Ewing Sarcoma / pnet

(Primitive Neuroectodermal Tumor)

 

Epidemiology and Etiology:

    • Bimodal
      • Peak 2nd decade
      • >50y
    • almost exclusively caucasian

 

Common Sites:

    • Long-bones
      • diaphysis
    • Deep-seated
    • Trunk
    • Lower limbs
    • Association with nerve trunk occasionally

 

Gross Features:

    • Rapidly enlarging
    •  

 

 

Histologic features:

    • Small round cell tumor
      • Sheets, lobules, trabeculae of uniform small, round cells, slightly larger than lymphocytes
      • Scant cytoplasm, may appear clear (glycogen) – use PAS & PASD
      • Nuclei 10-15 um
        • Finely granular chromatin, speckled with nucleoli
    • Little stroma apart from fibrous septae
    • Homer-Wright rosettes (with a central fibrillary space) maybe
    • Flexner-Wintersteiner rosettes rarely
    • Pseudorosettes (variable) maybe
    • Relatively few mitotic figures
    • Frequently hemorrhage & necrosis
    • Prominent capillary network
    • Intracytoplasmic glycogen

 

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

MIC2 (CD99)

(diffuse, membranous)

Nearly all

Not very specific

(lymphoblastic lymphoma & DSRCT, membranous)

PAS & PASD (glycogen) (dot cytoplasmic staining)

 

Not specific

Vimentin

100%

Not specific

FLI-1

Majority

Not very specific

NSE

 

 

LEU-7

 

 

Synaptophysin

 

 

Neurofilament

 

 

Chromogranin

 

 

S-100

 

 

 

Molecular features:

    • t(11;22)(q24;q12) in 80-90%
      • EWSR1-FLI1 fusion gene
        • EWSR1 is in TET family of genes with FUS and TAF15
          • RNA-binding motif
        • FLI1 is a member of the ETS family
        • 5’ EWSR1 binds to 3’ FLI1
      • type 1 transcript:
        • exon 7 of EWS to exon 6 of FLI1
        • may be better prognosis
      • type 2 transcript:
        • exon 7 of EWS to exon 5 of FLI1
      • other breakpoints (20%)
      • additional karyotype abnormalities in 2/3 of cases
        • +8 (one or more) (33%)
        • +12 (one or more) (20%)
        • +2 (10%)
        • +14 (10%)
        • +18 (10%)
        • +20 (10%) (maybe poor prognosis)
        • der(16)t(1;16)(q11-21;q11-13) (10%)
        • complex karyotype (>5 changes) maybe poor prognosis
        • > 50 chromosomes maybe poor prognosis
    • EWSR1 (22q12) - ERG (21q22) fusion gene (10-15%)
      • t(21;22)(q21;q12) rarely seen b/c they transcribe in opposite directions requiring a complex mechanism
    • t(7;22)(q22;q12) in < 1%
      • EWS-ETV1 fusion gene
    • t(17;22)(q12;q12)
      • EWS-E1AF
    • t(2;22)(q33;q12)
      • EWS-FEV
    • t(1;22)(p36;q12)
      • EWS-ZSG
    • Rare other EWSR1 rearrangements
    • Rare rearrangements involving other TET family genes (FUS, TAF15)
    • ?rare rearrangements involving other genes aside from TET family and ETS family?

 

Other features:

    • On EM: glycogen granules grouped around the nucleus
      • Some intermediate-type cell junctions
        • True desmosomes usually not seen
      • Neurosecretory granules maybe
        • But more pleomorphic and larger than those in neuroblastoma
    • Poor prognosis
      • 20-30% 5-year survival
    • Important prognostic factors:
      • Age (< 18 y favorable)
      • Size (< 8 cm favorable)
      • Site (extremity > pelvis)
      • Stage
      • Response to treatment is an important prognostic factor (Huvos classification):
        • Grade I – no necrosis (30% 3-year survival)
        • Grade IIA – 1-10% necrosis (30% 3-year survival)
        • Grade IIB – 11-90% necrosis (49% 3-year survival)
        • Grade III – 91-99% necrosis (73% 3-year survival)
        • Grade IV – 100% necrosis (100% 3-year survival)
    • Distance of tumour from all margins is important to document
      • Local recurrence
      • Radiation is indicated if wide margins are not adequate
    • High grade by definition

 

References:

    • Essentials of AP 2006
    • WHO book 2002
    • Heim & Mitelman.  Cancer Cytogenetics, 3rd ed. (2009)