1. GIST -Current Trends Prof SM Chandramohan Professor and HOD
Department of Surgical Gastroenterology
Center of Excellence for Upper GI Surgery
Rajiv Gandhi Government General Hospital
Madras Medical College
Chennai

3. Epidemiology Most common mesenchymal neoplasm of the GI tract.
0.1%-3% of all GI malignant tumors
Median age of 60 years (40-80)
No predilection for either gender
(Miettinen M, Eur J Cancer 2002,
Rossi CR, Int J Cancer 2003; )

4. Clinicopathological features, Treatment implications.
Unique
Biologic behavior,
Clinicopathological features,
Molecular mechanisms
Treatment implications.

5. Clinical Spectrum
Benign
Intermediate
Malignant

6. History 1960 Smooth muscle neoplasm of GIT 1980 Immunohistochemistry
Smooth muscle & neuronal differentiation and null
1983
MAZUR &CLARK
Coined the term GIST
1998
c-KIT proto-oncogene

7. Location
<

8. Multicentric GISTs - <5%
“Extra” GISTs
Sites Other than GIT,
- genito urinary,portal vein, pancreas
“Micro” GISTs - Size <2 cm
“Giant” GISTs - ? 5 cm ? 10 cm

9. CELL OF ORIGIN Interposed between smooth muscle and nerve endings.
Pacemaker—propagates intrinsic peristalsis
Interstitial” cells of CAJAL
Santiago ramon y cajal -1893

10. CELL OF ORIGIN –Nobel laureate

11. Biomarkers in GIST
C KIT

12. KIT is a 145-kDa glycoprotein
CD117
-epitope on the extra-cellular domain of the KIT receptor.
Steel factor (SLF)
stem-cell factor ligand for KIT.
Binding of SLF to KIT
-activation of KIT tyrosine kinase activity
-downstream signaling pathways
-uncontrolled cell proliferation

13. KIT Mutations 20 mutations Exon 11 Most common
Better response to imatinib
Exon 9
Common in small bowel
Poor response to imatinib.

14. Wild-type GIST (WT-GIST)
GISTs that have no detectable KIT or PDGFRA mutations- (10%-15%)
DOG gene
Discovered On GIST-1 gene in CH 11q13
DOG1 is a calcium dependent, receptor activated chloride channel protein expressed in GIST-independent of mutation type

15. Immunohistochemistry
Gastrointestinal Mesenchymal Tumor
C-kit (+) or CD 34 (+)
GIST (80%)
C-kit (-) or CD 34 (-)
SMA (+) or Desmin (+)
Leiomyoma (15%)
S-100 (+)
Neurinoma (5%)

16. GIST CD 117 - >95% CD 34 – 60-70% Vimentin Actin - 15-30% Lymphoma
B-cell- CD 20,CD 79
T-Cell- CD 3,CD 5

17. D/D

18. Pathology Few millimeters to more than 30 cm,
(median size -5 and 8 cm.)
Muscularis propria layer of GI wall
Exophytic growth.
Mucosal ulceration-50% cases.
Mass attached to the stomach, projecting into the abdominal cavity and displacing other organs.

19. Pathological types
Exophytic
Endophytic
Combined

20. Smooth
Gray and white tumors
Well circumscribed
Pseudocapsule
Small areas of hemorrhage
Cystic degeneration
Necrosis

21. Spindle cell Epitheloid Mixed pattern HistoPathology
Nuclear palisading or prominent perinuclear vacuolization pattern
Spindle cell
Solid pattern or a myxoid pattern, with a possible compartmental pattern
Epitheloid
Both spindle cell and epitheloid pattern
Mixed pattern

22. Histology
Spindle pattern
Epitheliod pattern

23. CLINICAL PRESENTATION…
Asymptomatic,
Especially early in tumor development,
Discovered incidentally by CT or endoscopy

24. Symptomatic GISTs Vague abdominal discomfort (60%-70%).
Bleeding (30%-40%).
Perforation (20%)
Anorexia, weight loss, nausea, anemia, and additional GI complaints

25. Site specfic symptoms Esophageal GISTs -dysphagia,
Gastric and small intestinal GISTs
- Bleeding &Intestinal obstruction.
Duodenal GISTs
- Biliary Obstruction
Colorectal GISTs –
-pain and GI obstruction, and lower intestinal bleeding.

26. Acute Presentation Bleeding peritoneal cavity- Ruptured Gist
GI tract lumen-
hematemesis, melena or anemia
Obstruction
Over growth
Intussusception
Volvulus

27. Syndromes linked to GISTs
(i) Carney triad
Gastric GISTs,
Paraganglioma,
Pulmonary chondromas.
(ii) Type-1 neurofibromatosis
Generally wild-type
Predominantly located at the small bowel
Possibly multicentric .
(iii) Carney-Stratakis syndrome
Germ-line mutations of succinate dehydrogenase Dyad of GIST and paraganglioma

28. UGI Scopy

29. EUS- Management process

30. Contrast enhanced computed tomography (CECT)
Modality of choice.
To characterize the lesion&evaluate its extent.
To assess the presence or absence of metastasis at the initial staging workup.
Monitoring response to therapy
Performing follow-up surveillance of recurrence

31. Magnetic Resonance Imaging
Provides better soft-tissue contrast resolution and direct multiplanar imaging
Helps to localise the tumour
Delineate the relationships of the tumour and adjacent organs.
Particularly of benefit in anorectal disease.

32. MRI Axial T2-weighted MR image
Extraluminal mass arising from the greater curvature of the stomach.
The mass shows high signal intensity

33. Benign gastric fundal GIST- MRI
Axial T1-weighted
Axial T2-weighted
Axial enhanced T1-weighted
Homogeneous
iso-intensity
Homogeneous
medium lintensity
Homogeneous
moderate enhancement

34. CT or MRI
large exophytic tumor with heterogeneous contrast enhancement, arising from the stomach or small bowel.
Metastases, if present, are usually to the liver or peritoneum.
Lymph node enlargement is uncommon.

35. CT&MRI-D/D Lymphomas Circumferential with homogeneous enhancement
Lymph node enlargement.
Carcinoid tumors
Found in the distal ileum,or root of the mesentery,
Desmoplastic reaction with calcifications.
Large carcinomas
More likely to cause visceral obstruction.

36. FDG-PET Reveals small metastases Establish baseline metabolic activity
Assess therapy response
Helps to clarify ambiguous findings seen on CT or MRI
To assess complex metastatic disease in patients who are being considered for surgery

37. Changes in the metabolic activity of tumors precede anatomic changes on CECT.
used to assess the response to Imatinib therapy.
Routine use of PET for surveillance after resection is not yet recommended

38. FNAC/BIOPSY FNA- controversial -risk of rupture and dissemination
Resectable lesion in the absence of metastatic disease
“Preoperative diagnosis may be unnecessary”

39. Biopsy-Indications If diagnosis would impact the extent of resection
Prior to Neoadjuant therapy
Unresectable GISTs
Metastatic GISTs

41. Fletcher 2002 Size Mitotic count Very Low risk <2 cm <5/50 HPF
Intermediate risk
<5 cm
5-10 cm
6-10/50 HPF
High risk
>5 cm
>10 cm
Any size
>5/50 HPF
Any count
>10/50 HPF

43. UICC 2010 TNM 7th Edition

44. Management Guidelines International Conference and Workshop,
ESOINDIA GUIDELINES
International Conference and Workshop,
Jan 2014,Chennai.

45. Management strategies
Surgery
Surgery + adjuvant Imatinib
Neoadjuvant Imatinib + surgery

46. Site specific surgery Esophagus: Esophagectomy
Esophageal sparing wide local excision
Stomach
Small-wedge resection
Large-subtotal/total gastrectomy
(BlumMG et al,AnnThoracSurg2007; WinfieldRDetal.AmSurg2006;
WayneJD et al SurgClinNorthAm2005).

47. Duodenum:
Partial duodenal resection
Whipple’s Procedure
Small Intestine:
Segmental resection
Colon:
Colectomy
Rectum:
Anterior resection/
Abdominoperineal resection
(Blay JY et ai.Ann Oncology 2005;16: )

48. Principles of surgery AIM:
To obtain complete resection with maximal organ preservation with macroscopic negative margin.
Great care should be taken to avoid rupture of pseudocapsule
Re resection is generally not indicated for microscopically positive margins on final pathology
Lymphadenectomy is not required

49. Irregular border
Cystic spaces
Ulceration
Echogenic foci
Heterogeneity

50. Resection margin 1-2 cm margin is necessary for an adequate resection
Tumor size
Main determining factor for survival
Complete resection with gross negative margin is acceptable.
De Matteo et al,Ann Surg 2000

51. Esophageal GISTs

52. Gastric GIST- CECT- Coronal multiple planar reformation
Exophtic-growth
Heterogeneous enhancement.
Intact mucosa

54. Laparoscopic Approach -NCCN Guidelines
Select GISTs in favorable anatomic locations
-Greater curvature or Anterior wall of stomach
-Jejunum or ileum
Preservation of pseudo capsule
Specimen retrieval through Plastic bag
-Avoidance of tumor spillage & port site seeding

55. Minimally invasive (Privette et all-2008)
Type1: Lap. Stapled partial gastrectomy
Type2: lap.distal gastrectomy
Type3: lap.transgastric resection.

56. Lap. Transgastric ….

57. LEGGS-Laparoscopic endoscopically- guided gastric surgery
LECS-Laparoscopic and endoscopic cooperative surgery

58. Laparoscopic and endoscopic cooperative surgery (LECS).
Mucosal&submucosal dissection – Endoscopy
Seromuscular resection by laparoscopy
Enables tumor resection with minimal surgical Margin.
Useful in esophagogastric junction or pyloric ring GISTs

59. Small bowel GISTs May occur throughout the small intestine
Signs and symptoms of obstruction or rarely with hemorrhage .
They may appear as intramural masses or intraluminal polyps, and may show extension into adjacent mesentery

60. Small bowel Vs Gastric GISTs
More commonly associated with Neurofibromatosis 1
More frequent exon 9 mutations
More frequently malignant
Intestinal obstruction more common than bleeding

61. Small bowel GIST-CT -exophytic mass with an irregular margin, heterogeneous contrast enhancement,
Central gas within the tumor with a gas-fluid level (arrow).
Central calcifications (arrow).

62. Extension into the adjacent small bowel colon, bladder, ureter, and abdominal wall may occur.
Adenocarcinoma
annular lesion in the proximal small intestine
Lymphoma.
similar features
associated lymphadenopathy

63. Anorectal GISTs
Well-defined, eccentric mural masses that expand the rectal wall and may contain mucosal ulceration.
The mass spreads via extension into the ischiorectal fossa, prostate, or vagina.
As in GISTs at other locations, central areas of hemorrhage can be seen

64. Rectal GIST
MRI should be used in rectal GIST as it provides better preoperative staging information
Endoscopic ultrasound and MRI assessment followed by biopsy and wide excision is the standard approach, regardless of tumor size.

65. Colonic GISTs
Transmural tumors that involve the intraluminal and extraserosal surfaces of the colon.
Cystic change, hemorrhage, necrosis, or calcification are common
Circumferential growth with secondary dilatation of the affected colonic segment.

66. Imatinib Therapy

67. Neoadjuvant imatinib
GIST that is resectable with negative margins but with significant morbidity
A multivisceral resection is indicated
To optimize timing of surgery
To facilitate organ function-sparing resections.

68. Imatinib-Dosage Initial dose 400 mg daily Dose escalation
Pts with Progressive disease
Pts with KIT mutation in exon 9
Upto 800mg daily(400 mg BD) depending upon the tolerance

69. Imatinib- Duration of Threapy
Preop
6–12 months until max.response is reached
Periop
stopped 2–3 days before surgery
resumed promptly when the patient recovers from surgery.
Post op
High Risk of relapse- 3 years (Level 1 a)
Low Risk Adjuvant therapy not recommended.
Intermediate Risk- Controversial

70. PET-Response to imatinib
Decreases the tumour avidity for 18F-FDG
PET imaging could detect the biological activity of imatinib far earlier than changes in anatomic measures on CT scanning.
PET changes as early as 24 hours following a single dose of imatinib.

71. Sunitinib
-second-line drug treatment.
-For patients whose GIST tumors become resistant to imatinib.
Regorafenib
-FDA-2013 approved as a third- line drug for patients whose tumors are not responding to imatinib or sunitinib.

72. Metastatic GISTs
Distant metastases most commonly involve liver (50-65%) & peritoneum (21-43%)
Only 10% of metastatic lesions occur in the lungs or bones
GISTs rarely spread to regional lymph nodes (<10%)
On presentation, 41-47% of malignant GISTs are metastatic.

73. Metastatic GISTs

74. Prognostic factors for RFS
Large tumor size,
High mitotic count,
Nongastric location,
Presence of rupture,
Male sex
(H. Joensuu et al, The Lancet 2011.)

75. Prognosis… The 5-year survival for malignant GIST 28 to 80%.
Median survival after incomplete surgery –23 months.
The median survival for metastatic or recurrent disease
12 to 19 months.

76. FOLLOW UP-ESMO Guidelines
High-risk patients
CT scan or MRI
Every 3–6 months for first 3 years
Every 3 months for next 2 years,
Every 6 months for next 3 years
Annually for an additional 5 years.
For low-risk tumors,
CT scan or MRI every 6–12 months for 5 years.
Very low-risk GISTs
-probably do not deserve routine followup, although one must be aware that the risk is not nil.