New Sarcoma Defined by BCOR-CCNB3 Fusion
Laila Moharram, Hussam Haddad
King Hussein Cancer Center
Case History
• 13 year old male• Left pelvic mass
Pediatric Round cell Sarcomas
• Rhabomyosarcoma• Ewing sarcoma/PNET• Neuroblastoma• Lymphoma/ leukemia• Small cell osteosarcoma• Mesenchymal
chondrosarcoma
• Sclerosing RMS• BRD/NUT carcinoma• Extrarenal rhabdoid
tumor• Desmoplastic small
round cell tumor• Undifferentiated
sarcoma
CD99 PAS
Myogenin Desmin
BAF47 BCL-2
Immunostains
PositiveCD99 (Weak)BCL-2CD56
Negativesynaptophysin desmin, myogeninS100 protein CD31EMA and CK-MNFFLI-1
EWSR1 Fusion Partners
• FLI1 (85%)• ERG (5-10%)• FEV• ETV1• E1Af
EWSR1-ETS
Working Diagnosis
Small round blue cell tumor of the bone• FISH is negative for EWSR1 rearrangement
EWSR1 fusion negative Ewing sarcoma
• Rare• FUS FISH• FUS-ERG or FUS-FEV
Diagnosis?
DX:
Undifferentiated spindle and round cell sarcoma.
Undifferentiated sarcoma
• Fusion negative Ewing-like neoplasms
• CD99: Positive, focal or negative.
• Proportion of cases shows new fusion CIC-DUX4
• t(4;19)
• t(10;19)
Consultation
CIC-DUX4 gene fusion negative
The tumor instead showed BCOR-CCNB3 fusion.
• Fusion-specific RT-PCR to screen a series of 594 sarcomas.
• 24 BCOR-CCNB3–positive tumors were identified
• Gene profiling experiments indicated that BCOR-CCNB3–positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma.
BCOR-CCNB3 Sarcoma
• Clinical description is similar to Ewing Sarcoma.
• Median age 13 years • Male predominance• Preferentially long bones, the spine and pelvis. • 20%: soft tissue tumor.
Pathology
• Undifferentiated, small round cell sarcoma, suggestive of the Ewing sarcoma.
• Half lacked strong membrane positivity for CD99.
BCOR and CCNB3 Genes
• Both on the X chromosome• BCOR encodes ubiquitous transcriptional
repressor that associates with BCL6 oncoprotein
• CCNB3 expression is tightly restricted to the testis, with CCNB3 encoding an early meiotic cyclin .
• Ectopic expression of CCNB3 as a result of the BCOR gene fusion may constitute a key oncogenic event.
Undifferentiated/ unclassifed Sarcomas
• Introduced a chapter on undifferentiated sarcomas.
• No reproducible immunophenotype.• Patchy CD99 • CD34+-: No discriminatory value.• EM: No evidence of differentiation.
Ewing or Ewing look-alike?
Undifferentiated Sarcoma
CIC-DUX4 sarcoma? BCOR-CCNB3 sarcoma
References 1. Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre J-M, Antonescu CR. High
prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1- negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 2012;51:207-218.
2. Pierron G et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Gen 2012; 44: 461-466.
3. Barr FG, Womer RB. Molecular diagnosis of Ewing family tumors too many fusions...? Journal of Molecular Diagnostics.2007;9(4):437–440.
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5. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol. 2004;22(20):4135–4139.
References 6. Ng TL, O’Sullivan MJ, Pallen CJ, Hayes M, Clarkson PW, Winstanley M, Sorensen PH,
Nielsen TO, Horsman DE. Ewing sarcoma with novel translocation t(2;16) producing an in-frame fusion of FUS and FEV. J Mol Diagn. 2007;9:459–463.
7. Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, Gotoh T, Motoi T, Fukayama M, Aburatani H, Takizawa T, Nakamura T. Fusion between CIC and DUX4 up- regulates PEA3 family genes in Ewing-like sarcomas with t (4;19)(q35;q13) translocation. Hum Mol Genet 2006;15:2125- 2137
8. Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A. Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors. Modern Pathology. 2006;19(1):1–8.