Carcinoid syndrome of neuroendocrine neoplasia

Question 11.1 from the first paper of 2012 represents the one and only time the carcinoid neuroendocrine neoplastic syndrome has appeared in the CICM fellowhsip exam. In this question, the candidates were expected to make this diagnosis on the basis of historical features (facial flushing, diarrhoea, fatigue) and the right-sided murmur of tricuspid regurgitation. Only 10% of the candidates were able to do this. In order to improve the ratio, the following chapter is a brief point-form summary of the important things a non-endocrinologist needs to know about this condition.

The majority of this material is derived from the UpToDate article on this topic, as well as the MJA article by Modlin et al (2010).

Definition of carcinoid syndrome

• A syndrome formed from the group of paraneoplastic symptoms which develop as the result of tumour secretory activity.
• Specifically,  the symptoms result from  the secretory activity of neuroendocrine tumours which store and release bioactive polypeptides, monoamines and prostaglandins.

Tumours responsible for carcinoid syndrome

• Gut: the most common locations are jejunum, ileum or caecum.
• Lung
• Pancreas
• When the tumours are intestinal, carcinoid syndrome develops only after liver metastases appear: the liver usually removes the bioactive mediators from the portal circulation, and they never make it into the systemic circulation.

Typical bioactive mediators responsible for carcinoid syndrome

• serotonin
• histamine
• tachykinins
• kallikrein
• prostaglandins
• In actual fact, there are up to 40 different possible mediators; but generally everybody blames the serotonin.

Clinical features of carcinoid syndrome

• Episodic facial flushing (in 85%) - sometimes associated with hypotension and tachycardia
• Diarrhoea (in 80%) - secretory, watery and nonbloody
• Pruritis 
• Bronchospasm (IN 10-20%)
• Venous telangiectasia (nose, upper lip, cheeks)
• Right heart failure with tricuspid disease

Pathophysiology of carcinoid syndrome

• Increased metabolism of dietary tryptophan  into serotonin (70% conversion rate, instead of the normal 1%)
• Serotonin is then metabolized to 5-hydroxyindoleacetic acid (5-HIAA)
• Serotonin causes cardiac fibrosis by stimulating fibroblasts (right side is more affected because the lung filters the bioactive mediators, protecting the left sided chambers)
• Histamine causes pruritis
• Bradykinins and prostaglandins cause facial flushing

Other problems indirectly associated with carcinoid syndrome

• Diversion of tryptophan metabolism  may result in niacin deficiency
• This in turn leads to decreased protein synthesis and hypoalbuminemia
• Pellagra (niacin deficiency syndrome) develops: rough scaly skin, glossitis, angular stomatitis, confusion.
• Muscle wasting may occur as a result of poor protein synthesis
• Retroperitoneal and mesenteric fibrosis, with ureteric obstruction

Investigations to confirm the diagnosis of carcinoid syndrome

• 24-hour urinary 5-HIAA
• Serum chromogranin-A
• CT of the abdomen with IV and oral contrast
• MRI of the liver looking for mets
• Somatostatin-receptor scintigraphy (OctreoScan) - using a radiolabelled octreotide analogue (111-indium pentetreotide) to detect tumours with a high level of somatostatin receptor expression.
• Endoscopy (for gastric carcinoids) or bronchoscopy (for bronchail carcinoids).
• TTE to investigate extent of cardiac involvement

Twenty-four-hour measurement of urinary 5-hydroxyindole-3-acetic acid (5-HIAA), which is the degradation product of serotonin, is apparently 88% specific for serotonin-producing carcinoid tumours.

The MJA article cautions that tryptophan/serotonin-rich foods (bananas, avocados, plums, eggplants, tomatoes, plantains, pineapples and walnuts) can produce a falsely elevated 5-HIAA level.

Serum chromogranin-A is a much better test, because it is more reliable, does not require 24 hours of urine collection, and can be later used to monitor treatment.