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GIST: CPC
Professor Ravi Kant
FRCS (England), FRCS (Ireland),
FRCS(Edinburgh), FRCS(Glasgow), MS, DNB,
FAMS, FACS, FICS,
President IASO 2006
1
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
2
Investigations
•
•
•
•
•
Chest X Ray
USG
CECT
EUS
Ba Swallow
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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. 1998 Apr;27(5):31924
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.
2001 Apr;144(4):825-31
Tamoxifen ►  GI
CA – Stomach,
not Colon, not Liver
• Wilking N, Isaksson E, Von Schoultz E. Tamoxifen
and secondary tumors. An update. Drug Saf.
1997 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. 2000 Dec;11(12):1537-43
• Newcomb PA in Breast Cancer Res Treat. 1999 Feb:
53(3):271-7 ►  Colon CA after 5y of Tx
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. 1999 Feb;53(3):271-7
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
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. 1996 Dec;104(12):891-4
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. 2001 Nov;51(3):679-90
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
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
E-G jn 
•
•
•
•
•
•
GIST
Leiomyoma
Lymphoma
Second primary from Breast
Angiosarcoma - ? RT induced
Linked to Dermatomyositis as arthritis +nt,
ANA +,
• Neurogenic tumors
• Tuberculosis
20 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
GIST + Neurogenic
• No relation to RT, CT
• Her 2 neu +
• Dermatomysositis
Diagnosis
• GIST, Lymphoma / 2nd primary at GI jn
♠ Submucosal ≡ ►
►GIST = first diagnosis
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
30
GIST…??
•
•
•
•
Uncommon
Mesenchymal tumors
Origin in the wall of G-I tract
Intestinal pacemaker cell called the
interstitial cell of Cajal.
31
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
• 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
Cajal cell
• Intestinal pacemaker cell
• Characteristics of both smooth
muscle and neural differentiation on
ultrastructural study
34
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
35
36
KIT
• role of the KIT and platelet-derived growth
factor receptor (PDGFR) tyrosine kinase
receptors
• KIT receptor tyrosine kinase (KIT RTK)
37
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
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
KIT & other markers
•
•
•
•
•
KIT
PDGFRA
Protein kinase C Theta ( PKCTheta)
DOG-1
Wild type = KIT negative GIST
40
PDGFR
Platelet derived growth receptor
alpha (PDGFR-a)
• Tyrosine kinase activator
• Similar to c-kit
• Helps define GIST
41
Pediatric
•
•
•
•
•
•
- KIT
- PDGFRA
Wild type
+ CD117
▲ Local recurrence
Slow growing
42
CD117
CD34
Actin &
Desmin
S-100
GIST
+
+
-
-
Desmoid
tumor
-
+
-
-
True
leiomyosarc
oma
-
+
-
Schwanoma -
-
-
+
43
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
44
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
45
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
GIST & chemoresistance
• ▲ P-glycoprotein [the product of the
multidrug resistance-1 (MDR-1) gene]
• ▲ MDR protein
48
▼ active tyrosine kinase enzymatic function
of the BCR-ABL oncoprotein ► critical to
the pathogenesis of chronic myeloid
leukemia (CML)
49
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
Distribution…
•
•
•
•
•
Stomach 50-60%
Small bowel 20-30%
Large bowel 10%
Esophagus 5%
Else where in abdomen 5%
51
52
53
54
55
Symptoms…
 Abdominal pain
 Dysphagia
 Gastrointestinal bleeding
 Symptoms of bowel obstruction
 Small tumors may be asymptomatic
56
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
Diagnosis = CD 117+
58
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
>5 cm
>10 cm
Any size
6-10/50 HPF
<5/50 HPF
>5/50 HPF
Any count
>10/50 HPF
High risk
59
NCCN Guidelines 2007
• JNCCI
Vol 5 Supplement 2 July 2007
page S1-S 31
Based on NCCN task force report
60
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
61
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
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
CT
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
63
IMATINIB
• Since activation of Kit played a crucial
role in the pathogenesis of GIST,
inhibition of Kit would be therapeutic

64
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
Sunitinb
•
•
•
•
•
Oral TK 1
▼ KIT & PDGFR
▼ VEGFR, RET
Anti-Angoiogenic + Antitumour
Indication: Imatinib resistant, Wild type
66
Neoadjuvant
• For unresectable tumours
(NCI-RTOG 2007)
67
Adjuvant ???
• For high risk of recurrence only
(ACS-OG Z9000, Z 9001)
(Scandinavian-German SSG VIII/AIO)
(EORTC 62024)
68
Recurrence or Metastaic
• Imanitib is MUST
• (Univ of Texas MD A)
• (MGH Boston)
69
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
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
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
Predictors of survival
•
•
•
•
Male sex,
Tumor size > 5cm
Incomplete resection
Mitotic index
significant
on
multivariate
analysis
73
GIST
• Case historysubmucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
•
•
•
•
•
•
•
Rx
Surgery
Chemoresistance
Imatininb
Sumanitib
Prognosis
Predictor factors
74
Present Complaints
• Bleeding P/V x 2 months (July
2005)
• Hematemesis, Wt loss • GPE N
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
CMF vs CAF
• Lancet 19988 Early Trialist Group
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
Tx
• 10 mg bd vs 20mg OD
• Current recommendations are 10mg BD
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
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.
Bleeding PV
• All causes +
• Tamoxifen induced hyperplasia, polyp,
carcinoma,
• Mets from Metastatic Lobular breast
CA
Tx►Polyps► hyperplastic or
metstatic
• Hysteroscopy is mandatory
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
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. 2003 Nov;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.
2005 Jun;9(3):166-8
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 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. 2000 Dec;11(12):1537-43
Summary
• Need of hysteroscopy for endometrial
polyp
• CAF for adjuvant
• Her 2 Neu + tumors need a distinct line of
management including aggressive chemo/
Herceptin
Provisional diagnosis
• Bleeding PV- Tx induced polyp
• Mets from Metastatic Lobular breast
Ca
• Her 2 neu related endometrial
cancer
Diagnosis
• Polyp / Metastases of Lobular Breast CA
in Ut
• GIST, Lymphoma / 2nd primary at GI jn
Thank you
93