GIST: CPCGIST: CPCProfessor Ravi KantProfessor Ravi Kant

FRCS (England), FRCS (Ireland), FRCS(Edinburgh), FRCS(Glasgow), MS, DNB,

FAMS, FACS, FICS,

President IASO 2006President IASO 2006

11

H: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 22

InvestigationsInvestigations

• Chest X Ray

• USG

• CECT

• EUS

• Ba Swallow

33

44

55

66

77

88

99

1010

1111

1212

1313

1414

1515

1616

Dermatomyosisits Dermatomyosisits ► ► GI & GI & Breast CABreast 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):319-24

Dermatomyosisits ~ MalignanciesDermatomyosisits ~ 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 Tamoxifen ► ► GI CA – Stomach, GI CA – Stomach, not Colon, not Livernot 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: 4Tamoxifen 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: 1Radiation 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: 2Radiation 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: 1Second 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: 2Second 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 tumorsGE 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 jE-G jnn

• GIST• Leiomyoma• Lymphoma• Second primary from Breast• Angiosarcoma - ? RT induced• Linked to Dermatomyositis as arthritis +nt,

ANA +,• Neurogenic tumors• Tuberculosis

220 0 primary after BCSprimary 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 + NeurogenicGIST + Neurogenic

• No relation to RT, CT

• Her 2 neu +

• Dermatomysositis

DiagnosisDiagnosis

• GIST, Lymphoma / 2nd primary at GI jn

♠ Submucosal ≡ ►

►GIST = first diagnosis

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

3030

GIST…??GIST…??

• Uncommon

• Mesenchymal tumors

• Origin in the wall of G-I tract

• Intestinal pacemaker cell called the interstitial cell of Cajal.

3131

History of GIST…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 differentiation3232

• 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

3333

Cajal cellCajal cell

• Intestinal pacemaker cell

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

3434

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

3535

3636

KITKIT

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

• KIT receptor tyrosine kinase (KIT RTK)

3737

KITKIT

• 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 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)

3939

KIT & other markersKIT & other markers

• KIT

• PDGFRA

• Protein kinase C Theta ( PKCTheta)

• DOG-1

• Wild type = KIT negative GIST

4040

PDGFRPDGFRPlatelet derived growth receptor

alpha (PDGFR-a)

• Tyrosine kinase activator

• Similar to c-kit

• Helps define GIST

4141

Pediatric Pediatric

• - KIT

• - PDGFRA

• Wild type

• + CD117

• ▲ Local recurrence

• Slow growing

4242

CD117 CD34 Actin & Desmin

S-100

GIST + + - -

Desmoid tumor

- + - -

True leiomyosarcoma

- - + -

Schwanoma - - - +

4343

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

4444

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

4545

DiagnosisDiagnosis

• 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 & chemoresistanceGIST & chemoresistance

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

• ▲ MDR protein

4848

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

4949

Definition…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

5050

Distribution…Distribution…• Stomach 50-60%

• Small bowel 20-30%

• Large bowel 10%

• Esophagus 5%

• Else where in abdomen 5%

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5252

5353

5454

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

5656

Cytologically…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

5757

Diagnosis = CD 117+Diagnosis = CD 117+

5858

Malignant Versus BenignMalignant 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 HPF5959

NCCN Guidelines 2007NCCN Guidelines 2007

• JNCCI Vol 5 Supplement 2 July 2007

page S1-S 31

Based on NCCN task force report

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GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

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Treatment…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

6262

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• CT

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

6363

IMATINIBIMATINIB• Since activation of Kit played a crucial

role in the pathogenesis of GIST, inhibition of Kit would be therapeutic

6464

IMATINIBIMATINIB

• Orally bioactive tyrosine kinase inhibitor

• Shown to be effective against GIST tumors in two trials in the US and Europe reported in 2001 & 2002

6565

SunitinbSunitinb

• Oral TK 1

• ▼ KIT & PDGFR

• ▼ VEGFR, RET

• Anti-Angoiogenic + Antitumour

• Indication: Imatinib resistant, Wild type

6666

NeoadjuvantNeoadjuvant

• For unresectable tumours

(NCI-RTOG 2007)

6767

Adjuvant ???Adjuvant ???

• For high risk of recurrence only

(ACS-OG Z9000, Z 9001)

(Scandinavian-German SSG VIII/AIO)

(EORTC 62024)

6868

Recurrence or MetastaicRecurrence or Metastaic

• Imanitib is MUST

• (Univ of Texas MD A)

• (MGH Boston)

6969

GIST: SummaryGIST: 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

7070

Prognosis…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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SurvivalSurvival & KIT & 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)

7272

Predictors of survivalPredictors of survival

• Male sex,

• Tumor size > 5cm

• Incomplete resection

• Mitotic index

significant on

multivariate analysis

7373

GISTGIST• Case history-

submucosal

• Cajal Cell

• Gene KIT

• PGDRF

• Diagnosis

• CT

• PET

• Rx

• Surgery

• Chemoresistance

• Imatininb

• Sumanitib

• Prognosis

• Predictor factors

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Present ComplaintsPresent Complaints

• Bleeding P/V x 2 months (July 2005)

• Hematemesis, Wt loss -

• GPE N

H: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 CAFCMF vs CAF

• Lancet 19988 Early Trialist Group

Her 2 Neu RxHer 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

TxTx

• 10 mg bd vs 20mg OD

• Current recommendations are 10mg BD

Tamoxifen Tamoxifen ►► Endometrial polyps, Endometrial polyps, hyperplasia & adenocarcinomahyperplasia & 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 Tamoxifen ►► Endometrial polyps, Endometrial polyps, hyperplasia & adenocarcinomahyperplasia & 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 PVBleeding PV

• All causes +

• Tamoxifen induced hyperplasia, polyp, carcinoma,

• Mets from Metastatic Lobular breast CA

TxTx►►PolypsPolyps►► hyperplastic or hyperplastic or metstaticmetstatic

• Hysteroscopy is mandatory

Tamoxifen Tamoxifen ►► Post M Bleed P/V Post M Bleed P/V ►►Hysteroscopy mandatoryHysteroscopy 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 Tamoxifen ►►Metastatic Lobular breast Ca Metastatic Lobular breast Ca

►Endometrial polyp►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 Tamoxifen ►► Endometrial Endometrial carcinomacarcinoma

• 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

SummarySummary

• Need of hysteroscopy for endometrial polyp

• CAF for adjuvant

• Her 2 Neu + tumors need a distinct line of management including aggressive chemo/ Herceptin

Provisional diagnosisProvisional diagnosis

• Bleeding PV- Tx induced polyp

• Mets from Metastatic Lobular breast Ca

• Her 2 neu related endometrial cancer

DiagnosisDiagnosis

• Polyp / Metastases of Lobular Breast CA in Ut

• GIST, Lymphoma / 2nd primary at GI jn

Thank youThank you

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