Carcinoid_syndrome_crisis_and_precipitating.pdf

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Edda Gomez Panzani, MDVice President Clinical Sciences -Neuroendocrinology

Edda Gomez Panzani, MDVice President Clinical Sciences -Neuroendocrinology

Carcinoid syndrome andcarcinoid crisis

February 7, 2009


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Neuroendocrine tumorsNeuroendocrine tumors

Arise from cells of the diffuse neuroendocrine system.

Enterochromaffin cells: cells that have characteristics of nerve

cells and of endocrine cells (can release hormones).

These cells do not form an actual organ; they are scattered

throughout other organs like the esophagus, stomach, pancreas,

intestines, and lungs.


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Clinically Significant GEP NETsClinically Significant GEP NETs

Carcinoid 56%

Insulinomas 17%Unknown 15%

Gastrinomas 9%

VIPomas 2%

Glucagonomas 1%

Somatostatinomas 1%

Annual incidence


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Origin of Carcinoid TumorsOrigin of Carcinoid Tumors

Digestive System

64%

28%

Bronchopulmonary

System8%

Other

Other

Colon and

Rectum

Small Intestine

Stomach28.5%

28%

4.6%

2.36%

Modlin IM et. Al. Cancer 2003, 97:934-959


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Carcinoid

SYNDROME


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Carcinoid SyndromeCarcinoid Syndrome

1954 Thorson and Waldenstrom

Malignant carcinoid of the small intestine

Metastases to the liver

Peripheral vasomotor symptoms (flushing)

Diarrhea

Valvular disease of the right side of the heart (pulmonarystenosis and tricuspid regurgitation without septal defects)

Bronchoconstriction

Abdominal pain


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When carcinoid tumors occur in the digestive tract

the amines and peptides are released into the

portal vein reaching the liver where they suffer

enzymatic degradation

When the carcinoid tumors metastasize to the liver

the released amines and peptides bypass liver

metabolism and through the hepatic vein, are

released into the blood stream resulting incarcinoid syndrome.


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The occurrence and severity of the syndrome is directlyrelated to tumor bulk in an area that drains into thesystemic circulation.

In the vast majority of cases this correlates to hepaticmetastases

Exceptions include:

Primary ovarian carcinoids

Extensive retroperitoneal metastasis

Peritoneal carcinomatosis

Primary bronchial carcinoids


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Frequency of Symptoms of CarcinoidSyndrome

Frequency of Symptoms of CarcinoidSyndrome

0

10

20

30

40

50

6070

80

90

100

Flushing

Diarrhea

Valvular Heart Disease

Cramping

Telangiectasia

Wheezing

Edema

Cyanosis

Pellagra

Arthritis

Creutzfeldt W, Stockmann F. World J Surg. 1996; 20:126-131

Percent


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Dyspnea

Palpitations

Low blood pressure

Fatigue/Asthenia

Dizziness

Other relatively uncommon symptoms include:

Myopathy

Arthritis Arthralgias

Changes in mental state

Other Symptoms of Carcinoid SyndromeOther Symptoms of Carcinoid Syndrome


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Carcinoid Syndrome - FlushingCarcinoid Syndrome - Flushing

Flushing (~92%)

Caused by an indirect vasodilatation mediated by endothelium-

derived relaxing factor or by nitric oxide released by 5-HTP during

platelet activation

May be brief (ie. 2-5 min) or may last for several hours

May be accompanied by tachycardia

Precipitated by:

Stress (physical and/or mental)

Infection Alcohol

Certain foods (spicy)

Drugs (ie. Catecholamines, calcium, pentagastrin etc.)


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Carcinoid Syndrome - DiarrheaCarcinoid Syndrome - Diarrhea

Diarrhea (~78%)

Incompletely understood

Serotonin and Substance P stimulate small bowel and colonicmotility

Post-prandial transit times in the small bowel and colon have beenreported (von der Ohne et al.) to be 2 to 6 times faster in carcinoidpatients than in healthy individuals. Fasting colonic times arenormal.

Malabsorption can result in fluid and electrolyte imbalance,malnutrition, pellagra etc.

May be accompanied by borborygmi, cramping and or pain


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Carcinoid Syndrome Carcinoid HeartDisease

Carcinoid Syndrome Carcinoid HeartDisease

Valvular Heart Disease (~52%)

About 1/3 of deaths are related to right ventricular failure secondary to

cardiac morphological changes (ie. Stenosis of the tricuspid and

pulmonary valves).

Lesions usually located on the mural and valvular endocardium

predominantly in the right side of the heart

Lesions consist of fibroblasts or myofibroblasts and a matrix-rich

fibrous stroma devoid of elastic fibers covered by endothelium.

Right sided valve dysfunction is attributed to the presence of

carcinoid plaques which cause thickening and retraction of the valve.


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Carcinoid Syndrome TelangiectasiaCarcinoid Syndrome Telangiectasia

Telangiectasia (~25%)

Small dilated blood vessels near the surface of the skin

or mucous membranes, measuring between 0.5 and 1

millimeter in diameter

Lesions can develop anywhere on the body but are

commonly seen on the face around the nose, cheeks

and chin.


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Carcinoid Syndrome PellagraCarcinoid Syndrome Pellagra

Pellagra (~7%)

Symptoms:

Diarrhea, dermatitis, dementia and death

Photosensitivity

Aggression

Red skin lesions

Alopecia

Edema

Glossitis

Diarrhea

Treatment:

Niacinamide (niacin produces flushing) 200-500 mg daily individed doses


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Other signs and symptoms by

primary organ site


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Complaints in GI NETs by primaryorgan site


Frequency

Gustafsson B. et al. Current Opinion in Oncolocy 2008;20:1-12.

> 50%

10- 50%

< 10%

Stomach

Asym

ptoma

tic

Carci

noid

Synd

rome

Pain/

Discomf

ort

Bleeding

Obstruc

tion

Palpa

bleMa

ss

Weigh

t Los

s


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Frequency


> 50%

10- 50%

< 10%

Small Bowel

Asym

ptoma

tic

Carci

noid

Synd

rome

Pain/

Discomf

ort

Bleeding

Obstruc

tion

Palpa

bleMa

ss

Weigh

t Los

s


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Frequency

Gustafsson B. et al. Current Opinion in Oncolocy2008;20:1-12.

> 50%

10- 50%

< 10%

Appendix

Asym

ptoma

tic

Carci

noid

Synd

rome

Pain/

Discomf

ort

Bleeding

Obstruc

tion

Palpa

bleMa

ss

Weigh

t Los

s


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Frequency


> 50%

10- 50%

< 10%

Colon & Rectum

Asym

ptoma

tic

Carci

noid

Synd

rome

Pain/

Discomf

ort

Bleeding

Obstruc

tion

Palpa

bleMa

ss

Weigh

t Los

s


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0

5

10

15

20

25

30

35

40

45

50

Bronchopulmonary carcinoidsBronchopulmonary carcinoids

Symptoms

(%

ofpatien

ts)

Gustafsson B. et al. Current Opinion in Oncolocy2008;20:1-12.

Signs and Symptoms

Asym

ptoma

tic

Carci

noid

Synd

romeCo

ugh

Pneumo

nia

Chest p

ain

Dyspne

aFe

ver

Hemo

ptysis


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Carcinoid Syndrome Alimentary triggersCarcinoid Syndrome Alimentary triggers

2004 Survey

Eighty-three participants

Seventy (84%) reported food reactions to thefollowing:

Amine containing foods (caffeine drinks, chocolate,

some cheeses, wine, etc.)

Fatty foods

Vegetables

Alcohol

Fruits Spicy Foods

Large meals

Courtesy of Monica Warner The Carcinoid Foundation.


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Carcinoid Syndrome TriggersCarcinoid Syndrome Triggers

Main complaints by trigger

35% Diarrhea83% Flushing40 (48)Alcohol

60% Flatulence and Bloating

75% Diarrhea41 (49)Fatty Foods

45% Flushing


80% Diarrhea61 (73)Amine containing foods

Main

Complaint/SymptomN (%)Trigger



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Carcinoid Syndrome TriggersCarcinoid Syndrome Triggers

Main complaints by trigger

16% Diarrhea16 (19)Large meals


88% Diarrhea20 (24)Spicy Foods


76% Diarrhea25 (30)Fruits

30% Diarrhea

33% Flatulence and Bloating35 (42)Vegetables

Main Complaint/SymptomN (%)Trigger



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Carcinoid Syndrome AminesCarcinoid Syndrome Amines

Foods Containing Very High levels of Amines

(Tyramine and Dopamine)

Aged cheeses (cheddar, Camembert, Stilton) Alcoholic beverages

Smoked, salted or pickled fish or meat (herring,salami, sausage, corned beef, bologna, pepperoni)

Any spoiled protein foods (chicken liver)

Yeast extracts and Brewers yeast, hydrolyzedproteins

Beans, sauerkraut, shrimp paste, some soybeanproducts, miso soup, soy sauce, tofu


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Carcinoid Syndrome AminesCarcinoid Syndrome Amines

Foods Containing Moderate levels of Amines

(Tyramine, Dopamine, Xanthenes and Theobromine)

Caffeine containing drinks, coffee (in large amounts), soda

Chocolate (in large amounts)

Some nuts (peanuts, coconuts, brazil nuts)

Some pizzas, raspberries, banana , avocado


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Carcinoid

crisis


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Carcinoid CrisisCarcinoid Crisis

Immediate onset of a debilitating and life-threatening condition associated

with carcinoid syndrome

May occur spontaneously or may be precipitated by anesthesia,

chemotherapy, infection, stress, catecholamines, tumor manipulation or

embolization procedures

Symptoms include prolonged severe flushing, diarrhea, hypotension,

tachycardia severe dyspnea, peripheral cyanosis and sometimes

hemodynamic instability.

Appropriate precautions include immediate therapyand close monitoring before, during and after surgical

treatment.

Oberg K. Williams Textbook of Endocrinology; 10th Ed. Saunders; 2003;1857-1876.


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Carcinoid CrisisCarcinoid Crisis

Retrospective study (1983 to 1996) of 119 patients who underwent

abdominal surgery for metastatic carcinoid tumors

45 patients (38%) received intraoperative octreotide; none

experienced intraoperative complications.

15 patients (12.6%) had perioperative complications or death

The presence of carcinoid heart disease and high urinary 5-

hydroxyindoleacetic acid (5-HIAA) preoperatively were statistically

significant risk factors for perioperative complications.

Kinney M.A.O. et al. Perianesthetic risks and outcomes of abdominal surgery for metastatic

carcinoid tumors. Br. J Anaesth; 2001;87:447-52.


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Carcinoid Crisis - PreventionCarcinoid Crisis - Prevention

Prophylactic administration of octreotide must be

given by continuous intravenous infusion at a dose

of 50 g/h for 12 hours prior to and at least 48

hours after the procedure to prevent a

cardiovascular carcinoid crisis.

Ramage JK et. Al. Guidelines for the management of gastroenteropancreatic

neuroendocrine (including carcinoid) tumours. Gut. 2005;54(suppl 4);iv1-16.


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ConclusionsConclusions

Carcinoid tumors are neuroendocrine tumors that can secrete

bioactive substances, which can lead to carcinoid syndrome

Carcinoid syndrome is typically associated with abdominal pain, diarrhea

and flushing. Carcinoid right heart disease may also be present.

Cramping, telangiectasia, wheezing, edema, cyanosis, pellagra and

arthritis are also associated with carcinoid syndrome

Carcinoid Crisis is a life-threatening condition associated with

carcinoid syndrome

Usually precipitated by stress

Of special concern in patients with cardiac disease

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