GI Carcinoid Tumors beutiful - USarpel.ppt

GI Carcinoid Tumors

1. Carcinoid Tumors
10/6/04
Umut Sarpel

2. Case presentation
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47M, asymptomatic
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PMHx: hypertriglyceridemia
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PSHx: R ACL repair, T&A
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1996: Incidental liver lesions seen on U/S

3. Case presentation
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MRI: multiple liver lesions, largest >8cm
no other masses seen
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Fine needle Bx: carcinoid tumor
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OctreoScan: activity in liver lesions,
no other areas of activity
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Mild Sx: bloating, diarrhea

5. Case presentation
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Unknown primary
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1998: Small bowel series, EGD,
colonoscopy - no neoplasm
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Carcinoid crises: flushing, headaches,
itching, diarrhea, hypo/hypertension
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Sandostatin - short-acting and depot
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Systemic chemotherapy - Streptozotocin
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Chemoembolization x 3

6. Case presentation
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Increasingly frequent and severe crises
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2001: Capsule endoscopy to search for
primary tumor: lesion in jejunum
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CT: new mesenteric mass - tumor and
bulky nodes
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Referred for cytoreductive surgery

8. Case presentation
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Operative findings:
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2.5cm white, hard lesion in jejunum,
grossly invading through wall
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Similar lesion on adjacent mesentery with
bulky nodes
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Liver riddled w/ metastases

9. Case presentation
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Small bowel resection including extensive
resection of adjacent mesentery, total
resection of 75cm small bowel
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Radiofrequency ablation x 2
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Liver wedge biopsy
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Prophylactic cholecystectomy

13. Pathology
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Multiple carcinoid tumors in small bowel
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Extensive serosal involvement / retraction
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Angiolymphatic invasion
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Margins negative for tumor
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5 /11 lymph nodes positive for carcinoid
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Gall bladder with focus of carcinoid on
subserosal aspect
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Liver Bx: focal carcinoid tumor

14. Introduction
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First described in 1888
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Carcinoid = “Cancer-like”
thought to be more indolent
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Most often diagnosed in 5th /6th decade
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55% female

15. Introduction
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Cell of origin: Kulchitsky cell, a
neuroendocrine cell found along
the primitive GI tract
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Highly biologically active tumors
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Secretion of several hormonal mediators

16. Introduction
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Incidence: reported as 3.8 per 100,000
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Much higher rate at autopsy:
20-yr study at Mayo Clinic, small bowel only,
found 97/14,852 (0.65%)
12-yr study in Sweden found 199/16,294 (1.2%)
Maggard MA et al. Ann Surg 2004; 240:117-122.

17. Distribution
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11,427 cases of carcinoid examined
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Largest ever study of distribution
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GI tract: 54.5%
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Lung / Bronchus: 30.1%
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Pancreas: 2.3%
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Ovarian: 1.2%
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Biliary: 1.1%
Maggard MA et al. Ann Surg 2004; 240:117-122.

18. Distribution
Within GI tract…
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Small bowel: 44.7%
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Rectum: 19.6%
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Appendix: 16.7%
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Colon: 10.6%
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Stomach: 7.2%
Maggard MA et al. Ann Surg 2004; 240:117-122.

19. Etiology
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Genetics have not been fully elucidated
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Reports of mutations in:
p53, bax, bcl-2, n-myc, and c-jun
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Overall increased malignant risk:
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28% with multiple carcinoid primaries
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Synchronous non-carcinoid cancer 17-53%
Schnirer II et al. Acta Oncologica 2003; 42(7): 672-92

20. Etiology
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MEN 1 - 5-10% have carcinoid tumor
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Hyperparathyroidism
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Pituitary tumors
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Pancreatic / duodenal tumors
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More often in thymus, bronchus
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Tend to be more aggressive tumors

21. Etiology
Gastric carcinoids:
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75% a/w chronic atrophic gastritis
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5-10% a/w gastrinoma
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15-25% sporadic cases
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High gastrin seen w/ first two groups
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Gastrin appears to be mitogenic

22. Symptoms
SymptomSymptom FrequencyFrequency CharacteristicsCharacteristics
FlushingFlushing 85-90%85-90% minutes to daysminutes to days
DiarrheaDiarrhea 70%70% secretorysecretory
Abdominal painAbdominal pain 35%35%
obstruction, ischemia, obstruction, ischemia,
hepatomegalyhepatomegaly
R heart diseaseR heart disease30%30% if metastaticif metastatic
TeleangiectasiaTeleangiectasia25%25% facialfacial
BronchospasmBronchospasm 15%15% --

23. Pellegra
99% 1%
Niacin
5-HIAA
5-HT
Dietary
Tryptophan
In carcinoid tumors, up to 60% of Tryptophan
can be shunted to 5-HT, causing pellegra
Triad: dermatitis, diarrhea, dementia

24. Mediators
SymptomSymptom MediatorMediator
FlushingFlushing 5-HT, substance P, 5-HT, substance P,
histamine, Kallikreinhistamine, Kallikrein
DiarrheaDiarrhea Gastrin, 5-HT, Gastrin, 5-HT,
prostaglandins, VIPprostaglandins, VIP
BronchospasmBronchospasm5-HT, histamine5-HT, histamine
Heart diseaseHeart disease5-HT, substance P5-HT, substance P

25. Diagnosis
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24hr Urinary 5-HIAA
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88% specificity
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Chromogranin A
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100% sensitive, but very non-specific
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Also released by hormonally inactive tumors
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Other tests include: substance P,
neurotensin, hCG, neuropeptide K,
neuropeptide PP, but none as useful

26. Imaging
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CT/MRI
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OctreoScan: 80-90% sensitive
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PET scan: high false-negatives / positives
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MIBG: 55-70% sensitivity, 95% specific,
may have a role in patients on long-acting
octreotide analogues
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Endoscopic U/S: can detect 2-3mm lesions

27. Prognosis
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Local tumors have excellent prognosis
regardless of site of origin
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Stomach, colon, and rectal tumors carry a
relatively worse prognosis if advanced
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Poor prognostic indicators
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Male gender
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Carcinoid syndrome
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Histological grade
Maggard MA et al. Ann Surg 2004; 240:117-122.

28. 5-year survival by location
SiteSite All stagesAll stagesLocalLocal DistantDistant
StomachStomach 75.1/55.3%75.1/55.3%90.2/69.6%90.2/69.6%18.0/9.0%18.0/9.0%
Small bowelSmall bowel76.1/54.6%76.1/54.6%94.5/70.4%94.5/70.4%51.2/32.4%51.2/32.4%
AppendixAppendix 76.3/65.0%76.3/65.0%95.6/87.8%95.6/87.8%37.5/26.8%37.5/26.8%
ColonColon 69.5/41.8%69.5/41.8%94.1/77.1%94.1/77.1%27.8/4.1%27.8/4.1%
RectumRectum 87.5/77.8%87.5/77.8%94.9/86.2%94.9/86.2%14.6/13.1%14.6/13.1%
* Cancer-specific survival / relative overall survival
Maggard MA et al. Ann Surg 2004; 240:117-122.

29. Medicinal Treatment
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Somatostatin: inhibits release of gastrin, secretin,
growth hormone, insulin, glucagon
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Directly cytostatic to tumor cells
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Somatostatin analogue: octreotide
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relieves symptoms
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appears to slow tumor growth - ?suvival benefit
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Formulations
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Octreotide half life: 90-120 min
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Depot octreotide ~3 weeks

30. Chemotherapy
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Systemic chemotherapy ineffective
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Single agent regimens
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5-FU, doxorubicin, actinomycin D, streptozocin
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< ~10% response rate
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Multi-agent regimens
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3 RCT’s of 5-FU/streptozocin
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No difference between arms

31. Interferons
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Mechanism not well understood
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May block tumor cell cycle
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Inhibition of angiogenesis
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Human Leukocyte Interferon
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Pooled data ~ 12% tumor response
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Interferon 
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Pooled data ~ 12% tumor response
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May have higher level of side effects
Schnirer II et al. Acta Oncologica 2003; 42(7): 672-92

32. Surgical Treatment
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Resection - only true chance for cure
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Cytoreductive surgery / Debulking of
primary tumor or hepatic metastases
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Decreased tumor burden provides palliation
from symptoms & carcinoid crises
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Correlate with decrease in 5-HIAA levels
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Evidence supports prolonged survival
Sarmiento et al. J Am Coll Surg 2003; 197: 29-37

33. Liver Resection
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Studies include all neuroendocrine tumors
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Mayo Clinic - 90% with improvement in
symptoms, 73% 4-year survival
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Memorial - 76% 5-year survival
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No case-controlled comparisons
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Historically, 5-year survival w/o Tx ~ 30-40%
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Newest data, 5- year w/Tx ~ 60-65%
Sarmiento et al. J Am Coll Surg 2003; 197: 29-37

34. Chemo-embolization
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Embolization of branches of hepatic artery
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Tumors primarily receive blood supply from artery
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Normal parenchyma - 60-70% from portal vein
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Local chemotherapy + vascular occlusion
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Ischemia may sensitize tissue to chemo
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Various protocols in effect
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Effective for palliation of symptoms, unclear of
any effect on survival
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No RCT’s for carcinoid, all based on
extrapolation from studies on HCC

35. Radiofrequency ablation
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Induce thermal injury to tumor
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Metal electrode inserted into tumor,
connected to radiofrequency generator
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Patient is part of closed-loop circuit,
alternating electric field created w/in tissue
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High electrical resistance of tissue causes
heat to be produced in focused area
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No RCT’s in carcinoid patients, but found
to increase survival in pts w/ HCC
Lencioni R, et al. Liver Transplant 2004; 10:S91-97.

36. Liver Transplantation
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< 150 published cases of transplantation
for neuroendocrine tumors
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Mount Sinai 2003: 11 patients (3 carcinoid)
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1-yr survival: 73%
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5-yr survival: 36%
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“Liver transplantation for the treatment of
neuroendocrine tumors is radical.
Although cure is not impossible, it is
improbabale.”
Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, Fishbein T,
Emre S, Miller C, Schwartz M. J Gastrointest Surg 2004; 8: 208-212.

37. Precautions
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Patients require special preparation prior
to any interventional procedure
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Must be loaded with somatostatin
analogue to counter effects of sudden
hormone release
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Close blood pressure monitoring
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Should not receive epinephrine or
norepinephrine - may induce crisis