Edit concept Question Editor Create issue ticket

Malignant Carcinoid Syndrome

Carcinoids are neuroendocrine tumors most commonly originating from the midgut. Primary tumors and possibly existing metastases produce a variety of hormones and hormone-like mediators that provoke systemic symptoms like flushing, diarrhea and cardiac insufficiency - the entirety of these symptoms is referred to as malignant carcinoid syndrome.


Presentation

Only minor shares of gastrointestinal NET ever become symptomatic and if patients experience complaints, they have usually been living with carcinoid tumors for years. NET may cause local and systemic symptoms, whereby the former are generally not considered part of the MCS. Either type of symptom may dominate the clinical picture and thus, MCS-associated complaints may be the cause of initial presentation. In these cases, a diagnosis of gastrointestinal NET has not been established previously.

The most characteristic symptoms of MCS are flushing, diarrhea, cardiac insufficiency, and bronchoconstriction.

  • Flushing may be restricted to face and neck or extend to shoulders, arms, and thorax. In some cases, flushing is intermittent and subsides spontaneously after a few minutes. In other patients, vasodilation persists for hours. Hypotension may or may not occur.
  • Diarrhea is generally severe and debilitating; patients may be dehydrated and lose weight. In some cases, abdominal pain and other gastrointestinal symptoms worsen after meals, particularly if they are accompanied by alcohol. Because the combination of chronic diarrhea and abdominal pain that aggravates after food ingestion is also typical for irritable bowel syndrome, MCS patients have repeatedly been misdiagnosed with irritable bowel syndrome [9].
  • Tricuspid valve stenosis is the most frequent cause of cardiac insufficiency in MCS patients [10]. This condition is related to symptoms of right heart failure, i.e., to dyspnea that worsens under exercise, unproductive cough and edema.
  • Bronchoconstriction is usually intermittent and patients claim asthma attacks during which wheezing, dyspnea, cyanosis and tachycardia can be observed.

Less commonly, myalgia, arthralgia, loss of libido and erectile dysfunction are reported by MCS patients.

With regards to local symptoms induced by the respective primary tumor, appendiceal carcinoids may mimic acute appendicitis, i.e., they may cause an acute onset of abdominal pain in the lower right quadrant, nausea, vomiting and/or acute abdomen.

Weight Loss
  • Any therapeutic gain experienced by these patients seemed to be outweighed by the frequency and severity of toxic reactions, which consisted primarily of chills and fever, fatigue, anorexia, weight loss, leukopenia, and abnormalities of liver function[ncbi.nlm.nih.gov]
  • Clinical features WDHA syndrome (Watery Diarrhea, Hypokalemia, Achlorhydria ) Weight loss Abdominal pain, nausea, vomiting Achlorhydria iron and B 12 absorption anemia Diagnosis Serum VIP concentration ( 75 pg/mL) Hypokalemia, hypercalcemia, hyperglycemia[amboss.com]
  • This can cause diarrhea and weight loss.[cancer.org]
  • Practice CMAJ June 23, 2009 180 (13) 1329; DOI: A 72-year-old man was admitted to hospital with congestive heart failure, weight loss and chronic diarrhea.[cmaj.ca]
  • Colonic carcinoid tumours tend to be associated with weight loss and anorexia and are often larger and multiple at diagnosis.[healthed.com.au]
Pulmonary Valve Stenosis
  • valve stenosis due to carcinoid-syndrome, Cardiovasc Med, 1979 , vol. 4 (pg. 871 - 81 ) The Author 2012.[doi.org]
  • Clinical features Because the pulmonary circulation is a low-pressure system, many patients may tolerate gradual and progressive increases of tricuspid or pulmonary valve stenosis or regurgitation.[ecancer.org]
Cough
  • Pulmonary adenosquamous carcinoma with hepatic metastasis was found in a 60-year-old Japanese male who was complaining of fever, cough and haemosputum.[ncbi.nlm.nih.gov]
  • When symptoms are present, usually there is coughing or wheezing. The cough might produce blood in the phlegm or sputum. If the tumor is large enough to block an air passage, a person might develop an infection called post-obstructive pneumonia.[my.clevelandclinic.org]
  • , which may make you cough up blood, and cause wheezing, shortness of breath, chest pain and tiredness a tumour in the stomach may cause pain, weight loss, tiredness and weakness Some tumours may not cause any symptoms and are discovered by chance.[nhs.uk]
  • Certain drugs, including guaifenesin (found in many cough syrups), methocarbamol (a muscle relaxant), and phenothiazines (antipsychotics), also interfere with test results.[merckmanuals.com]
  • ., to dyspnea that worsens under exercise, unproductive cough and edema. Bronchoconstriction is usually intermittent and patients claim asthma attacks during which wheezing, dyspnea, cyanosis and tachycardia can be observed.[symptoma.com]
Diarrhea
  • Additionally, symptomatic treatment may be indicated to relieve cardiac disorders and diarrhea.[symptoma.com]
  • Serotonin acts on smooth muscle to cause diarrhea, colic, and malabsorption. Histamine and bradykinin, through their vasodilator effects, cause flushing.[msdmanuals.com]
  • Chemotherapy can be used with metastatic disease, and other drugs are prescribed as indicated to manage the hypotension, diarrhea, flushing, and other symptoms.[medical-dictionary.thefreedictionary.com]
  • The effect of intravenous somatostatin infusion was investigated in a patient with severe secretory diarrhea due to malignant carcinoid syndrome.[ncbi.nlm.nih.gov]
Abdominal Pain
  • The right upper quadrant abdominal pains accompanied by symptoms that resemble even part of the carcinoid syndrome should initiate the investigational process including proximal gastrointestinal endoscopy to avoid delay in diagnosis of duodenal carcinoid[ncbi.nlm.nih.gov]
  • In some cases, abdominal pain and other gastrointestinal symptoms worsen after meals, particularly if they are accompanied by alcohol.[symptoma.com]
  • Carcinoid syndrome may cause signs and symptoms such as facial flushing due to widened blood vessels on the face, abdominal pain, diarrhea, and rapid heart rate.[medicinenet.com]
  • Signs and symptoms of carcinoid syndrome include: Skin flushing Facial skin lesions Diarrhea Breathing difficulty Rapid heartbeat Abdominal pain Bronchoconstriction Nausea and vomiting Various complications in patients that may be caused by carcinoid[primeoncology.org]
  • Clinical features WDHA syndrome (Watery Diarrhea, Hypokalemia, Achlorhydria ) Weight loss Abdominal pain, nausea, vomiting Achlorhydria iron and B 12 absorption anemia Diagnosis Serum VIP concentration ( 75 pg/mL) Hypokalemia, hypercalcemia, hyperglycemia[amboss.com]
Nausea
  • Usual side effects were mild sedation and dry mouth, but three patients found it impossible to sustain treatment due to nausea and vomiting. Most patients had significant relief of diarrhea, frequently associated with weight gain.[ncbi.nlm.nih.gov]
  • High acid levels can lead to irritation of the lining of the stomach and even stomach ulcers, which can cause pain, nausea, and loss of appetite. Severe ulcers can start bleeding.[cancer.org]
  • […] symptoms occur if liver metastases are present or if tumor venous blood flow bypasses the liver Symptoms Vasomotor disturbances (cutaneous flushes, cyanosis of face and anterior chest, intermittent hypertension), palpitations, intestinal hypermotility (nausea[pathologyoutlines.com]
  • Signs and symptoms of carcinoid syndrome include: Skin flushing Facial skin lesions Diarrhea Breathing difficulty Rapid heartbeat Abdominal pain Bronchoconstriction Nausea and vomiting Various complications in patients that may be caused by carcinoid[primeoncology.org]
  • The most common adverse events associated with Xermelo include nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decrease appetite, and[pharmacytimes.com]
Abdominal Cramps
  • Carcinoid syndrome develops in some people with carcinoid tumors and is characterized by cutaneous flushing, abdominal cramps, and diarrhea. Right-sided valvular heart disease may develop after several years.[msdmanuals.com]
  • Excessive contraction of the intestine may result in abdominal cramping and diarrhea. The intestine may not be able to absorb nutrients properly, resulting in undernutrition and fatty, foul-smelling stools.[merckmanuals.com]
  • References: [3] [4] [5] [1] [6] [7] Clinical features Asymptomatic Abdominal pain Carcinoid syndrome Diarrhea and abdominal cramps Cutaneous flushing Possible triggers: alcohol consumption, food intake, stress In severe cases, may be accompanied by tachycardia[amboss.com]
  • Frequent, watery stools sometimes accompanied by abdominal cramps may occur in people who have carcinoid syndrome. Difficulty breathing.[mayoclinic.org]
  • Diarrhea - Frequent and watery stools, sometimes accompanied by abdominal cramps Breathing Difficulty - Asthma-like symptoms, such as wheezing and shortness of breath, which may occur with skin flushing.[general.surgery.ucsf.edu]
Chronic Diarrhea
  • Practice CMAJ June 23, 2009 180 (13) 1329; DOI: A 72-year-old man was admitted to hospital with congestive heart failure, weight loss and chronic diarrhea.[cmaj.ca]
  • Carcinoid syndrome causes redness or a feeling of warmth in your face and neck (skin flushing), chronic diarrhea, and difficulty breathing, among other signs and symptoms. Carcinoid heart disease.[mayoclinic.org]
  • Given the chronic diarrhea and the mesenteric mass, carcinoid syndrome was suspected.[karger.com]
  • Because the combination of chronic diarrhea and abdominal pain that aggravates after food ingestion is also typical for irritable bowel syndrome, MCS patients have repeatedly been misdiagnosed with irritable bowel syndrome.[symptoma.com]
  • This causes chronic diarrhea and concomitant dehydration, metabolic alkalosis, and elevated bicarbonate.[lecturio.com]
Hepatomegaly
  • […] hypertension), palpitations, intestinal hypermotility (nausea, vomiting, diarrhea, cramps) Also asthmatic attacks with bronchospasm, fibrosclerosis of AV and tricuspid valves, elastotic sclerosis of mesenteric vessels causing ischemia, dermal sclerosis, hepatomegaly[pathologyoutlines.com]
  • […] due to tricuspid stenosis from serotonin action Other common problems – Asthma, wheezing, palpitations, hypotension, dizziness Physical Pay attention to: heart murmur, asthma-like symptoms, pellagra, electrolyte deficieny/dehydration from diarrhea, hepatomegaly[openanesthesia.org]
  • She was found to have non-tender hepatomegaly. Therefore, referred pain to the right shoulder from underlying hepatomegaly versus bone pain from metastasis was suspected.[jmedicalcasereports.biomedcentral.com]
  • […] metastatic carcinoid tumours, increased conversion of tryptophan to serotonin may lead to tryptophan and niacin deficiency, presenting as hypoalbuminaemia and pellagra. [ 4, 8 ] Examination is often normal but may reveal a right-sided abdominal mass, hepatomegaly[patient.info]
  • Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated hepatomegaly and numerous liver lesions.[academic.oup.com]
Hypertension
  • […] bradykinin, others) released from carcinoid tumors Clinical symptoms occur if liver metastases are present or if tumor venous blood flow bypasses the liver Symptoms Vasomotor disturbances (cutaneous flushes, cyanosis of face and anterior chest, intermittent hypertension[pathologyoutlines.com]
  • Intraoperative handling of tumor Histamine releasing drugs (probably should be avoided in patients with carcinoid tumors, although these drugs have been used frequently in the past without complications) Diagnosis Severe hypotension/hypertension Flushing[openanesthesia.org]
  • Nearly 95% of patients with present with right-sided heart valve disease, characterized by tricuspid insufficiency and pulmonary stenosis and the subsequent development of pulmonary hypertension.[endocrinediseases.org]
  • Labetalol infusion has been used to tackle prolonged hypertension.[jscisociety.com]
  • Uses of "malignant" in oncology: * Malignancy, malignant neoplasm and malignant tumor are synonymous with cancer * Malignant ascites * Malignant transformation Non-oncologic disorders referred to as "malignant": * Malignant hypertension * Malignant hyperthermia[dbpedia.org]
Palpitations
  • […] aberration, and excretion of large quantities of 5-hydroxyindoleacetic acid. carcinoid syndrome the systemic effects of serotonin-secreting carcinoid tumors, which include flushing, diarrhea, cramps, skin lesions resembling pellagra, labored breathing, palpitations[medical-dictionary.thefreedictionary.com]
  • […] released from carcinoid tumors Clinical symptoms occur if liver metastases are present or if tumor venous blood flow bypasses the liver Symptoms Vasomotor disturbances (cutaneous flushes, cyanosis of face and anterior chest, intermittent hypertension), palpitations[pathologyoutlines.com]
  • Cutaneous flushing Possible triggers: alcohol consumption, food intake, stress In severe cases, may be accompanied by tachycardia and fluctuating blood pressure D yspnea, wheezing ( asthma -like attacks) Possible weight loss despite normal appetite Palpitations[amboss.com]
  • The syndrome may also be accompanied by stomach pain, blockage of the arteries in the liver, heart palpitations and excessive peptide excretion in the urine.[rarediseases.org]
  • […] appendectomy Rectum – 1.5 cm abdominoperineal resection Chemoembolization of liver lesions Anesthetic Considerations History Some develop right heart problems due to tricuspid stenosis from serotonin action Other common problems – Asthma, wheezing, palpitations[openanesthesia.org]
Cyanosis
  • He had flushing of the face and cyanosis, and telangiectasia were present in the cheek area ( Figure 1 ). Figure 1: A 72-year-old man with carcinoid syndrome, showing flushing, cyanosis and telangiectasia.[cmaj.ca]
  • […] vasoactive amines (serotonin, histamine, bradykinin, others) released from carcinoid tumors Clinical symptoms occur if liver metastases are present or if tumor venous blood flow bypasses the liver Symptoms Vasomotor disturbances (cutaneous flushes, cyanosis[pathologyoutlines.com]
  • Bronchoconstriction is usually intermittent and patients claim asthma attacks during which wheezing, dyspnea, cyanosis and tachycardia can be observed.[symptoma.com]
  • […] of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis[wikiecho.org]
Heart Murmur
  • Patients with valvular lesions may have a heart murmur. A few patients have asthmatic wheezing, and some have decreased libido and erectile dysfunction. Pellagra develops rarely.[msdmanuals.com]
  • Over a long time, these hormone-like substances can damage heart valves, causing shortness of breath, weakness, and a heart murmur (an abnormal heart sound). Not all GI carcinoid tumors cause the carcinoid syndrome.[cancer.org]
  • murmur, asthma-like symptoms, pellagra, electrolyte deficieny/dehydration from diarrhea, hepatomegaly (from metastasis) Carcinoid heart disease Typically right side of heart Fibrous deposits on valvular endocardium Thickening of endocardium of cardiac[openanesthesia.org]
  • murmur, heart failure blocked arteries in the liver bowel obstruction In extremely rare cases, acute symptoms such as low blood pressure, palpitations, faintness, and shortness of breath may become life-threatening.[healthline.com]
  • We said that suspicion comes first, then examining the patient, feeling a lump or hearing a heart murmur, or seeing a flush. Then, after that, we look at the markers.[carcinoid.org]
Systolic Murmur
  • Systolic murmur along the lower left sternal border suggestive of tricuspid regurgitation. Pellagra, due to increased utilization of tryptophan by the carcinoid tumor that results in reduced nicotinic acid production and niacin deficiency.[cancertherapyadvisor.com]
Arthritis
  • These cause symptoms such as flushing, diarrhoea, cramping abdominal pain, serious heart damage, arthritis and asthma.[medical-dictionary.thefreedictionary.com]
  • He endorsed a 40-pound unintentional weight loss over 2 years and use of NSAIDs for arthritis, but was unable to quantify NSAID use.[karger.com]
  • […] chromogranin A levels include the following: chronic atrophic gastritis, liver cirrhosis, chronic hepatitis, pancreatitis, inflammatory bowel disease, heart failure, renal failure, hyperthyroidism, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis[cancertherapyadvisor.com]
  • Some people will have fatigue, edema, some muscle pain, or finally arthritis. The problem with carcinoid is both the good news and the bad news.[carcinoid.org]
Arthralgia
  • Less commonly, myalgia, arthralgia, loss of libido and erectile dysfunction are reported by MCS patients.[symptoma.com]
  • Other symptoms include fatigue, palpitation, hypotension and aesthenia, and rarely irritability, myopathy and arthralgia.[healthed.com.au]
Flushing
  • Histamine and bradykinin, through their vasodilator effects, cause flushing.[msdmanuals.com]
  • Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups.[ncbi.nlm.nih.gov]
  • The most characteristic symptoms of MCS are flushing, diarrhea, cardiac insufficiency, and bronchoconstriction. Flushing may be restricted to face and neck or extend to shoulders, arms, and thorax.[symptoma.com]
  • This is an acute carcinoid flush. It disappeared within a matter of a minute or two. And here he is, now, feeling obviously much better, but you see residual mask-like flush of which he is not even aware.[carcinoid.org]
Pruritus
  • 2019 Vol. 381 No. 19 October 31, 2019 Vol. 381 No. 18 October 24, 2019 Vol. 381 No. 17 Browse full issue index Browse recently published Browse full issue index Recently Published Articles A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus[nejm.org]
  • Gastric neuroendocrine tumors can cause patchy, well demarcated, serpiginous, cherry red flushing with intense pruritus due to secretion of histamine.[ncbi.nlm.nih.gov]
  • In January 1998, he presented with flushing, pruritus, and watery diarrhea.[bcmj.org]
  • […] tract, the sites most commonly affected are the small bowel, the rectum and the stomach. 4 The vasoactive hormones secreted by the tumour give rise to the so-called “carcinoid syndrome”, characterised by facial flushing, arterial hypotension, diarrhoea, pruritus[elsevier.es]
Alopecia
  • […] registration; in addition, prior treatment (somatostatin analogs excepted) must be completed at least 4 weeks prior to initiation of study drug; treatment-related toxicities must have improved to grade 1 prior to registration, with the exception of alopecia[clinicaltrials.gov]
  • Although these agents are more toxic than somatostatin analogs, they may exhibit greater antitumor activity, but substantial adverse effects include fever, fatigue, anorexia, and weight loss as well as alopecia, autoimmune diseases and myelosuppression[scielo.br]
Pruritic Rash
  • He also had recurrent erythematous pruritic rashes over the face and trunk initially felt to be a drug rash, but the rash did not improve with change of antibiotics.[karger.com]
Decreased Libido
  • A few patients have asthmatic wheezing, and some have decreased libido and erectile dysfunction. Pellagra develops rarely. Urinary 5-hydroxyindoleacetic acid (5-HIAA) Serotonin -secreting carcinoids are suspected based on their symptoms and signs.[msdmanuals.com]
Facial Edema
  • Carcinoid of the foregut produces a more intense and erythematous flush, sometimes associated with itching, conjunctival suffusion, and facial edema suggestive of histamine.Occasionally, gastric carcinoids cause an urticarial reaction, which may be inhibited[aboutcancer.com]
  • Facial edema, macular erythema, periorbital edema. Steatorrhea, chronic diarrhea. Pulm. Systolic & Diastolic heart murmur; Pulmonic valve stenosis, Tricuspid insufficiency Wheezing; tremor, telangictasis. Alcohol intolerance.[enotes.tripod.com]
Facial Redness
Sexual Dysfunction
  • After evaluation of side effects, the patient underwent several medication changes until he was stable with minimal side effects and no reports of sexual dysfunction on a regimen of 10 mg/day of escitalopram and 1 mg of clonazepam twice daily.[healio.com]
  • Dysfunction; CSSS, Carcinoid Symptom Severity Score; EORTC QLQ-GINET.21, European Organisation for Research and Treatment of Cancer Quality of life Questionnaire – Gastrointestinal Neuroendocrine Tumors; Norfolk QLQ-NET, Norfolk Quality of life Questionnaire[dovepress.com]

Workup

If a patient's medical history comprises a previous diagnosis of gastrointestinal NET, diagnosis of MCS is largely facilitated. In most cases, though, the treating physician has to make both the diagnosis of malignant NET and MCS.

With regards to the former, magnetic resonance imaging and computed tomography scans are first-line diagnostic tools to detect gastrointestinal tumors, hepatic and extra-hepatic metastases. It is not uncommon to see multiple carcinoid tumors in the digestive tract and multiple metastases. Findings obtained by diagnostic imaging are very helpful when establishing a therapeutic plan.

Diagnosis of MCS is based on the presence of characteristic symptoms in a patient who has been shown to suffer from metastatic NET. In order to assess which mediators account for the observed symptoms, laboratory analyses of blood samples should be conducted.

Thrombocytosis
  • Laboratory data were remarkable for significant anemia with hemoglobin of 5.9 g/dL (3 years prior: 11.7 g/dL; normal: 14.0–17.5 g/dL), leukocytosis with a WBC of 24,000/µL, and thrombocytosis of 722,000/µL.[karger.com]
  • […] neuroleptic malignant syndrome includes the following: Increased LDH Increased creatine kinase (50-100% of cases) Increased AST and ALT Increased alkaline phosphatase Hyperuricemia Hyperphosphatemia Hyperkalemia Myoglobinemia Leukocytosis (70-98% of cases) Thrombocytosis[emedicine.medscape.com]
Serotonin Increased
  • Serotonin increases intestinal motility Systemic Carcinoid Syndrome: These patients develop bronchospasm. Why? Histamine causes bronchospasm Systemic Carcinoid Syndrome: These patients develop skin flushing, diarrhea, and bronchospasm.[quizlet.com]

Treatment

MCS treatment consists in a cure of the underlying disease and symptomatic therapy of MCS-associated disturbances as long as they persist.

With respect to the primary NET and its metastases, only surgical resection has been proven effective. Neither radiation therapy nor chemotherapy is indicated in case of carcinoids; symptoms relieve may be achieved by applying these techniques, but recurrence has to be expected. Resection of regional lymph nodes and hepatic metastases is usually a greater challenge than complete removal of the primary tumor. Nevertheless, surgery is recommended and patients may even benefit from incomplete resection: Symptoms subside and life quality improves. Because NET are very slow growing tumors, survival times can be significantly prolonged by such measures. Complete resection often leads to a permanent cure.

Distinct drugs are available to counteract peripheral effects of hormones and hormone-like substances produced by the tumor. Octreotide is a somatostatin analogue that binds to surface receptors expressed by NET cells and thereby inhibits release of the aforementioned substances, mainly of serotonin [11]. It is currently the mainstay of drug therapy of MCS. Serotonin synthesis inhibitors like telotristat etiprate may be used in patients who don't respond satisfactorily to octreotide [12]. Conventional antihistamines may be applied to further reduce flushing and bronchoconstriction. MCS-related diarrhea may be treated with antidiarrheals like loperamide, diphenoxylate, and opiates.

Prognosis

According to the pathophysiological mechanisms that lead to MCS, the vast majority of patients presenting with this syndrome suffers from a malignant neoplasm that already spread to the liver and/or regional lymph nodes. However, these tumors are generally very slow growing and thus, the overall prognosis is relatively good when compared with individuals affected by other types of cancer.

The individual prognosis of a patient may depend on whether the primary tumor and all metastases can be removed surgically. If the entire tumor tissue can be resected, complete cure is possible. Life quality and life expectancy can also be improved or prolonged by debulking, i.e., by removal of as much cancerous tissue as possible. A 5-year survival rate of 76% has been reported for those patients whose primary tumor has been resected [3]. This value decreases drastically if untreated patients are considered. Urinary excretion of serotonin metabolites has been proposed as a prognostic factor whereby excretion of high quantities of 5-hydroxyindoleacetic acid relates to a worse outcome.

Etiology

Precise triggers of carcinoid development or malignant degeneration of NET are not known. In some cases, they may be presented by patients who suffer from multiple endocrine neoplasia, a genetic disorder characterized by multiple tumors of endocrine glands.

MCS, in turn, does directly result from metastasizing NET. The primary tumor is most often located in ileum or cecum, but may also be encountered in the colon. Rectal carcinoids are rarely associated with MCS. Of note, malignant NET may also originate from other tissues, namely from the lungs, ovaries, and testes. Malignant carcinoids in other organs have only been described in isolated cases.

Epidemiology

Epidemiological data regarding NET and MCS are scarce and their reliability is doubtful. With respect to gastrointestinal NET, annual incidence rates of 1-2 per 100,000 inhabitants have been reported [4]. These values are most likely underestimates since the majority of NET patients never manifests any symptoms. Thus, retrospective studies can only be based on symptomatic NET.

Soga and colleagues conducted such a study and reported the following [3]:

  • About 8% of symptomatic NET patients developed MCS.
  • Metastatic spread, particularly to the liver, strongly predisposes for MCS.
  • MCS prevalence increased with age.
  • MCS was associated with higher serotonin activity.

Neither racial nor gender predilections have been reported.

Sex distribution
Age distribution

Pathophysiology

The likelihood of developing MCS in the case of NET correlates well with the presence of metastases. MCS is most commonly described in patients who present hepatic metastases of gastrointestinal NET; some MCS patients suffer from NET that spread to the regional lymph nodes, and in few cases, metastases cannot be encountered. The latter presumably results from the inability to detect small metastases with available imaging techniques. Induction of MCS by primary gastrointestinal tumors is unlikely since vasoactive substances secreted by these neoplasms are degraded upon the first pass through the liver and won't reach peripheral organs [5].

NET and their metastases may produce a plethora of biogenic amines, protein and peptide hormones, kinins, eicosanoids, growth factors and enzymes. The interested reader is referred to a recently published review regarding this broad topic [6].

Serotonin activity seems to play a major role in MCS pathophysiology and in general, serotonin activity is higher in NET patients with MCS than in those that do not present the syndrome [3]. In fact, not too long ago a case report has been published about an older woman who manifested MCS because of a serotonin-secreting pituitary tumor [7]. Serotonin has been shown to induce cardiac valve lesions and heart failure is the main cause of premature death in MCS patients. Although serotonin release has also been related to MCS-associated diarrhea, tachykinins may significantly contribute to it [8]. Serotonin and tachykinins are also implied in bronchoconstriction [5]. Flushing, in contrast, is primarily mediated by histamine. Therefore, histamine-producing stomach carcinoids may mimic an incomplete MCS.

Prevention

MCS patients should avoid situations or drugs that may contribute to increased serotonin activity. Both physical and psychological stress, as well as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, should be avoided [13].

Summary

Carcinoid, carcinoid tumor and neuroendocrine tumor (NET) are all medical termini referring to neoplasms originating from the neuroendocrine system. The vast majority of NET are located in the gastrointestinal tract, mainly in ileum and cecum, but such tumors may also be encountered in more proximal or distal parts of the digestive tract, in pancreas or lungs.

Most NET are functionally active, i.e., they produce hormones and hormone-like substances that may be released into circulation. Biogenic amines serotonin and histamine, as well as kinins, shall be mentioned as examples, but individual NET may differ largely regarding their secretory profiles. If the aforementioned mediators reach the bloodstream, they may exert distinct effects in peripheral organs, namely in the cardiovascular system, in the respiratory tract or in the gastrointestinal tract. This results in flushing, cardiac insufficiency, bronchoconstriction, and diarrhea, respectively. The entirety of these symptoms is known as carcinoid syndrome.

NET may be benign or malignant neoplasms. It has generally been assumed that NET who measure less than a centimeter in diameter are most likely benign; they have rarely been shown to grow invasively and spread lymphogenically or hematogenously. However, this hypothesis has recently been challenged [1]. Retrospective studies have shown that 12% of small NET metastasize, mainly into local lymph nodes. The share of malignant tumors is even greater among NET measuring more than a centimeter in diameter.

According to current knowledge, carcinoid syndrome preferentially occurs in patients suffering from malignant NET, which is why this symptom complex is also designated as malignant carcinoid syndrome (MCS). Strictly speaking, MCS can only be diagnosed in patients who have previously been shown to suffer from malignant NET, which is most commonly achieved by demonstrating the existence of hepatic metastases [2] [3]. Carcinoid syndrome in patients diagnosed with non-metastatic or benign NET is rare.

Ideally, gastrointestinal primary tumors and all metastases are surgically removed - if this can be achieved, complete cure of NET and MCS is possible. MCS itself is treated with medication that counteracts the effects of serotonin, histamine and possibly other mediators released by tumor metastases. Additionally, symptomatic treatment may be indicated to relieve cardiac disorders and diarrhea.

Patient Information

Carcinoid, carcinoid tumor and neuroendocrine tumor (NET) are all medical termini referring to neoplasms originating from hormone-producing cells located in distinct organs. Many NET develop in the gastrointestinal tract, and they may be either of benign nature or malignant.

NET often produce hormones and hormone-like substances themselves, in an uncontrolled manner. As long as the tumor does not spread from the intestines to other tissues, these substances are transported to the liver and degraded there before they can reach peripheral organs. However, malignant NET tend to spread to regional lymph nodes and the liver. Functionally active tumors may now release serotonin, histamine and a variety of other compounds that are directly secreted into the circulation. They easily reach the cardiovascular system, the bronchial tubes or different parts of the digestive tract. Here, they mediate flushing, cardiac insufficiency, bronchoconstriction, and diarrhea, respectively. The entirety of these symptoms is known as malignant carcinoid syndrome (MCS).

MCS may only be diagnosed in patients who have previously been found to suffer from NET. But because NET are generally very slow growing tumors, they may not cause symptoms for years, and MCS may be the first manifestation of this pathology. Thus, diagnostic imaging, localization of primary tumor and metastases, along with laboratory analyses of blood samples is applied to assess the dissemination of tumor cells and to identify those hormone-like substances that cause complaints.

Treatment consists in surgical resection of the primary tumor and all metastases as well as reduction of serotonin- and histamine-mediated effects. Life quality and life expectancy can be significantly improved by these measures; if all tumors can be resected, complete cure is possible.

References

Article

  1. Walsh JC, Schaeffer DF, Kirsch R, et al. Ileal “carcinoid” tumors—small size belies deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. Human Pathology. 2016;56:123-127.
  2. Feldman JM, Jones RS. Carcinoid syndrome from gastrointestinal carcinoids without liver metastasis. Ann Surg. 1982; 196(1):33-37.
  3. Soga J, Yakuwa Y, Osaka M. Carcinoid syndrome: a statistical evaluation of 748 reported cases. J Exp Clin Cancer Res. 1999; 18(2):133-141.
  4. Stalberg P, Westin G, Thirlwell C. Genetics and epigenetics in small intestinal neuroendocrine tumours. J Intern Med. 2016.
  5. Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, and management. Heart. 2004; 90(10):1224-1228.
  6. Gedam BS, Bansod PY, Shah Y, Kale VB, Kate S. Gastrointestinal carcinoids: A case report and review of literature. Int J of Biomed & Adv Re. 2015; 6(11): 801-806.
  7. Lynggard LA, Nielsen EH, Laurberg P. Carcinoid syndrome caused by a serotonin-secreting pituitary tumour. Eur J Endocrinol. 2014; 170(2):K5-9.
  8. Cunningham JL, Janson ET, Agarwal S, Grimelius L, Stridsberg M. Tachykinins in endocrine tumors and the carcinoid syndrome. Eur J Endocrinol. 2008; 159(3):275-282.
  9. Wilson HM. Chronic subacute bowel obstruction caused by carcinoid tumour misdiagnosed as irritable bowel syndrome: a case report. Cases J. 2009; 2(1):78.
  10. Paredes A, Valdebenito M, Gabrielli L, Castro P, Zalaquett R. [Tricuspid and pulmonary valve involvement in carcinoid syndrome. Report of two cases]. Rev Med Chil. 2014; 142(5):662-666.
  11. Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006; 17(12):1733-1742.
  12. Kulke MH, O'Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014; 21(5):705-714.
  13. Furse RM, Green CJ, Mee AS. Carcinoid syndrome unmasked by fluoxetine, a selective serotonin reuptake inhibitor. Clin Gastroenterol Hepatol. 2008; 6(8):e27-28.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 20:20