1. Gastrointestinal Stromal Tumor
Dr. Tsui Ka Kin David
Department of Surgery
North District Hospital
20th December 2003

2. Contents Background Epidemiology Clinical Presentation Pathology
Diagnosis & Prognosis
Treatment
Conclusion

3. Background
Until 20 years ago most gastrointestinal mesenchymal tumors were considered to be of smooth muscle origin
Includes leiomyoma (benign) or leiomyosacroma (malignant)

4. Background
Mazur and Clark in 1983 reported that many supposed smooth muscle tumors lacked immunohistochemical or electron microscopic evidence of neural immunoreactivity
Hence they suggested that the term Gastrointestinal Stromal Tumor (GIST) would be more appropriate
Mazur MT, Clark HB, Am J S Path

5. Background
With the frequent use of immunohistochemical studies, Interstitial cells of Cajal, an intestinal pacemaker cell, showed similar features to GIST:
Positive for c-kit and CD34
Negative for desmin and S-100
Proposed as the cellular origin of GIST

6. Gastrointestinal Stromal Tumor
GIST express a growth factor receptor with tyrosine kinase activity term KIT
KIT was a product of proto-oncogene c-kit, can be detected by immunohistochemical staining for CD117

7. Gastrointestinal Stromal Tumor
ALL GISTs are immunohistochemically positive for KIT (CD117)
70% of GISTs also showed positive for CD34, 20% showed positive for smooth muscle actin

8. Epidemiology Account for 0.1% to 3% of all GI neoplasms
150 new cases / yr in US
Occurs predominantly middle-aged or older-aged group, median age = 60
Equal sex distributions
Locations:
Stomach %
Intestine %
Oesophagus 2-3%

9. Presentation Bleeding Ulceration Palpable Mass Pain
Metastasis (Local invasion rather than lymph node metastasis)
Asymptomatic

10. Pathology 2 broad cytological types: Spindle cell GIST (60-70%)
Epithelioid GIST

11. Genetics
Loss of chromosomes 14 and 22 are common in both benign and malignant GIST
Loss of chromsomes 1p and 9p are reported less frequently
Berman JJ et al, GIST Workshop 2001

12. Pathogenesis
Within recent years, discovered that most GIST had mutation in c-kit proto-oncogene
Most of them are mutations of exon 11
Results in activation of KIT receptor tyrosine kinase and an unopposed stimulus of cell growth

13. KIT Mutations Stem Cell Factor Kinase Enzyme Domain
(Extracellular Portion)
(Intracellular Portion)
Homodimerization
Activation of KIT kinase
Phosphorylation
Tumerigenesis (Proliferation, adhesion, apotosis and differentiation)

14. KIT mutations
These mutant KIT are more likely to be high grade tumor with frequent recurrence and higher mortality

15. Diagnosis
GI Endoscopy

16. Diagnosis
Endoscopic Ultrasound (EUS)

17. Diagnosis
CT scan

18. Prognosis Most significant indicators are:
Tumor size
Mitotic index
Resection margin
Approximate 30% GIST are malignant
40% had recurrence after resection

19. Prognosis
Fletcher CD et al, Hum Pathol

20. Survival
Regardless of presentation, disease-specific survival rates for malignant GISTs are:
1 year 69%
3 years %
5 years %
DeMatteo RP et al, Ann Surg (1) 51-8

21. Treatment Surgery remains primary treatment for GIST
Extent of excision ?
Lymphatic dissection ?
Method - ? Open surgery vs Laparoscopic wedge excision
DeMatteo RP et al, Ann Surg (1) 51-8

22. Surgery
Langer et al had retrospective review of 48 GISTs from 39 patients in which complete surgical resection is the most important means of cure
Resection margin status strongly influences outcome (R0 – no residual tumor, R1 – microscopic residual tumor, R2 – macroscopic residual tumor)
Langer C et al, Br J Surg (3) 332-9

23. Surgery
Overall risk of recurrence of GIST was high even for complete resection with no residual tumor (R0 resection)
Place for development of adjuvant therapy
Langer C et al, Br J Surg (3) 332-9

24. Surgery
Aim to have complete resection (en bloc removal) of all gross disease
Incomplete resection should only performed for palliation of symptoms due to bleeding, pain or mass effect

25. Surgery Localized Gastric GIST Extensive Gastric GIST
Wedge excision with negative margins
Extensive Gastric GIST
Total gastrectomy or en bloc resection of adjacent organs
Small bowel / Colon GIST
Segmental removal + Removal of contigous organs

26. Surgery
No differences in terms of survival was noted between patients with systemic lymph node dissection and those not having LN dissection
But essential to avoid tumor spillage which have been associated with increase risk of peritoneal recurrence
Yoshida M et al, World J Surg
Pidhorecky I et al, Ann Surg Onco (9)

27. Other Treatment
Poor response to chemotherapy and radiotherapy

28. New Treatment
KIT-selective tyrosine kinase inhibitor, Imatinib mesylate, STI571, commercially known as Gleevec / Glivec (Novartis Pharma) was started to treat advance GIST
Demetri et al, N Eng J Med 347:

29. Imatinib (Gleevec / Glivec)
Mechanism of Imatinib
Stem Cell Factor
Kinase Enzyme Domain
(Extracellular Portion)
(Intracellular Portion)
Homodimerization
Imatinib (Gleevec / Glivec)
Activation of KIT kinase
Phosphorylation
Tumerigenesis (Proliferation, adhesion, apotosis and differentiation)

30. New Treatment with Imatinib

31. New Treatment with Imatinib
Multicentre trial of imatinib for the treatment of irresectable or metastatic GIST was initiated in July 2000
Partial response rate (at least 50% decrease in size of lesion) was 53.7%
13.6% showed disease progression
1 year survival was 88%
Demetri et al, N Eng J Med 347:

32. New Treatment with Imatinib
Its role in adjuvant or neoadjuvant therapy is still not well studied yet

33. Summary
GIST is defined as KIT (CD117) positive mesenchymal tumor in GI tract
Frequent mutations in GIST resulted in KIT signalling and thus uncontrolled cell proliferation and resistance to apoptosis
Primary treatment is surgery with en bloc resection

34. Summary
Imatinib (Gleevec/Glivec) is selective inhibition of tyrosine kinase which was effective in advance / metastatic GIST
Clinical trials of neoadjuvant and adjuvant use of imatinib are planned

35. Thank You