AIMS: CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. METHODS AND RESULTS: Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. CONCLUSIONS: DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

Biopticka laborator Ltd Pilsen Czech Republic

Department of Pathology and Laboratory Medicine Diagnostic Institute Cleveland Clinic Cleveland OH USA

Department of Pathology Charles University Faculty of Medicine in Pilsen Pilsen Czech Republic

Zobrazit více v PubMed

Bridge JA, editor. Chapter 3: undifferentiated small round cell sarcomas of bone and soft tissue. In WHO Classification of Tumours Editorial Board . Soft tissue and bone tumours. 5th ed.; Vol. 3. Lyon, France: International Agency for Research on Cancer, 2020. https://publications.iarc.fr/588 Accessed May 24, 2024

Kawamura‐Saito M, Yamazaki Y, Kaneko K PubMed

Antonescu CR, Owosho AA, Zhang L PubMed PMC

Simón‐Carrasco L, Jiménez G, Barbacid M, Drosten M. The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer. Cell Cycle 2018; 17; 702–711. PubMed PMC

Italiano A, Sung YS, Zhang L PubMed PMC

Choi EYK, Thomas DG, McHugh JB PubMed

Specht K, Sung Y, Zhang L, Richter GHS, Fletcher CD, Antonescu CR. Distinct transcriptional signature and immunoprofile of PubMed PMC

Ehrlich M, Jackson K, Tsumagari K, Camaño P, Lemmers RJFL. Hybridization analysis of D4Z4 repeat arrays linked to FSHD. Chromosoma 2007; 116; 107–116. PubMed PMC

Sparber‐Sauer M, Corradini N, Affinita MC PubMed PMC

Palmerini E, Gambarotti M, Italiano A PubMed

Le Guellec S, Velasco V, Pérot G, Watson S, Tirode F, Coindre JM. ETV4 is a useful marker for the diagnosis of CIC‐rearranged undifferentiated round‐cell sarcomas: a study of 127 cases including mimicking lesions. Mod. Pathol. 2016; 29; 1523–1531. PubMed

Hung YP, Fletcher CD, Hornick JL. Evaluation of ETV4 and WT1 expression in CIC‐rearranged sarcomas and histologic mimics. Mod. Pathol. 2016; 29; 1324–1334. PubMed

Kao Y, Sung Y, Chen C PubMed PMC

Yoshida A, Arai Y, Kobayashi E PubMed

Smith SC, Buehler D, Choi EYK PubMed

Brčić I, Brodowicz T, Cerroni L PubMed

Smith SC, Palanisamy N, Martin E PubMed

Siegele B, Roberts J, Black JO, Rudzinski E, Vargas SO, Galambos C. DUX4 immunohistochemistry is a highly sensitive and specific marker for CIC‐DUX4 fusion‐positive round cell tumor. Am. J. Surg. Pathol. 2017; 41; 423–429. PubMed

Snider L, Geng LN, Lemmers RJLF PubMed PMC

Klubíčková N, Dermawan JK, Mosaieby E PubMed

Dermawan JK, Cheng YW, Tu ZJ PubMed

Šteiner P, Andreasen S, Grossmann P PubMed

Black MA, Charville GW. Diagnosis of soft tissue tumors using immunohistochemistry as a surrogate for recurrent fusion oncoproteins. Semin. Diagn. Pathol. 2022; 39; 38–47. PubMed PMC

Anderson WJ, Hornick JL. Immunohistochemical correlates of recurrent genetic alterations in sarcomas. Genes Chromosomes Cancer 2019; 58; 111–123. PubMed

Baranov E, McBride MJ, Bellizzi AM PubMed PMC

Sugita S, Arai Y, Aoyama T PubMed

Sugita S, Arai Y, Tonooka A PubMed

Le Loarer F, Pissaloux D, Watson S PubMed

Huang SC, Zhang L, Sung YS PubMed PMC

Kojima N, Arai Y, Satomi K PubMed

Siegele BJ, Stemmer‐Rachamimov AO, Lilljebjorn H PubMed

Ko JS, Marusic Z, Azzato EM PubMed

Linos K, Dermawan JK, Bale T PubMed PMC

Mancarella C, Carrabotta M, Toracchio L, Scotlandi K. CIC‐rearranged sarcomas: an intriguing entity that may lead the way to the comprehension of more common cancers. Cancer 2022; 14; 5411. PubMed PMC

Kim JW, Ponce RK, Okimoto RA. Capicua in human cancer. Trends Cancer 2021; 7; 77–86. PubMed PMC

Tanaka M, Yoshimoto T, Nakamura T. A double‐edged sword: the world according to PubMed PMC

Yoshimoto T, Tanaka M, Homme M PubMed PMC