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Round Cell Pattern
• ES/PNET
• Alv RMS
• DSRCT
• Neuroblastoma
• Small cell/Merkel cell
• Lymphoma
• Mesenchymal CS
• Round cell LS
• Poorly diff SS
• “Ewing-like”
• CIC-DUX
• BCOR-CCNB3
• CIC-FOXO4
PAS/D
ES/PNET: Histologic Spectrum
ES PNET
Cell shape regular irregular
Chromatin fine coarse
Nucleoli pinpoint prominent
Glycogen abundant scant
Rosettes absent present
ES/PNET: Ultrastructure
ES/PNET: Ultrastructural Spectrum
Feature ES PNET
Organelles scarce abundant
Dense-core granules absent abundant
Neurotubules absent abundant
Neuritic processes absent abundant
CD99
MIC - 2 Gene Product (CD99)
Diagnosis Positive (%)
ES/PNET 93%
Small Cell Osteosarcoma 12%
Desmoplastic Round Cell Tumor 20%
Neuroblastoma 0%
Rhabdomyosarcoma 15%
Small Cell Carcinoma 9%
T-LL/ALL 92%
ES/PNET: Cytogenetics
t(11;22)(q24;q12) – FLI1;EWSR1 Translocation
EWSR1 FLI1
NH2 COOH
ETS DNA binding domain
t(21;22)(q22;q12) ERG/EWSR1
t(7;22)(p22;q12) ETV1/EWSR1
t(17;22)(q12;q12) FEV/EWSR1
t(2;22)(q33;q12) E1AF/EWSR1
Very rare involvement of FUS in lieu of EWSR1
EWSR1 (22q12) Break-apart probe
t(11;22), t(21;22) – EWSR1/PNET (FLI1/EWSR1, ERG/EWSR1)
t(11;22) - DSRCT (WT-1/EWSR1)
t(12;22) – Clear Cell Sarcoma (ATF1/EWSR1)
t(9;22) – ES Myxoid Chondrosarcoma (NR4A3/EWSR1)
t(12;22) – Myxoid/Round Cell Liposarcoma (DDIT3/EWSR1)
t(2;22) – Angiomatoid fibrous histiocytoma (CREB1/EWSR1)
t(6;22) – Soft tissue myoepithelioma (Pou5F1/EWSR1)
Rhabdomyosarcoma International Classification
Favorable Prognosis
• Botryoid
• Spindle cell
Intermediate Prognosis
• Embryonal
Poor Prognosis
• Alveolar
Newton WA et al, Cancer 1995
MyoD1/Myogenin
• part of the Myo-D superfamily of genes
• encode for DNA binding proteins which
activate transcription of skeletal muscle-
specific genes
• results in commitment to skeletal muscle
differentiation
• can detect skeletal muscle differentiation
at an earlier stage than with markers
currently available Myogenin
Myogenin in Pediatric Tumors
Tumor Cases stained
Rhabdomyosarcoma (69) 69/69 (100%)
• Alveolar (48)
• Embryonal (20)
• Spindle cell (1)
Other pediatric sarcomas (50) 0/50 (0%)
• ES/PNET (16)
• DSRCT (6)
• Neuroblastoma (4)
• Others (24)
Kumar S et al, Mod Pathol 2000
Alveolar Rhabdomyosarcoma
t(2;13)(q35;q14) t(1;13)(q36;q14)
PAX3/FOXO1A PAX7/FOXO1A
*up to 25% lack t(2;13) or t(1;13)
FOXO1A Break Apart Probe
“Ewing-like” Sarcoma
CIC-DUX BCOR-CCNB3
CIC-FOXO4
• Lobular growth
• Geographic necrosis
• Round cells
• High-grade nuclei
• Patchy clear cytoplasm
• Foci of myxoid change
CIC-DUX Sarcomas
CIC-DUX Sarcomas
Immunophenotype
S-100 protein negative
TLE1 negative
Desmin negative
Myogenin negative
WT1 positive
INI1 retained
CIC-DUX Sarcomas
Immunophenotype
CD99 7/7
(focal 5/7; cytoplasmic, not membranous)
ERG 9/10
FLI1 8/8
Choi et al. AJSP 2013
Smith et al. Mod Pathol 2014
CIC-DUX Sarcomas
Other Findings
• t(4;19) 8/10
• t(10;19) 2/10
• Trisomy 8 3/3
• MYC staining 10/10 (diffuse)
• MYC amplification (FISH) 6/7
Smith et al. Mod Pathol 2014
CIC-DUX Sarcomas
Clinical Outcome (N=13)
• Died of disease 8 (9-17 mos; mean: 12 mos)
• Alive with disease 1 (24 mos)
• No evidence of disease 4 (6-30 mos)
• Metastases: Lung (10); Brain (2); Pelvis (2); Bone (1)
BCOR-CCNB3 Sarcomas
• Gender: 9M / 1F
• Age: 11-18 yrs
• Location: 7 bone / 3 deep soft tissue
• Follow-up: 5-189 mos (median: 695 mos)
• AWOD 6/10
• AW mets 1/10
• DOD 3/10
Puls et al AJSP 2014
BCOR-CCNB3 Sarcoma • Morphology
• Round cell resembling atypical Ewing sarcoma : 7 cases
• Spindle cell sarcoma: 3 cases
• Immunophenotype
• CCNB3 10/10
• bcl2 9/10
• CD99 7/10
• CD117 6/10
• Desmin 0/10
• AE1/3 0/3
• RT-PCR: 9/9 BCOR-CCNB3 fusion
Puls et al AJSP 2014
BCOR-CCNB3 CCNB3 stain
Courtesy of Dr. Florian Puls
BCOR-CCNB3 CCNB3 stain
Courtesy of Dr. Florian Puls
Round Cell Pattern CD99 TdT Myo Cam 5.2 Des WT1
ES/PNET + - - 20% - -
A-RMS 15% - + 50% + -
Lymphoma >90% + - - - -
DSRCT 20% - - + + +
CIC-DUX + (focal) - - - - +
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