What is CIC (CIC-DUX4) sarcoma?

CIC-DUX4 Sarcoma: Characteristics and Clinical Implications

CIC-DUX4 sarcoma (CDS) is a rare, aggressive undifferentiated round cell sarcoma characterized by a specific CIC-DUX4 fusion gene, which is distinct from Ewing sarcoma despite some morphological similarities. 1

Definition and Classification

• CIC-DUX4 sarcoma belongs to the family of undifferentiated round cell sarcomas and is now recognized as a distinct clinicopathological entity 2
• It is characterized by a specific oncogenic translocation CIC::DUX4 that induces ETV4 overexpression 2
• Previously considered an "Ewing-like sarcoma," CDS is now classified separately from Ewing sarcoma due to its unique molecular profile and more aggressive clinical behavior 1
• The fusion typically results from translocation t(4;19)(q35;q13) or t(10;19)(q26;q13) 1

Epidemiology and Clinical Presentation

• CDS represents less than 1% of all sarcomas, making it extremely rare 2
• It predominantly affects young adults 2
• CDS most commonly arises in soft tissues rather than bone, unlike classical Ewing sarcoma 1, 2
• A high proportion of cases present with advanced disease and lung metastases at diagnosis 2, 3
• The tumor has been reported in various locations including limbs, trunk, and rarely in visceral organs such as the kidney 2, 3

Diagnostic Features

• Diagnosis requires molecular confirmation of the CIC-DUX4 fusion gene 1
• Molecular testing methods include:
  • RT-PCR or anchored, multiplex PCR-based targeted NGS (preferred when frozen tissue is available) 1
  • FISH for EWSR1 rearrangements (when only FFPE tissue is available) 1
  • Comprehensive genomic profiling (CGP) when standard testing is negative 1
• The tumor shows partial morphologic and immunohistochemical overlap with Ewing sarcoma, which can lead to misdiagnosis without molecular confirmation 3

Clinical Behavior and Prognosis

• CDS demonstrates an aggressive clinical course with significantly worse outcomes compared to Ewing sarcoma 2, 3
• The tumor shows high propensity to metastasize, particularly to the lungs 2, 3
• CDS is generally less responsive to standard chemotherapy regimens than Ewing sarcoma 2, 3
• Poor prognosis is observed regardless of treatment approach 2

Treatment Approaches

• Currently, there is no consensus on whether CDS should be treated with:
  • An Ewing sarcoma-like approach (most commonly used) 2
  • Protocols for high-grade soft tissue sarcomas 2
• When feasible, combination regimens including anthracyclines and alkylating agents are recommended 2
• Therapeutic de-escalation should be avoided due to the aggressive nature of the disease 2
• For patients with Ewing-like round cell sarcomas including CIC::DUX4, multiagent chemotherapy for at least 9 weeks prior to local therapy is recommended 1
• Preclinical studies have identified potential targeted therapies:
  • Bortezomib and crizotinib have shown activity against CDS cells in laboratory models 4
  • Actinomycin D and doxorubicin demonstrated efficacy among standard Ewing sarcoma therapies 4

Molecular Biology and Research

• CDS is driven by the CIC-DUX4 fusion which acts as a neomorphic transcriptional activator 5
• The fusion protein affects ETS family transcription factors, which appear to be cooperative and redundant drivers of the core regulatory circuitry in CDS 5
• Patient-derived xenografts and cell lines have been established to facilitate research and drug development 4, 6
• These models show high Src kinase activities, suggesting potential therapeutic targets 4

Clinical Recommendations

• Patients with suspected CDS should undergo comprehensive molecular testing to confirm diagnosis 1
• Treatment should be determined by a multidisciplinary team at a specialized sarcoma center 2
• Registration within clinical trials and prospective registries is strongly recommended due to the rarity and poor prognosis of the disease 2
• Aggressive multimodal therapy should be considered, as de-escalation of treatment is not recommended 2