Pathology of TranslocationAssociated Sarcomas tSTS

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Pathology of Translocation-Associated Sarcomas
(t-STS)

• Cristina Antonescu, MDMemorial Sloan-Kettering
  Cancer Center

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Overview

• Pathology Findings
• Diagnostic pitfalls
• Impact of molecular diagnosis
• specific diagnostic marker
• prognostic impact
• therapeutic implications

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Ewing Sarcoma
CD99
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Ewing Sarcoma

• Diagnostic Pitfalls
• Atypical morphology
• Unusual IHC
• Insufficient / Inadequate Material
• Unusual clinical presentation

Molecular Diagnosis

• Differential Diagnosis
• Lymphoma
• NEC
• other primitive sarcomas (DRCT, PD-SS)

KER
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Molecular Diagnosis

• RT-PCR
• primer design
• contamination

• FISH
• No info Re the partner gene

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Alveolar Rhabdomyosarcoma

• Differential Diagnosis
• other SBRT primitive sarcomas (DRCT, ES)
• ERMS

Desmin
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Differential Diagnosis

• Embryonal Rhabdomyosarcoma

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Mixed Alveolar-Embryonal RMS?
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Pitfalls Rhabdomyoblastic differentiation after
adjuvant chemotherapy
Post-Chemo ERMS
Pre-Chemo ARMS
Caution in determining histologic subtype of RMS
after chemo
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Alveolar Rhabdomyosarcoma Genetics

• t(213)(q35q14)
• PAX3-FKHR
• (55)

• t(113)(p36q14)
• PAX7-FKHR
• (22)

FISH amplification of PAX7-FKHR

• Unusual clinical presentation
• Differential diagnosis with ERMS
• Post-chemo sample

• Prognostic factors
• more aggressive and less chemosensitive than
  ERMS
• PAX7-FKHR younger age, extremity location,
  localized disease

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MYXOID LIPOSARCOMA
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MYXOID LIPOSARCOMA

• Clinical Aspects
• young age
• mutifocality (synchronous/metachronous)
• bone metastases (spine)

• Differential Diagnosis
• Retroperitoneal WDLS/Dedif LS

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GI Clear Cell Sarcoma
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EWS-CREB1 a recurrent variant gene fusion in GI
CCS
B
A
CREB1 exon 7
EWS exon 7
Y G Q Q I A I T
Q G
EWS-CREB1 cases 1 2 3 -
A
16000
14000
Case 1
12000
CCS1
10000
MITF-C
8000
CCS2
Expression level
6000
CCS3
MITF-M
4000
CCS4
2000
PGK
0
MITF
TYRP1
TYR
CREB1
SOX10
Antonescu CR et al. Clin Cancer Res 2006
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Angiomatoid Fibrous Histiocytoma
Spindle cell type
Small cell type
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Small cell component of AFH a diagnostic
pitfall
Desmin
O13
CD68
Frequent positivity for desmin and O13
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Literature Review of Molecular Subtype of AFH
confirmed by t(1222)(q13q12) ? misdiagnosed
as Ewing sarcoma or high grade undifferentiated
sarcoma by an expert pathologist
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EWSR1 gene rearrangement
EWSR1-CREB1 fusion the most frequent molecular
abnormality
Cytogenetic Analysis
Antonescu CR et al. Gene Chr Cancer 2007 Rossi S
et al. Clin Cancer Res 2007
CREB1 gene rearrangement
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• EWS-ATF1 t(1222)
• Clear cell sarcoma of soft parts
• Clear cell sarcoma of GI tract
• AFH

• EWS-CREB1 t(222)
• Clear cell sarcoma of soft parts
• Clear cell sarcoma of GI tract
• AFH

RNA BD
Zn Ran BD
EWS
pKID
bZIP
CREB1
EWS-CREB1

pKID
bZIP
ATF1
EWS-ATF1

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Low Grade Fibromyxoid Sarcoma (Evans Tumor)
t(716) FUS-CREB3L2 t(1116) FUS-CREB3L1
Reid et al 2003 Storlazzi CT et al 2003 Mertens
F et al 2005.
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Fibrosarcoma with Giant Rosettes Hyalinizing
spindle cell tumor with giant rosettes a giant
rosette-containing variant of LG FMS
Lane et al. AJSP 1997 Guillou L et al. AJSP 2007
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Sclerosing Epithelioid Fibrosarcoma
Guillou L et al. AJSP 2007
3 SEF tumors FUS-CREB3L2
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Summary