Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome

Cristina R. Antonescu, Adepitan A. Owosho, Lei Zhang, Sonja Chen, Kemal Deniz, Joseph M. Huryn, Yu-Chien Kao, Shih Chiang Huang, Samuel Singer, William Tap, Inga Marie Schaefer, Christopher D. Fletcher

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.

Original languageEnglish
Pages (from-to)941-949
Number of pages9
JournalAmerican Journal of Surgical Pathology
Volume41
Issue number7
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Ewing's Sarcoma
Sarcoma
Neoplasms
Survival
Gene Rearrangement
Phenotype
Epithelioid Cells
Gene Fusion
Young Adult
Cohort Studies
Extremities
Bone and Bones
Control Groups

Keywords

  • CIC
  • DUX4
  • round cell sarcoma
  • SBRCT

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Antonescu, C. R., Owosho, A. A., Zhang, L., Chen, S., Deniz, K., Huryn, J. M., ... Fletcher, C. D. (2017). Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome. American Journal of Surgical Pathology, 41(7), 941-949. https://doi.org/10.1097/PAS.0000000000000846

Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome. / Antonescu, Cristina R.; Owosho, Adepitan A.; Zhang, Lei; Chen, Sonja; Deniz, Kemal; Huryn, Joseph M.; Kao, Yu-Chien; Huang, Shih Chiang; Singer, Samuel; Tap, William; Schaefer, Inga Marie; Fletcher, Christopher D.

In: American Journal of Surgical Pathology, Vol. 41, No. 7, 01.01.2017, p. 941-949.

Research output: Contribution to journalArticle

Antonescu, CR, Owosho, AA, Zhang, L, Chen, S, Deniz, K, Huryn, JM, Kao, Y-C, Huang, SC, Singer, S, Tap, W, Schaefer, IM & Fletcher, CD 2017, 'Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome', American Journal of Surgical Pathology, vol. 41, no. 7, pp. 941-949. https://doi.org/10.1097/PAS.0000000000000846
Antonescu, Cristina R. ; Owosho, Adepitan A. ; Zhang, Lei ; Chen, Sonja ; Deniz, Kemal ; Huryn, Joseph M. ; Kao, Yu-Chien ; Huang, Shih Chiang ; Singer, Samuel ; Tap, William ; Schaefer, Inga Marie ; Fletcher, Christopher D. / Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome. In: American Journal of Surgical Pathology. 2017 ; Vol. 41, No. 7. pp. 941-949.
@article{57e6b3f03fab460db72cded76cf0352e,
title = "Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome",
abstract = "CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86{\%}), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12{\%}) and rarely in the bone (3{\%}). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84{\%} cases, with a diffuse pattern only in 23{\%} of cases, whereas nuclear WT1 was seen in 92{\%}. A CIC-DUX4 fusion was detected in 57{\%} of cases, with either DUX4 on 4q35 (35{\%}) or on 10q26 in 25 (22{\%}) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43{\%}, which was significantly lower than the 77{\%} 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.",
keywords = "CIC, DUX4, round cell sarcoma, SBRCT",
author = "Antonescu, {Cristina R.} and Owosho, {Adepitan A.} and Lei Zhang and Sonja Chen and Kemal Deniz and Huryn, {Joseph M.} and Yu-Chien Kao and Huang, {Shih Chiang} and Samuel Singer and William Tap and Schaefer, {Inga Marie} and Fletcher, {Christopher D.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1097/PAS.0000000000000846",
language = "English",
volume = "41",
pages = "941--949",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Sarcomas with CIC-rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome

AU - Antonescu, Cristina R.

AU - Owosho, Adepitan A.

AU - Zhang, Lei

AU - Chen, Sonja

AU - Deniz, Kemal

AU - Huryn, Joseph M.

AU - Kao, Yu-Chien

AU - Huang, Shih Chiang

AU - Singer, Samuel

AU - Tap, William

AU - Schaefer, Inga Marie

AU - Fletcher, Christopher D.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.

AB - CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.

KW - CIC

KW - DUX4

KW - round cell sarcoma

KW - SBRCT

UR - http://www.scopus.com/inward/record.url?scp=85016122979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016122979&partnerID=8YFLogxK

U2 - 10.1097/PAS.0000000000000846

DO - 10.1097/PAS.0000000000000846

M3 - Article

C2 - 28346326

AN - SCOPUS:85016122979

VL - 41

SP - 941

EP - 949

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

IS - 7

ER -