TERAPEUTIC CONSEQUENCES FROM TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR GIST MOLECOLAR BIOLOGY FOR GIST PATIENTS AFFECTED BY PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1 NEUROFIBROMATOSIS TYPE 1 Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P CTOS-Seattle, November 2007 supported by Conticanet Mannheim University Hospital, Germany Bonn University Hospital, Germany Istituto Nazionale Tumori, Italy
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TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR GIST PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1 Mussi C, Schildhaus HU, Gronchi A, Wardelmann E,
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TERAPEUTIC CONSEQUENCES TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR FROM MOLECOLAR BIOLOGY FOR
GIST PATIENTS AFFECTED BY GIST PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1NEUROFIBROMATOSIS TYPE 1
Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P
CTOS-Seattle, November 2007
supported by Conticanet
Mannheim University Hospital, Germany
Bonn University Hospital, Germany
Istituto Nazionale Tumori, Italy
BACKGROUNDBACKGROUND
• Patients affected by Neurofibromatosis type 1 have an
increased risk of GIST developing
• NF-1 associated GISTs seem to be wild type for
KIT/PDGFRA mutations
• This subset of GIST has likely a different oncogenic
molecular mechanism
• Lack of data on imatinib and other tyrosine kinases
inhibitors activity in this different setting
QUESTIONSQUESTIONS
• Should these patients enrolled in the ongoing
trials of imatinib?
• Should this decision taken on the basis of the
molecular analysis?
PATIENTSPATIENTS
28 PATIENTS OPERATED
• 13 MALES
• 15 FEMALES
• M:F=0,87:1
• Median age 57 (range 28-72)
DIAGNOSISDIAGNOSIS
NEUROFIBROMATOSIS TYPE 1
>2 following criteria:• > 6 cafe-au-lait macules (>5mm before puberty, >15 mm after)
• skin-fold freckles (groin, axilla, neck base)
• > neurofibromas (1 plexiform)
• skeletal dysplasia (orbital or tibial)
• Lisch nodules (>2 iris amartomas)
• optic glioma
• family history
DIAGNOSISDIAGNOSIS
GIST
• The diagnosis was confirmed histologically in terms
of morphology and immunophenotyping
• Seven tumors were reclassified as GIST after
pathologic review
• 2 MPNST
• 1 Schwannoma, 1 Neurofibroma
• 2 Leiomyosarcoma
• 1 Leiomyoma
All tumors were sympthomatic except one
PRESENTATIONPRESENTATIONPRESENT SERIES SPORADIC GIST
• Age 57 yrs (28-72)
• M:F=0,87:1
• LOCALIZED 82%
• METASTATIC 18%
• RISK STRATIFICATION
•High 30,5%
•Intermediate 39%
•Low/very low 30,5%
• Age 60 yrs (20-80)
• M:F=1,3:1
• LOCALIZED 50-85%
• METASTATIC 15-50%
• RISK STRATIFICATION
•High 23-35%
•Intermediate 20%
•Low/very low 45%
70%
SITESITEPRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
25%14%
68%
Other: 11%
60%
30%
Other: 10%
7%
NUMBERS OF TUMORSNUMBERS OF TUMORS
PRESENT SERIES SPORADIC GIST
MULTIPLE TUMORSMULTIPLE TUMORS
43 % Occasional
IMMUNOCHEMISTRYIMMUNOCHEMISTRY
PRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
• CD 117 pos 100%
• CD 34 pos 86%
• S-100 pos 19%
• Actine pos 24%
• PDGFRA pos 37,5%
• BCL-2 pos 43%
• CD 117 pos 95%
• CD 34 pos 70%
• S-100 pos 10%
• Actine pos 25%
• PDGFRA pos 70%
• BCL-2 pos 20-93%
PATHOLOGYPATHOLOGY
PRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
• Spindle cell 75%
• Epithelioid 15%
• Mixed 10%
• Skenoid fiber 33%
• Associated Cajal
cell hyperplasia 21%
• Spindle cell 38-77%
• Epithelioid 8-38%
• Mixed 14-23%
• Skenoid fiber 34%
MOLECULAR ANALYSISMOLECULAR ANALYSIS
• c-KIT exons 9, 11,13,17
• PDGFRA exon 12, 14, 18
DNA extracted from paraffin embedded DNA extracted from paraffin embedded microdissected sections was sequenced for:microdissected sections was sequenced for:
25 PTS
MOLECULAR ANALYSISMOLECULAR ANALYSIS
• exon 11 (V560del)
• exon 9 (A504_Y505)
• Exon 18 (D842V)
PRIMARY MUTATIONSPRIMARY MUTATIONS
MOLECULAR ANALYSISMOLECULAR ANALYSIS
Exon 17 D820N mutation in metastatic
lesions after gleevec therapy
SECONDARY MUTATIONSECONDARY MUTATION
MOLECULAR ANALYSISMOLECULAR ANALYSIS Series N° of Pts KIT mut PDGFRA mut NF1 mut