GIST: CPC Professor Ravi Kant FRCS (England), FRCS (Ireland), FRCS(Edinburgh), FRCS(Glasgow), MS,...
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Transcript of GIST: CPC Professor Ravi Kant FRCS (England), FRCS (Ireland), FRCS(Edinburgh), FRCS(Glasgow), MS,...
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
4646
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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
5555
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
6060
GISTGIST• Case history-
submucosal
• Cajal Cell
• Gene KIT
• PGDRF
• Diagnosis
• CT
• PET
• CT
• Surgery
• Chemoresistance
• Imatininb
• Sumanitib
• Prognosis
• Predictor factors
6161
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
7171
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
7474
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
9393