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Practice Essentials

Intestinal carcinoid tumors are gastrointestinal neuroendocrine tumors (GI-NETs). They are conventionally considered to originate from the serotonin-secreting enterochromaffin cells (ECs) of the intestine (also known as Kulchistky cells), but technically, intestinal carcinoid tumors include any collection of well-differentiated neuroendocrine cells within the digestive tract that are capable of secreting bioactive hormones and/or amines.^[1]

As tumor localization techniques have improved over the years, the incidence profile of carcinoid tumor location within the digestive tract has changed. Historically, the most common site of gastrointestinal (GI) carcinoid tumors was the appendix; currently, however, the most common site of carcinoids in the GI tract is the small intestine (30%), followed by the rectum (19.6%).^{[2, 3, 4, 5]}In most studies, the appendix is only the third most common site of GI carcinoids, and in some studies it is fourth most common.^{[6, 7, 5]}

Of neoplasms in the appendix, carcinoid tumors remain the most common. Carcinoids are also the most common neoplasm of the small bowel, accounting for approximately 48% of all small bowel neoplasms. However, small bowel neoplasms (benign and malignant) comprise only 4% of all GI tract neoplasms.^[8]

Carcinoids follow a more benign clinical course than most other malignancies. The most common symptom associated with carcinoid tumors is vague abdominal pain, with diagnosis occurring either incidentally or late in the course of disease, when the lesion may manifest as a complication of mechanical effects or as a result of significant hormone production. Overall, clinical manifestations will vary depending on the primary tumor location, particularly with respect to the non-hormonal manifestations (see Presentation). Symptoms related to the tumor's secretion of bioactive substances can sometimes be seen on presentation, with one center reporting that up to 74% of patients present with hormone-release–related symptoms.

Though rare, the carcinoid syndrome, which often presents as diarrhea, flushing, and cardiac valvular disease,^[2]is classically associated with carcinoid tumors. The carcinoid syndrome is seen in as many as 20% of patients diagnosed with carcinoid tumors in any location; most commonly, however, the primary tumor is in the small bowel.^{[6, 9]}Of patients who present with carcinoid syndrome, 95% have liver metastases at presentation.

Treatment is directed toward reduction of hormonal effects and elimination of the lesion itself.^{[10, 11, 12]}Surgical resection is the standard therapeutic modality, while medical care is mostly for symptomatic relief. (See Treatment and Medication.)

Terminology

Collectively, the recognition that carcinoid tumors have functional potential occurred within a 50-year timeframe. In 1907, by which time carcinoid tumors were already histologically described and had been classified as carcinoma, Oberndorfer used the term "carcinoid" (carcinoma-like) as a modifier in order to distinguish their indolent behavior from other common gastrointestinal neoplasms.^[13] ^[14]

Between 1952 and 1953, serotonin [5-hydroxytryptamine (5-HT)] was identified as the secretory product of enterochromaffin cells (ECs) and isolated from a carcinoid tumor of the small bowel. Shortly thereafter, in 1954, Thorson and colleagues were the first to report an association between carcinoid tumors and the carcinoid syndrome symptoms (ie, flushing, diarrhea, bronchoconstriction, and cardiac disease).^[15]Finally, when elevated levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, were discovered in the urine of patients with the carcinoid syndrome, investigators realized that the carcinoid syndrome may be a humorally-mediated disorder caused by production and secretion of ectopic serotonin by carcinoid tumors.

Carcinoids have also been referred to synonymously with other descriptors, such as argentaffinoma, which was used to describe the similarity between carcinoid granules and ECs in their affinity for staining with chrome salts and ability to reduce silver salts in an argentaffin reaction.^[16]The term carcinoid was also used interchangeably with APUDoma, so named by Pearse in the 1960s, who developed the concept of the amine precursor uptake and decarboxylation (APUD) system after observing the ability of the secretory granules to take up and decarboxylate amino acid precursors of biogenic amines, such as serotonin and catecholamines.^[17]

Classification

Carcinoids can be classified according to embryology, anatomic location, differentiation, functionality, and other histologic features. They were initially classified into three groups according to their embryonic origin by Williams and Sandler in 1963, as follows^[16]:

Foregut (intrathoracic, stomach, pancreas, duodenum)
Midgut (ie, ligament of Treitz to mid transverse colon)
Hindgut (ie, mid-transverse colon, descending colon, rectum) ^[18]

Gastric carcinoids are uniquely classified into three groups:

Type 1 (associated with chronic atrophic gastritis due to hypergastrinemia)
Type 2 (associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 [MEN1])
Type 3 (sporadic)

In 2000, the World Health Organization (WHO) distinguished gastroenteropancreatic (GEP) carcinoids and further classified NETs as follows^[19]:

Well-differentiated endocrine tumors (WDETs)
Well-differentiated endocrine carcinomas (WDECs)
Poorly-differentiated endocrine carcinomas (PDECs)

In 2010, the WHO classification of NETs was modified to include variations in the histologic characteristics of these lesions, taking into account their proliferative activity (as indicated by the degree of expression of the Ki67 nuclear antigen) in addition to their differentiation. As such, NETs were classified into the following three groups^[19]:

G1-NETs (carcinoids): well-differentiated, Ki67 < 2%
G2-NETs: well-differentiated, Ki67 2-20%
G3-NETs: poorly differentiated, Ki67 > 20%

Embryology

Intestinal carcinoid tumors are epithelial tumors located in the gastrointestinal (GI) tract, with predominant differentiation of neuroendocrine cells distributed throughout the mucosa and submucosa.^{[20, 21, 22]}Carcinoid tumors are endodermal in origin, classicallyconsidered to originate from the enterochromaffin cells (ECs; also known as the Kulchitsky cells), which are located in the crypts of Lieberkühn throughout the digestive tract.^[23]Note that ECs stain yellow-brown after chromate fixation and are diffusely distributed in the tissues derived from the primitive gut. Shared among all carcinoids, the neural cell origin and common cell lineage of these tumors is evidenced by the expression of chromogranin A (CgA), synaptophysin, and neuron-specific enolase (NSE).^[1]

Endocrine Components

The GI tract contains 14 different types of endocrine cells that comprise less than 1% of the mucosa and contain secretory granules that release various bioactive hormones. Normally, these endocrine cells (with the exception of ECs) are not evenly distributed throughout the GI tract, with some located within the gastric pits of the stomach and others within the crypts of the small intestine, colon, or rectum. This is relevant when the clinician is tasked with determining whether a clinical presentation may be due to ectopic secretion of certain bioactive peptides located at only certain anatomic locations.^[3]

Technically, carcinoids may arise from cells other than the ECs, with which they are classically associated. These other sources include cells such as the enterochromaffin-like (ECL) cells or bronchial endocrine cells. Tumors derived from neuroendocrine cells may produce hormones other than serotonin, such as gastrin, calcitonin, insulin, vasoactive intestinal peptide, neurotensin, catecholamines, or corticotropin (adrenocorticotropin hormone)—this again relates to their cell of origin.^[18]

Biochemistry

Characteristically, carcinoid tumors secrete serotonin, and patients with these tumors have elevated urinary excretion of 5-HIAA. Patients with foregut carcinoid tumors frequently have low activity of L-amino acid decarboxylase, which converts 5-hydroxytryptophan (5-HTP) to serotonin. Thus, these tumors primarily secrete 5-HTP. Midgut tumors may secrete 5-HTP in addition to serotonin.

After 5-HTP is secreted, it is converted to serotonin and its metabolites by other tissues in the body. Therefore, although foregut carcinoid tumors do not usually directly secrete large quantities of serotonin, elevated urinary 5-HIAA levels are found in patients with these tumors. In contrast, hindgut carcinoid tumors do not usually secrete large amounts of either 5-HTP or serotonin, and patients with these tumors do not have elevated urinary excretion of 5-HIAA.

Plasma chromogranin A (CgA) is elevated in 80-100% of patients with carcinoid tumors, regardless of the tumors' functional status. The sensitivity and specificity of CgA is reported between 77%-100% and 85.3-96%, respectively. Plasma CgA has been correlated with neuroendocrine differentiation of the tumor and the total tumor burden, and as such it is often used to assess treatment response.^[2]

Genetics

Studies of the genetic and molecular events associated with carcinoid tumors have elucidated the limited knowledge of carcinoid tumorigenesis. The most common phenomenon implicated is loss of chromosome 18, reported by some to occur in up to 88% of patients with NETs; other chromosomal losses have been demonstrated on chromosomes 3p, 9p (exclusive to GI carcinoids, seen in 21%), 11q, 13, and 16.^{[1, 24]}

Chromosomal gains observed in GI carcinoids have been described most frequently in chromosomes 17, 19, and 20. The mammalian target of rapamycin (mTOR) signaling pathway is an intracellular mediator involved in cellular functions including tumorigenesis, and alterations of its normal activity or that of related kinases have been identified in carcinoids^{[1, 24]}

Carcinoid Syndrome

The carcinoid syndrome is technically a paraneoplastic syndrome characterized by flushing, diarrhea, bronchoconstriction, and sometimes cardiac disease, due to the ectopic hormonal manifestations of carcinoid tumors, specifically serotonin. Most patients with carcinoid tumors do not develop carcinoid syndrome, but most patients who develop carcinoid syndrome have midgut primary tumors.

The development of carcinoid syndrome is related to total tumor mass and the extent of metastasis, as the syndrome will only occur when high amounts of bioactive substances reach the systemic circulation. This may occur via direct release of hormone into the systemic circulation, as seen in ovarian teratomas and bronchial carcinoids, or via bypass of the portal circulation, as is the case in liver metastases, which circumvent hepatic inactivation because venous drainage from a metastatic tumor in the liver is directly into the systemic circulation.^[25]

Nonhormonal Features

Nonhormonal features of GI NETs correlate with tumor size. Often these lesions are asymptomatic for years given their slow rate of growth. Over time, these tumors can induce clinically significant fibrosis of local structures, including fibroelastosis of the vasculature, which can lead to mesenteric angiopathy, or desmoplastic reactions within the bowel segments that can result in bowel obstruction.^[26]

Etiology

A prospective study by Cross et al identified the following risk factors for malignant small-intestine carcinoids^[27]:

Age (3.31 hazard ratio [HR] for ≥ 65 years versus 50-55 years)
Male sex (1.44 HR)
Obesity (1.95 HR for body mass index [BMI] ≥ 35 versus BMI 18.5-25)
In women, current menopausal hormone therapy use (1.94 HR)

According to an international meta-analysis of 24 studies conducted by Leoncini et al, risks associated with the development of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and non-GEP NETs included family history of cancer (all sites), elevated BMI (for stomach, small intestine, and pancreas), smoking (stomach, small intestine, lung, pancreas), and alcohol consumption (for rectum and pancreas). Family history was the most significant risk factor associated with NETs ^[28].

Genetic syndromes associated with increased risk for carcinoid include multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1, tuberous sclerosis complex, and von Hippel-Lindau disease. MEN1 may be responsible for approximately 10% of carcinoid tumors.^[29]

A population-based study from Sweden and Finland by Kharazmi et al found a high incidence of small-intestine carcinoid tumors in first-degree relatives of patients with the disease. Because of the rareness of small-intestine carcinoid, however, the absolute risk remains moderate even within affected families.^[30]

Epidemiology

Carcinoids are considered rare tumors, which according to the definition adopted by the American Cancer Society (ACS) are cancers with fewer than six cases per 100,000 people per year.^[8]An increase in the incidence rate of carcinoids over the past decades has been observed. In 2006, a Surveillance, Epidemiology, and End Results (SEER) population-based study by Yao et al reported that the incidence rate of NETs diagnosed per 100,000 persons per year had increased from 1.09 cases in 1973 to 5.25 cases in 2004.^[31]

More recently, Yao et al reported the annual age-adjusted incidence of NETs continues to rise, with 6.98 cases per 100,000 persons per year diagnosed in 2012, a 6.4-fold increase in incidence from 1973 to 2012.^[32]Incidence has increased across all anatomic sites, with gastroenteropancreatic (GEP) NETs at 3.56 per 100,000 persons and lung at 1.49 cases per 100,000. NETs accounted for approximately 1.5% of all newly diagnosed malignancies in 2012.^[33].

The prevalence of carcinoids in 2012 was 0.048%, and the prevalence of NETs in the US population in 2014 was 171,321.^[32]The prevalence of NETs is increasing in the same manner as the incidence rate, and these changes are largely attributed the dramatic increase in use of endoscopy and/or imaging studies as diagnostic aids.^{[9, 34, 32, 35, 36, 31, 7]}This is supported by the highest increase in incidence for localized and grade 1 NETs, which is likely in part due to earlier and/or incidental diagnosis of asymptomatic carcinoid tumors at the time of screening studies or full-body imaging utilized for evaluation of a different presenting issue.^[29]

As regards patient demographics, carcinoid tumors are diagnosed most commonly in whites, females, and older persons (age approximately 63 years or older).^{[9, 34, 32, 35, 7]}The dearth of cases diagnosed in patients younger than 4 years of age is consistent with the pathobiology of disease, as children that young lack argentaffin cells.^[37]

Of all NETs, most are diagnosed when localized (52.4%) and classified as grade 1 (61.6%), although these vary when analyzing data according to primary site.^[34]Contrary to prior studies, in which carcinoid tumors (including those of the small intestine and rectum) were found more frequently in blacks, more recent data demonstrate that carcinoids are most common in whites.^{[29, 38, 39]}Females are affected slightly more than men in most studies.^{[29, 34, 32]}

Site of Primary Tumor

Carcinoids are found most frequently in the gastrointestinal (GI) tract and the bronchopulmonary system. Approximately 55% of carcinoids are located in the GI tract, with consensus that the small intestine is the most common location within the digestive tract, followed by the rectum and then the appendix.^{[18, 23, 16, 34]}The incidence of gastroenteropancreatic (GEP) NETs was 3.56 per 100,000 persons, compared with 1.49 cases per 100,000 persons for lung NETs. Of GEP NETs, small intestine NETs had the highest incidence (1.05 per 100,000 persons), followed by rectum NETs (1.04 per 100,000 persons).

The rectum is the site with the highest prevalence for all NETs, including GI NETs, which may reflect these tumors receiving an earlier diagnosis relative to other NETs due to implementation of screening colonoscopy prior to the age at median diagnosis of carcinoids. Indeed, Taghavi et al reported an increase in the diagnosis of rectal carcinoids since the implementation of screening colonoscopy in 2000, which is reflected in the 9-fold increase in the incidence of rectal carcinoid diagnosed between 1973 and 2012. Moreover, those authors reported an increase in the diagnosis of rectal carcinoids relative to others, particularly small intestine, as seen in graphical representations prior to 2009; however, the incidence of small intestine carcinoid continues to rise following 2009, at which point that of rectal carcinoid plateaus.^{[39, 34, 32, 35, 36]}

Most rectal carcinoids are localized at diagnosis (93.2%), which is a rate far greater than that for carcinoids at other sites.^[7]Age at diagnosis is also unique for rectal carcinoids, with most patients being 40-59 years-old (55.8%). Most patients with rectal carcinoids are female (51.5%), and 51.5% are whites.

In the most recent epidemiologic study of small-intestine carcinoids, the 5-year prevalence and 1-year incidence per 100,000 persons were 9.2 and 14.2, respectively; these values are greater than those previously cited, however the authors contend a more precise measurement than preceding studies, given the large study cohort and updated time interval between 2012 and 2017.

Small bowel carcinoids were more common in whites (77%) and patients at least 65 years of age (56%); however, both genders were affected equally (50%).^[32]. These results are similar to previous studies on GI NETs with the exception of gender, in which small- intestine carcinoids were diagnosed more often in males (52.2%) than in females (47.8%).

Carcinoids of the appendix comprise 43-57% of all appendiceal growths and are found in < 1% of appendectomies.^{[37, 5]}The median age of patients diagnosed with carcinoids of the appendix is 38 to 48 years, which is less than that of all NETs.^[6]In contrast to small-intestinal carcinoids, a gender preference is seen in carcinoids of the appendix, with 59.8% of cases diagnosed in females.^[7]Nearly all studies identified non-Hispanic whites as the race most frequently diagnosed with carcinoids of the appendix.^{[34, 7]}

The diagnosis of gastric carcinoid has increased nearly 15-fold according to some studies, but less than10% of carcinoids arise in the stomach.^{[32, 40]} Similar to other carcinoids, most patients diagnosed with carcinoids of the stomach are female (58.5%), white (64.4%), and older than 60 years (55.6%).^[7]Approximately 77.9% of patients diagnosed with gastric NETs have localized disease, which, similarly to rectal carcinoids, is a much higher rate than with other carcinoids. As with rectal carcinoids, this may be explained to more frequent use of endoscopy.

As with other carcinoids, most patients with colonic carcinoids are female (54.8%), white (75%), and older than 60 years (58.9%). Colonic carcinoids most often present with advanced-stage disease (38%).^[7]

Carcinoid Syndrome

The carcinoid syndrome is seen in approximately 20% of all NETs, whereas previously 10% of NETs where associated with carcinoid syndrome.^{[25, 6]}In a SEER-based study of elderly patients (65 years old or greater) diagnosed with NETs, carcinoid syndrome was seen in 19% of patients within 6 months of diagnosis.^[6]

Rates of carcinoid syndrome vary with primary tumor location, ranging from 22% to 32% of all small bowel NETs and 8% of all lung NETs.^{[9, 6]}Carcinoid syndrome occurs less frequently in patients with bronchial carcinoids, is rarely observed with appendiceal carcinoids, and does not occur in patients with rectal carcinoids, even when the rectal carcinoid is at an advanced stage and has metastasized.

In general, individuals who have carcinoid syndrome will most commonly have primary carcinoids located in the small bowel (40%), followed by the lung or the colon/rectum. Most of these will be grade 1 carcinoids (73%). Carcinoid syndrome is more common in females (61%) and in whites (83%).^[6]Disease stage is most often distant (29%) rather than local or regional, although some studies indicate up to 13% of patients diagnosed with the carcinoid syndrome do not have hepatic metastases.^[25]

Mortality/Morbidity

The median overall survival for all NETs 9.3 years (112 months).^[7]Overall survival correlates with stage, primary tumor site, race, and age at diagnosis. The median overall survival according to stage is as follows:

Localized disease: > 30 years
Regional disease: 10.2 years
Distant disease: 12 months

Median survival according to grade is as follows:

Grade 1: 16.2 years
Grade 2: 8.3 years
Grade 3: 10 months

Median survival according to primary tumor site is as follows^[32]:

Appendix: > 30 years
Rectum: 24.6 years
Lung: 5.5 years
Pancreas: 3.6 years

In a SEER-based study of patients diagnosed with GI NETs between 1973 and 2008, the 5-year disease-free survival was greatest for carcinoids of the rectum (95.6%) and appendix (90.3%).^[7]The 5-year disease-free survival for carcinoids in the small intestine was 86.2%, 82.7% for the stomach, and 67.4% for the colon. See Table 1 for survival of patients with distant G1/G2 NETs.

Table 1. Median Survival of Patients wth Distant Stage G1/G2 Neuroendocrine Tumors Diagnosed from 2000-2012^[32] (Open Table in a new window)

Site	Median Survival (months)	3-Year Survival Rate (%)	5-Year Survival Rate (%)
Cecum	98	70	61
Colon	14	33	29
Lung	24	39	32
Pancreas	60	62	50
Rectum	33	48	28
Small Intestine	103	80	69
Stomach	29	45	32

Prognosis

In certain patients, aggressive operative extirpation of neuroendocrine neoplasm hepatic metastases allows for long-term survival.^[41]However, disease progression is still common. Thus, a multimodality treatment approach is needed in patients with progressive disease. Combining knowledge of identified prognostic factors can improve patient selection and can help identify patients at greatest risk for treatment failure. As would be expected, overall survival is worse with regional and distant-stage disease than with localized NET, and G1 NETs have better survival compared with G2 NETs and G3/G4 NETs. Compared with pulmonary carcinoids, the site with the worst overall survival is the liver.^[32]

Overall, survival has improved. Survival has improved for both women and men diagnosed with small intestinal NETs, and for patients of all races diagnosed with colonic carcinoids.^[7]In general, the risk of death following a diagnosis of NET has improved, with a 21.3% lower risk of death reported between 2009 and 2012, and 17.1% between 2005 and 2008.^{[32, 7]}The 5-year survival rates are as follows^[34]:

Localized grade 1 GI NETs: 85.4%
Regional grade 1 GI NETs: 77.5%
Localized grade 2 carcinoids: is 79.5%

Potential complications of small-intestine carcinoids and the percentage of patients affected are as follows^[9]:

Carcinoid syndrome: 22%
Small-bowel obstruction (often due to desmoplastic reaction): 30%
Gastrointestinal (GI) bleed (often due to ulceration of mucosa): 19%
Perforation: 3%
Flush: 2%
Volvulus: 1%
Intussusception: < 1%

Other complications of GI carcinoids include intestinal ischemia or infarction, which can be due to mesenteric angiopathy, characterized by a desmoplastic mesenteric reaction.

Carcinoid Abdominal Crisis

Carcinoid abdominal crisis is a rare acute abdominal syndrome characterized by severe abdominal cramping without a mechanical bowel obstruction. The mechanism of the crisis is believed to be intestinal ischemia caused by vasoactive substances elaborated by the carcinoid tumor, combined with a decreased mesenteric blood supply due to perivascular fibrosis. The large-scale and continuous release of bioactive substances may also cause severe hypotension and watery diarrhea. Edema of the face, rapid pulse, and pruritus may also be present. These episodes are often self-limited but can lead to necrosis of the bowel, requiring operative intervention in some cases.^[42]

Carcinoid Crisis

Carcinoid crisis is an extreme complication of excess hormone production and most often diagnosed perioperatively. The diagnosis is clinical, characterized by hemodynamic instability (hypotension, tachycardia, and/or arrhythmia), hyperthermia, flushing, and bronchial obstruction.^[2]

Patients at risk for carcinoid crisis include those with preoperative evidence of large tumor burden, prominent flushing, or carcinoid heart disease; preoperative use of octreotide has been shown to prevent intraoperative and/or post-operative carcinoid crisis ^[2]. Providers should be suspicious of carcinoid crisis in patients who have known carcinoid tumors with sudden onset of cardiovascular collapse that is unresponsive to fluids or vasoactive agents; acutely, these patients should be treated with intravenous octreotide.^[2]

Carcinoid Heart Disease

Right-sided cardiac valvular disease usually develops only after many years of the syndrome and manifests in approximately half the patients with long-standing carcinoid syndrome. Serotonin stimulation induces irreversible endocardial fibrosis of the tricuspid and pulmonary valves, resulting in valvular dysfunction (stenosis or incompetence). The lungs metabolize serotonin and protect the left heart from fibrosis. Carcinoid heart disease may ultimately result in cardiac insufficiency, usually with right-sided heart failure.

Clinical Presentation

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Media Gallery

Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 1. Courtesy of Memorial Sloan-Kettering Cancer Center.
Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 2. Courtesy of Memorial Sloan-Kettering Cancer Center.
Postprocedure computed tomography scans after bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors. Courtesy of Memorial Sloan-Kettering Cancer Center.

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Intestinal Carcinoid Tumor

Practice Essentials