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

2. H:
59 y ,Postmenopausal, Dysphagia, & bleeding p/v, (year 2005 at AIIMS)
ANA +, Arthritis, Malar pigmentation
 Ca ® Breast pT2N0M0 (July ‘ 02)
BCS
Breast RT + electron boost
Adjuvant CMF 6#
ER, PR & HER 2-neu +
Tamoxifen 20 mg OD

3. Investigations
Chest X Ray
USG
CECT
EUS
Ba Swallow

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 Apr;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 Apr;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 Feb;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 Dec;11(12):
Newcomb PA in Breast Cancer Res Treat 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 Feb;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 Dec;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 Nov;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 Jun;18(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 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. 20 primary after BCS No Yes 16%
Obedian E, JClin Oncol 2000 Jun;18(12):
Yes 16%
Hanlon FB, Freedman G., Nicolaou N., Anderson P. Int J Radiat Oncol Biol Phys nov 1;51(3):679-90

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

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

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

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

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

33. These mutations result in:
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

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

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

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

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

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)

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

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

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

43. + CD117 CD34 Actin & Desmin S-100 GIST - Desmoid tumor
True leiomyosarcoma
Schwanoma

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

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

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

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

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

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

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

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

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

58. Diagnosis = CD 117+

59. Malignant Versus Benign
Size
Mitotic count
Very Low risk
<2 cm
<5/50 HPF
Low risk
2-5 cm
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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

76. H: 59 y ,Postmenopausal  Ca ® Breast pT2N0M0 (July ‘ 02) BCS
Breast RT + electron boost
Adjuvant CMF 6#
ER, PR & HER 2-neu +
Tamoxifen 20 mg OD

77. CMF vs CAF
Lancet Early Trialist Group

78. Her 2 Neu Rx Her 2 +ve indicates 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 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 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 Nov;102(5):
Al-Brahim N, Elavathil LJ. Metastatic breast lobular carcinoma to tamoxifen-associated endometrial polyp: case report and literature review. Ann Diagn Pathol Jun;9(3):166-8

89. Tamoxifen ► Endometrial carcinoma
Wilking N, Isaksson E, Von Schoultz E. Tamoxifen and secondary tumors. An update. Drug Saf Feb;16(2): (? Risk of 20 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 Dec;11(12):

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
Mets from Metastatic Lobular breast Ca
Her 2 neu related endometrial cancer

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

93. Thank you