The document discusses gastrointestinal stromal tumors (GISTs), which arise from interstitial cells of Cajal in the gastrointestinal tract. GISTs most commonly occur in the stomach and small intestine. Over 85% of GISTs have activating mutations in the KIT gene. Surgery is the primary treatment for localized GISTs, while targeted therapy with tyrosine kinase inhibitors such as imatinib is used for advanced or metastatic GISTs. Prognosis depends on factors like tumor size, mitotic rate, and mutation status, with smaller, lower grade GISTs having a better prognosis. Lifelong follow-up is important due to the risk of recurrence even after complete resection.

1. Dr. Dinesh M Gunasagar
Professor , Dept. of Surgery
J.J.M.Medical College
Davanagere

2. GIST
 Gastrointestinal stromal tumors (GISTs)
 Most common mesenchymal neoplasms of GI tract(80%)
 Thought to arise from pacemaker interstitial cells of Cajal
 Rare clinically, only 1% of all GI malignancies
 95% of GISTs stain positively for KIT (CD117)
 Also express CD34(80%)

3. GIST
 Occur anywhere in GI tract
 Stomach 40-60%
 Small intestine 30%
 Colon & rectum 15 %
 Esophagus <5%
 Omentum, mesentery, bladder(extraintestinal GISTs)
 Behavior is driven by mutations in the KIT gene (85%),
PDGFRA gene (10%), or BRAF kinase (rare)

4. GIST
 In 1983 “GIST” term was coined by Mazur & Clark
 In 1998 Hirota et all reported
 Near universal expression of transmembrane receptor
tyrosine kinase KIT in GIST
 Mutations in c-kit proto-oncogene
 Classified as leiomyomas, leiomyosarcomas,
Schwannomas prior to this

5. Pathophysiology
Tyrosine kinase receptor mutations in GIST
 Over 85% of GISTs have activating KIT mutations
 Commonly occur in
 Exon 11(57-71%)
 Exon 9 (10-18%)
 Exon13 (1-4%)
 Exon 17(1-4%)
 One third of GISTs lacking KIT mutations have mutations in
gene encoding PDGFRA,
 Mutated KIT remain active in the absence of ligand binding
resulting in unregulated growth and malignant transformation
 Wild type GISTs are few that do not show KIT or PDGFRA
mutations

6. KIT & PDGFRA MUTATIONS IN GIST

7. GIST-Pathology
 Gross
 Well-circumscribed lesions arising within the wall of the stomach
or intestine
 Fleshy tan-white, cut-surface with foci of cystic degeneration,
hemorrhage, or necrosis.
 Ulceration of mucosa when large
 Microscopy
 Spindle cell
 Epethelioid cell
 Mixed
 Spread
 Spread to lymph nodes is rare
 Liver, peritoneum and omentum – common

8. GIST-Pathology
 Microscopy
Spindle cell Epithelioid cell Mixed cell

9. GIST-Pathology
Immunohistochemistry-KIT expression in GIST
Diffuse cytoplasmic Dot like

10. GIST-Epidemiology
 Age
 Can present at any age
 Median age at diagnosis is 60 years
 Range 40-80 years
 Rare in children as a familial syndrome/ part of Carney’s
triad
 Sex
 Equal in males and females
 Race and ethnicity
 No predilection

11. GIST-Epidemiology
Hereditary GIST
 Majority are sporadic
 GISTs due to germline KIT & PDGFRA mutation
 Younger, multifocal disease & rare metastatic disease
 GISTs occur in 7% cases of von Recklinghausen’s
neurofibromatosis

12. GIST-Epidemiology
Hereditary GIST
 Carney’s triad
 Gastric GISTs, pulmonary chondromas & paragangliomas
 Carney-Stratakis syndrome
 Gastric GISTs
 Paraganglioma

13. GIST-Epidemiology
INCIDENCE
 In US
 5000 new cases per year
 In Europe
 11-14.5 cases per million/year

14. GIST-Clinical features
 Generally detected when they become symptomatic
 Nonspecific symptoms,
 Vague abdominal pain & fullness
 Early satiety, malaise, fatigue
 Symptoms due to obstruction or bleeding
 Haematemesis or malena
 Dysphagia(Esophageal)
 Obstructive jaundice(duodenal tumor)
 Features of small bowel obstruction or peritonitis
 Constipation(colorectal)

15. GIST-Clinical features
 Smaller GISTs(<4cms)
 Incidentally on radiologic studies, endoscopy or laparotomy
 Mass abdomen- primary or liver metastasis

16. GIST-Differential diagnosis
 Lymphoma
 Metastatic melanoma
 Schwannoma
 Leiomyoma
 leiomyosarcoma
Immunohistochemistry helps in differentiating GISTs from
these lesions

17. GIST-Diagnosis
Investigations
 X-ray erect abdomen for intestinal obstruction/peritonitis
 Upper GI endoscopy/ colonoscopy/ barium series
 USG abdomen & pelvis for mass abdomen
 Contrast CT of abdomen & pelvis
 MRI of abdomen & pelvis
 FDG-PET
 Masses ambiguous on CT
 Monitor response to therapy

18. CT scan in GIST
Gastric GIST with endoluminal growth

19. GIST-Diagnosis
Investigations
 Endoscopy, FNAC/biopsy
 Submucosal lesion ± ulceration

20. GIST-Diagnosis
Investigations
 EUS
 Not routinely required
 Guided FNAC may be attempted
 Immunohistochemistry to detect CD117
 PCR analysis for KIT mutations for diagnosis/ prognosis

21. GIST-Diagnosis
 Routine biopsy is not necessary for suspected GIST that is
resectable
 Biopsy is appropriate
 For neoadjuavant therapy
 Metastatic disease
 D/D being lymphoma

22. GIST-TNM staging
Primary tumour(T)
TX Primary tumor can not be assessed
T0 No evidence of primary tumor
T1 Tumor smaller than 2cm, localized
T2 Tumor 2-5cm
T3 Tumor 5-10cm
T4 Tumor >10cm in greatest dimension
Regional lymph node(N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Metastasis(M)
M0 No distant metastasis
M1 Distant metastasis
Mitotic index
Low ≤ 5/50 HPF
High > 5/50 HPF

23. GIST-AJCC Staging 7th ed.2010
For gastric and omental GISTS
Group T N M Mitosis
Stage IA T1or T2 N0 M0 Low
Stage IB T3 N0 M0 Low
Stage II T1 N0 M0 High
T2 N0 M0 High
T4 N0 M0 Low
Stage IIIA T3 N0 M0 High
Stage IIIB T4 N0 M0 High
Stage IV Any T N1 M0 Any rate
Any T Any N M1 Any rate

24. GIST-AJCC Staging 7th ed.2010
For GISTs of small intestine, esophagus, colorectum, mesentery
& peritoneum
Group T N M Mitosis
Stage I T1or T2 N0 M0 Low
Stage II T3 N0 M0 Low
Stage III A T1 N0 M0 High
T4 N0 M0 Low
Stage IIIB T2 N0 M0 High
T3 N0 M0 High
T4 N0 M0 High
Stage IV Any T N1 M0 Any rate
Any T Any N M1 Any rate

25. GIST-Treatment
Localized GIST
 Surgery is the definitive therapy for localized GIST
 Principle is to achieve negative microscopic margin(R0)
 En bloc resection of adjacent involved organs, such as
colon, spleen, or liver for locally invasive tumor
 Routine lymphadenectomy not indicated
 Adjuvant treatment with imatinib has improved recurrence
free survival
 400mg PO/day X 3 years
 Neoadjuvant treatment with imatinib is undergoing
various trials with encouraging results

26. GIST-Treatment
Localized GIST
 Wedge or segmental resection of the involved stomach or
bowel more often is feasible.
 Large gastric tumors require total/subtotal gastrectomy
 Subcentimeter gastric GISTs may be followed up by
endoscopy
 Risks and benefits of surgery versus observation should be
discussed with patient for gastric GISTs 1-2cm

27. GIST-Treatment
Localized GIST
 Non gastric GISTs of any size should be resected because
of aggressive behaviour
 Rarely pancreaticoduodenectomy or APR may be done
depending on location of tumor
 Laparoscopic resection of primary GISTs is safe & feasible
particularly in small gastric GISTS

28. GIST-Treatment
Unresectable/metastatic GIST
 Targeted therapy with tyrosine kinase inhibitors(TKI)
 Imatinib mesylate 400mg PO/day
 400mg twice daily in progressive disease
 Sunitinib malate 50mg PO/day for 4 weeks + 2 weeks of
drug free interval as second line treatment
 Regorafenib 160mg PO/day for 21 days of 28days cycle
when advanced GISTs no longer respond to imatinib or
sunitinib
 Surgery
 Palliative resection may benefit in select cases responding to
targeted therapy

29. Scheme of management of GIST

30. GIST-Prognosis
 Despite a macroscopically complete resection, 50 %
recurrences are noted at median of 24 months
 Overall 5 year survival rates
 30-60%
 Localized primary
 Median survival of 5 years
 Metastatic or recurrent disease
 Median survival 10-20 months

31. GIST-Prognostic factors
 Tumor size
 Smaller the size better prognosis
 Mitotic index
 Low mitotic rate ≤ 5 – better prognosis
 Tumor site of origin
 Gastric GISTs have better prognosis
 Stage of disease
 localized primary have better prognosis
 R0 or R1 resection has better prognosis than R2
 Mutational status
 KIT exon11 mutation has better prognosis

32. GIST – Follow up
NCCN consensus panel recommends
 Localized GIST
 History, physical examination and contrast CT abdomen &
pelvis every 3-6 months for the first 3-5 years then annually
 Endoscopic surveillance for gastric GISTs without high risk
features at 6-12 months interval
Metastatic/gross residual GIST
 History and physical examination and abdominal/pelvic CT
every 3-6 months.

33. S.N. Sex/age Clinical features Investigations Treatment HPE/Post
op.
diagnosis
Follow up
1 M/70 Mass abdomen CT-heterogeneous
mass arising from
stomach 3x4 cm
Endoscopy- smooth
endoluminal mass in
body of stomach
Wedge
resection of
stomach/Elect
ive
Epithelioid
GIST/low
grade of
stomach
2months
2 F/50 Mass abdomen CT- Heterogeneous
mass from mesentery
7x5 cm
Segmental
resection of
jejunum/Elect
ive
Spindle type
GIST/high
grade of
jejunum
3 months
3 M/40 Hemetemesis Endoscopy –
ulcerated
endoluminal mass
near pylorus
CT- heterogeneous
mass 3x2 cms
Wedge
resection of
stomach/Elect
ive
Spindle type
GIST/ low
grade of
stomach
2 years
4 M/70 Pain abdomen
Features of
subacute int.
obstruction
CT-Heterogeneous
mass from jejunum
10.5x6cms
Heterogeneous mass
near ileocolic
junction 5x4cms
Resection of
jejunal
segment and
ileocecal
resection/Elec
tive
Multicentric
jejunal &
ileocolic
GIST /high
grade
2 months

34. GIST – Conclusions
 (GISTs) are the most common mesenchymal neoplasms of GI
tract(80%)
 95% of GISTs stain positively for KIT (CD117)
 Over 85% of GISTs have activating KIT mutations
 Every GIST carries risk of malignancy from very low to very
high
 Occurs in stomach more commonly(40-60%)
 Surgery is the principal & only potentially curative treatment
for GIST
 The treatment of localized GIST is R0 resection + adjuvant
Imatinib
 Targeted therapy using TKI form the mainstay of treatment for
advanced GISTs

35. GIST – Conclusions
 TKI therapy has shown improved prognosis of localised &
advanced GISTs
 Cytoreductive surgery may be considered in a subset of
patients with advanced disease
 Recurrences are common needing lifelong follow up
 Future studies will focus on integration of surgery with
targeted therapy and the development of new agents for
drug resistant GISTs

36. Thank you