- Gastrointestinal stromal tumor (GIST) is an uncommon mesenchymal tumor that originates from interstitial cells of Cajal in the gastrointestinal tract. - Risk factors include sporadic occurrence, familial syndromes associated with mutations in cKIT or PDGFRA genes, and tumor syndromes like Carney triad. - Diagnosis is based on immunohistochemistry showing CD117 positivity and molecular testing for mutations. - Complete surgical resection is the main treatment, with adjuvant imatinib to prevent recurrence in high risk cases. Imatinib or other tyrosine kinase inhibitors are given for advanced or recurrent disease. - Prognosis depends on tumor size,

1. GASTROINTESTINAL
STROMAL TUMOR(GIST)
-MANOJIT SARKAR
-KRISHNENDU MONDAL
DEPT OF SURGERY
NRSMCH

2. INTRODUCTION
• Uncommon MESENCHYMAL TUMOR
• Orginates from INTERSTITAL CELLS OF CAJAL-GUT
PACEMAKER
• 0.1-o.3% of all gastrointestinal neoplasm
• Coined by Mazur & Clark(1983)
• Previously classified as
leiomyoma/leiomyosarcoma/leiomyoblastoma

3. INCIDENCE
• 3.2-7/million in us & 15-20/million in europe/korea/hongkong
• Predominantly in middle age or elderly individual with peak
incidence in 50-60yrs of life(more than 80%- >50yrs)
• Male:female(1:1)-adult;pedia-(female>male)

4. SITES
• GISTS CAN OCCUR ANYWHERE IN THE GI TRACT
• STOMACH(50-60%)
• SMALL INTESTINE(30-40%)
• COLORECTAL(7%)
• ESOPHAGUS(1%)
• MESENTERY/RETROPERITONEUM/OMENTUM-LESS
COMMON SITES

5. RISK FACTORS
• MOST OF THE GISTS ARE SPORADIC
• IT MAY ARISE IN VARIOUS TUMOR SYNDROMES-
üFAMILIAL GISTS->
ØAD,heritable mutations in kit exon 8/11/13 or 17 & germline mutations
in the PDGFRA exon 12.
ØAssociated findings-pigmented skin macules with urticaria pigmentosa
üCARNEY’S TRIAD->
ØLoss of expressions of succinate dehydrogenase b(SDHB)enzyme
ØNon-heritable,young female,
ØThe combination of gastric gist,extra adrenal paraganglioma &
pulmonary chondroma

6. üCARNEY-STRATAKIS SYNDROME-
ØGIST with extra adrenal paraganglioma
ØAD pattern of inheritance with incomplete penetrance
üTYPE 1 NF-
ØNF 1 gene mutation
ØMultiple small GISTs in intestine with NF-1

10. CD11
7
CD34 Actin &
Desmin
S-100
GIST + + - -
Desmoid
tumor
- + - -
True
leiomyosar
coma
- - + -
Schwano
ma
- - - +
IMMUNHISTOCHEMISTRY

11. GENETICS & MOLECULAR BIOLOGY
• cKIT gene mutation
• PDGFRA GENE
• WILD TYPE-NO DETECTABLE CKIT OR PDGFRA
MUTATIONS
• DOG1-POSITIVE IN 97% GIST.IT IS NOT SEEN IN OTHER
MESENCHYMAL TUMOR

12. CLINICAL PRESENTATIONS
• SYMPTOMATIC(70%)
• GI BLEEDING(ANEMIA/HEMATOCHEZIA/MELENA)-M/C
• POST PRANDIAL FULLNESS
• PAIN ABDOMEN
• RUPTURE
• PERFORATION/PERITONITIS
• CONSTIPATION/OBSTRUCTION-COLORECTAL GIST
• OBSTRUCTIVE JAUNDICE-DUODENAL GIST
• MICRO GIST(<1CM)-ASYMPTOMATIC

13. INVESTIGATIONS

16. MANAGEMENT
OF GIST

17. SURGICAL MANAGEMENT
• The treatment of choice for primary GISTs is complete surgical resection with
negative margins (R0 resection).
• The macroscopic margin of 1-2cm is sufficient to achieve microscopically
negative margins.
• Precaution is taken not to rupture tumor pseudocapsule as large lesions are
typically soft,fragile with thin capsule.
• GIST usually have exophytic growth without infiltrating the organ from which they
arise,they push the adjacent structure rather infiltrating them.Thus wedge
resection of the stomach and segmental resection of the small bowel are
adequate.

18. • Sometimes excision of mass with removal of neighbouring
organs or “block excision” becomes necessary then also a
multivisceral resection should be avoided.
• Spontanous or intraoperative capsule rupture should be
considered as a very poor prognostic factor and hence should
be avoided in all cases.
• All cases with capsule break are best cinsidered as
disseminated lesion and all of them will relapse as
disseminated unresectable peritoneal disease.Thus all cases
with capsular rupture are candidate for imatinib treatment.

19. • Preoperatively unresectability can be detected on CT
demostration of infiltration of celiac trunk ,superior mesenteric
artery or to portal vein.
• Lymph node dissection is generally not indicated as lymph node
metastasis are rare.However in pediatric,syndromic type and
SDH deficient GISTs arising in young individual has lymphnode
metastasis in 20-59% cases.
• It is uncertain whether residual microscopic disease at resection
margins (R1 resection) will affect outcome or not.Therefore re-
resection is recommended only when the site of microscopic
disease left behind can be identified and operative procedure
has no major morbidity.

20. • Endoscopic removal is not recommended on esophagus and
gastric tumors because of difficulty to get R0 complete
resection.
• A laparoscopic approach may be considered for tumors in
favourable anatomical locations by expert surgeons,only in
situations where a complete resection without capsule rupture is
feasible and should be removed in plastic bag.
• Lparoscopic approach is strongly discouraged in patient with
voluminous tumors.

21. • The management of small gastric GIST ( less than 2 cm)
discovered incidentally is controversial.
• In the presence of high risk features as diagnosed on EUS
(echogenic foci,ulceration,irregular margins) some surgeons
advocate serial monitoring of lesions with imaging or endoscopy.
• Endoscopic resection has dis advantage of positive
margin,perforation and tumor spillage.
• According to current NCCN guidelines for small gastric GISTs (
less than 2 cm) in absence of high risk features on EUS should
have survillance endoscopy done every 6-12 months.

22. NEOADJUVANT TREATMENT
• In locally advanced and unresectable GIST,there are few cases that would
eventually become resectable after introduction treatment with imatinib.
• Cytoreductive surgery with imatinib can be attempted only for those GISTs
where present location and size warrants a mutilating surgery.
• Preoperative imatinib should be considered when an extended procedure
such as a Whipple’s operation for deodenal GIST or APR for rectal GIST is
needed to remove the tumor.
• Imatinib is effective for in reducing the size of tumor prior to
resection,increasing likelihood of negative margins without significant
morbidity.

23. ADJUVANT TREATMENT
• Recurrence rate of upto 50% is seen despite of the fact that complete
resection is feasible in most localised GIST cases.
• Imatinib is an oral,selective,small molecule tyrosine kinase inhibitor which
targets the KIT protein and the PDGFRA.
• Its role as an adjuvant treatment to prevent recurrence has been assessed in
several american and eiropian clinical trial such as ACOSSOG and SSGX-VII
study.
• In view of these results,both NCCN and ESMO recommended 3years of
adjuvant treatment with imatinib in high risk patients.

24. IMATINIB FAILURE OR RESISTANT
GIST
• The first recommended measure to carry out when a patient with metastatic GIST
progress on imatinib is to check adherence to treatment and to rule out drug interactions.
• For tumors that progresses on a standard dose of imatinib(400 mg orally and
daily),increasing imatinib dose (if patient can tolerate) or changing to a second line TKI is
recommended.
• Sunitinib is a multitargeted or selective TKI active inhibitor that is active against alpha and
beta PDGFR and VEGFR is used as second line therapy.
• Drugs that have the potential to overcome secondary resistance because they inhibit
multiple tyrosine kinases(c-kit,PDGFRA etc) have been tested ad third line
therapy.Regorafenib is a multikinase inhibitor which is used as a third line therapy.

25. MANAGEMENT PROTOCOL

26. MANAGEMENT OF METASTATIC OR
RECURRENT GIST

27. PROGNOSTIC AND RISK
FACTORS
• The majority of GISTs (60-70%) are benign.An assessment of malignancy is based on tumor
size,mitotic index(no of mitoses per 50 HPF) and spreading outside the GIT.
• GISTs with high mitotic activity (greater than 50 mitoses per HPF) are considered high grade and
demonstrate aggressive behaviour.
• Immunostaining for thr ki 67 antigen has suggested as an alternative for mitosis counting.
• Tumor rupture before or during the surgery are identified as independent prognostic factors for
recurrence.
• Gastric GISTs have a lower risk of recurrence compared with non gastric GISTs. Small bowel
GISTs appear to follow a more aggressive course ,compared to gastric tumors of the same size.

28. PROGNOSTIC FACTORS

29. RECURRENCE
• Recurrence of GIST is common (40%) and tends to involve the
peritoneal surface,liver (63%),and local site (52%).
• The overall risk of recurrence for patients who undergo resection of a
primary GIST tumor is approximately 30%.
• The median time of recurrence in these patients is 12-16months and
80% of the recurrences occur within 2years of initial resection.
• A true local recurrence at the at the site of prior resection is uncommon.

30. • Although patients with low metastatic burden were considered
for surgery,re resection alone was almost never curative.
• In patients with recurrent disease,imatinib is the first line of
therapy.
• Upto 80% patients with metastatic GIST attain a partial or
complete response with imatinib.

31. FOLLOW-UP
• The optimum follow up regimn is unknown.As most patients with
GISTs may have recurrent disease within first 3-5years,thus intense
follow up is done during this period.
• All patients on adjuvant therapy should undergo physical
examination,blood cell counts and biochemistry evalustion at 1-
3month interval.
• Imaging like CT or MRI abdomen and pelvis to be done every 3-
6months for the first two years,twice a year for next 3-5 years and
then anually.

32. THANK YOU