CIC-rearranged sarcoma

Last revised by Raymond Chieng on 27 May 2022

CIC-rearranged sarcomas or CIC-DUX4 sarcomas are aggressive undifferentiated small round cell sarcomas with CIC-gene fusions most frequently CIC-DUX4. It is an ultra-rare high grade undifferentiated sarcoma, distinct in terms of clinical presentations and molecular characteristics 6.

Most CIC-rearranged sarcomas are found in young adulthood in the third and fourth decade, even though they have been observed in a wide age range including children and elderly people. Males are slightly more frequently affected 1,2.

The diagnosis of CIC-rearranged sarcomas is made by histology, immunohistochemistry and molecular pathology 1.

Diagnostic criteria according to the WHO classification of bone tumors (2020 - blue book) 1:

  • prevalent round cell morphology with minor epithelioid and/or spindle cell elements
  • mild nuclear pleomorphism
  • variably myxoid stroma
  • variable CD99 and frequent WT1 and ETV4 positivity

Molecular confirmation of the CIC gene rearrangement is desirable in selected cases.

Tumors can present as swelling or mass with or without pain or with symptoms from their metastases 1.

CIC-rearranged sarcomas are small round cell tumors 1.

The etiology of CIC-rearranged sarcomas is unknown 1.

Common locations of CIC-rearranged sarcomas are the deep soft tissues of the limbs and trunk 1-3. Less common locations include the head and neck area, the retroperitoneum or the pelvis. Primary tumors in visceral organs as the kidney, the gastrointestinal tract and the brain occur in about 10% of cases. Primary involvement of bone occurs in <5% 1.

Macroscopically CIC-rearranged sarcomas are characterized by a tannish-white color commonly with signs of hemorrhage and necrosis. They are usually large at the time of diagnosis 1.

Microscopically CIC-rearranged sarcomas are characterized by the following histological features 1,2:

  • sheets of undifferentiated round cells (with high nuclear to cytoplasmatic ratio)
  • a minor part of epithelioid or spindle cells
  • at least partly lobulated growth pattern
  • mild nuclear pleomorphism with abundant eosinophilic cytoplasm
  • reticular or pseudoacinar arrangement in a variably myxoid stroma

Immunohistochemistry stains show a mostly patchy and less commonly diffuse and membranous CD99 expression with additional positivity of WT1 and ETV4 in >90%. NKX2-2 is typically negative. NUT protein might be positive in sarcomas with CIC-NUTM1 fusions 1,2.

Approximately 95% of CIC-rearranged sarcomas are characterized by CIC-DUX4 gene fusions. The remainder includes the involvement of partner genes as FOXOE4, LEUTX, NUTM1 and NUTM2a 1-4.

On CT CIC-rearranged sarcomas have been described as isodense or hypodense to muscle with heterogeneous enhancement 5.

On MRI CIC-rearranged sarcomas have been described as large enhancing necrotic masses with perilesional edema in the majority of the cases, flow voids and/or of them and about one fifth showing fluid-fluid levels 5. Signal characteristics have been described as follows 5:

  • T1: intermediate to high intensity
  • T2: heterogeneously high signal intensity
  • T1 C+ (Gd): heterogeneous enhancement

On PET-CT avid uptake of FDG has been reported 5.

The radiological report should include a description of the following:

  • form and location
  • tumor margins and transition zone
  • relations to the muscular fascia
  • relation to adjacent neurovascular structures
  • relations to bones

The usual treatment regimens for CIC-rearranged sarcoma are surgical resection, chemotherapy, and adjuvant radiation. However, 55% of those received such treatment developed metastasis in a median time of 10.5 months 6.

CIC-rearranged sarcomas show an aggressive course and do not respond very well to the chemotherapy regimen used for Ewing sarcoma 1-3. They commonly metastasize to the lung. Prognosis is poor with an estimated 5-year survival rate of 17-43% 1

Apart from other undifferentiated round small cell tumors, CIC-rearranged sarcomas can mimic the appearance of other soft tissue sarcomas 1,5.

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