GIST: CPC

Professor Ravi Kant

FRCS (England), FRCS (Ireland),
FRCS(Edinburgh), FRCS(Glasgow), MS, DNB,
FAMS, FACS, FICS,
President IASO 2006

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 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

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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):319-
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 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
 2 primary after BCS
0

• 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 history- • CT
submucosal • Surgery
• Cajal Cell • Chemoresistance
• Gene KIT • Imatininb
• PGDRF • Sumanitib
• Diagnosis • Prognosis
• CT • Predictor factors
• PET
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GIST…??
• Uncommon
• Mesenchymal tumors
• Origin in the wall of G-I tract
• Intestinal pacemaker cell called the
interstitial cell of Cajal.

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 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
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• 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
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Cajal cell

• Intestinal pacemaker cell

• Characteristics of both smooth
muscle and neural differentiation on
ultrastructural study

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 GIST
• Case history- • CT
submucosal • Surgery
• Cajal Cell • Chemoresistance
• Gene KIT • Imatininb
• PGDRF • Sumanitib
• Diagnosis • Prognosis
• CT • Predictor factors
• PET
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KIT
• role of the KIT and platelet-derived growth
factor receptor (PDGFR) tyrosine kinase
receptors
• KIT receptor tyrosine kinase (KIT RTK)

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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

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

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

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

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 CD117 CD34 Actin & S-100
Desmin

GIST + + - -
Desmoid - + - -
tumor

True - - + -
leiomyosarc
oma

Schwanoma - - - +

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

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

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

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 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

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

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

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 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
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Diagnosis = CD 117+

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 Malignant Versus Benign

Size Mitotic count

Very Low risk <2 cm <5/50 HPF
Low risk 2-5 cm <5/50 HPF
Intermediate <5 cm 6-10/50 HPF
risk 5-10 cm <5/50 HPF
High risk >5 cm >5/50 HPF
>10 cm Any count
Any size >10/50 HPF
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 NCCN Guidelines 2007
• JNCCI
Vol 5 Supplement 2 July 2007
page S1-S 31

Based on NCCN task force report

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 GIST
• Case history- • CT
submucosal • Surgery
• Cajal Cell • Chemoresistance
• Gene KIT • Imatininb
• PGDRF • Sumanitib
• Diagnosis • Prognosis
• CT • Predictor factors
• PET
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 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
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 GIST
• Case history- • CT
submucosal • Surgery
• Cajal Cell • Chemoresistance
• Gene KIT • Imatininb
• PGDRF • Sumanitib
• Diagnosis • Prognosis
• CT • Predictor factors
• PET
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IMATINIB
• Since activation of Kit played a crucial
role in the pathogenesis of GIST,
inhibition of Kit would be therapeutic


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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

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

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 Neoadjuvant
• For unresectable tumours
(NCI-RTOG 2007)

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

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

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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

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 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

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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)

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 Predictors of survival

• Male sex,
significant
• Tumor size > 5cm on
• Incomplete resection multivariate
analysis
• Mitotic index

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

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