GIST (Gastrointestinal Stromal Tumor).ppt

GIST (Gastrointestinal Stromal Tumor) is a rare type of tumor that occurs in the digestive tract, typically in the stomach or small intestine. It arises from the interstitial cells of Cajal, which are cells that help regulate digestion.

GISTs can be:

1. Benign (non-cancerous)
2. Malignant (cancerous)

Symptoms may include:

- Abdominal pain or discomfort
- Bleeding or anemia
- Nausea and vomiting
- Abdominal mass or lump
- Weight loss

Treatment options for GISTs depend on the size, location, and malignancy of the tumor and may include:

1. Surgery to remove the tumor
2. Targeted therapy (e.g., imatinib) to slow tumor growth
3. Chemotherapy
4. Radiation therapy

Prognosis and survival rates vary depending on the tumor's characteristics and response to treatment. Early detection and treatment can improve outcomes.

Note: GISTs are distinct from other gastrointestinal tumors, such as carcinomas, and require specialized care.

1. GIST: CPC
Professor Ravi Kant
FRCS (England), FRCS (Ireland),
FRCS(Edinburgh), FRCS(Glasgow), MS, DNB,
FAMS, FACS, FICS,
President IASO 2006
1

2. H:
•59 y ,Postmenopausal, Dysphagia, &
bleeding p/v, (year 2005 at AIIMS)
•ANA +, Arthritis, Malar pigmentation
•Ca ® Breast pT
2N
0M
0 (July ‘ 02)
•BCS
•Breast RT + electron boost
•Adjuvant CMF6#
•ER, PR & HER2-neu +
•Tamoxifen20mg OD 2

3. Investigations
•Chest X Ray
•USG
•CECT
•EUS
•Ba Swallow
3

4. 4

5. 5

6. 6

7. 7

8. 8

9. 9

10. 10

11. 11

12. 12

13. 13

14. 14

15. 15

16. 16

17. Dermatomyosisits ►GI &
Breast CA
Maoz CR, Langevitz P, Livnch A,
Blumstein Z, Sadeh M, bank I, et al.
High incidece of malignancies in
patients with dermatomyositis and
polymyositis: an 11-yr analysis. Semin
Arthritis Rheum. 1998Apr;27(5):319-
24

18. Dermatomyosisits ~ Malignancies
•Risk factors: age (>45y), male
sex
Chen YJ, Wu CY, Shen JL. Predicting
factors of malignancy in
dermatomyositis and polymyositis: a
case-control study. Br J Dermatol.
2001Apr;144(4):825-31

19. Tamoxifen ►GI CA –Stomach,
not Colon, not Liver
•Wilking N, Isaksson E, Von Schoultz E. Tamoxifen
and secondary tumors. An update.Drug Saf.
1997Feb;16(2):104-17
•Matsuyama Y, Tominaga T, Nomura Y, Koyama H,
Kimura M, Sano M, et al. Second cancers after
adjuvant tamoxifen therapy for breast cancer in Japan.
Ann Oncol. 2000Dec;11(12):1537-43
•Newcomb PA in Breast Cancer Res Treat. 1999 Feb:
53(3):271-7 ►Colon CA after 5y of Tx

20. Tamoxifen S/E: 4
•Liver: X, Gastrointestinal cancer
(stomach and colon): 
Newcomb PA, Solomon C, White E.
Tamoxifen and risk of large bowel cancer in
women with breast cancer. Breast Cancer
Res Treat. 1999Feb;53(3):271-7

21. Radiation Therapy S/E: 1
•Radiaton-induced sarcoma after
BCS and RT
Mason RW, Einspanier GR, Caleel RT.
Radiation-induced sarcoma of the
breast. J Am Osteopath Assoc. 1996;
96(6):368-70

22. Radiation Therapy S/E: 2
•Small bowel angiosarcoma
Hansen SH, Holck S, Flyger H, Tange
UB. Radiation-associated angiosarcoma
of the small bowel. A case of multipolidy
and a fulminant clinical course. Case
report. APMIS. 1996Dec;104(12):891-4

23. Second Cancers after BCS: 1
•10 y incidence 16%
•Risk factors: non breast Ca: age
Fowble B, Hanlon A, Freedman G, Nicolaou
N, Anderson P. Second cancers after
conservative surgery and radiation for stages
I-II breasyt cancer: identifying a subset of
women at increased risk. Int J Radiat Oncol
Biol Phys. 2001Nov;51(3):679-90

24. Second Cancers after BCS: 2
•Second malignancies X
Obedian E, Fischer DB, Haffty BG.
Second malignancies after treatment of
early-stage breast cancer: lumpectomy
and radiation therapy versus
mastectomy J Clin Oncol. 2002
Jun;18(12):2406-12

25. GE junction tumors
•GIST
•Sarcomatoid carcinoma
(carcinosarcoma)
•Synovial sarcoma
–Billings SD, Maisner LF, Cummings OW,
Tejada E. Synovial sarcoma of the upper
digestive tract: a report of two cases with
demonstration of the X;18 translocation by
fluorescent in situ hybridization. Mod Pathol.
2000 Jan;13(1):68-76

26. E-G jn
•GIST
•Leiomyoma
•Lymphoma
•Second primary from Breast
•Angiosarcoma -? RT induced
•Linked to Dermatomyositis as arthritis +nt,
ANA +,
•Neurogenic tumors
•Tuberculosis

27. 2
0
primary after BCS
•No
–Obedian E, JClin Oncol 2000
Jun;18(12):2406-12
•Yes 16%
–Hanlon FB, Freedman G., Nicolaou N.,
Anderson P. Int J Radiat Oncol Biol Phys..
2001 nov 1;51(3):679-90

28. GIST + Neurogenic
•No relation to RT, CT
•Her 2 neu +
•Dermatomysositis

29. Diagnosis
•GIST, Lymphoma / 2
nd
primary at GI jn
♠Submucosal ≡ ►
►GIST = first diagnosis

30. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
30

31. GIST…??
•Uncommon
•Mesenchymal tumors
•Origin in the wall of G-I tract
•Intestinal pacemaker cell called the
interstitial cell of Cajal.
31

32. History of GIST…
•late1960’s smooth muscle neoplasms
of the gastrointestinal tract
•Immuno-histochemistry in the 1980’s 
some lacked features of smooth muscle
differentiation
•Mazur and Clark 
–“Gastrointestinal stromal tumors” =
Neurogenic or Myogenic differentiation
32

33. •Mutations c-kit gene can cause
constitutive activation of the tyrosine
kinase function of c-kit
•These mutations result in:
–Auto-phosphorylation of c-kit
–Ligand-independent tyrosine kinase
activity
–Uncontrolled cell proliferation
–Stimulation of downstream signaling
pathways
33

34. Cajal cell
•Intestinal pacemaker cell
•Characteristics of both smooth
muscle and neural differentiation on
ultrastructural study
34

35. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
35

36. 36

37. KIT
•role of the KITand platelet-derived growth
factor receptor (PDGFR) tyrosine kinase
receptors
•KIT receptor tyrosine kinase (KIT RTK)
37

38. KIT
•approximately 5% of GIST cells show not
activation and aberrant signaling of the
KIT receptor, but rather mutational
activation of a structurally related kinase,
PDGFR-(PDGFRA).
•90% rate of mutations seen in a more
recent series searching for potential
mutations in each of exons 11, 9, 13, and
17
38

39. Survival & KIT
•Exon 11 worse than PDGFR
•Exon 9 worse than Exon 11
•Small intestine worse than stomach or
colon
•Exon 11 not dose dependent (Imatinib)
•Exon 9 dose dependent (Imatinib)
•( EORTC, NA Swog S0033, B2222 phase
II)
39

40. KIT & other markers
•KIT
•PDGFRA
•Protein kinase C Theta ( PKCTheta)
•DOG-1
•Wild type = KIT negative GIST
40

41. PDGFR
Platelet derived growth receptor
alpha (PDGFR-a)
•Tyrosine kinase activator
•Similar to c-kit
•Helps define GIST
41

42. Pediatric
•-KIT
•-PDGFRA
•Wild type
•+ CD117
•▲Local recurrence
•Slow growing
42

43. CD117CD34 Actin &
Desmin
S-100
GIST +
+ - -
Desmoid
tumor
- + - -
True
leiomyosarc
oma
- - + -
Schwanoma- - - +
43

44. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
44

45. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
45

46. Diagnosis
•FDG PET = mandatory
►FDG-PET CT scan is ideal
•MD-CE-CT = image modality of choice for
abdomen (if FDG-PET-CT is not available)
•MR
•Evaluate by Chol or RECIST criterion
46

47. 47

48. GIST & chemoresistance
•▲P-glycoprotein [the product of the
multidrug resistance-1 (MDR-1) gene]
•▲MDR protein
48

49. ▼active tyrosine kinase enzymatic function
of the BCR-ABL oncoprotein ►critical to
the pathogenesis of chronic myeloid
leukemia (CML)
49

50. Definition…
•GI submucosal mesenchymal tumor
that is not myogenic (eg,
leiomyosarcoma) or neurogenic (eg,
schwannoma) in origin.
•GI mesenchymal tumors that express
the CD117 and/or CD34 antigen
50

51. Distribution…
•Stomach 50-60%
•Small bowel 20-30%
•Large bowel 10%
•Esophagus 5%
•Else where in abdomen 5%
51

52. 52

53. 53

54. 54

55. 55

56. Symptoms…
Abdominal pain
Dysphagia
Gastrointestinal bleeding
Symptoms of bowel obstruction
Small tumors may be asymptomatic
56

57. Cytologically…
1.Spindle cell GISTs
2.Epithelioid cell GISTs
•Although GISTs can differentiate
along either or both cell types,
some show NO significant
differentiation at all
57

58. Diagnosis = CD 117+
58

59. Malignant Versus Benign
Size Mitotic count
Very Low risk<2 cm <5/50 HPF
Low risk 2-5 cm <5/50 HPF
Intermediate
risk
<5 cm
5-10 cm
6-10/50 HPF
<5/50 HPF
High risk >5 cm
>10 cm
Any size
>5/50 HPF
Any count
>10/50 HPF
59

60. NCCNGuidelines 2007
•JNCCI
Vol 5 Supplement 2 July 2007
page S1-S 31
Based on NCCN task force report
60

61. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
61

62. Treatment…
•Surgical excision is primary treatment
option but recurrence rates are high
•Resistant to standard chemotherapy
regimens due to over-expression of
efflux pumps
•Radiation therapy limited by large
tumor sizes and sensitivity of adjacent
bowel
62

63. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•CT
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
63

64. IMATINIB
•Since activation of Kit played a crucial
role in the pathogenesis of GIST,
inhibition of Kit would be therapeutic

64

65. IMATINIB
•Orally bioactive tyrosine kinase
inhibitor
•Shown to be effective against GIST
tumors in two trials in the US and
Europe reported in 2001 & 2002
65

66. Sunitinb
•Oral TK 1
•▼KIT & PDGFR
•▼VEGFR, RET
•Anti-Angoiogenic + Antitumour
•Indication: Imatinib resistant, Wild type
66

67. Neoadjuvant
•For unresectable tumours
(NCI-RTOG 2007)
67

68. Adjuvant ???
•For high risk of recurrence only
(ACS-OG Z9000, Z 9001)
(Scandinavian-German SSG VIII/AIO)
(EORTC 62024)
68

69. Recurrence or Metastaic
•Imanitib is MUST
•(Univ of Texas MD A)
•(MGH Boston)
69

70. GIST: Summary
•All have malignant potential
•CD 34 , CD 117, PET for Diagnosis
•Complete surgical resection important
•Metastatic disease responds to Imatinib
•Role of Imtanib
•No role of chemo or radiation
70

71. Prognosis…
•The overall survival rate 35% at 5
years
•complete resection 54% at 5 years
•Incomplete resection 12 months
•Metastasis 19 months
•Local recurrence 12 months
71

72. Survival& KIT
•Exon 11 of KIT worse than PDGFR
•Exon 9 of KIT worse than Exon 11
•Small intestine worse than stomach or
colon
•Exon 11 not dose dependent (Imatinib)
•Exon 9 dose dependent (Imatinib)
( EORTC, NA Swog S0033, B2222 phase II)
72

73. Predictors of survival
•Male sex,
•Tumor size > 5cm
•Incomplete resection
•Mitotic index
significant
on
multivariate
analysis
73

74. GIST
•Case history-
submucosal
•CajalCell
•Gene KIT
•PGDRF
•Diagnosis
•CT
•PET
•Rx
•Surgery
•Chemoresistance
•Imatininb
•Sumanitib
•Prognosis
•Predictor factors
74

75. Present Complaints
•Bleeding P/V x 2 months (July
2005)
•Hematemesis, Wt loss -
•GPE N

76. H:
•59 y ,Postmenopausal
•Ca ® Breast pT
2N
0M
0 (July ‘ 02)
•BCS
•Breast RT + electron boost
•Adjuvant CMF6#
•ER, PR & HER2-neu +
•Tamoxifen 20mg OD

77. CMF vs CAF
•Lancet 19988 Early Trialist Group

78. Her 2 Neu Rx
•Her 2+veindicates a more severe
disease
•Another reason not to use the CMF and
rather use Anthracycline
•Aggressive tumors in presence of
Dermatomyositis
•Rx by Herceptin

79. Tx
•10 mg bd vs 20mg OD
•Current recommendations are 10mg BD

83. Tamoxifen ►Endometrial polyps,
hyperplasia & adenocarcinoma
•Hysteroscopy: pretreatment and
annual
•Endoscopic myomectmy
Nomikos IN, Elemenoglou J, Papatheophanis
J. Tamoxifen-induced endometrial polyp. A
case report and review of literature. Eur J
Gynaecol Oncol. 1998;19(5):476-8

84. Tamoxifen ►Endometrial polyps,
hyperplasia & adenocarcinoma
•Hysteroscopy: pre-Rx & annual
•Endometrial resection
•Goldenberg, Nezhat C, Mashiach S., Seidman
DS. J AM Assoc Gynecol Laparosc. 1999
Aug:6(3):285-8.

85. Bleeding PV
•All causes +
•Tamoxifen induced hyperplasia, polyp,
carcinoma,
•Mets from Metastatic Lobular breast
CA

86. Tx►Polyps►hyperplastic or
metstatic
•Hysteroscopy is mandatory

87. Tamoxifen ►Post M Bleed P/V
►Hysteroscopy mandatory
Taponeco F, Curcio C, Fasciani A, Giuntini A,
Artini PG, Fornaciari G, et al. Indication of
hysteroscopy in tamoxifen treated breast cancer
patients. J Exp Clin Cancer Res. 2002
Mar;21(1):37-43
Malignancy in 7.8%+ 4% premalignant lesions in
Postmenopausal Tx ►3y

88. Tamoxifen ►
Metastatic Lobular breast Ca
►Endometrial polyp
•Alvarez C, Ortiz-Rey JA, Estevez F, De la Fuente A.
Metastatic lobular breast carcinoma to an endometrial
polyp diagnosed by hysteroscopic biopsy. Obstet
Gynecol. 2003Nov;102(5):1149-51
•Al-Brahim N, Elavathil LJ. Metastatic breast lobular
carcinoma to tamoxifen-associated endometrial polyp:
case report and literature review. Ann Diagn Pathol.
2005Jun;9(3):166-8

89. Tamoxifen ►Endometrial
carcinoma
•Wilking N, Isaksson E, Von Schoultz E. Tamoxifen
and secondary tumors. An update. Drug Saf. 1997
Feb;16(2):104-17 (? Risk of 2
0
GI CA)
•Andersson M, Storm HH, Mouridsen HT. Carcinogenic
effects of adjuvant tamoxifen therapy and radiotherapy
for early breast cancer. Acta Oncol. 1992;31(2):259-63
•Matsuyama Y, Tominaga T, Nomura Y, Koyama H,
Kimura M, Sano M, et al. Second cancers after
adjuvant tamoxifen therapy for breast cancer in Japan.
Ann Oncol. 2000Dec;11(12):1537-43

90. Summary
•Need of hysteroscopy for endometrial
polyp
•CAF for adjuvant
•Her 2 Neu + tumors need a distinct line of
management including aggressive chemo/
Herceptin

91. Provisional diagnosis
•Bleeding PV-Tx induced polyp
•Metsfrom Metastatic Lobular breast
Ca
•Her 2 neu related endometrial
cancer

92. Diagnosis
•Polyp / Metastases of Lobular Breast CA
in Ut
•GIST, Lymphoma / 2
nd
primary at GI jn

93. Thank you
93