Intestinal Carcinoid Tumor 

Updated: Dec 20, 2021
Author: Rachel E Lewis, MD; Chief Editor: N Joseph Espat, MD, MS, FACS 

Overview

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.)

Background

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%

Pathophysiology

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.

 

Presentation

History

Most intestinal carcinoids are asymptomatic, and their diagnosis is usually made incidentally or at autopsy. Presenting symptoms are due to either the size of the tumor or the secretion of biologically active peptides or amines into the bloodstream. Additionally, the presence of symptoms will vary depending on the location of the primary tumor (see Table 2).

Table 2. Presentation of Intestinal Carcinoids (Open Table in a new window)

Location

Nonhormonal Symptoms

Stomach

 

Pain

Pernicious anemia

Small intestine

 

Pain

Intestinal obstruction

Appendix

 

Appendicitis

Incidental finding

 

Colon

 

Pain

Bleeding

Weight loss

Rectum

 

Pain

Constipation

Bleeding

 

Constitutional symptoms, such as anorexia, weight loss, and fatigue, are common to the clinical presentation. They can be related to local or distant spread, which is present in up to 47.5% of patients at the time of diagnosis.[7] In such cases, the disease is typically estimated to have been present for more than 8 years before diagnosis. Early diagnosis is often difficult because the patient generally reports only vague abdominal symptoms or flushing.

Most patients complain of abdominal pain. Patients with carcinoid tumors are often misdiagnosed with irritable bowel syndrome or idiopathic flushing. Flushing can occur spontaneously without the carcinoid syndrome, and it is reported in approximately 2% of patients with small-intestine primary tumors.

Patients with midgut carcinoids frequently have symptoms for long periods (ie, 2-5 years or more) before a specific diagnosis is made. In this group of patients, early diagnosis can potentially lead to a cure by surgical resection of the primary tumor. The most common symptoms and signs of an intestinal carcinoid are abdominal pain, intermittent obstruction, and a palpable abdominal mass.

Obstruction usually occurs after invasion of the mesentery, and the resulting desmoplastic reaction with scarring and matting of small bowel loops, in turn, can produce a mass and intermittently obstruct the intestine. The clinical picture of recurrent intermittent intestinal obstruction should raise the suggestion of carcinoid tumor. Because this process is extraluminal, results of endoscopic examination may be normal approximately half the time.

Carcinoid Syndrome

The syndrome is characterized by hepatomegaly, diarrhea, and flushing in 80% of patients; right heart valvular disease in 50%; and asthma in 25%. Malabsorption and pellagra (ie, dementia, dermatitis, and diarrhea) are occasionally present and are thought to be caused by the excessive diversion of dietary tryptophan to serotonin.

Diarrhea is the most common feature of carcinoid syndrome, affecting 80% of patients. It is usually episodic, often occurring after meals. The diarrhea is due to elevated circulating levels of serotonin, which stimulate the secretion of small-bowel fluid and electrolytes and increase intestinal motility.

Asthma (25% of patients) is due to bronchoconstriction, which may be attributed to serotonin, bradykinin, or substance P elaborated by the carcinoid tumor. The treatment of asthma associated with carcinoid syndrome must be conducted very carefully because adrenergic drugs may cause the release of humoral agents from the tumor, resulting in status asthmaticus.

Physical Examination

Physical examination findings may be normal, and the patient may appear to be healthy.

Patients in carcinoid crises can have face, neck, and upper chest flushing lasting for hours to days. They can have hypotension, increased lacrimation, and fever and can be in moderate to severe distress. The typical patient is 61-66 years old and experiences flushing when performing a Valsalva maneuver.

Skin findings include facial telangiectasias, usually bimalar. Extremity rash is usually a finding in severe, uncontrolled, end-stage disease, thus implying niacin deficiency.

Examination of the lungs may reveal wheezing. Cardiac examination usually yields normal results, but with prolonged, uncontrolled serotonin secretion, patients may have evidence of tricuspid valve regurgitation and, less commonly, pulmonic stenosis.

The abdomen may be distended and nontender. Bowel sounds may be normal or high pitched. Hepatomegaly is possible.

Examination of the extremities may demonstrate bilateral lower extremity edema.

 

DDx

 

Workup

Laboratory Studies

In patients with carcinoid syndrome, levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) are usually significantly elevated. This is because tryptophan metabolism is diverted from protein and nicotinic acid metabolism to serotonin, with consequent breakdown to 5-HIAA. A very high (usually more than five times normal values) level of urinary 5-HIAA in a 24-hour collection is diagnostic, provided that foods and drugs that may interfere with test results are avoided before the test.

Foods that contain high levels of 5-HIAA precursor and should be excluded from the diet for at least 24 hours before the test include avocados, bananas, plums, walnuts, pineapples, tomatoes, and eggplants (aubergines). Drugs that may interfere with test results, and which typically should be excluded for at least 48 hours before the test, include cough medicines, antihistamines, acetaminophen, and monoamine oxidase inhibitors.

In very rare cases, usually in bronchial carcinoids or gastric tumors (derived from the foregut), the tumor cells lack the aromatic amino acid decarboxylase enzyme, and hence the secretion of 5-hydroxytryptophan (5-HTP) is increased. If this is the situation, then 5-HIAA urinary excretion would be normal. The diagnosis is confirmed by measuring total 5-hydroxyindole excretion. Such measurement includes 5-HTP, serotonin, and 5-HIAA.

Well-known biomarkers common to neuroendocrine tumors (NETs) include synaptophysin, chromogranin A (CgA), and neuron-specific enolase (NSE), among others. Of these neuroendocrine biomarkers, synaptophysin and CgA are recommended for routine use in practice because synaptophysin is considered the most sensitive and CgA the most specific in the evaluation of NETs.[43] Given the low specificity of NSE for NETs relative to synaptophysin and CgA, it is not recommended for routine use in practice.

Massironi and colleagues evaluated the diagnostic and prognostic value of plasma CgA in 181 patients with pancreatic or gastrointestinal neoplasms. CgA values at diagnosis were above the upper reference limit in 148 patients (82%). Median CgA levels were significantly higher in functioning tumors compared with non-functioning tumors and in patients with metastases compared with those without metastases. CgA levels were significantly associated with disease stage after adjustment for patient age, sex, and tumor site. An early decrease in CgA, a low Ki-67 index, and type of treatment were positively correlated with survival. Increased CgA levels predicted recurrence after radical surgery.[44]

In a study of 125 patients with neuroendocrine tumors, 29 patients without neuroendocrine tumors who were being treated with proton pump inhibitors, and 50 controls, a polymerase chain reaction (PCR)–based 51-transcript signature was significantly better than plasma CgA for detecting tumors, and was unaffected by the use of acid suppression therapy. PCR had a sensitivity of 98.4%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 97.8%; corresponding metrics for CgA were all less than 60 %.[45]

Imaging Studies

Ultrasound

Ultrasound has limited use, particularly in lesions smaller than 1 cm.

Endoscopic ultrasound is useful for detecting gastric, duodenal, and pancreatic lesions; experience in this technique is mainly in detecting duodenal gastrinomas and is highly operator dependent.[46] It is also used to detect anal lesions.

Computed Tomography

Noncontrast CT scan is the investigation of choice for carcinoid tumors because metastatic carcinoid tumors are usually extremely vascular; consequently, they tend to become isodense in the presence of contrast.[47]

CT scan can also detect mesenteric involvement with tumor in 50% of patients with metastatic disease.

Magnetic Resonance Imaging

In the past, availability and the speed of the procedure initially limited use of this investigation. Another dilemma was the difficulty in distinguishing between small (< 2 cm) vascular intrahepatic lesions and benign hemangiomas. With technical improvements, MRIs are increasingly being used as the supplemental abdominal investigation of choice.

Radionucleotide Scans

Radionucleotides injected into the bloodstream can bind to the neuroendocrine tumor cells and thus help localize the site of the tumor.

Commonly, octreotide (an analogue of somatostatin) is labelled with a radioactive isotope and injected. Carcinoid tumors often have somatostatin receptors on their surface. The radio-labelled analogue (111In-octreotide) therefore binds to the tumor cells. Radiography then allows the tumor to be visualized. This test is particularly useful when other routine modalities have failed to localize the site of the carcinoid. Another compound used less commonly is I131 MIBG.

Positron Emission Tomography

This modality uses the ability of certain tumors to take up radiolabeled tracers and thus be used to assess the function of different metabolic pathways specific to the tissue being scanned. It is useful in those instances in which scintigraphy with In111 octreotide has been inconclusive.

FDG (F18 labelled deoxyglucose) is the tracer that is useful in detecting less-differentiated neuroendocrine tumors, as they have a higher metabolic rate. Well-differentiated tumors have slower metabolic rates and therefore do not take up FDG as avidly. These tumors are better visualized on PET scans, which use the tracer C15 5-HTP.

Recently, gallium-68 (68Ga)-DOTATATE PET/CT scanning has become the preferred modality for somatostatin receptor imaging due to its higher sensitivity and reduced exposure to radiation. It has a sensitivity greater than 94% and specificity greater than 92%. Use of 68Ga-DOTATATE PET/CT imaging has been reported for baseline staging, detection of metastases, and identification of the primary site.[4]

Other Tests

Gastric and anal carcinoid tumors can be evaluated by endoscopic techniques. Standard gastroscopy is of limited use except in patients with multiple gastric carcinoids.

Staging

There is no single system of classification and staging of carcinoid tumors. Different systems classify these tumors on the basis of site of origin (lung or gastrointestinal), malignant potential, and spread.

The World Health Organization (WHO) classifies carcinoids as neuroendocrine tumors (benign) or neuroendocrine cancers (malignant). Neuroendocrine cancers are further subclassified as either well differentiated (less aggressive) or poorly differentiated (aggressive).

Classification based on spread is as follows:

  • Localized - Limited to the organ of origin
  • Regional spread - Limited infiltration into surrounding tissues
  • Distant metastasis - Disease present in organs other than the primary

Histologic Findings

In general, gastrointestinal carcinoid tumors are described as submucosal or intramural lesions that are nodular or polypoid in shape with yellow-tan coloration.[48]  They may appear ulcerated in advanced lesions, indicated spread beyond the mucosa and submucosa. The typical histologic appearance of carcinoids is describe as a "salt-and-pepper" pattern, which is the chromatin within granules. They are small, with relatively uniform round to oval nuclei. They have an organoid shape with a nesting or trabecular like pattern. Carcinoids characteristically stain positive for CgA and synaptophysin. 

 

Treatment

Approach Considerations

Surgical resection is the standard therapeutic modality for intestinal carcinoid tumors; medical care is usually only for symptomatic relief. Chemotherapy response rates are variable but rarely exceed 30%. When response does occur, the results are usually short-lived, lasting less than 1 year. 5-Fluorouracil and streptozocin (Zanosar)–based regimens are commonly used in patients with metastatic carcinoid tumors. The value of using newer agents (eg, taxanes, gemcitabine [Gemzar], irinotecan [Camptosar]) remains unproven.

Chemotherapeutic regimens are best used only for palliative purposes. If eligible, patients should be entered into a clinical trial of investigational therapy. Similarly, radiation therapy has only a palliative role, particularly for painful bony metastasis.

Medical Care

High doses of sodium iodine-131–labeled metaiodobenzylguanidine, low-dose interferon-alfa, and octreotide have all been used, with some reduction in symptoms; however, tumor reduction is rarely observed. When reductions occur, they are only transient.[49] The somatostatin analog octreotide may provide control of carcinoid symptoms if findings on OctreoScan are positive or if somatostatin receptors are found in tumor tissue.

A randomized, placebo-controlled phase 3 trial found that everolimus plus octreotide long-acting repeatable (LAR) improved progression-free survival in patients with advanced neuroendocrine tumors associated with intestinal carcinoid syndrome.[50]

The US Food and Drug Administration (FDA) has approved the radiolabeled somatostatin analog Lutathera (lutetium Lu 177 dotatate) for the treatment of adult patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which would include intestinal carcinoids. Approval was based on the results of two studies: the first showed longer progression-free survival for patients taking Lutathera with octreotide compared with patients who received octreotide alone; the second showed complete or partial tumor shrinkage in 16% of 360 patients with GEP-NETs treated with Lutathera.[51]

The North American Neuroendocrine Tumor Society (NANETS) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) have published a practical consensus guideline for the administration of 177Lu-dotatate. The guideline covers patient screening, maintenance therapy requirements, treatment location and room preparation, drug administration, and patient release, along with radiation safety, toxicity monitoring, management of potential complications, and follow-up. To prevent interference with somatostatin receptor binding, the guideline recommends waiting at least 4 weeks after the last dose of long-acting somatostatin analog (SSA) therapy or at least 24 hours after the last dose of a short-acting SSA before administering 177Lu-dotatate.[52]  

Telostristat ethyl (Xermelo) is approved by the FDA for carcinoid syndrome diarrhea in combination with SSA therapy in adults inadequately controlled by an SSA. Telostristat ethyl is a prodrug that is metabolized to telotristat, which inhibits tryptophan hydroxylase, the rate-limiting step in serotonin biosynthesis.

The safety and efficacy of telotristat were established in a 12-week, double-blind, placebo-controlled trial in 135 patients who were experiencing 4 or more bowel movements per day despite the use of an SSA and were randomly assigned to add placebo or telotristat three times daily. Reduction in bowel movement frequency of ≥30% from baseline for ≥50% of the double-blind treatment period was observed in 44% of patients given telotristat ethyl 250 mg, 42% of those given telotristat ethyl 500 mg, and 20% of those receiving placebo. The FDA approved the 250 mg TID dosage regimen.[53]

Patients with problematic diarrhea usually benefit from antidiarrheal medication. Cyproheptadine and histamine-2 receptor blockers may work because they suppress the production of vasoactive amines or block their peripheral effects.

Surgical Care

Surgical resection is the standard therapeutic modality. The operative approach varies with the location and extent of the tumor.

Appendiceal Carcinoids

For tumors smaller than 1.5 cm in greatest diameter that are confined to mucosa, appendectomy is adequate, with no need for follow-up care. Cure rates are 100%.

Tumors 2 cm or larger in diameter, those at the base of the appendix, or those with mesenteric lymphadenopathy are not common but are considered potentially malignant. Consider more aggressive surgery in the form of a right hemicolectomy and lymphadenectomy, similar to that performed for colonic adenocarcinoma.

Invasion of only the mesoappendix does not alter the long-term prognosis, but cecal involvement necessitates further surgery.

A study by Cashin et al investigated the use of cytoreductive surgery and intraperitoneal chemotherapy in patients with appendiceal adenocarcinoids. The study found that the completeness of cytoreduction score (CC) correlated with overall survival. Candidates for this treatment should be referred early in order to attain a better CC score. The study also confirmed that drugs used for colorectal cancer also seemed adequate for appendicial adenocarcinoid, although other drugs may be more active.[54]

Small Bowel Carcinoids

At laparotomy, perform a thorough examination of the small bowel because multiple lesions are fairly common.

Macroscopic tumor size is a fairly good indicator of malignant potential. For tumors smaller than 1 cm in diameter, local resection is usually adequate. Tumors larger than 1.5 cm have a risk of recurrence, hence the need for a segmental bowel resection with lymphadenectomy.

Rectal Carcinoids

Tumor size is of essence with regard to the extent of resection. A systematic review by McDermott et al concluded that carcinoids up to 1 cm in size that have no adverse features can be treated with endoscopic or local excision; management of tumors between 1 and 2 cm is controversial, but those up to 1.6 cm without adverse features are suitable for local or endoscopic excision, with careful histopathological assessment.[55]

In tumors of up to 1 cm in diameter, local excision or fulguration results in cure rates close to 100%.[56] Consider large tumors (≥2 cm) malignant, and manage them similarly to adenocarcinoma of the rectum, with extensive resection. Tumors of 1-2 cm can be treated either by limited or more aggressive resection, with each case is guided according to the size, invasive nature, and anatomic location.

All patients except for those with lesions smaller than 1 cm require conscientious follow-up care.

Metastatic Intestinal Carcinoids

Surgery is considered worthwhile in most cases because this is the best form of palliation, regardless of whether the tumor is of the secretory type. Tailor the procedure accordingly, and avoid attempts at major debulking procedures.

All patients with advanced-stage carcinoid tumors should be evaluated for possible multimodal surgical therapy. Primary tumors should be resected, even in the presence of distant metastases, to prevent future intestinal obstruction. The "wait and see" method of management of this slow-growing cancer no longer has merit.[57]

Obstructive small bowel lesions could be resected (if possible) or bypassed.

Multiple liver metastases in patients with carcinoid syndrome are resected, cauterized, or ablated with percutaneous alcohol injections, because this usually results in a dramatic relief of symptoms.

Hepatic artery ligation or embolization (eg, collagen fibers, gel foam, alcohol) can result in significant tumor necrosis and is of value in patients with bulky, inoperable, or symptomatic liver metastasis, with up to a 60% reduction of tumor bulk in some cases.

The videos below demonstrate bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors.

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.

Hepatic artery ligation or embolization can be combined with intrahepatic chemotherapeutic infusion. However, it can result in toxic effects, particularly fever, nausea, vomiting, and abdominal pain. Occasionally, the carcinoid symptoms may worsen.[58]

Diet

As previously mentioned, patients may experience symptoms due to NETs or treatment with medications like somatostatin analogs; these may include diarrhea, abdominal pain, flatulence, bloating, skin changes, and fatigue. Key nutritional recommendations for symptoms are listed below[59] :

  • For prevention of flushing, avoidance of spicy foods and alcoholic beverages
  • For prevention of diarrhea, substitute raw, high-fiber fruits and vegetables
    • Introduce ripe bananas, pureed vegetables, cooked fruits, rice, pasta, and potatoes
    • Avoid cream cheese, butter, and white breads - use jams, jellies, and whole-grain breads instead
    • Replace cream-based soups with broth
    • Replace doughnuts and butter cookies with pretzels or crackers
    • Ingest high-electrolyte replacement drinks in place of sodas or juices
    • Ingest lactose-free beverages in place of milk
  • Niacin supplementation to replenish low stores due to high metabolism of tryptophan associated with NETs
  • Pancreatic enzyme supplementation for steatorrhea or other symptoms associated with fat malabsorption

Long-Term Monitoring

Surveillance of treated carcinoid patients depends on the initial stage at presentation and the type of treatment that was offered, as follows:

  • For appendicular carcinoids that are less than 2 cm and localized to the appendix, no further follow-up is required after the patients have had an appendectomy
  • For those patients who have had a right hemicolectomy, blood markers (5-HIAA, chromogranin A) need to be monitored at 3 months after resection, along with imaging in the form of a CT scan or MRI
  • For rectal carcinoids 2 cm or less, which have been amenable to transanal excision, follow-up is required in the form of a proctoscopy at 6 and 12 months, and further investigations are warranted only if clinically indicated
  • For other patients with intestinal carcinoid tumors, long-term monitoring is required. This involves blood markers every 6 months for the first 3 years and then yearly thereafter; additional imaging is performed based on the results of the markers and clinical findings [60]

 

 

Guidelines

Guidelines Summary

Guidelines Contributor: Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

The following organizations have issued clinical guidelines for the management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs):

  • National Comprehensive Cancer Network (NCCN)
  • North American Neuroendocrine Tumor Society (NANETS)
  • European Neuroendocrine Tumor Society (ENETS)
  • European Society for Medical Oncology (ESM0)
  • UK and Ireland Neuroendocrine Tumour Society (UKI NETS)

Grading and Staging

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS) both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs).[61, 62, 63]  

Tumors fall into one of the following three grades:

  • G1: well differentiated, low grade
  • G2: well differentiated, intermediate grade
  • G3: poorly differentiated, high grade

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.[60]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.[60]  The AJCC uses separate staging systems for carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix.[64]

For staging of GEP-NETs, the European Society for Medical Oncology (ESMO) guidelines, updated in 2020, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2019 WHO grading system.[65]  

In 2012, the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) released updated guidelines for the management of GEP-NETs. Recommendations for grading and staging are as follows[66] :

  • For grading: WHO 2010 grading system
  • For staging: 8 th edition of the AJCC Cancer Staging Manual
  • Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system
  • The TNM classification used should be specified
  • Underlying features of the T-stage classification (e.g., tumor size, extent of invasion) should be documented to allow for translation between different classification systems

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage.[67]

 

Treatment

Treatment for locoregional disease

NCCN guidelines recommend resection as the primary treatment for most carcinoid tumors of the gastrointestinal (GI) tract. Specific recommendations vary by tumor subtype. However, for neuroendocrine tumors at any site, cholecystectomy is recommended during surgical resection if treatment with a somatostatin analog (ie, octreotide, lanreotide) is planned, due to the increased rate of biliary problems associated with long-term use of these agents.[60]

Gastric tumors

For gastric tumors, the NCCN recommendations are as follows[60] :

  • With hypergastrinemia and tumors ≤ 2 cm: Endoscopic resection of prominent tumors with endoscopic surveillance every 2-3 years
  • With hypergastrinemia and tumors > 2 cm: Resection of primary gastrinoma or consider endoscopic surveillance and/or octeotide or lanreotide and manage gastric hypersecretio with high-dose proton pump inhibitors (PPIs)
  • With normal gastrin levels: Radical gastric resection and regional lymphadenectomy (preferred); endoscopic or wedge resection can be considered for tumors ≤ 2 cm

NANETS 2010 guidelines subclassify gastric carcinoids into the following three distinct groups[68] :

  • Type I – Those associated with chronic atrophic gastritis/pernicious anemia (70-80%)
  • Type II – Those associated with Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (MEN I) (5%)
  • Type III – Sporadic NETs of the stomach (15-20%)

NANETS 2013 updated guidelines include the following recommendations for treatment of gastric carcinoid tumors by subtype[67] :

  • Type I or II, < 1 cm: Surveillance or endoscopic removal
  • Type I, 1 cm to < 2 cm: Surveillance with repeat endoscopy every 3 years or endoscopic resection
  • Type II, 1 cm to < 2 cm: Endoscopic resection
  • Type I, ≥2 cm (≤6 polyps), or type II ≥2 cm: Endoscopic resection, if possible, or open surgical resection
  • Type I, ≥2 cm (>6 polyps): Individualized treatment required; surveillance, endoscopic resection, or surgical resection
  • Type III: Partial gastrectomy and lymph node dissection

The 2016 revised ENETS guidelines prefer conservative management strategies over surgery for type I tumors. The guidelines recommend resection of tumors ≥ 10 mm performed by experienced endoscopists in gastric tumors using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[69]

For type II tumors, local or limited excision can be recommended, but this should be patient tailored at multidisciplinary NET centers of excellence. Type III tumors should be treated similarly to gastric adenocarcinoma with surgery (partial or total gastrectomy with lymph node dissection). Systemic therapies is required for inoperable or stage 4 disease.[69]

Duodenal tumors

For duodenal tumors, the NCCN recommends the following treatments[60] :

  • Endoscopic resection with follow-up upper endoscopy
  • Transduodenal local excision with or without lymph node sampling
  • Pancreatoduodenectomy

ENETS guidelines provide the following recommendations for treatment of duodenal tumors[69] :

  • All localized tumors should be removed
  • Endoscopic resection for tumors ≤1 cm confined to the submucosal layer, without lymph node or distant metastasis
  • Surgical resection with lymphadenectomy for tumors in the periampullary region
  • Surgical resection for tumors >2 cm and tumors of any size with lymph node metastases

Bowel tumors

NCCN recommendations are as follows[60] :

  • Surgical resection with lymphadenectomy
  • Careful examination of the entire bowel and assessment of proximity to or involvement of the superior mesenteric artery and superior mesenteric vein
  • Prophylactic cholecystectomy if further treatment with octreotide or lanreotide is planned

The NANETS guidelines include the following recommendations[67] :

  • Tumors of the cecum: Right hemicolectomy with node dissection
  • Tumors of the jejunal or ileum: Resection with node dissection; full bowel examination required
  • Distal colon and rectum tumors < 1 cm: Endoscopic resection (polypectomy, endoscopic mucosal resection, endoscopic submucosal dissection) for mucosal or submucosal tumors
  • Distal colon and rectum tumors 1-2 cm: Transanal excision via rigid or flexible dissection; could also be considered after endoscopic resection with positive margins
  • Distal colon and rectum tumors >2 cm: Surgical resection (low anterior resection or abdominoperineal resection) for larger tumors, tumors invading muscularis propria, or those with lymphadenopathy

The ENETS guidelines provide following recommendations[70, 71] :

Rectal Tumors[70]

  • Endoscopic resection by simple polypectomy, endoscopic mucosal resection (EMR) with modified EMR band ligation, endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEMS).
  • For lesions < 10 mm and no involvement of the muscularis propria, EMR is adequate, but EMR band-assisted ligation may improve the number of complete resections 
  •  If EMR results in an incomplete resection, then ESD or TEMS may be indicated as salvage therapy

 Jejunum and Ileum Tumors[71]

  • Curative resection of the primary tumor and dissection of the locoregional lymph node metastasis along the superior mesenteric root and around the mesentery
  • Lymphatic mapping it is not a standardized procedure and not generally recommended 

Appendix tumors

NCCN recommendations for appendix NETs are as follows[60] :

  • Tumors ≤ 2 cm confined to the appendix: Appendectomy
  • Tumors ≤ 2 cm with lymphovascular or mesoappendiceal invasion or atypical histologic features: More aggressive treatment can be considered
  • Incomplete resection or tumors > 2 cm: Staging with abdominal/pelvic CT or MRI; if no distant disease, reexploration with a right hemicolectomy

The NANETS guidelines include the following recommendations[67] :

  • Excision for tumors ≤ 2 cm; consider right hemicolectomy with node dissection if high- risk features are present
  • Tumors > 2 cm: Right hemicolectomy with node dissection

The 2016 ENETS revised guidelines recommendations include[72] :

  • Tumors ≤ 2 cm: simple appendectomy unless incompletely resected
  • Right hemicolectomy with node dissection only in rare tumors measuring 1–2 cm but with positive or unclear margins or with deep mesoappendiceal invasion (ENETS T2), higher proliferation rate (G2) and/or vascular invasion
  • Tumors > 2 cm: right hemicolectomy with node dissection

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic carcinoid tumors of the GI tract include the following[60] :

  • Somatostatin scintigraphy to assess sites of metastases and somatostatin receptor status if octreotide or lanreotide is considered
  • Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases
  • Unresectable hepatic progressive disease: Radiofrequency ablation or cryoablation or hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization)
  • Palliative small bowel resection for patients with abdominal pain from bowel obstruction or ischemia related to the primary tumor
  • Octreotide or lanreotide to control tumor growth in patients with clinically significant tumor burden or progressive disease; everolimus can be considered for advanced tumors
  • Consider capecitabine if no other options are feasible (category 3)
  • Malignant carcinoid syndrome: Octreotide or lanreotide; cardiology consultation, and echocardiogram to assess for heart disease. If poorly controlled, consider telotristat for persistent symptoms.
  • Liver transplantation is investigational and not recommended as routine care

Note that the use of ablative techniques for hepatic disease is associated with increased infectious complications. Although the NCCN guidelines cite category 2b evidence for cryoablation and radiofrequency ablation, most centers use radiofrequency or microwave ablation. Cryoablation is generally used only in centers providing ablation for renal cell cancers, and it is associated with a small but definite risk of subsequent acute respiratory distress syndrome.[73]

 

 

Medication

Medication Summary

Pharmacotherapy is usually for symptomatic relief only. Chemotherapy response rates rarely exceed 30% and are usually short lived; chemotherapeutic regimens are best used for palliative purposes.

Antineoplastic agents

Class Summary

These agents inhibit cell growth and differentiation.

Streptozocin (Zanosar)

Cell-cycle phase-nonspecific antineoplastic agent that alkylates DNA, causing interstrand cross-linking. Also inhibits DNA synthesis by blocking incorporation of DNA precursor and inhibiting cell proliferation. May be helpful in symptom palliation for patients with progressive disease. Dosage is related to body surface area. May cause a complete remission of disease. Administration must be suspended only when desired response or toxicity occurs. Streptozocin may determine severe nephrotoxic effects.

Antisecretory agents

Class Summary

These agents may provide control of carcinoid symptoms.

Octreotide (Sandostatin)

Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

Telotristat ethyl (Xeromelo)

Telotristat, the active metabolite of telotristat ethyl, inhibits tryptophan hydroxylase, which mediates the rate limiting step in serotonin biosynthesis. Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract, and is overproduced in patients with carcinoid syndrome. It is indicated for carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.

Somatostatin Analogs

Lanreotide (Somatuline Depot)

Used in treatment of carcinoid syndrome, to reduce frequency of rescue therapy, or for gastreoenteropancreatic neuroendocrine tumors, to improve progression-free survival.

Biological Response Modifiers

Interferon alfa 2b (Interferon alfa-2b, Intron A)

Second-line therapy in functional NETs with low proliferation capacity, such as small intestinal carcinoids

Radiopharmaceuticals

Lutetium Lu 177-dotatate (Lutathera)

Radiolabeled somatostatin analog; binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor-expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. Beta emission from Lu 177 induces cellular damage by forming free radicals in somatostatin receptor-positive cells and in neighboring cells