Gastrointestinal Stromal Tumor(GIST)

Dr. Amit Goswami

IntroductionMazur and Clark(1983)Mesenchymal tumorFrom embryological mesoderm of

gastrointestinal tract<1% of all GIT tumorsHirota et.al(1998):Mutation in KITInterstitial cell of Cajal: Common precursor?

DemographyIncidence:15-20 per millionM>FAge:40-80yrs(median age 60yrs)Mostly sporadicFamilial( Neurofibromatosis, Carney triad)

Eisenberg BL,Judson I.Surgery and imitanib in the management of GIST:emerging approaches to adjuvant and neoadjuvant therapy.Ann Surg Oncol 2004;11:465-475

Gold JS,Matteo RP.Combined surgical and molecular therapy: The gastrointestinal stromal tumor model.Ann surg 2006;244:176

DeMatteo RP,Lewis JJ,Leung D et al.Two hundred Gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.Ann surg 2000;231(1):51-8

Takazawa Y,sakurai S,Sakuma Y et al.Gastrointstinal stromal tumors of neurofibromatosis type I.Am J surg Pathol 2005;29(6):755-63

Location

Stomach :50% MCEsophagus:5%Small Intestine:25%Colon and rectum:10%Extra-intestinal:10%

Rubin BP.Gastrointestinal stromal tumors: an update.Histopathology 2006;48:83-96Clin Cancer Res 9(9):2003

Clinical PresentationNon specificDepends on siteGIST of GIT: GI bleeding MCOthers -Abd. Mass -Pain abdomen -Abd.distension -Intestinal obstruction Asymptomatic:30%

PathologyMost commonly involves muscularis propriaUlceration:50%Well circumscribedCut surface: Tan/Grey, fibrous to fleshySpindle cell type: MC

Malignant Potential• Features favoring benign lesions :

– Size less than 5 cm

– Low number of mitosis per HPF

– No mucosal invasion

– Low cellularity

– Low markers of cell proliferationTumor site: Stomach vs bowelSite of metastasis:

Liver(50%),peritoneum(20-40%)

M. Miettinen, et al. Am J Surg Pathol. 2005

DiagnosisClinical, radiological and pathological

characteristics

CECT- Imaging modality of choice

Endoscopic ultrasound: Small tumor

MRI: Rectal GISTs

PET scan: Assessment of therapy

Blay JY,Bonvalot S,Casali P et al.Consensus meeting for the management of gastrointestinal stromal tumors.Ann Oncology 2005;16:566-578

CECTHeterogenous appearance with central

necrosis and areas of cystic degenerationExtension to other structuresDistant spreadLow attenuating liver metastasis

King DM.The radiology of gastrointestinal stromal tumors(GIST).Cancer Imaging 2005;5:150-156

MRI

Solid portion-low intensity on T1 weighted and high intensity on T2 weighted images

Enhancement with gadolinium

Endoscopic UltrasoundSmooth protrusion of bowel wall lined by

normal mucosaHypoechoic mass contiguous with fourth

hypoechoic layer(muscularis propria)Benign Vs Malignant

EndoscopyGastric and colorectal GISTSubmucosal mass

Pre-op BiopsyUsually not done -Tumor seedling -BleedingEndoscopic biopsy -Less bleeding -Confirm diagnosis

TreatmentSurgical resection is preferred

Locally advanced: Targeted therapy

Radiation/Chemotherapy: Ineffective

DemetriGD,BenjaminRS,BlankeCD,etal.NCCNTaskForcereport:managementofpatientswithgastrointestinalstromaltumor(GIST)dupdateoftheNCCNclinicalpractice

guidelines.JNatlComprCancNetw2007;5(Suppl2):S1–29

Surgical therapyComplete en-block removalSite specificAvoidance of tumor ruptureLymphadenectomy not advocatedFinal goal: complete tumor resection with a

negative margin, intact pseudocasulePositive resection margin: Re-excision

DeMatteo RP,Lewis JJ,Leung D et al.Two hundred Gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.Ann surg 2000;231(1):51-8

Blay JY,Bonvalot S,Casali P et al.Consensus meeting for the management of gastrointestinal stromal tumors.Ann Oncology 2005;16:566-57

Site specific surgery

Esophagus: esophagestectomy/esophageal sparing wide local excision

Stomach Small-wedge resection Large-subtotal/total gastrectomy

BlumMG,BilimoriaKY,WayneJD,etal.S urgical considerations for the management andResection of esophageal gastrointestinal stromal tumors.AnnThoracSurg2007;84(5):

1717–23.WinfieldRD,HochwaldSN,VogelSB,etal. Presentation and management of gastrointes-

tinal stromaltumors of the duodenum.AmSurg2006;72(8):719–22[discussion:722–3

WayneJD,BellRHJr.Limited gastric resection.SurgClinNorthAm2005;85(5):1009–20,

vii.

Small intestine

Duodenum: Partial duodenal resection/Whipple’s

Small Intestine: Segmental resectionColorectum

Colon: Colectomy

Rectum: Anterior resection/Abdominoperineal

resectionExtra-intestinal: En block resection with

adequate marginBerman J,O’Leary TJ.Gastrointestinal stromal tumor workshop.Hum Pathol 2001;32:578-582

Blay JY,Bonvalot S,Casali P et al.Consensus meeting for the management of gastrointestinal stromal tumors.Ann Oncology 2005;16:566-57

Molecular targeted therapy(TKI)Joensuu and colleague(2001)Success: Lack of progressionStandard starting dose :400 mg/dayIdeal dose: not determinedNeoadjuvant role: -Severe organ dysfunction (eg: for rectal

or esophageal tumors) -Negative margin difficultResistance: Primary/Secondary

Imitanib trialsTRIALS DOSE PARTIAL

RESPONSESTABLE DIS

PROGRESS

COMMENTS

EORTC2001,2002

400,600,800 or 1000mg/d

51% 31% 8% TTR 1WKMTD 800mg/d

US MULTICENTER2002,2004

400mg/d600mg/d

67%66%

16%18%

17%8%

No difference

EORTC2003

400mg/d800mg/d

50%54%

32%32%

13%8%

32% severe tox50%severe toxImproved PFS for 800mg/d

INTERGROUP2003

400mg/d800mg/d

49%48%

22%22%

36%severe tox52%severe toxNo difference in PFS

TTR=Time to recurrence, MTD=Maximal tolerated dose, PFS=Progression free survivalGoldJS,DeMatteoRP.Combined surgical and moleculartherapy:the gastrointestinal

stromal tumor model. AnnSurg2006;244:176

Newer ApproachesSUNITINIB: multitargated tyrosine kinase

inhibitorHACE/RFA: liver metastasisOther TKI: -Nilotinib -Mastitinib -BMS-354,825

KobayashiK,GuptaS,TrentJC,etal.Hepatic artery chemoembolization for 110Gastrointestinal stromal tumors.Cancer2006;107(12):2833–41.

SummaryRareMostly sporadic and singleAnywhere in GI Tract- Stomach MCEvaluation – EUS, CT, PET CTVaried clinical presentation- GI bleed MCTreatment of choice – Surgery, potentially

curative

Summary Regular follow up Imatinib mesylate ( both neoadjuvant and

adjuvant) Definite role Improved outcome Problem - Resistance to imatinib

High recurrence

Currently Available Trials

Neoadjuvant study RTOG S-0132/ACRIN 6665 Patients with recurrent or measurable

peritoneal disease 8 wks Imatinib followed by resection

Currently Available TrialsAdjuvant study EORTC 64024 Patients with R0 resections eligible Patients stratified according to risk

factors Patients randomized to either

Imatinib 400 mg/day X 2 years Observation

Thank you