Carcinoid Syndrome

Carcinoid syndrome is the most common systemic syndrome caused by carcinoid Tumors. The syndrome describes a symptom complex resulting from the secretion various bioactive amines secreted by carcinoid tumors. In addition to carcinoid syndrome other bioactive substances may also be secreted by the tumor especially in case of foregut carcinoids.
These include:

1. GI peptides: Most commonly Pancreatic Polypeptide secreted.
2. Ectopic ACTH secretion - Cushing Syndrome
3. Acromegaly - Growth hormone releasing factor (NOT GF per se!!).
4. Somatostatinoma Syndrome: Seen in Duodenal carcinoids - the syndrome is characterized by Insulin defeciency (DM and IGT - Often with ketoacidosis like Type I DM) ; Cholelithiasis - Due to defeciency of CCK - PZ enzyme - leading to impaired GB motility ; Steatorrhea - Secondary to pancreozyme defeciency - malabsorbtion ; Achlorhydria - secondary to Gastrin secretion inhibition.

Carcinoid Syndrome is characterized by several symptoms which can occur in a variety of combinations.
Overall about 8% of all patients have carcinoid syndrome - more common in patients with hepatic mets and larger tumors. The most common type is ileal carcinoids.
The main symptoms are:

• Flushing :
  
• Seen in 30 -60% patients
• Precipated by stress / exercise or certain foods and medicines
• Occurs due to excess secretion of serotonin by the tumor - majority is stored in platlets and a small amount reaches the systemic circulation,
• The typical flushing episode is a diffuse erythema of the face, neck and upper trunk associated with lacrimation, sweating, palpitations and itching.
• Flushing in case of bronchial carcinoids is more intense , prolonged and diffuse and associated with greater degree of symptoms
• In case of gastric carcinoids the flushing is patchy but intensly pruritic.
• Usually flushing lasts for 2 -5 mins but may be prolonged.
• Diarrhea:
• Typically in the form of watery diarrhea - it is secondary to decresed transit time due to increased colonic motility.
• Again serotonin is believed to be causative for the symptom,
• Diarrhea is associated with flushing in 85% patients and typically associated with an episode of flushing
• It may be associated with abdominal pain too.
• Cardiac Manifestations:
• These are in the form of fibrosis of the endomyocardium - secondary to TGF - beta production by the increased serotonin exposure
  
• As a result of the fibrosis there is Pulmonic stenosis as the valve is fibrosed in the closed position and there is also Tricuspid Regurgitation as the TV is fibrosed in the open position.
• Cardiac manifestations will be seen iin 10-66% of the patients but the severity is not related to the syndrome.
• Other manifestations:
• Wheeze due to asthma
• Pellagra like skin leison due to nicotinamide defeciency
• RA and athalgia
• Retroperitoneal fibrosis - uretral fibrosis and pyronnies disease

Diagnosis rests on the demonstration of raised 5-HIAA level in the urine - levels above 8 mg in a 24 hour sample is considered suggestive with symptoms.
Atypical carcinoid syndrome is seen in case of foregut carcinoids - here the serotonin is not formed but there is excretion of 5 - Hydroxy tryptamine which is converted to serotonin prior to excretion in the kidney - so that the urine shows increased serotonin excretion without increased serum serotonin.
Diagnostic accuracy is increased by the the measurement of urine and platelet serotonin estimations.

Presence of carcinoid syndrome is a poor prognostic factor - as they are usually in the presence of metastatic disease,

Treatment is directed towards possible surgical extripation of any removable tumor and hepatic mets specially if solitary or small.
Pharmacological treatment aims to ameliorate the symptoms by:

• Heart Failure - Diuretics
• Wheezing - bronchodilators
• Diarrhea - Loperamide + Serotonin receptor antagonists.
• Preventing action of serotonin:
• Blocking synthesis : Parachlorophenylalanine and alfa methyl dopa - obsolete.
  
• Serotonin receptor antagonists:
• Cyproheptadine, Ketanserine, Methesergide - Block 5 HT 1 and 5 HT2 receptors.
• 5HT 3 receptor antagonists - Ondansetrone, Alosetrone, tropisetron - control nause , diarrhea and flushing.
• Somatostatin analouges: These reduce secretion of serotonin and ameliorate the symptoms
• These are now the drugs of choice to control carcinoid syndrome.
• Octerotide and Lanreotide are used.
• Octreotide is started in doses of 100mg TDS S/C increased gradually - the main S/E are chronic like Steatorrhea, Cholelitiasis and DM
  
• Control is maintained for 1 year in 60% of the patients.
• Lanreotide is a sustained release preperation.
• Interferon Alfa - Has been used in combination with Octreotide - useful in combination with hepatic artery embolization. Can be combined with octreotide in patients resistent to either agent alone.
• Chemotherapy:
• Systemic Chemotherapy : DTIC + Adriamycin+ 5 FU with streptozotocin
• Chemoembolization - Adriamycin, Mitomycin C, Cisplatin and 5 FU