SLIDE 1 The Royal Marsden
IAP , Amman, Oct 2018 Case 1
Khin Thway
MD, FRCPath
Consultant Pathologist, S arcoma Unit, The Royal Marsden Hospital, London, UK Reader in Translational Pathology, Molecular Pathology, The Institute
- f Cancer Research, London, UK
SLIDE 2
Case 1
39 year old male S evere abdominal pain CT: 12cm polypoid gastric tumor, resting on transverse colon 12cm partially necrotic gastric mass
SLIDE 3
Tumor in muscularis propria
SLIDE 4
Epithelioid cells
SLIDE 5
Clear cells
SLIDE 6
Pleomorphic cells
SLIDE 7
Pleomorphic cells
SLIDE 8
Pleomorphic cells
Necrosis Atypical mitoses
SLIDE 9
Pleomorphic cells
Abrupt transition between bland areas and pleomorphic areas
SLIDE 10
Immunohistochemistry
AE1/AE3 AE1/AE3
SLIDE 11
Immunohistochemistry
CD117 DOG1
SLIDE 12
Immunohistochemistry
CD117 CD117
SLIDE 13
Immunohistochemical findings
Positive Negative
AE1/ AE3 DOG1 CD117 CK7, CK20 Desmin, S MA, h-caldesmon CD34 S 100 protein HMB45, Melan A
SLIDE 14
Molecular findings
Mutation in exon 18 of PDGFRA No EWS R1-CREB1 or EWS R1-ATF1 fusions detected No evidence of MDM2 amplification
SLIDE 15
Epithelioid cells Pleomorphic cells
SLIDE 16
Diagnosis
Dedifferentiated gastrointestinal stromal tumor PDGFRA mutation No previous clinical history De novo dedifferentiation
SLIDE 17
Gastrointestinal stromal tumor
SLIDE 18 Gastrointestinal stromal tumor
S tromal tumors of GI tract
morphology Immunohistochemically positive for KIT (CD117) Activating mutations in KIT or PDGFRA proto-oncogenes
SLIDE 19 Gastrointestinal stromal tumor
Esophagus 5 Stomach 52 Small intestine 25
duodenum 15 j ej unum 35 ileum 45
Colorectal 11 Extra GI 7
SLIDE 20 Gastrointestinal stromal tumor
5-10%
1%
M > F >50 yrs Pain, bleeding, mass Incidental Metastasis
SLIDE 21
Gastrointestinal stromal tumor
SLIDE 22
Gastrointestinal stromal tumor
Paranuclear vacuolation Skenoid fibers
SLIDE 23
Epithelioid GIS T
SLIDE 24
Gastrointestinal stromal tumor
Patterns Cytology Organoid
Fascicular S pindle S toriform Epithelioid Palisaded Plasmacytoid S heet-like S ignet ring Myxoid Granular cell Organoid Giant cell
SLIDE 25
Gastrointestinal stromal tumor
Plasmacytoid
Patterns Cytology Fascicular S pindle S toriform Epithelioid Palisaded Plasmacytoid S heet-like S ignet ring Myxoid Granular cell Organoid Giant cell
SLIDE 26 GastrointestinaI stromal tumor
10 20 30 40 50 60 70 80 90 100 CD117 DOG1 CD34 bcl2 SMA des cald calp S100 CK EMA
%
DOG1
About 5%
T are KIT-negat ive; 75% posit ive for prot ein kinase C t het a
SLIDE 27
Response to imatinib therapy in GIS T
Before After
SLIDE 28 Response to imatinib therapy in GIS T
KIT mutations
Exon 11 best (83.5% ) Exon 9 good (48% )
high dose, sunitinib
Exon 13 good Exon 17 good Wild type poor
± S
DH loss
PDGFRA mutations
Exon 12 good Exon 18 resistant (D842V)
SLIDE 29
Wild-type GIS T
S DH-deficient BRAF-mutant NF1-associated
SLIDE 30
GIS T
Conventional Pleomorphic
SLIDE 31 Pleomorphic GIS T
Chronic imatinib treatment
Altered morphology Loss of CD117
Pauwels et al., 2005 Vassos et al., 2011 Antonescu et al., 2016
SLIDE 32 Dedifferentiated GIS T
Dedifferentiated features can also
Antonescu et al., 2016
SLIDE 33 Dedifferentiated GIS T
Mostly in stomach S mall bowel, colon, rectum M>F Older adults
Antonescu et al., 2016
SLIDE 34 Dedifferentiated GIS T
‘ Normal’ / original areas of GIS T: S pindle cells Rarely epithelioid cells
Liegl et al., 2009 Antonescu et al., 2016
SLIDE 35 Dedifferentiation in GIS T
Morphology
Pleomorphic/ anaplastic Rhabdomyosarcomatous Epithelioid/ pseudopapillary 1 case ‘ angiosarcomatous’ Mitoses, necrosis
Pauwels et al., 2005, Liegl et al., 2009, Zheng et al., 2013, Jiang et al., 2015, Antonescu et al., 2016
SLIDE 36 Dedifferentiation in GIS T
Dedifferentiated GIST CD34
Complete CD117 loss (8/ 8) CD34 loss (5/ 8)
Antonescu et al., 2016 Jiang et al., 2015
SLIDE 37 Dedifferentiation in GIS T
Dedifferentiated GIST Cytokeratin
Gain of cytokeratin Gain of desmin
Pauwels et al., 2005 Antonescu et al., 2016
SLIDE 38 Dedifferentiation in GIS T
Mutational analysis
No difference in KIT genotype between conventional and dedifferentiated components
Pauwels et al., 2005 Antonescu et al., 2016
SLIDE 39 Dedifferentiation in GIS T
FISH in CD117-negative component
Loss of 1 KIT gene (3 cases) Low level amplification of KIT (2 cases) Genomic instability
Antonescu et al., 2016
SLIDE 40
Dedifferentiated tumors
SLIDE 41 Dedifferentiated tumors
Dedifferentiation GIST
S ubset of neoplasms High grade tumor, without evidence of line of differentiation
SLIDE 42 Dedifferentiation
Chondrosarcoma
Chondrosarcoma Chordoma Liposarcoma S
MPNS T Dermatofibrosarcoma GIS T Carcinoma Melanoma
SLIDE 43 Dedifferentiation
Solitary fibrous tumor
Arises de novo or as complication
- f recurrent, previously well
differentiated tumor Abrupt transition Confers more aggressive behavior
SLIDE 44
Dedifferentiation
Genetics
S ame driving genetic mechanisms as original tumor Additional genetic abnormalities
SLIDE 45
Dedifferentiation
Dedifferentiated solitary fibrous tumor STAT6 loss
NAB2-STAT 6 gene fusion
Maj or pathogenic driver STAT6 protein loss in dedifferentiated S FT but not malignant S FT
SLIDE 46
Dedifferentiation
Dedifferentiated solitary fibrous tumor Dedifferentiated liposarcoma
SLIDE 47
Differential diagnosis
Pleomorphic neoplasm GI tract/ viscera Cytokeratin positive
SLIDE 48
S arcomatoid carcinoma
History of prior carcinoma Overlying epithelial dysplasia Features of glandular or other epithelial differentiation in other areas
SLIDE 49
‘ Collision tumor’ of pleomorphic tumor and GIS T
e.g. S arcomatoid carcinoma with GIS T DDL with GIS T Rare
SLIDE 50
Pleomorphic sarcoma
Diagnosis of exclusion Not associated with KIT or PDGFRA mutations No specific/ recurrent genetic findings Complex karyotypes
SLIDE 51 Dedifferentiated liposarcoma
Dedifferentiated liposarcoma
Most retroperitoneal MFH (UPS ) are dedifferentiated liposarcomas
Coindre et al. 2003
SLIDE 52
Dedifferentiated liposarcoma
Previous history of, or coexistent, well-differentiated liposarcoma
SLIDE 53
Dedifferentiated liposarcoma
Previous history of, or coexistent, well-differentiated liposarcoma CDK4, p16 and MDM2 expression
CDK4
SLIDE 54
Dedifferentiated liposarcoma
Previous history of, or coexistent, well-differentiated liposarcoma CDK4, p16 and MDM2 expression MDM2 amplification with FIS H
SLIDE 55
Dedifferentiated GIS T
Dedifferentiated GIST Pleomorphic sarcoma
SLIDE 56
Dedifferentiated GIS T
Clinical implications
Distinct genetic background KIT or PDGFRA mutations Potential for targeted therapeutic strategies in future
SLIDE 57
Conclusions Dedifferentiated GIS T
Diagnostic awareness
Adequate sampling CD117 and CD34 loss Cytokeratin / desmin gain Post-imatinib or de novo Targeted therapies in future
SLIDE 58 The Royal Marsden
IAP , Amman, Oct 2018 Case 1
Dr Khin Thway
MD, FRCPath
Consultant Pathologist S arcoma Unit, The Royal Marsden Hospital, London, UK Reader in Translational Pathology Molecular Pathology, The Institute of Cancer Research, London, UK
