.)
Rectum — The vast majority of rectal NETs are asymptomatic and found incidentally on endoscopy that is performed for another reason [45,48]. They are most commonly diagnosed in patients in their 60s [49]. Uncommon manifestations include rectal bleeding, change in bowel habits, or pain; carcinoid syndrome is rare because most are nonsecretory.
The majority (75 to 85 percent) are localized at diagnosis [45]. However, size correlates closely with the likelihood of metastases. Tumors smaller than 1 cm are rarely metastatic [25,50], while approximately 6 percent of tumors between 1 and 1.9 cm, and 24 percent of those over 2 cm metastasize to the liver [31,50-52]. Other poor prognostic features include deep invasion (into the muscularis propria or deeper), lymphovascular invasion, and a high mitotic rate (≥2 per 50 high-power fields) [52,53].
Staging, prognosis, and treatment are discussed in detail elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Rectum'.)
Genitourinary — NETs rarely arise in the genitourinary system; however, both renal and testicular primary tumors have been described in case reports and case series [54-57]. In addition to primary tumors, renal and testicular NETs may represent metastatic spread from another site [57,58]. These lesions commonly present as an abdominal or testicular mass, but some have manifestations of carcinoid syndrome. (See "Clinical features of carcinoid syndrome".)
OVARY — Ovarian NETs are rare neoplasms that may be primary or metastatic. Primary ovarian NETs are usually unilateral, localized to the ovary, and composed of gastrointestinal or respiratory epithelium; they often arise within a cystic teratoma or dermoid tumor [59,60]. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis".)
The coexistence of an ovarian germ cell tumor may have prognostic implications. In one report, 189 of 329 primary ovarian NETs (57 percent) coexisted with cystic teratomas/dermoid tumors [60]. When compared with NETs without associated germ cell tumors, these NETs were significantly smaller (45 versus 90 mm), less likely to have liver metastases (2 versus 15 percent), and less likely to have carcinoid syndrome (14 versus 23 percent), and the five-year survival rates were modestly better (94 versus 84 percent).
Metastatic NETs to the ovaries occur most commonly in patients with intestinal primary tumors [61]. Unlike primary ovarian NETs, which are typically unilateral, metastatic NETs to the ovaries are usually bilateral, originate in the small intestine, and are associated with peritoneal carcinomatosis [61].
Rarely, ovarian NETs can produce carcinoid syndrome without hepatic metastases due to their direct drainage into the systemic circulation [62]. Some ovarian NETs that produce peptide YY, a gastrointestinal hormone responsible for decreased gut motility, have been associated with severe constipation [63]. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y".)
OTHER RARE SITES — Primary well-differentiated NETs have rarely been diagnosed at other sites, including the liver, gallbladder, cystic duct, thymus, and middle ear. While many patients present with liver-only disease, it is debatable whether some of these tumors are true liver primaries or represent metastases from an occult primary site. (See "Neuroendocrine neoplasms of unknown primary site".)
METASTATIC TUMORS — Regardless of primary site, NETs are characterized by a strong propensity to metastasize to the liver [41]. Patients with liver metastases may experience symptoms related to tumor burden (eg, pain, jaundice, early satiety) or hormonal symptoms (eg, flushing and diarrhea, the main symptoms of carcinoid syndrome). Even when extensive, metastatic well-differentiated NETs can often cause significant hepatomegaly without any abnormalities of liver function. (See "Clinical features of carcinoid syndrome", section on 'Clinical features'.)
Other common metastatic sites associated with small intestinal (midgut) NETs include the mesentery and peritoneum. Tumors in the root of the mesentery may be unresectable and lead to recurrent bowel obstruction or ischemia. Likewise, patients with peritoneal carcinomatosis may experience chronic obstruction, weight loss, and malnutrition [40].
Bone metastases are observed increasingly commonly in patients with metastatic NETs, particularly with the use of sensitive somatostatin-receptor-based imaging modalities, such as integrated positron emission tomography (PET)/computed tomography (CT) using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC [64]. Other metastatic sites include the retroperitoneal lymph nodes, ovaries, breasts, supraclavicular lymph nodes, and retroorbital sites. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)
SUMMARY
●Distribution – Well-differentiated neuroendocrine tumors (NETs) are rare neoplasms that can arise at several body sites. The majority originate in the gastrointestinal tract (55 percent) and lungs (30 percent); they rarely arise in the genitourinary tract. (See 'Distribution' above.)
●Classification and grading
•NETs arise from enterochromaffin cells. They have traditionally been classified based on their origin from the embryonic divisions of the alimentary tract: the foregut (bronchial, stomach), midgut (small intestine, appendix, cecum), or hindgut (distal colon, rectum, genitourinary). (See 'Embryonic classification' above.)
•Histologically, NETs are classified based on histologic grade and differentiation. (See 'Pathology and grading' above.)
-Well-differentiated NETs are further subdivided into low grade (G1), intermediate grade (G2), and high grade (G3) according to proliferative rate. In general, clinical behavior of low/intermediate NETs is relatively indolent.
-Poorly differentiated neuroendocrine carcinomas are high-grade malignancies that resemble small cell or large cell neuroendocrine carcinoma of the lung. They generally behave in a biologically aggressive fashion.
●Clinical behavior
•Most well-differentiated NET are relatively slow growing. The metastatic potential of localized well-differentiated NETs correlates with tumor size, location, and histologic grade. Metastatic tumors can become much more aggressive over time.
•Clinical symptoms may be general, or they may correlate with the location of the tumor and be organ related. Symptoms of carcinoid syndrome (eg, flushing and diarrhea) typically occur in patients with metastatic NETs originating in the small bowel. (See 'Midgut tumors' above.)
Rarely, carcinoid syndrome is observed in non-metastatic tumors that can release hormones directly into the systemic circulation (eg, lungs, ovaries). (See 'Lung' above and 'Ovary' above.)
•Gastric tumors are typically asymptomatic and they are subclassified into three types that have different clinical presentation and malignant potential. (See 'Stomach' above.)
•Small intestinal NETs often present with abdominal pain and/or intermittent obstruction. (See 'Jejunoileal small bowel tumors' above.)
•Appendiceal NETs are the most common neoplasm found in the appendix; they are most often discovered incidentally during appendectomy. (See 'Appendix' above.)
•Transverse colon, descending colon, and rectal NETs may present with changes in bowel habit, obstruction, or bleeding. However, the great majority of rectal NETs are discovered incidentally at the time of rectal examination or endoscopy. (See 'Hindgut tumors' above.)
•Ovarian NETs may be primary or metastatic. Primary ovarian NETs are often associated with an ovarian germ cell tumor. (See 'Ovary' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Stephen Goldfinger, MD, who contributed to an earlier version of this topic review.
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