joint hospital surgical grand round gastrointestinal stromal tumor dr. tsui ka kin david department...

Joint Hospital Surgical Grand Round

Gastrointestinal Stromal TGastrointestinal Stromal Tumorumor

Dr. Tsui Ka Kin DavidDr. Tsui Ka Kin David

Department of SurgeryDepartment of Surgery

North District HospitalNorth District Hospital2020thth December 2003 December 2003

Joint Hospital Surgical Grand Round 2003

ContentsContents

• Background

• Epidemiology

• Clinical Presentation

• Pathology

• Diagnosis & Prognosis

• Treatment

• Conclusion


BackgroundBackground

• Until 20 years ago most gastrointestinal mesenchymal tumors were considered to be of smooth muscle origin

• Includes leiomyoma (benign) or leiomyosacroma (malignant)



• 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



• 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 TumorGastrointestinal 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 TumorGastrointestinal 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


EpidemiologyEpidemiology

• 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%


PresentationPresentation

• Bleeding

• Ulceration

• Palpable Mass

• Pain

• Metastasis (Local invasion rather than lymph node metastasis)

• Asymptomatic


PathologyPathology

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


GeneticsGenetics

• 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


PathogenesisPathogenesis

• 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 MutationsKIT Mutations

Activation of KIT kinase

Phosphorylation

Stem Cell Factor Kinase Enzyme Domain

(Extracellular Portion) (Intracellular Portion)

Tumerigenesis (Proliferation, adhesion, apotosis and differentiation)

Homodimerization


KIT mutationsKIT mutations

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


DiagnosisDiagnosis

• GI Endoscopy


DiagnosisDiagnosis

• Endoscopic Ultrasound (EUS)


DiagnosisDiagnosis

• CT scan


PrognosisPrognosis

• Most significant indicators are:– Tumor size– Mitotic index– Resection margin

• Approximate 30% GIST are malignant

• 40% had recurrence after resection


PrognosisPrognosis

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


SurvivalSurvival

• 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


TreatmentTreatment

• 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


SurgerySurgery

• 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


SurgerySurgery

• 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


SurgerySurgery

• 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


SurgerySurgery

• Localized Gastric GIST– Wedge excision with negative margins

• Extensive Gastric GIST– Total gastrectomy or en bloc resection of adja

cent organs

• Small bowel / Colon GIST– Segmental removal + Removal of contigous o

rgans


SurgerySurgery

• 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 TreatmentOther Treatment

• Poor response to chemotherapy and radiotherapy


New TreatmentNew 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


Mechanism of ImatinibMechanism of Imatinib

Activation of KIT kinase

Phosphorylation

Stem Cell Factor Kinase Enzyme Domain

(Extracellular Portion) (Intracellular Portion)

Tumerigenesis (Proliferation, adhesion, apotosis and differentiation)

Homodimerization

Imatinib (Gleevec / Glivec)


New Treatment with ImatinibNew 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



• Its role in adjuvant or neoadjuvant therapy is still not well studied yet


SummarySummary

• 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


SummarySummary

• 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

Joint Hospital Surgical Grand Round

Thank YouThank You

joint hospital surgical grand round gastrointestinal stromal tumor dr. tsui ka kin david department...

Documents

cd117 slide

epithelioid gist slide

cellular origin of gist

kit cd117

mutant kit

leiomyosacroma malignant

ckit protooncogene

smooth muscle actin