Malignant Carcinoid Syndrome

Practice Essentials

Malignant carcinoid syndrome is characterized by an array of signs and symptoms—in particular, hot, red flushing of the face; severe and debilitating diarrhea; and asthma attacks—caused by vasoactive hormones secreted by metastases from carcinoid tumors.^{[1, 2, 3]}  Carcinoid tumors are of neuroendocrine origin and derive from primitive stem cells, which can give rise to multiple cell lineages. Malignant carcinoid syndrome occurs in fewer than 10% of patients with a carcinoid tumor.

Carcinoid tumors arise from neuroendocrine cells, which are widespread in the human body, especially in the organs derived from the primitive intestine (see the image below).  Carcinoid tumors and related syndromes may be a part of multiple endocrine neoplasia.

View Image

A section (on the right) of an intestinal carcinoid mass arising from the mucosa (150 X). Image courtesy of Professor Pantaleo Bufo, University of Fog....

These intensely vascularized tumors follow the so-called rule of one third, which states as follows:

• One third of these tumors are multiple
• One third of those in the gastrointestinal (GI) tract are located in the small bowel
• One third of patients have a second malignancy
• One third of these tumors metastasize

Typically, 90% of carcinoid tumors originate from the distal ileum or appendix (the embryologic midgut.^[4] ) Carcinoid tumors represent 90% of appendiceal tumors.

Tumors arising from the foregut and hindgut are considered atypical; however, tumors can originate from any cell of the amine precursor uptake and decarboxylation system and, therefore, produce several intestinal hormones. Most of these tumors produce 5-hydroxytryptamine, which, in physiologic conditions, is taken up and stored in the platelets while the excesses are inactivated in the liver and lung and transformed into 5-hydroxyindoleacetic acid (5-HIAA).

In order of frequency, carcinoids may occur in the appendix (35%), ileum (28%), rectum (13%), and bronchi (13%). Incidence is less than 1% in the pancreas, gallbladder, liver, larynx, testes, and ovaries; however, tumors in these locations frequently metastasize and spread through the mesenteric lymph nodes (see image below) and portal vein. After spreading to the liver, carcinoids can metastasize to the lungs,^[5] bone, skin, or almost any organ.

View Image

A section of a rare lymph node metastasis from adenocarcinoid tumor (250 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.

Carcinoids do not produce the malignant carcinoid syndrome until they are no longer confined to the small bowel or mesentery, perhaps because the liver breaks down the secretory products of tumors restricted to those locations. Ovarian carcinoids may be considered exceptions; a patient with ovarian teratomas, whose secretory products enter into the systemic circulation, may present with this syndrome without liver metastasis.^{[6, 7]}

Diagnosis of carcinoid syndrome

If a patient is thought to have carcinoid syndrome, blood and urine tests must be performed to determine levels of bioactive substances secreted by carcinoid tumors. Bochemical diagnosis of carcinoid tumors is based on the measurement of the serotonin metabolite 5-HIAA in urine. Follow-up assays of other bioactive substances vary according to the location of the carcinoid tumor. See Workup.

Imaging studies also must be performed to detect the sites of either primary tumors or metastases. Recommended studies include multiphasic CT and MRI. Scintigraphy with indium-111 diethylenetriamine pentaacetic acid (DTPA) octreotide (In-111 DTPA Octr), or OctreoScan, localizes the primary carcinoid and eventual recurrences, as well as other neuroendocrine tumors, with high sensitivity and specificity. T

Treatment of carcinoid syndrome

Complete surgical removal of all tumor tissues, when feasible, is the best treatment. Systemic therapy should be used to control humorally mediated symptoms when the cancer spreads elsewhere. The somatostatin analogs (SSAs) octreotide and lanreotide are used to control carcinoid symptoms and tumor progression in advanced inoperable disease. Patients with diarrhea that is not controlled with somatostatin analog therapy can be treated with telostristat ethyl, a tryptophan hydroxylase inhibitor.  Other options for second-line therapy include dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, and liver-directed therapies.^[8] See Treatment and Medication.

• References

Background

In 1888 Lubarsch first described a carcinoid tumor,^[9] but Oberndorfer called a group of small, benign-appearing tumors karzinoide tumoren (carcinoid) for the first time in 1907.^[10]

The name was chosen to separate these tumors from ordinary malignancies (carcinomas), but by the 1950s, the fact that carcinoids could be malignant was obvious, thanks to Erspamer and Asero (1952), who identified serotonin production by carcinoid tumors.^[11] This finding, built on research conducted in the first half of the 20th century, is summarized as follows:

• In 1914, Gosset and Masson demonstrated that carcinoid tumors might arise from enterochromaffin cells (Kulchitsky cell) within glands of Lieberkühn using silver impregnation techniques.^[12]
• In 1928, Masson established characterization of carcinoids as argentaffin cell tumors.^[13]
• In 1980, the World Health Organization (WHO) applied the term carcinoid to all tumors of the diffuse endocrine system (synonymous with amine precursor uptake and decarboxylation [APUD] and neuroendocrine cell system).

• References

Pathophysiology

Pathophysiology is closely related to the sites of the primary tumors. When these tumors spread to the liver, patients usually begin to develop malignant carcinoid syndrome. In fact, this syndrome develops when vasoactive substances produced by a carcinoid tumor escape hepatic degradation and gain access to the systemic circulation.

Carcinoids arising in the stomach are usually associated with low gastric acid production, a condition termed hypochlorhydria or achlorhydria. These tumors rarely become malignant and never metastasize, but they sometimes produce histamine.

Carcinoid tumors arising in the lung generally produce serotonin, gastrin, adrenocorticotropic hormone (ACTH), and histamine. Carcinoids that develop outside the appendix are often malignant, while tumors developing in the appendix are usually benign if smaller than 2 cm in diameter. Rectal carcinoid tumors often produce polypeptides (PPs), polypeptide Y, neuropeptide Y, and other peptides, but none of the patients with this disease location have symptoms related to the production of such molecules. Few patients have liver metastases, but if they do have liver metastases, they do not have hormone-related symptoms.

Physiologically, serotonin causes vasodilation and can increase blood clotting by stimulating platelet aggregation, which may result in disseminated intravascular coagulation (DIC); however, serotonin is converted to 5-HIAA in the body. To date, it is well known that the carcinoids also may produce PPs and amines:

• Acid phosphatase
• α-glycoprotein
• α1-antitrypsin
• Amylin
• Atrial natriuretic polypeptide
• Calbindin-D28k
• Catecholamines
• Chromogranin A and B (CgA/CgB)
• Dopamine
• Fibroblast growth factor (FGF)
• Gastrin
• Gastrin-releasing peptide (bombesin)
• Glucagon/glicentin
• 5-Hydroxyindoleacetic acid (5-HIAA)
• 5-Hydroxytryptamine (5-HT)
• Histamine
• Insulin
• Kallikrein
• Motilin
• Neuron-specific enolase (NSE)
• A-Neuropeptide
• K-Neuropeptide
• Neurotensin
• Pancreastatin
• Pancreatic polypeptide
• Platelet-dermal growth factor (PDGF)
• Prostaglandins
• Pyroglutamyl-glutamyl-prolinamide
• Secretin
• Serotonin
• Somatostatin
• Substance P
• Somatotropin release-inhibiting factor (SRIF)
• Tachykinins
• β-transforming growth factor (β-TGF)
• Vasoactive intestinal polypeptide (VIP)

The molecules listed above are responsible for the extreme symptoms of this condition. For example, the reason some patients develop heart disease is not definitively known,^[14] but the serotonin produced by the tumor is probably involved. Bronchial constriction, which accounts for the asthmalike attacks, seems related to the tumoral tachykinins. Carcinoid diarrhea has been correlated with circulating tachykinins.^[15]

Symptoms may also relate to overproduction of PPs in the pro-opiomelanocortin family (eg, endorphin, enkephalin). Frequently, the enteric blood supply is impaired, which is caused by the desmoplastic reaction of mesenteric peritoneum and determines kinking and angulation of the loops of the small bowel, with result in bowel obstruction.

Serotonin is derived from the amino acid tryptophan, which also serves as a precursor to niacin and several proteins. Increased metabolism of tryptophan by the tumor has been linked to symptoms in patients with carcinoid.^[16]

The main clinical characteristics of the carcinoids arising in the digestive tract that most often cause malignant carcinoid syndrome are as follows:

1. Gastric carcinoid tumors are sporadic in 15-25% of cases, usually solitary and larger than 1 cm, arising in normal-appearing mucosa from enterochromaffin-like cells in the gastric fundus. These tumors are generally located in the body or fundus of the stomach and identified endoscopically. A large number of patients have metastases at the time of presentation, and over 50% have pernicious anemia. Gastric carcinoid tumors are more common in women during their sixth or seventh decade of life. It may be associated with atypical carcinoid syndrome manifested by flushing and mediated by histamine.
2. Carcinoid tumors of the small bowel arise from intraepithelial endocrine cells producing 5-HT and account for one third or fewer of small-bowel tumors. Often located in the distal ileum, these tumors are frequently multicentric, and most patients present with metastases to the lymph nodes or liver. Although tumor size is an unreliable predictor of metastatic disease, the 5-year survival rate closely correlates with the stage of disease at presentation (35% of patients survive if one or more distant metastases are present; 65% for localized or regional disease). Patients usually present in the sixth or seventh decade of life, and 5-7% present with carcinoid syndrome.
3. Appendiceal carcinoids are the most common cancers of the appendix and arise from the subepithelial endocrine cells from the lamina propria and submucosa. In 75% of cases, appendiceal carcinoids are located at the tip. Fewer than 10% of appendiceal carcinoids are located at the base. Appendiceal carcinoids are most frequently diagnosed in women in the fourth or fifth decade of life, and 10% or more are symptomatic. Patients may often be misdiagnosed as having appendicitis. The tumor size is the best prognostic predictor, with a 5-year survival rate of 94% for patients with local disease, 85% if there are regional metastases, and 34% if the patient has one or more distal metastases. It is noteworthy that more than 95% of appendiceal carcinoids are 2 cm or less, with rare metastases, while one third of tumors 2 cm or larger have either nodal or distant metastases. Carcinoid syndrome has been reported in patients with liver metastases.
4. Carcinoid tumors of the colon account for 1% or fewer of colon tumors and usually arise from serotonin-producing epithelial endocrine cells present in the colon mucosa. Most of the affected patients are in the seventh decade of life and present with abdominal pain, anorexia, and weight loss. At the time of diagnosis, the average tumor diameter is approximately 5 cm, and more than two thirds of patients have either nodal or distant disease. The 5-year survival rate is reported to be near 70% for local disease, 44% if regional metastases exist, and 20% in cases with distant metastases. The 5% of patients with metastatic disease show a malignant carcinoid syndrome.
5. Rectal carcinoid tumors are responsible for up to 2% of all rectal tumors. The disease usually affects persons in the sixth decade of life and most commonly presents as rectal bleeding, pain, or constipation, while 50% of patients are asymptomatic, with tumors found during routine endoscopy. Generally, the tumor cells contain glucagon and glicentin-related peptides rather than serotonin. The 5-year survival rate is 81% with local disease, 47% for regional disease, and 18% for distant metastases. Note that patients rarely present with carcinoid syndrome, and the syndrome is closely related to tumor size.

• References

Epidemiology

Frequency

United States

Probably 7-8 cases of carcinoid are diagnosed in the United States per year, but the actual frequency is almost certainly higher, because many patients never develop the related syndrome. Some researchers estimate that the incidence may be 1-2 cases per 100,000 individuals.

International

Epidemiologic studies have reported incidences of carcinoid tumors ranging from 0.79 to 1.88 per 100,000 population; a study from the Netherlands found an incidence of 1.95 per 100,000 population.^[17] These numbers are probably underestimates, because a large number of affected individuals do not develop the related syndrome. A Swedish autopsy study reported an incidence of 8.4 cases per 100,000 population.^[18] Carcinoid tumors are discovered in approximately 1-2 appendectomy cases per 200-300 per year.

Mortality/Morbidity

Tumors that are smaller than 1 cm in diameter rarely metastasize, while lesions larger than 2 cm often metastasize. The presence of a few small metastases to the liver is associated with a longer life expectancy. Morbidity is related to vasoactive amine production. The survival rate usually correlates inversely with the levels of daily urinary 5-HIAA excretion. Death is usually caused by cardiac or hepatic failure and by complications associated with tumor growth. Factors associated with higher mortality are high plasma levels of neuropeptide K and chromogranin A, location of the tumor in the large bowel, advanced disease, and a concomitant second malignancy. Mucus-producing tumors developing in the appendix also have some malignant characteristics.

Sex

This syndrome affects men and women equally.

Age

Carcinoids occur most frequently in patients aged 50-70 years. Age at diagnosis ranges from 10-93 years (mean age 55 y).

• References

Race-, Sex-, and Age-related Demographics

No racial prevalence is known. This syndrome affects men and women equally.

Carcinoids occur most frequently in patients aged 50-70 years. Age at diagnosis ranges from 10-93 years (mean age 55 y).

• References

History

Carcinoid tumors grow slowly, and symptoms may not occur for several years, if at all. When symptoms do develop, they are ill defined and may be neglected for a long time before being properly diagnosed. In some cases, carcinoid tumors present as acute appendicitis or chronic pain in the lower right abdominal quadrant. For this reason, the condition is frequently misdiagnosed as irritable bowel syndrome.^[19] Alcohol intolerance and weight loss also may be associated manifestations.

Severity of symptoms varies. Onset of symptoms may be spontaneous or may be precipitated by certain foods and beverages (eg, alcohol), pharmacologic agents, and physical or emotional stress.

Diarrhea is common, as is flushing of the face and neck.^[20] These manifestations result from tumoral hormone production; however, even if a carcinoid tumor produces these molecules, some patients do not experience any symptoms.

Flushing is a phenomenon in which transient vasodilation causes reddening of the face, head, neck, and the upper chest and epigastric areas.^[21] Flushing is the most frequent symptom and may be brief (eg, 2-5 min) or may last for several hours, usually in later disease stages.

Flushing may be accompanied by tachycardia, while the blood pressure usually falls or does not change. Malignant carcinoid syndrome is not a cause of sustained hypertension, and a rise in blood pressure during flushing is rare.

In addition to cutaneous vasodilation, some patients also develop telangiectasia, primarily on the face and neck, which is most marked in the malar area.

Right heart problems may develop because the tricuspid valve is stenosed by serotonin action, causing shortness of breath after a few years.

Other common problems include the following:

• Asthma
• Wheezing
• Dyspnea
• Palpitations
• Low blood pressure
• Fatigue
• Dizziness
• Asthenia

Uncommon symptoms include the following:

• Myopathy
• Arthritis
• Arthralgias
• Irritability, aggression, and lack of impulse control; these have been linked with low levels of plasma tryptophan and presumably with low brain serotonin^[16]

Intestinal obstruction may result from the primary tumor or from the sclerosing reaction in the surrounding mesentery. Necrosis of hepatic tumor masses may produce a typical acute syndrome with fever, abdominal pain, tenderness, and leukocytosis.

• References

Physical

Wheezing, facial telangiectasis with cyanosis and edema, pallor, flushing, macular erythema, and periorbital edema, accompanied by hepatomegaly, pellagralike skin lesions, steatorrhea, and chronic diarrhea, all suggest the diagnosis.

During chest examination, a pulmonary systolic and diastolic heart murmur may be heard if cardiac involvement is present. Cardiac involvement is associated with pulmonic valve stenosis and/or tricuspid insufficiency.^[22]

Bronchospasms, which cause asthmalike attacks, are generally most pronounced during flushing attacks. Bronchospasms are a less common sign of malignant carcinoid syndrome but may be severe.

Any sign of niacin deficiency (pellagra) must be investigated carefully.^[23]

Debilitating diarrhea is common and may have a secretory component.

• As many as 20 episodes of diarrhea per day are possible and cause marked debilitation due to fluid, electrolyte, and protein depletion.
• The diarrhea persists with fasting, fails to disappear when the patient is fed intravenously, and is usually accompanied by flushing; however, diarrhea occurs alone in approximately 15% of patients.
• Abdominal borborygmi and cramping or pain may be present. When severe, malabsorption may occur and may even cause death.
• Primary tumors seldom cause gastrointestinal bleeding.

Hepatomegaly from metastases is usually present, but extensive metastatic liver involvement may occur before liver function test results become abnormal.

Carcinoid heart disease is reported in approximately 50-60% of all patients with malignant carcinoid syndrome and is severe in approximately 25%.

• Carcinoid heart disease occurs primarily on the right side of the heart but may involve the left side to a minimal degree.
• Fibrous deposits adhering to the surface of the valvular endocardium may occur as part of this condition.^[24]
• Thickening of the endocardium of the cardiac chambers and papillary muscles and thickening and deformation of the valve cusps and chordae tendineae can lead to heart failure, influencing valvular function and causing regurgitation, stenosis, or combined functional lesions.
• The tricuspid valve is affected most commonly.

• References

Causes

As with many other cancers, the exact cause is unknown. Malignant carcinoid syndrome does not generally appear to be hereditary.

A study of genetic alterations in small bowel carcinoid tumors found that loss of all or most of chromosome 18 was the most common finding. Heterozygosity was also lost on chromosome arms 9p and 16q. Although the amplitude of observed gains was modest in comparison with those reported in some other tumor types, one focal region of recurrent gain on 14q mapped to the locus of the gene encoding the antiapoptotic protein DAD1.^[25]

• References

Laboratory Studies

Hormones in blood and urine are measured to monitor the growth, activity, and eventual recurrence of the primary tumor. The biochemical diagnosis of carcinoid tumors is based on the measurement of the serotonin metabolite 5-HIAA in a 24-hour urine collection (normal value [NV] = 0-8.9 mg/d; plasma serotonin NV is 0.04–0.2 mg/mL).

Consumption of foods that contain serotonin can complicate the biochemical diagnosis of malignant carcinoid syndrome; in fact, the following foods contain an amount of serotonin that can produce abnormally elevated excretion of urinary 5-HIAA after ingestion:

• Spinach
• Eggplant
• Cheese (eg, parmesan, Roquefort)
• Wine (chianti, burgundy)
• Caffeine
• Tomatoes
• Kiwi fruit
• Bananas
• Walnuts
• Pineapples
• Red plums
• Avocados

The following drugs may have the same effects:

• Isoniazid
• Phenothiazine
• Phenacetin
• Monoamine oxidase inhibitors
• Acetaminophen
• Fluorouracil
• Iodine solutions

If dietary (or pharmaceutical) 5-hydroxyindoles are excluded, a urinary excretion of 5-HIAA of 25 mg/d is diagnostic of carcinoid. If the range value is 9-25 mg/d, the differential diagnosis includes carcinoid syndrome, nontropical sprue, or acute intestinal obstruction.

The measurement of other bioactive amines (eg, serotonin, catecholamines, histamine, histamine metabolites^[26] ) in the platelets, plasma, and urine of patients with carcinoid tumors is of interest but has less diagnostic value than an assay of the major metabolite of serotonin in the urine.

Some authors have used high-performance liquid chromatography and gas chromatography mass spectrometry to characterize carcinoids. According to these authors, the platelet serotonin level seems to have a higher sensitivity for detection of carcinoid tumors and is more consistently elevated than urinary 5-HIAA, especially with tumors characterized by a low rate of serotonin production. However, in patients with a high rate of serotonin secretion, the platelet serotonin level reaches a maximum, whereas urinary 5-HIAA does not, indicating that the platelet compartment is saturable. Differing from urinary 5-HIAA, platelet serotonin is not influenced by the consumption of a serotonin-rich diet; therefore, the measurement of platelet serotonin should be preferred for making the primary diagnosis.

Platelet serotonin levels are also monitored during different treatments to evaluate the effect of therapy. According to one study, chromogranin A measurement with a cutoff range of 84 to 87 U/L yields a specificity of 95% and a sensitivity of 55% for the diagnosis of endocrine tumors. These authors recommended the high cutoff range in order to exclude patients in whom the chromogranin A level was elevated as a result of other non-neoplastic diseases.^[27]

Recommended follow-up studies vary according to the location of the carcinoid tumor, as follows:

• Hindgut carcinoids - Chromogranin A, alpha human chorionic gonadotropin (α-HCG), beta human chorioinic gonadotropin (β-HCG), and polypeptides are essential assays
• Lung carcinoids - Gastrin, adrenocorticotropic hormone (ACTH), growth hormone (GH), α-HCG, and β-HCG are helpful
• Midgut carcinoids - Levels of urinary 5-HIAA, chromogranin A, and tachykinins are useful

Apart from measuring daily urinary 5-HIAA secretion, determining the presence of other bioactive amines enables more sensitive detection and also may indicate specific measures in particular patients.

Platelet aggregation testing may show increased aggregation with certain agonists. This test helps to diagnose platelet dysfunction and to distinguish between inherited and acquired bleeding problems (eg, DIC occurring in some patients with malignant carcinoid syndrome). Platelet aggregation normally occurs within 3-5 minutes.

Total protein levels in blood are often low because of malabsorption. Tryptophan levels may be low for the same reason, but also because of conversion to serotonin by the tumor.

N-terminal pro-brain natriuretic peptide (NT-pro-BNP) may serve as a biomarker for the detection of carcinoid heart disease. One study found that at a cut-off level of 260 pg/ml, NT-pro-BNP has a sensitivity of 92% and a specificity of 91% for detection of carcinoid heart disease.^[28]

Routine allergy test results are not usually positive in cases that simulate an anaphylactic attack.

• References

Imaging Studies

Modalities that have been evaluated for the diagnosis of carcinoids include the following:

• Barium examinations
• Iodine-131 metaiodobenzylguanidine (MIBG) scanning^[29]
• Octreotide scanning
• Computed tomography (CT)
• Angiography
• Venous blood sampling with radioimmunoassay of tumor products
• Echocardiography^[30]
• Magnetic resonance imaging (MRI)^[31]

For imaging studies, current National Comprehensive Cancer Network (NCCN) guidlines recommend multiphasic CT or MRI for the evaluation of carcinoid tumors, as follows^[32] :

• Gastrointestinal tumors: Abdominal/pelvic multiphasic CT or MRI
• Bronchopulmonary tumors: Chest CT and abdominal multiphasic CT or MRI
• Thymus tumors: Chest/mediastinal multiphasic CT and abdominal multiphasic CT or MRI

The NCCN recommends additional studies (eg, somatostatin scintigraphy) as appropriate.

Scintigraphy

Scintigraphy with indium-111 diethylenetriamine pentaacetic acid (DTPA) octreotide (In-111 DTPA Octr), or OctreoScan, localizes the primary carcinoid and eventual recurrences, as well as other neuroendocrine tumors, with high sensitivity and specificity. The 3-day half-life of this radionuclide allows for a scan after 24, 48, and 72 hours.

This diagnostic tool also has obviated many of the problems of differential diagnosis with other neuroendocrine tumors that are frequent, using iodine-131 MIBG or iodine-123 tyrosine 3 octreotide scanning.

False-negative results are possible in 2% of cases (the mean percentage of carcinoids without receptors).

A positive test result usually predicts a good patient response to treatment with octreotide.

When administering a radioactive somatostatin analogue (In-111 DTPA-D-Phe1 octreotide), some authors have attempted to provide internal radiation therapy, hoping to kill the tumor cells, but adverse effects limit the clinical application of this therapy.

Radiography

Barium examination is rarely diagnostic but may show a benign-appearing submucosal lesion or a large bulky ulcerating mass with bowel deformity.

A smooth polyp observed in the terminal ileum should always be considered a probable carcinoid tumor.

The importance of angiography for carcinoid diagnosis has been decreased by the availability of more recent imaging methods.

Computed tomography

CT scanning may be used to find the primary tumor or to check for any disease spread. Primary carcinoids of the bowel are usually not observed on CT scanning; otherwise, this study allows the assessment of the extent of tumor spread to the mesentery and bowel wall and metastases to the lymph nodes and liver.

CT scanning typically shows a homogeneous, ill-defined mesenteric mass with calcifications. A stellate or curvilinear fibrosis radiating from the mass, representing thickened neurovascular bundles and distorting surrounding bowel loops, is usually observed.

Positron emission tomography (PET) scanning

Considerations regarding PET scanning are as follows:

• Experience with PET scanning to detect carcinoids is very limited
• Either tryptophan or its metabolite 5-hydroxytryptophan (5-HTP) has been used as a tracer substance
• PET scanning seems to be capable of identifying carcinoid metastases to various sites, and it may be valuable in the follow-up care of treated patients
• According to initial reports, only C11-5-HTP is taken up by serotonin-producing tumors

Ultrasonography

Ultrasonographic examination of the abdomen is usually not the first diagnostic method; instead, it is used to further confirm the diagnosis and establish the site and extent of the disease.

• References

Other Tests

Several provocation tests have been developed for carcinoid syndrome. Intravenous infusion of pentagastrin appears to provoke flushing and other symptoms more reliably than the traditional test, which uses alcohol (10 mL PO), calcium (10 mg/kg of calcium gluconate in 4 h), or catecholamines (norepinephrine 1-20 mcg). These tests must be performed with caution because they can trigger crises.

• References

Procedures

A percutaneous or laparotomy biopsy may be performed, when possible, after the primary tumor and its eventual metastases are detected. Fine-needle biopsy of hepatic lesions can precipitate carcinoid crisis in a patient with carcinoid liver metastasis, however, so personnel performing these procedures should be prepared for this possibility.^[33]

Diagnostic and operative endoscopy of the lower and upper GI tract may be helpful for diagnosis.^[34]

• References

Histologic Findings

In 1963, Williams and Sandler began to classify the carcinoid tumors anatomically and clinically according to embryologic origin from the foregut, midgut, or hindgut. Grossly, these tumors appear as submucosal or intramural masses (see images below), and they are usually single but may be multiple. After fixation, the tumor mass appears yellow or brownish, small, and firm. The intestinal mucosa over the tumor is often intact. Submucosal infiltration, often extending beyond the muscularis propria, is the rule.

View Image

A section (on the right) of an intestinal carcinoid mass arising from the mucosa (150 X). Image courtesy of Professor Pantaleo Bufo, University of Fog....

View Image

A section of a carcinoid mass (350 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.

Histologically, the tumor consists of uniform small cells arranged as islands separated by a fibrous stroma. Cells show a scant pink cytoplasm that is finely granulated and stippled with small round nuclei and small nucleoli. Several patterns can be observed in carcinoid tumors (ie, trabecular and tubular arrangements may be present and include intraluminal mucin). All carcinoids react positively with antichromogranin A antibodies and usually Masson staining, which indicates serotonin production and is positive in midgut primary tumors. Two main histologic features are described by observing with 10X high-power fields, as follows:

• Typical, showing fewer than 2 mitoses per 2 mm² of viable tumor and lacking necrosis
• Atypical, showing 2-10 mitoses per 2 mm² with or without foci of necrosis

• References

Staging

No internationally accepted staging system exists for carcinoid tumors.

• References

Medical Care

Systemic therapy should be used to control humorally mediated symptoms when the cancer spreads elsewhere. Initially, somatostatin analogs are useful in approximately 40% of patients.^[35] Histamine blockers may also be useful. Diarrhea generally responds to standard antidiarrheal medications, but serotonin antagonists should be administered, if necessary, to control diarrhea and malabsorption. Severe and prolonged carcinoid crises associated with bronchial or stomach carcinoids may respond to corticosteroid treatment.

Somatostatin Analogs

The somatostatin analogs octreotide and lanreotide are used to control carcinoid symptoms and tumor progression in advanced inoperable disease.^{[36, 37]} These synthetic somatostatin analogs have high affinity for somatostatin receptors and are preferred to native somatostatin because of a longer half-life (average half-life of somatostatin is 2 min; that of octreotide is 2 h, and that of lanreotide, 23-36 days).

The PROMID Study Group demonstrated the ability of somatostatin analogs to control the growth of well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors (NETs).^[38] The phase IIIB study randomized 85 treatment-naive patients with mid-gut NETs to receive either placebo or octreotide long-acting repeatable (LAR) 30 mg IM monthly until tumor progression or death.

Median time to tumor progression (the primary efficacy endpoint) proved significantly longer in treatment with octreotide LAR than with placebo (14.3 vs 6 months, hazard ratio [HR] = 0.34; 95% confidence interval [CI], 0.20-0.59; P = 0.000072). Secondary endpoints included tumor response and survival time. At 6 months of treatment, more patients had stable disease in the octreotide LAR group compared with placebo (66.7% vs 37.2%) with similar responses in functionally active and inactive tumors. Survival analysis was reported as not confirmatory due to the low number of deaths.

Octreotide LAR significantly extends the time to tumor progression compared with placebo for patients with midgut NETs. A randomized, placebo-controlled phase 3 trial found that everolimus plus octreotide LAR improved progression-free survival in patients with advanced NETs associated with carcinoid syndrome.^[39]

A retrospective study suggested a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The 5-year survival benefit for was significant for patients with distant-stage disease (HR, 0.61; P ≤ .001) but not for the patients with local/regional stage disease.

In the CLARINET study, lanreotide was associated with significantly prolonged progression-free survival compared with placebo (median not reached vs. median of 18.0 months, P< 0.001). The study included patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor–positive neuroendocrine tumors of grade 1 or 2, who received extended-release aqueous-gel formulation of lanreotide at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks.^[40]

Tryptophan hydroxylase inhibitor

Telostristat ethyl (Xermelo) was approved by the US Food and Drug Administration (FDA) in 2017 for carcinoid syndrome diarrhea in combination with somatostatin analog (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.^[41]  

A long-term safety study found that telotristat ethyl is well tolerated and has a favorable safety profile in patients with carcinoid syndrome. Mean duration of exposure and follow-up was 1.3 years (range,1 week to 5.7 years), with 309 total patient-years of exposure. No deaths were attributable to telotristat ethyl.^[42]

Other approaches

Patients benefit from specific drugs that either suppress production of vasoactive amines or block the peripheral effects. These agents include alpha-adrenergic blocking drugs, cyproheptadine, and H2-receptor blockers.

Interferon-alpha may help control carcinoid symptoms or arrest tumor growth and reportedly may be effective in patients in whom octreotide treatment has failed; however, benefits are generally transient and accompanied by adverse effects. The combination of interferon-alpha and continuous infusion of 5-fluorouracil (5-FU) has demonstrated antitumoral and antihormonal activity and can provide symptom palliation.^[43]

Radiotherapy or chemotherapy with streptozotocin, cisplatin, etoposide, and doxorubicin, either alone or in combination, has been used, and reports show some success; a good response occurs in only 20-30% of cases. The role of radiation therapy in the management of carcinoid tumors with distant metastasis is restricted to symptomatic palliation of the painful bone metastases. This therapy is not useful for treating liver metastases or for other nonskeletal tissues. However, Jia and Wang reported that radioembolization with yttrium-90 (⁹⁰Y) microspheres can improve the survival rate and tumor response in patients with unresectable liver metastases.^[44]

Therapy with metaiodobenzylguanidine (MIBG) has  been studied. In a review that included 20 patients with advanced metastatic carcinoid tumors, Ezziddin et al reported that treatment with ¹³¹iodine-MIBG provided safe and effective palliation of symptoms and stabilization of disease.^[45]  

Little evidence suggests that chemotherapy, either traditional or by continuous infusion, helps improve patient survival rates. Failure to respond to one chemotherapy combination does not necessarily mean another combination will also be ineffectual.

• References

Surgical Care

Complete surgical removal of all tumor tissues, when feasible, is the best treatment because it may result in a complete and permanent cure. The aim of surgical therapy is to reduce the tumor mass and obtain symptom remission. Performing a curative resection, mass debulking, or hepatic embolization is possible.

Cytoreductive surgery has been reported to have the best impact on symptom regression and overall survival.^[46] An extensive surgical excision, including the adjacent mesentery, must be performed.

Surgical considerations include the following:

• Surgery should always be considered in patients with large or extensive hepatic metastases involving surgically accessible areas of the liver.
• For lesions in the distal ileum, a right hemicolectomy is necessary to remove the lymphatic drainage adequately.
• For tumors located in the appendix that are smaller than 1.5 cm in diameter, appendectomy is suitable and curative in 100% of patients. The involvement of the mesoappendix does not alter the patient's prognosis, but invasion of the cecum mandates more radical surgery (eg, right hemicolectomy with regional lymphadenectomy). Carcinoids in children usually occur in the appendix, and the appendectomy results in a complete cure.
• Rectal carcinoids, if smaller than 1.5 cm in diameter, should be treated with local excision; if rectal carcinoids are larger than 1.5 cm, they must be considered malignant, and abdominoperineal resection (Miles operation) or low anterior resection should be performed.

Hepatic transplantation has also been attempted in selected patients, with promising results; however, generalization for this treatment option, because it is extremely expensive and debilitating, is not possible without more long-term studies.

Surgery should also be considered for resection of hepatic recurrence, even after previous resection, but only if the lesions are in an area where resection can be performed with minimal morbidity.

• The whole intestine should be examined at the time of surgery to detect eventual multiple lesions.^[47]
• Chemoembolization with hepatic artery infusion of 5-FU or doxorubicin, combined with embolization of the hepatic artery with collagen fibers, causes substantial tumor necrosis. This procedure reportedly decreases tumor bulk of liver metastases from carcinoid tumors by more than 50% in as many as 60% of patients.^[48]
• Adverse effects of embolization are frequent and may be severe (see Tumor Lysis Syndrome).
• Other surgical techniques, ablative but nonresective, include cryosurgery and percutaneous alcohol injections.

For any patient with controlled carcinoid symptoms and heart involvement, cardiac surgery must be considered for symptomatic carcinoid heart disease and must be performed by an experienced team (including medical, surgical, and anesthesiology experts) in order to provide the best management of this condition.^{[49, 50]} For patients with silent disease and symptomatic carcinoid heart disease, valve replacement should be considered.^[51]

Surgical resection can provide effective palliation in carefully selected patients. Debulking hepatic metastases may palliate systemic symptoms, and intestinal resection is highly effective in relieving symptoms of intestinal obstruction and ischemia.^[52]

For pulmonary carcinoids, surgical resection remains the gold standard. However, minimally invasive endobronchial procedures have emerged as a parenchyma-sparing alternative for tumors located in the central airways.^[53]

Palliative surgery may be associated with substantial morbidity, and the effects are often transient. However, a retrospective nonrandomized study suggests that patients with carcinoid heart disease who undergo hepatic resection have decreased cardiac progression and improved prognosis.^[54]

• References

Consultations

Consult with either a cardiologist or pneumologist for cardiac and respiratory assessment. A systematic psychotherapeutic intervention may be very helpful in patients with carcinoid.

• References

Diet

In patients with malignant carcinoid syndrome, diarrhea and weight loss are severe problems that need to be controlled.

• The major nutrients are absorbed easily and do not exacerbate the diarrhea, while most vegetables are very irritating.
• Patients with severe diarrhea should be careful to avoid dehydration or vitamin deficiency. Nicotinamide and niacin supplements are very useful and must be prescribed, along with potassium, magnesium, iron, and essential elements.
• Always recommend increased protein in the diet.

• References

Activity

Mild (not stressful) physical activity is not harmful and is possible if desired. No intense physical activities are allowed.

• References

Medication Summary

Currently, octreotide is considered the drug of choice worldwide for treating both carcinoids and related malignant syndromes.^[55] Somatostatin is rarely administered because of its poor half-life. In patients with diffuse metastases, antiproliferative drugs may be useful for symptom palliation.^[56]  

Telotristat ethyl should be considered in addition to somatostatin analog (SSA) therapy for diarrhea not controlled by SSA therapy. It is a tryptophan hydroxylase inhibitor that decreases biosynthesis of serotonin.^[41]

• References

Octreotide (Sandostatin)

• Dosing, Interactions, etc.

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

• References

Telotristat ethyl (Xermelo)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Class Summary

These drugs are used to reduce blood levels of GH and IGF-I in patients with an inadequate response to surgery, radiation, and bromocriptine.

• References

Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  Anthracycline antibiotic that can intercalate with DNA, affecting many DNA functions, including synthesis. Administered IV and distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. Does not cross blood-brain barrier and is excreted primarily in bile. May be helpful in symptom palliation for patients with progressive disease.

• References

Streptozocin, streptozotocin (Zanosar)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Fluorouracil, 5-FU (Adrucil)

• Dosing, Interactions, etc.

Clinical Context:  Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with RNA synthesis and function. Has some effect on DNA. Useful in symptom palliation for patients with progressive disease.

• References

Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits DNA synthesis and thus cell proliferation by causing DNA crosslinks and denaturation of double helix. May help with symptom palliation for patients with progressive disease.

• References

Etoposide (Toposar, VePesid)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G₂ portion of the cell cycle. May help with symptom palliation for patients with progressive disease.

• References

Class Summary

These agents inhibit cell growth and proliferation.

• References

Interferon alfa 2a (Roferon-A, Intron-A)

Clinical Context:  Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Therapeutic trials in selected patients.

• References

Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.

• References

Cyproheptadine (Periactin)

• Dosing, Interactions, etc.

Clinical Context:  Competitively inhibits H1 receptor, which mediates bronchial constriction, smooth-muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias. Prevents histamine release in blood vessels and is more effective in preventing histamine response than in reversing it. May be useful in patients with syndromes sustained by histamine-producing tumors.

• References

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth-muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

• References

Ranitidine (Zantac)

• Dosing, Interactions, etc.

Clinical Context:  Competitive and reversible H2-receptor blockers. Highly selective antagonists that do not affect the H1 receptors and may be administered contemporary to H1-receptor antagonists. May be useful for treatment of severe itching, flushing, and urticaria.

• References

Class Summary

The combination of H1 and H2 antagonists may be useful in chronic idiopathic urticaria not responding to H1 antagonists alone. They may also be useful for itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis (IV).

• References

Clonidine (Catapres)

• Dosing, Interactions, etc.

Clinical Context:  Stimulate alpha2 adrenoreceptors in brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.

• References

Class Summary

These agents improve the hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. They are useful in reducing some symptoms of malignant carcinoid syndrome (eg, diarrhea, hypertension, tachycardia).

• References

Inpatient & Outpatient Medications

See the list below:

• Always assess the color of the urine. Dark-brown or intensely yellow urine usually indicates dehydration, and  fluids must sometimes be given intravenously to keep up with the fluid loss from diarrhea.
• Weigh the patient daily and replace the essential elements and vitamins, either by diet or by commercial supplements.
• Other clinical problems associated with carcinoid syndrome, such as tachycardia and asthmalike attacks, should be managed by a cardiologist and pulmonologist.
• Severe flushes may be treated with clonidine.
• Patients need to avoid conditions or substances that cause flushing (eg, stress, alcohol, epinephrine, epinephrinelike drugs).

The safety of antidepressants—especially selective serotonin reuptake inhibitors (SSRIs)—in patients with neuroendocrine tumors (NETs) has been questioned, since serotonin secretion by NETs contributes to carcinoid syndrome. However, Isenberg-Grzeda et al reviewed antidepressant treatment in 92 patients with NETs, including 16 with carcinoid, and found that none of the patients developed carcinoid syndrome or carcinoid crisis during antidepressant use.^[57]

• References

Deterrence/Prevention

Patients must avoid any physical and emotional stress and any food or drug that may trigger a crisis. For example, monamine oxidase inhibitors should be avoided because they can exacerbate the syndrome by inhibiting serotonin degradation.

• References

Complications

Complications may include the following^[58] :

• Hypotension related to massive vasodilation can increase the risk of falls and subsequent injuries.
• Increased platelet aggregation causes a high risk for strokes, deep venous thromboses, and similar disorders.
• Gastrointestinal bleeding is very rare. Bowel obstruction from tumor mass or, most frequently, from mesenteric adhesions is also very rare.
• Right-sided heart failure is more frequent
• Analysis of catecholamines and associated metabolites shows consistent elevation of dopamine, norepinephrine, and epinephrine metabolites in more than 30% of midgut carcinoids. This explains some adverse effects (eg, arrhythmias, perioperative carcinoid crisis) in patients in whom octreotide premedication is indicated.
• Usually, urinary levels of histamine metabolites are less elevated, but increased histamine production can cause specific symptoms (eg, angioedema), which should be treated specifically.
• Acute renal failure after liver chemoembolization of carcinoid metastases is an infrequent but well-known complication.
• Metastasis

Risk of metastasis correlates with size of primary tumor, as follows:

• Tumors ≤1 cm metastasize in only 2% of cases
• Tumors 1-2 cm metastasize in 50% of cases
• Tumors ≥2 cm metastasize in 85% of cases

• References

Prognosis

The prognosis for patients with malignant carcinoid syndrome is relatively good compared with the prognosis for patients with other malignancies, but the prognosis for any treated patient with progressing, recurring, or relapsing disease is poor. The median survival rate after 5 years is 30-67%. Survival for 8.5 years and 23 years has been reported.

In patients with malignant carcinoid syndrome who are cured with surgery, follow-up care does not need to be intensive. For patients with advanced disease, follow-up care should be scheduled on a regular basis. The frequency of follow-up care depends on the general condition of patients and their disease. In each follow-up session, blood tests, x-ray films, and other studies may need to be performed complementary to patient examination.

For many patients, the treatment options for carcinoid syndromes have prolonged life, but it is very important to understand the patient’s perception of symptoms and the influence of treatment, which may affect quality of life as well as disease progression.^{[59, 60]}

The incidence of metastasis is estimated at 1-2 cases per 100,000 affected people, and the best treatment remains controversial. Lymph nodes and liver are the most common sites of metastasis, and bone and lung are less commonly affected. Involvement of distant sites (eg, ovary, orbit) is very rare. Most patients with metastases are asymptomatic and have an indolent course. If patients are left untreated, survival at 5 years is 30%.

• References

Patient Education

See the list below:

• Avoidance of any physical and emotional stress and any food or drug that may trigger a crisis is mandatory.
• Patient information is available online at The Carcinoid Cancer Foundation.
• For patient education information, see the Cancer Health Center.

• References