This document provides an overview of gastrointestinal stromal tumors (GISTs). It discusses the epidemiology, molecular mechanisms, clinical presentation, imaging, treatment, and outcomes of GISTs. GISTs are the most common mesenchymal tumors of the gastrointestinal tract. They originate from interstitial cells of Cajal and are characterized by gain-of-function mutations in KIT or PDGFRA genes. Treatment involves surgery when possible as well as targeted therapy with drugs like imatinib, which inhibits KIT and other oncogenic proteins. Close monitoring is important after treatment due to the risk of recurrence.

1. Dr. N.ANJAN KUMAR
MODERATOR : Dr. SAMBASHIVA RAO,
ASSOCIATE PROFESSOR,
DEPT. OF GENERAL SURGERY.

2. LAYOUT
 INTRODUCTION
 EPIDEMIOLOGY
 IMMUNO-HISTOCHEMISTRY
 RISK ASSESSMENT
 MOLECULAR MECHANISMS OF CARCINOGENESIS
 CLINICAL PRESENTATION
 IMAGING
 TREATMENT
 IMATINIB AND OTHER NEWER DRUGS
 OUTCOME

3. INTRODUCTION
• Golden and Stout in 1941: described the mesenchymal
tumors arising in bowel as tumors arising from smooth
muscle cells; leiomyoblastoma, leiomyoma and
leiomyosarcoma.
• Term GIST was 1st used by Mazur and Clark in 1983.
• In 1998 Japanese research workers (Hirota et al.) discovered
KIT mutations in GIST that possibly distinguish GIST from
other tumors.

4.  Most common mesenchymal tumours of the
Gastrointestinal tract.
 Classified separate from leiomyomas and
leiomyosarcomas in 1980s after demonstration by
immunohistochemistry and electron microscopy.
 Although they represent only 0.1–3% of all
gastrointestinal (GI) malignancies, they account for
80% of gastrointestinal mesenchymal neoplasms.

5. EPIDEMIOLOGY
 Annual incidence: 15 per million.
 Age: 50-80 years; median age: 6th decade.
 Gender: M=F.
 Mostly: sporadic.
 Associations:
- Carney’s triad (GIST, paragangliomas, pulmonary
chondromas)
- Neurofibromatosis
- Familial GIST syndrome

6. IMMUNO-HISTOCHEMISTRY
 Immuno-histochemical staining demonstrated decreased
staining for desmin and smooth muscle actin (markers
that are typically expressed in smooth muscle tumors).
 In the early 1990s, the extracellular membrane protein
CD34 was identified in GIST but only rarely in
leiomyomas, and the distinct classification became more
widely accepted.

7.  Further research identified immuno-histochemical
staining for the protein CD117, which is the tyrosine
kinase receptor known as KIT, with a sensitivity
greater than 95% and a high specificity.
 CD117 immuno-histochemistry staining is now widely
accepted as a criterion for a pathologic diagnosis of
GIST.

8.  Additional research has identified a new immuno-
histochemical stain called DOG1—literally Discovered
On GIST-1.
 Liegl et al. in 2009 examined the sensitivity and
specificity of a specific monoclonal antibody, DOG 1.1,
directed against DOG1 and suggested that this new
antibody may have improved sensitivity compared with
KIT for the diagnosis of GIST.

9.  95% of GISTs positive for KIT (CD117),
 60–70% positive for CD34,
 30–40% for SMA (SMA – smooth muscle actin), 5% for S100.
 1–2% positive for desmin or keratin.
 5% DOG1 antigen helps in identification of CD 117 negative.
 KIT positivity is usually diffuse and strong, with a cytoplasmic,
membranous or paranuclear ‘dotlike’ distribution.

10. CELL OF ORIGIN
 Despite the original theory that these tumors arose from
smooth muscle or nerve cells, GIST is now widely recognized
as originating from the interstitial cells of Cajal (ICC),
given the similar expression of CD34 and CD117.
 They arise from mesenchymal cells and are thought to play
an integral role in the propagation of intrinsic slow-wave gut
peristalsis.
 Outside of GI tract, they are also found in the genitourinary
system, portal vein and pancreas.

11. INCIDENCE
 Stomach: 50-60%
 Small intestine: 25%
 Duodenum – 10-20 %
 Jejunum – 27-37%
 Ileum : 27-53%
 Colorectal : 10%
 Oesophagus: 2%
 Other less common areas: Omentum, Mesentery,
pancreas, genitourinary tract, gall bladder, liver.

12. MALIGNANT POTENTIAL
 Initially GISTs were classified as benign and malignant.
 Later it has been recognised that all GISTs have some
potential to metastasise.
 Small lesions have a lower risk, can become invasive if left
untreated.
 A study by Fletcher et al. in 2002 characterized the
malignant potential of GISTs and is widely cited.

13. RISK ASSESSMENT FOR GIST

15. MOLECULAR MECHANISM OF CARCINOGENESIS
 Hirota and group (1998) described the role played by the
KIT receptor tyrosine kinase (RTK) in cell growth and
development.
 C-KIT(CD117) a type III receptor tyrokinase(RTK) that is
involved in the development and maintainance of RBC,
melanocytes,mast cells, germ cells and interstitial cells of
cajal(ICC).
 Basic pathophysiology: Gain of excess function mutation at
the tyrosine kinase receptor (KIT) on the cell membrane.

16.  Normal physiology consists of a monomeric tyrosine
kinase receptor that binds to an extracellular ligand,
stem cell factor (SCF), which then causes dimerization
of the receptor.
 This dimerization allows for subsequent
autophosphorylation, activating downstream
intracellular signaling pathways.

17. KIT protooncogene mutations lead to activation of the c-kit receptor
resulting in spontaneous receptor activation not requiring a ligand

18. EXONS INVOLVED IN KIT MUTATION IN GIST
 EXON 9 encoding the extracellular transmembrane
domain.
 EXON 11 encoding the intracellular juxtramembrane
domain.
 EXON 13 encoding the first portion of the split kinase
domain.
 EXON 17 encoding the kinase activation loop.

19. PDGFRA MUTATIONS
 Approximately 5% to 15% of GISTs have been found to be negative
for KIT mutations.This is due to weak exon 11 mutant staining.
 Platelet-derived growth factor receptor alpha (PDGFRA) was
identified as an alternative oncogene responsible for activation of
the intracellular phosphorylation cascade.
 WILD-TYPE TUMORS: wild-type mutations involve those GISTs
that are negative for both c-KIT and PDGFRA mutations but still
display gain-of-function activity and have similar histologic
features.

20. Gross Appearance of GIST
 Well circumscribed but unencapsulated
 Whorled fibroid-like or a softer more fleshy appearance on
the cut surface

21.  Occur in the submucosa , muscularis propria or serosa.
 Grow in an endophytic or exophytic way perpendicular
to the bowel lumen.
 Seeding of tumour deposits into the serosa or
omentum is a sign of malignancy.

23. CELLULAR MORPHOLOGY
Three relatively distinctive types
Spindle cell type – 70 percent
Epithelioid type – 20 percent, more commonly c-kit
negative and found in omentum and mesentery
Mixed type – 10 percent
Histologic type may be of prognostic significance, worse
with epithelioid.

24. ATYPICAL PRESENTATIONS OF GIST
PEDIATRIC GIST: Pediatric GISTs are exceptionally
very rare.
 Fewer than 200 cases of GISTs in patients under the
age of 18 years have been reported.
 The tumors are more often epithelioid instead of
spindle cell morphology .
 M<F.
 The most common presenting symptom is severe
anemia, and the most common site of tumor is the
stomach.

25.  GISTs tumors in pediatrics have a higher rate of
presenting with metastases.
 However, the tumors tend to follow a more indolent
course and have a more favorable long-term prognosis.
 Surgery remains the mainstay of treatment for
pediatric cases.
 One of the main biological differences is that pediatric
patients lack activating mutations in the oncogenes
that drive tumor formation in adults.

26.  Several more recent studies are identifying the role of
insulin like growth factor 1 receptor (IGF1R).
 Pediatric GIST is a relatively new and enigmatic entity
that requires further study.

27. FAMILIAL GIST
 Is an heriditary snydrome that increase a persons risk
of developing GIST.
 In familial gist tumors appear most ofen in small
intestine . The tumors are ofen diagnosed between the
age of 25 and 45 instead of after age 50 which is when
sporadic gist tends to develop.
 The two most common genes affected are KIT and
PDGFRE.
 Increasing research are finding mutations in other
genes such as SDH.

28. DIFFERENTIAL DIAGNOSES
 Leiomyoma,
 Leiomyosarcoma,
 Schwannoma,
 Neuroendocrine tumor,
 Malignant peripheral nerve sheath tumour,
 Gastrointestinal autonomic nerve tumor (GANT).

29. CLINICAL MANIFESTATIONS
- Often asymptomatic
- Discovered incidentally during endoscopic or barium studies.
Symptoms and signs depend on the site of tumor.
1. 1) Overt GI bleeding — 50 percent
2. 2)GI obstruction — 10-30 percent
3. 3)Abdominal pain — 20-50 percent
 4)Asymptomatic – 20 percent

30.  The vast majority of GIST metastases at presentation are
intra-abdominal, either with metastases to the liver,
omentum, or peritoneal cavity .

31. STAGING FOR GIST

34. IMAGING
CT scan:
 For initial evaluation and surveillance for recurrence.
 Most effective way to image primary lesions in the stomach.
 Also essential to stage the extent of disease completely and
accurately.
 Typically enhance with IV contrast.
 Primary GISTs are typically well−circumscribed masses
within the walls of hollow viscera.

36. MRI:
 Useful for the
assessment of liver
metastases.
 And also primary
perirectal disease .

37. Endoscopic Ultrasonography:
 Determines size and extent of the tumor .
 Useful technology because of their submucosal localization.
 Endoscopic ultrasound (EUS) is not necessary to evaluate a
confirmed GIST.
 Low risk – regular margins, tumor size 3 cm or smaller,
homogeneous echogenicity pattern.
 High risk- size larger than 4 cm, irregular extraluminal
borders, echogenic foci larger than 3 mm, cystic spaces larger
than 4 mm, ulceration, heterogeneity.

38. Endoscopy:GIST presenting as an asymptomatic submucosal
mass in the proximal along the lesser curvature.

39. Endoscopic ultrasound

40. ROLE OF EUS-FNA
 EUS− guided fine− needle aspiration (FNA) may be
attempted to establish diagnosis.
 Nevertheless, EUS−FNA is not consistently diagnostic.
 Additional cytologic morphology, immunohistochemistry,
and reverse−transcriptase polymerase chain reaction
analysis for KIT mutations may be required to confirm a
diagnosis.

41. PET-CT:
 Reveals small metastases and establish baseline metabolic
activity and assess therapy response.
 To aid assessment when radical surgery is required, particularly of
the rectum and oesophagus.
 Important role in monitoring response to therapy, emerging
resistance to medical treatment.
 Should be considered in all moderate to high risk patients who are
about to be started on imatinib.
 Recommended for all patients with metastatic disease, prior to
commencing imatinib.

42. PET-CT
 PET scan and CT scans in a patient with a GIST metastatic to the liver, before
(left) and after treatment with imatinib mesylate

43. ROLE OF BIOPSY:
 GIST lesions can be highly vascularized - present an
unacceptable risk for biopsy.
 Risk of tumor rupture, tumor cell seeding along the
biopsy tract, or spreading tumor cells via peritoneal or
mesenteric contamination.
 Biopsy not to be performed if resection is planned.
 Must be performed in cases of unresectable GIST to
make the diagnosis.

44. TREATMENT
SURVEILLANCE
SURGERY
BIOLOGICAL AGENTS

45.  For every small Gastric GIST <2cm-
1. EUS-FNA.
2. Abdominal/pelvic CT with contrast.
 Patients with no high risk EUS features can be considered
for endoscopic surveillance every 6 to 12 months interval.
 Patients with high risk EUS features should be considered
for complete surgical resection. They should be followed up
with contrast enhanced CT every 3 – 6 months for 3 to 5
years, then annually.

46.  Tumors >2 cms can be-
1. Localized or potentially resectable.
2. Definitively unresectable or with metastasis.
 For localized tumors, if preoperative imatinib is not
considered. Resection is advised followed by pathology
result and risk assessment.
 For high risk patients, imatinib should be considered.

47.  If pre-operative imatinib is considered, biopsy should
be taken to confirm the diagnosis.
 If biopsy confirms GIST, then-
1. It can be resectable without significant risk of
morbidity.
2. Or resectable with signicificant morbidity
/unresectable.These patients should be given
preoperative imatinib.

48.  After resection –
 Completely resected - consider imantinib in
intermediate and high risk patients otherwise observe
 R2 resection with or without preoperative imatinib-
continue imatinib
 Metastatic disease- continue imatinib.

49.  Debulking surgery in unresectable disease- in case of
intestinal obstruction or pressure effects due to large
tumour.
 High rate of recurrence: 40-50%
 Follow-up after surgical resection:
1. serial CT scans every 3 months for the first 2 years,
followed by,
2. annual CT scan upto 5 years.

50. MINIMALLY INVASIVE TARGETED APPROACHES
 Laparoscopic resection technique.
 2004 consensus guidelines recommend laparoscopic
procedures only for tumours less than 2cm in size.
 With advent of newer and safer techniques and better
expertise of surgeons, good results have been achieved for
tumours >5cm also.
 It is important to remove the specimen in a contained
sealed system to prevent tumour spillage.

51. Based on tumour location (Privette et
al.)
 Type I tumours- fundus or greater
curvature- Laparoscopic stapled
partial gastrectomy
 Type II tumours- antrum/
prepyloric region- Laparoscopic
distal gastrectomy
 Type III tumours- lesser curvature
and GI junction- Laparoscopic
transgastric resection

52. Unresectable/ Metastatic lesions
 Imatinib (Gleevec) – oral medication approved by the
FDA in 2002.
 Selective inhibitor of – c-Abl, PDGFR, and the c-KIT.
 Used as first-line treatment/ neoadjuvant drug for
unresectable and metastatic GIST.
 Improves progression-free survival to a median
survival of 57 months.

53. IMATINIB(GLEEVEC)
 DOSAGE: 4OOmg daily.
 If progression of disease is documented and in exon 9
mutations, increase dose to 800mg.
 Can be used as both neo-adjuvant and adjuvant drug.
 Post-operatively: for 36 months to improve recurrence free
survival and overall survival.
 Most common side effects: Periorbital and peripheral
edema, diarrhea, fatigue, mild hypertension, GI bleeding.

54. IMATINIB MESYLATE:MECHANISM OF ACTION
 Imitabin mesylate occupies
the ATP binding pocket of the
cKIT kinase domaine.
 This prevents substrate
phosphorylation and
signaling.
 A lack of signaling inhibits
proliferation and survival.
SIGNALING
P
PP P
ATP
Imatinib
mesylate
c KIT

55. Resistance to Imatinib
• Primary resistance : no achievement of stable disease or progressing
disease within 6 months of an initial clinical response (KIT exon 9
mutation or no detectable kinase mutation – wild-type tumors).
• Secondary resistance: disease progression after more than 6 months
clinical response (new acquired kinase mutation in KIT or PDGF-R
that interfere with Imatinib activity)
• Use of other kinase inhibitors (Sunitinib).

56. SUNITINIB
 Indicated in cases of tumours which are refractory to
Imatinib or in severe Imatinib toxicity
 37.5 mg daily dose or 50mg for 4 weeks with 2 week interval
 Inhibits CD117, PDGFRs, VEGFRs
 Prevents angiogenesis and tumorigenesis
 Adverse effects: HTN, palmar-plantar erythrodysesthesia
(hand-foot syndrome), oral cavity mucosal irritation
hypothyroidism
 Median time to tumour progression of 27 weeks.

57. Newer drugs:
 Regorafenib,
 Sorafenib,
 Nilotinib,
 Dasatinib,
 Pazopanib.
 In resistant tumours: embolisation of tumour

58. REFERENCES

59. FDA Algorithm for management of GIST

60. OUTCOME
 Surgery is the primary treatment modality for GIST .
 5 year survival is 50-65%.
 Recurrence if occurs is after a decade or more .
 If incomplete resection or metastatic at presentation
median survival would be <1 year, 5 year survival would
be <35%.

61.  Unresectable disease – median survival is 9-12 months.
 Commonest smooth muscle tumour .
 Better prognosis compared to Ca stomach.
 GISTs falling into pelvis can be mistaken for adnexal
tumours like ovarian tumours.

62. REFERENCES
1) Shackelford’s Surgery of the Alimentary Tract, 7th
edition.
2) Sabiston Textbook of Surgery, 19th edition.
3) NCCN guidelines version 1.2017. Gastrointestinal
stromal tumours (GIST)
4) Maingot’s abdominal operations 12th edition.

63. Thank you