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GIST

MD FRCSEd



. . .

GIST
;

(incidence) 6.5-14.5/million/year,
(prevalence) :
: GIST (<10mm) 22.5% !!!
Agaimy A, Wunsch PH, Hofstaedter F, et al. Minute gastric sclerosing
stromal tumors (GIST tumorlets) are common in adults and frequently
show c-KIT mutations. Am J Surg Pathol 2007;31:113-20

GIST -
(TKI)

GIST

GIST

'Smooth muscle neoplasms' (, , ) Stout AP.


Bizarre smooth muscle tumors of the stomach. Cancer 1962;15:400-9
:
.... ;....

'Stromal tumors' Mazur MT, Clark HB. Gastric stromal tumors.


Reappraisal of histogenesis. Am J Surg Pathol 1983;7:507-19
GIST CD34
Cajal ! Miettinen M, Virolainen M, Maarit Sarlomo R. Gastrointestinal
stromal tumors--value of CD34 antigen in their identification and
separation from true leiomyomas and schwannomas. Am J Surg Pathol
1995;19:207-16
c-KIT GIST
KIT- GIST ! Hirota S, Isozaki K, Moriyama
Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal
stromal tumors. Science 1998;279:577-80
GIST !

GIST STI-571 (Imatinib


mesylate- Gleevec; Novartis, Basel, Switzerland)
TKI tyrosine kinase inhibitor : !!! Joensuu H,
Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor
STI571 in a patient with a metastatic gastrointestinal stromal tumor. N
Engl J Med 2001;344:1052-6
imatinib GIST : US
Food and Drug Administration, February 2002
platelet-derived growth factor receptor alpha (PDGFRA) gene mutations :
Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating
mutations in gastrointestinal stromal tumors. Science 2003;299:70810 .... GIST
sunitinib FDA, Jan 2006
imatinib GIST : Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy
and safety of sunitinib in patients with advanced gastrointestinal stromal
tumour after failure of imatinib: a randomised controlled trial. Lancet
2006;368:1329-38

CD117 c-kit
CD117 is a receptor tyrosine kinase type III, which binds to stem cell factor (a substance that causes certain types of cells to
grow), also known as "steel factor" or "c-kit ligand". When this receptor binds to stem cell factor (SCF) it forms a dimer that
activates its intrinsic tyrosine kinase activity, that in turn phosphorylates and activates signal transduction molecules that
propagate the signal in the cell. Signalling through CD117 plays a role in cell survival, proliferation, and differentiation

Cluster of differentiation molecules: ,


, ,

CD117
CD117 stem cells Cajal

CD117

To imatinib 2phenylamino
pyrimidine


ATP

GIST

80 %

10 %
PDGFRA
10% wild type (SDH
mutations)

To PDGFRA -

, 6

Incidence 0.02/million/year 21 (Stiller C.

Childhood cancer in Britain: incidence, survival, mortality. Oxford University Press


Oxford. 2007)

Incidence 6.5 14.5 / million / year. 140


(Panhellenic Report of the Gastrointestinal Stromal Tumors.
Gastrointestinal Divisision of the Greek Pathology Sosciety. 12th Seminar of Clinical
Oncology, Nov 2004, Creta, Greece)

.
Carney (gastric Gist+paragaglioma+pulmonary
chondroma), Carney-Stratakis (gastric Gist+paragaglioma),
neurofibromatosis type I
Ca Ca

80% ,
, ,
,

60%

30%

5%

4%

8.9 cm
2.7


... :

, , , , ,
, , , , ,

2 .

US
CT MRI
FNA core biopsy ( endo-US )
PET scan

US


. FNA
.

- CT

imatinib

imatinib

PET scan

.
.
,

Spindle cell type 70%, epithelioid type 20-25%, mixed type

GIST

CD117 (A),
DOG1 (B)
CD34 (C)
200

-
Relative frequency

Anatomic distribution

Exon 8

Rare

Small intestine

Exon 9 insertion AY502-503

10%

Small intestine and colon

Exon 11 (deletion, single nucleotide substitution and insertions

67%

All sites

Exon 13 K642E

1%

All sites

Exon 17 D820Y, N822K and Y823D

1%

All sites

Exon 12 (such as V561D)

1%

All sites

Exon 14 N659K

<1%

Stomach

Exon 18 D842V

5%

Stomach, mesentery and momentum

Exon 18 (such as deletion of amino acids IMHD 842-846

1%

All sites

Genetic type
KIT mutation (relative frequency 75-80%)

PDGFRA mutation (relative frequency 5-8%)

KIT and PDGFRA wild-type (relative frequency 12-15%


BRAF V600E

~7-15%

SDHA, SDHB, SDHC and SDHD mutations

~2%

HRAS and NRAS mutation

<1%

Sporadic pediatric GISTs

~1%

Stomach

GISTs as part of the Carney triad

~1%

Stomach

NF1-related

Rare

Small intestine

Stomach and small intestine

-imatinib
Disease-specific survival in patients with primary
disease who underwent complete resection

54%
GIST

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):5158

-imatinib


GIST
66% high
risk GIST

high
risk 40%
10-30

Cancer
Volume103,Issue4,pages821-829,12JAN2005DOI:
10.1002/cncr.20862
http://onlinelibrary.wiley.com/doi/10.1002/cncr.20862/full#fig1

GIST





high risk GIST

Flecher risk table

Fletcher et al, 2002, Human Pathology, 33(5):459-65

Miettinen et al

Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin
Diagn Pathol. 2006;23(2):7083

- Union for International Cancer


Control

nomogram after surgical resection


of a primary GIST

Gold JS, Gnen M, Gutirrez A, Broto JM, Garca-del-Muro X, Smyrk TC, Maki RG,Singer S, Brennan MF, Antonescu CR,
Donohue JH, DeMatteo PR Lancet Oncol. 2009 Nov;10(11):1045-52

nomogram after surgical resection


of a primary GIST -

RCTrials

Phase III Adjuvant Treatment Trials


North North America America
ACOSOG Z9001: Imatinib x 1 yr vs. placebo
Published results 2009 (CliniclTrials.gov, NCT00041197)

Europe
SSG SSG XVIII XVIII Imatinib Imatinib 1 r s 3 rs 1 yr
vs. 3 yrs
Published results 2011 (clinicaltrials.gov, NCT00116935)

RCTrials
ACOSOG Z9001: Imatinib x 1 yr vs. placebo
Published results 2009 (CliniclTrials.gov, NCT00041197)

DeMatteo et al. Lancet. 2009; 373(9669):1097 - 1104

RCTrials

RCTrials

one year RFS : 98% (imatinib) vs 83% (placebo)

RCTrials

: Tumors > 10 cm (96% v. 67% 1-yr RFS)

RCTrial in Resected High


Risk GIST
SSG SSG XVIII XVIII Imatinib Imatinib 1 r s 3 rs 1 yr vs. 3 yrs
Published results 2011 (clinicaltrials.gov, NCT00116935)

One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor
JAMA. 2012;307(12):1265-1272. doi:10.1001/jama.2012.347

RCTrial in Resected High


Risk GIST

One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor

RCTrial in Resected High


Risk GIST

SSGXVIII/AIO RC Trial, 2011

12mofimatinib

36mofimatinib

RFS

47.9

65.6

OS
(overall survival)

81.7

92

(recurrence-free survival)

RCTrials in metastatic GIST

... !