GIST GASTER

KASUS :
Wanita 43 tahun, MRS dengan melena sejak 1 tahun
yang lalu, disertai nyeri epigastrum terutama setelah
makan dan cepat rasa kenyang, ada mual kadangkadang muntah.
4 bulan terakhir teraba benjolan diepigastrium dan
cepat membesar
di epigastrium dan nyeri.
Sebelumnya dirawat di bag,Penyakit Dalam dan
riwayat transfusi
Fisik : teraba tumor di epigastrium, padat dapat
digerakkan
Hb : 6,8 gr%

 Telah

dilakukan pemeriksaan

esofagogastroduodenoskopi
Esofago
Hasil

gastroduodenographi

sebagai berikut :

Endoskopi

 Apakah

perlu pemeriksaan lain ?

 Diagnose

 Kalau

ini suatu GIST, stadium ?

 Tindakan

GIST
I Made Adi Sunantara

History of GIST
1983

Mazur & Clark, 28 cases of

gastric leiomyoma 29% expressed for
S100 (neural marker), very few stained for
myofilament
1998 Hirota, et al., GIST mutated form
of Kit receptor tyrosine kinases
Stained for Kit and CD34 antibody &
similar ultrastructure (electron microscopy)
to interstitial cell of Cajal (ICC)

GIST= Gastro-Intestinal Stroma

Tumor
Rare

tumor (1% of GI malignancies)

Grow from primitive mesenchymal tissue?
Interstitial Cells of Cajal
Affecting gaster and small intestine
> 90% stained + for CD117(c-kit protein) and
CD34
Specific origin not clear
Heterogenous clinical behaviour and
pathological findings

GISTs
Origin of GISTs
interstitial cells of Cajal

S. Cajal; Spanish anatomist-histologist (18521934); Winner Nobelprice 1906

Origin of GISTs
interstitial cells of Cajal
pacemaker cells of the GItract
Function gut motility

GIST= Gastro-Intestinal Stroma

Tumor
20%

of small bowel malignancies

(lymphoma excluded)
Thought from the muscle layer of the
stomach or intestines
Criteria for malignant size, cellularity,
mitosis (>1-5/ 50 hpf), necrosis,
invasion, metastasis, c-kit gene mutation
Correlate to Carney - Triad

GISTMalignant Behaviour
at Time of Diagnosis
Malignant (10% to 30%)

GIST

Metastatic
Invasion of adjacent organs,
structures

Uncertain Malignant Potential

(70% to 90%)

Miettinen M et al. Hum Pathol. 1999;30:1213-1220.

Spectrum of Mesenchymal Tumor

Differentiation
Well Differentiated
Myoid (leiomyoma, leiomyosarcoma)
Neural (schwannoma)
Ganglionic Plexus Phenotypes
(ganglioneuronoma, Plexosarcomas)
Incomplete or Undifferentiated
GANT (=gastro=intestinal Autonomic
Nervous Tumor) electron microscopy
GIST?

Leiomyoma/ sarcoma >< GIST

Leimyoma/sarcoma

- Vimentin positive
- Actin (SMA)
mostly +
- Desmin mostly +
- CD34 can be +
- CD 117 -

GIST

- Vimentin positive
- Actin (SMA) pachy/
absent
- Desmin mostly
- CD34 mostly +
- CD 117 + (100%)

Histopathology of GIST: Biological Markers

Used in Diagnosis of GIST

GISTs positive for

CD117 (c-Kit receptor tyrosine kinase)
Positive in >95%
CD34 (mesenchymal/haematopoietic
precursor cell marker)
Positive in 60% to 70%
Vimentin and smooth muscle actin
Positive in 15% to 60%

GISTs do not express

Desmin
S-100

CD117 (c-Kit)positive
staining GIST

Kinase
Receptors

C-kit & other Genes Mutation

Most

common point mutation at exon 11, less

common at exon 9, and least common at
exon13 & 17
C-kit mutations and PDFR mutation correlate to
better response to c-kit protein inhibitor.
Mutation at Exon 9 or no proven mutation
resistance to Kinase inhibitors & poorer
prognosis
98% of GIST expresses DOG1 transmembrane
protein (function?)
Protein Kinase C (PKC ) also expressed in
GIST alternative Dx/ if C-kit protein
negative

Diagnosis of GIST
CLINICAL
Double Contrast GI study smooth lining
defect on GI wall
Endoscopy bulging with intact
mucous membrane
EUS hypoechoic mass in continuation
with smooth muscle/ musculus propria.
Malignancies irregular intraluminal
border, non-homogenous or cystic spaces

Diagnosis of GIST
CLINICAL
Biopsy

should be tried (difficult to obtain

representative tissue) difficult to diagnose
with small available tissue
CT Scan or MRI delineating the tumor and
organ affected
Clinical pain (41%), GI bleeding (28%),
anemia/ melena, and palpable (huge) mass (>
30%), obstructive jaundice, ileus (not specific!!)

Diagnosis Pathology
Conventional

Pathology (HE staining,

morphology difficult for specific Dx)

Three common types
Spindle Cell Type
Epitheloid Types
Mixed Types

Diagnosis - Molecular
Immuno-Histo-

Chemistry Staining (IHC)

Monoclonal Antibody:
- CD117 (c-kit prot.)
- CD34
- SMA (smooth muscle actin)
- Desmin
- Vimentin
- S100

Diagnosis - Genetics
Molecular

analysis of GIST C-kit mutation

(exon 11/ majority, 9, 13, 17); PDGFR-alpha ( exon

18 / majority, 12 & 14.

Neurofibromatosis

related GIST has

no c-kit gene mutation NF-1 mutation
(sometimes)
Carney Triad has no c-kit or PDGFRA
mutation

Diagnostic, Prognostic (?) &

Predictive (?)
Sequencing

mutation on Exon 11
(often), Exon 9, Exon 13, and Exon 14
Mutation on Exon 11 sensitive to
imatinib
Mutation on Exon 9 resistant to
imatinib primary resistance
Mutation on Exon 17 secondary
resistance secondary resistance
other Kit inhibitors sunitinib?

Treatment
Complete

surgical removal of GIST is the most

important modality
However surgery alone is insufficient
Adjuvant molecular targeting therapy
target c-kit protein c-kit protein inhibitor
(STI-571/ Gleevec)
Neo-adjuvant therapy molecular targeting
therapy to c-kit protein did not significantly
worked
Resistant to chemotherapy and radiation
therapy (BCl-2 overexpression, MDR)

Surgery alone
(Survival)

Surgery + Continuous Imatinib

Imatinib Therapy
Response

rate varies 70 90&

Resistance 12 14%
GIST with c-kit mutation at exon 11
response better than mutation at exon 9
GIST with no mutation on c-kit or PDFRalpha genes response poor to
imatinib

Exon Mutation resistency to Kit-inhibitor

STI 571
Tyrosine kinase is responsible
for cell signaling (proliferation,
cell growth)

Pharmacology
Of Imatinib

Prognosis
Depending on
Complete Surgical Removal negative margin.
No Spilage during surgery
Ki-67 expression
Adjuvant with molecular targeting therapy ckit protein inhibitor (STI-571/ Gleevac/ Imatinib)
20 30% frankly malignant the rest are
potentially malignant
Benign>< malignant low risk & high risk
Tumor location (small intestine worse
prognosis)

IHC
Tested

on one case Ny. S.M. (case no

3)
Results
CD117 + in 50% (weak); CD34 + in 40%,
S100 -, SMA + (strong) in 70%
Conclusion: GIST or Leiomyosarcoma?
Others being tested.