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How to spot zebras - carcinoid syndrome

Dr Paolo d’Arienzo and Dr Mairéad McNamara on what signs should alert GPs to this rare syndrome

What is it?

Carcinoid syndrome is a constellation of symptoms and clinical signs that can arise in patients with advanced neuroendocrine tumours (NETs). These malignancies originate from neuroendocrine cells, which are present in a number of organs including lung and bronchi, thymus, stomach, small and large bowel and pancreas.1

Neuroendocrine cells secrete a variety of neuroamines and active peptides in the bloodstream, features that well-differentiated NETs can maintain and amplify.1,2 The term ‘carcinoid’ is now used to refer to NETs originating from the embryological intestine (lung or small bowel), which are serotonin producers, as opposed to NETs secreting other hormones (such as insulinomas or gastrinomas), and non-functioning NETs, which do not secrete substances causing a typical clinical syndrome.3

Epidemiology

Neuroendocrine tumours are rare pathological entities, with incidence estimated to be around five cases per 100,000 people per year.2 They can arise in all age groups, but the diagnosis is most often made in patients from the fifth decade onward.

Gastroenteropancreatic NETs account for about 2% of all gastrointestinal malignancies, while 1-2% of all primary lung neoplasms are lung carcinoids. According to a recent population-based analysis from the American Surveillance, Epidemiology, and End Results database, 19% of patients newly diagnosed with an intestinal or pulmonary NET also had carcinoid syndrome at diagnosis.4

Presentation

Carcinoid syndrome in patients with intestinal NETs is strongly associated with the presence of liver metastases. Serotonin, tachykinins, bradykinin, histamine and prostaglandins, which are secreted by the primary tumour into the portal circulation, are metabolised by hepatocytes, while mediators produced by liver metastases are released in the systemic circulation and exert the peripheral effects of the syndrome.5

Clinically, carcinoid syndrome is associated with skin flushing, secretory diarrhoea (caused when tumour secretagogues impair electrolyte balance in the bowel), intermittent bronchoconstriction, right heart valvulopathies and heart failure. Flushing and diarrhoea are the cardinal symptoms and are equally prevalent, being present in about 80-90% of patients.6 Flushing is a consequence of the vasodilatory effect of the mediators released by the tumour and can be pink-red-purple in colour, usually localised on the face and trunk. Diarrhoea can be the most distressing symptom for the patient, with some subjects experiencing more than 20 bowel motions per day. Intermittent wheeze is less frequent (10-20% of patients). Carcinoid heart disease, the most worrying complication of the syndrome (30% of subjects), is caused by endocardial fibrosis in the right heart, leading to valvulopathies – typically tricuspid regurgitation or pulmonary stenosis. It manifests clinically as right heart failure. A significant proportion of patients (around 40%) also complain of abdominal pain, which is multifactorial in origin: mesenteric fibrosis leading to partial obstruction, dysmotility of the bowel wall, or intestinal ischaemia. Alternatively, large tumour burden in the liver can lead to capsular pain.6

The different manifestations of carcinoid syndrome can seem unrelated and better explained by the co-existence of more common pathologies, meaning the diagnosis is difficult and diagnostic delay is common. The lag between initial symptoms and diagnosis can be several years.7 Therefore, you should keep this syndromic picture in mind, and rule it in or out with appropriate investigations (see below). In the presence of one or two suggestive symptoms, the patient should be asked about the presence of others.

Investigation

Diagnostic imaging can include abdominal ultrasound for detection of liver metastases, while a CT abdomen or pelvis can check for hepatic, mesenteric or lymph node metastases and can often image the primary intestinal NET. A CT chest can be used to diagnose or exclude a bronchial carcinoid. Functional imaging (preferably 68Ga-PET/CT, and if not available, an Octreoscan8) has a sensitivity of about 90% for the detection of a primary tumour and >95% for liver metastases, and is therefore useful for initial diagnosis and staging.6

Useful biochemical tumour markers include 5-hydroxyindoleacetic acid (5-HIAA), the final catabolite of serotonin, and the pan-neuroendocrine marker chromogranin A (CgA)9. 5-HIAA can be measured in serum and 24-hour urine collection, acting as a specific (>90%) and relatively sensitive (70%) marker for serotonin-producing NETs. CgA may be falsely positive in patients on a PPI or who have atrophic gastritis, chronic kidney disease, cirrhosis or heart failure. High 5-HIAA levels may also be caused by various medications or serotonin-rich foods.

For a diagnosis of carcinoid heart disease, BNP/NT-pro BNP have been reported to be quite sensitive for diagnosing early disease, with transthoracic echocardiogram being the most important diagnostic test.

Differential diagnosis

Some features of the cardinal symptoms and additional tests may help to distinguish carcinoid syndrome from differential diagnoses. Carcinoid flushing is intermittent, while alcoholism causes constant flushing. Follicle stimulating hormone levels can be useful to exclude menopause-induced intermittent flushing. Diarrhoea is typically watery in carcinoid syndrome, while mucous or bloody diarrhoea is associated with inflammatory bowel disease (ulcerative colitis or Crohn’s disease). Patients with irritable bowel syndrome usually do not have nocturnal diarrhoea and their abdominal discomfort is often relieved by defecation. More common malignancies of the digestive tract, such as colorectal cancer, can present with anaemia, rectal bleeding or alternating diarrhoea and constipation, which are unusual for gastrointestinal NETs. A colonoscopy will exclude alternative intestinal pathology, and in the case of distant ileal carcinoids may allow visualisation of the tumour.

Multidisciplinary management and follow-up

On diagnosis, cases are discussed by the multidisciplinary team. In localised disease, surgery can offer a chance of cure but carcinoid syndrome is rarely present in these cases. Advanced NETs can be treated with a variety of agents, depending on the primary site and the patient’s fitness, including administration of somatostatin analogues, the tryptophan hydroxylase inhibitor telotristat ethyl, interferon-alpha, everolimus, sunitinib, chemotherapy, hepatic embolisation, peptide receptor radionuclide therapy and palliative surgery on the primary tumour or liver metastases.10

Because of the indolent nature of well-differentiated NETs, survival can exceed five years in a significant number of patients (dependent on performance status, comorbidities, primary site and extent of disease), who will have to deal with the symptoms of carcinoid syndrome for an extended period. Management therefore has two goals: maintaining quality of life by suppressing symptoms and survival extension.

 

Dr Paolo Davide d’Arienzo is an academic foundation doctor at the Royal Liverpool University Hospital with a special interest in medical oncology.

Dr Mairéad G. McNamara is an honorary consultant in medical oncology at The Christie NHS Foundation Trust and a senior lecturer at the University of Manchester.

Conflicts: none declared

 

References

  1. Rosai J. The origin of neuroendocrine tumors and the neural crest saga. Mod Pathol 2011; 24(Suppl 2): S53-7.
  2. Yao J et al. One hundred years after ‘carcinoid’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 6: 3063-72.
  3. Öberg K et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23(Suppl 7): vii124-130.
  4. Halperin D et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol 2017; 18: 525-34.
  5. Massironi S. et al. Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol 2008; 14: 5377-84.
  6. Niederle B et al. ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum. Neuroendocrinology 2016; 103: 125-38.
  7. Toth-Fejel S. & Pommier R. Relationships among delay of diagnosis, extent of disease, and survival in patients with abdominal carcinoid tumors. Am. J. Surg. 2004; 187: 575-79.
  8. Buchmann I et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2007; 34: 1617-26.
  9. Öberg K. et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology 2017; 105: 201-11.
  10. Pavel M et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology 2016; 103: 172-85.

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