Carcinoid Tumour and Carcinoid Syndrome

Question 1

Carcinoid tumours are neoplasm that arise from __.
They are under a broader group known as __, but not all of them secrete __ to cause carcinoid syndrome

Classification of carcinoud tumour:
1. Foregut carcinoids: __
2. Midgut carcinoids: __
3. Hindgut carcinoids: __

Answer 1

Enterochromaffin cells
Neuroendocrine tumours
Humoral mediators

1. Foregut: bronchus, stomach, duodenum, bile ducts, pancreas
2. Midgut: jejunum, ileum, appendix, caecum, ascending colon
3. Hindgut: transverse and descending colon, rectum

Question 2

Carcinoid syndrome and its symptoms

Answer 2

Constellation of symptoms due to NETs secreting large amounts of humoral mediators

Commonest occurrence when midgut NETs metastasized to liver
Rarely associated with foregut and hindgut NETs (unless they do not pass through portal veins)

1. Cutaneous flushing (85-90%)
2. Hypotension
3. Secretory diarrhoea (75-80%)
4. Bronchospasm (10-20%)
5. Cardiac fibrosis - endocardium, right heart valves
6. Pleural fibrosis
7. Peritoneal or retroperitoneal fibrosis

Question 3

Characteristic flushing appearance of carcinoid syndrome

Answer 3

Midgut NETs:
1. Episodic reddish to purplish flushing of face, neck and chest
2. Cutaneous burning sensation
3. Complicated by hypotension, tachycardia
4. Duration: 30 seconds to 30 minutes
5. Eventual development of telangiectasia over malar areas, nose, upper lips (prolonged vasodilation in cutaneous vasculature)

_Foregut NETs (gastric tumours, pulmonary):
1. Patchy, serpiginous, bright red flush
2. Very pruritic
3. Duration: hours to days
4. Hypotension, tachycardia
5. Anxiety, disorientation
6. Periorbital oedema
7. Lacrimation and salivation
8. Dyspnoea, wheezing

Question 4

Pathogenesis of carcinoid syndrome
Biochemical mediators of carcinoid syndrome

Answer 4

Humoral mediators secreted by NETs reaches systemic circulation.
Midgut NETs metastasized to liver and causes:
1. Impairment of liver metabolism of mediators
2. Direct secretion via hepatic vein into circulation

Extraintestinal carcinoids may cause carcinoid syndrome without mets to liver, if they do not have to pass through portal veins

Main humoral mediators: serotonin, histamine, kallikrein, bradykinin, tachykinin, prostaglandin
- Serotonin - diarrhoea, fibrosis formation
- Histamine - flushing
(some degree for kallikrein, brady/tachykinins for both symptoms)

Other mediators: CRF, ACTH, GF (more in bronchial and pancreatic carcinoid
- Causing Cushing’s syndrome, acromegaly

Question 5

Niacin deficiency and pellagra in carcinoid syndrome

Answer 5

Large amounts of tryptophan diverted from niacin synthesis to produce serotnin

Pellagra - glossitis, angular stomatitis, rough scaly skin, mental confusion, hypoproteinaemia

Question 6

Diagnostic investigations for carcinoid syndrome

Answer 6

1. Elevated 24-hour urinary 5-HIAA excretion
   (5-HIAA is a breakdown product of serotonin)
   - Normal: < 8mg/day
   - Confirmatory: >100mg/day
   - Borderline: 30mg/day
   (Avoid tryptophan rich food 3 days prior to collection necessary - see subsequent card)
2. Serum serotonin, platelet rich plasma serotonin, urinary serotonin (not established)
3. Chromogranins A, B, C
   - Elevated A in carcinoid (false positive in PPI use)
4. CT TAP
5. 68-Ga DOTATATE or octreoscan

Question 7

What are causes of abnormal 5-HIAA secretions?

Answer 7

Causes of abnormal 5-HIAA
1. Malabsorption disorders
2. Tryptophan rich food - bananas, pineapples, kiwi, plums, avocados, eggplant, pecans, walnuts, hickory nuts
3. Medications - paracetamol, ephedrine, guaifenesin, caffeine, nicotine, methamphetamine, phenobarbital, phentolamine, warfarin, flurouracil

Question 8

Management of carcinoid syndrom

Answer 8

Symptom control
1. Long acting somatostatin analogues +/- inhibit tumour growth - octreotide, lanreotide
- IM octreotide LAR 20-30mg every 4 weeks (uptitrate to 60mg every 4 weeks)
- IM lanreotide 60-120mg every 4 weeks
- Additional short acting octreotide 100-150mcg Q8H for berakthrough symptoms

2. Tryptophan hydroxylase inhibitor - telotristat
   - Reduces progression of carcinoid heart disease
3. Others

Definitive treatment / palliation
1. Surgical resection
(However 90% patients have extensive metastases at time of diagnosis)

2. Chemotherapy - etoposide-cisplatin combination
3. ISTs under investigations
   - Everolimus
   - Vatalanib, sunitnib, sorafenib, bevazuzimab
4. Palliative surgery
   - Hepatic resection for focal liver mets
   - Hepatic artery embolisation
   - Chemoembolisation
   - Peptide receptor radioligand therapy

Question 9

Carcinoid crisis

Answer 9

Life threatening episode of hypotension, flushing, bronchospasm triggered by tumour manipulation, anaesthesia, chemotherapy, embolisation or therapy.

Also provoked by adrenergic agents (epinephrine), sympathomimetic amines, MAOIs

Question 10

Management of carcinoid crisis

Answer 10

1. Prevention: pre-treatment with IV/SC octreotide 300-500mcg 1 hour pre-procedure, then repeat dosing as necessary intra-procedure
2. Management
   - IV octreotide
   - IV corticosteroid
   - Others: methotrimeprazine, methoxamine, phentolamine, ondansetron, glucagon