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

Contents Background Epidemiology Clinical Presentation Pathology Diagnosis & Prognosis Treatment Conclusion

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

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 1983 7 507-19

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

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

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

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 60-70% Intestine 20-25% Oesophagus 2-3%

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

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

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

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

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

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

Diagnosis GI Endoscopy

Diagnosis Endoscopic Ultrasound (EUS)

Diagnosis CT scan

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

Prognosis Fletcher CD et al, Hum Pathol 2002 33 459-65

Survival Regardless of presentation, disease-specific survival rates for malignant GISTs are: 1 year 69% 3 years 38-44% 5 years 29-35% DeMatteo RP et al, Ann Surg 2000 231(1) 51-8

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 2000 231(1) 51-8

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 2003 90(3) 332-9

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 2003 90(3) 332-9

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

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

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 1007 21 440-3 Pidhorecky I et al, Ann Surg Onco 2000 7(9) 705-12

Other Treatment Poor response to chemotherapy and radiotherapy

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: 472-80

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)

New Treatment with Imatinib

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: 472-80

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

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

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

Thank You