Diagnosis -- CIC-rearranged Sarcoma


FINAL DIAGNOSIS

CIC-rearranged sarcoma.

DISCUSSION

CIC-rearranged sarcoma, included in the 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone, is a high-grade round cell undifferentiated sarcoma defined by the presence of CIC-related gene fusions [1].

CIC-rearranged sarcomas occur in a wide age range, with a median age of 25 to 35 years. These tumors typically occur in the deep soft tissues of extremities or trunk and less commonly in the head and neck, retroperitoneum or pelvis. Approximately 10% of these tumors involve the visceral organs (e.g., kidney, gastrointestinal tract, or brain), while primary bone tumors are rare [1-2].

Grossly these tumors are usually large, circumscribed, white to tan, and fleshy masses, with frequent necrosis and hemorrhage. Histopathologically, CIC-rearranged sarcomas are composed of diffuse sheets of small round cells with mild to moderate nuclear pleomorphism, vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, often with clearing. The tumor often displays a lobular architecture delineated by fibrotic stroma. Stromal myxoid change and a minor component of spindle or epithelioid cells may be seen in a subset of cases. High brisk mitotic rate and geographic necrosis with perivascular preservation in necrotic areas are common. By far, the most common CIC rearrangement partner is DUX4, accounting for 95% of cases [3]. Rare cases of CIC sarcomas are associated with non-DUX4 partners, including FOXO4, LEUTX, NUTM1, or NUTM2A [4-7].

By immunohistochemistry, CIC-rearranged sarcomas often express CD99 (patchy), WT1 (90-95%), and ETV4 (95-100%) [8]. This pattern of staining is particularly useful given the potential for false negativity with RNA sequencing algorithms and FISH studies [9]. Sarcomas with CIC::NUTM1 fusions express NUT protein. CIC-rearranged sarcomas pursue an aggressive clinical course that is markedly worse than Ewing sarcoma. The 5-year overall survival is estimated at 17-43%, with an inferior response to the current Ewing sarcoma chemotherapy regimens [1,2].

In conclusion, CIC-rearranged sarcomas are newly described high-grade round cell poorly differentiated sarcomas, defined by CIC fusion with different gene partners, most commonly CIC::DUX4, that are characterized by an aggressive clinical course and low survival rate.

REFERENCES

  1. Antonescu CR et al., "CIC-rearranged sarcoma," In: WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours, 5th ed. vol. 5. Lyon (France): International Agency for Research on Cancer (IARC), 2020, ch. Undifferentiated small round cell sarcomas of bone and soft tissue, pp. 330-332.
  2. Antonescu CR et al., "Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases," The American journal of surgical pathology, vol. 41, no. 7, 2017 Jul 2017, doi: 10.1097/PAS.0000000000000846.
  3. Italiano A et al., "High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas," Genes, chromosomes & cancer, vol. 51, no. 3, 2012 Mar 2012, doi: 10.1002/gcc.20945.
  4. Kawamura-Saito M et al., "Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation," Human molecular genetics, vol. 15, no. 13, 07/01/2006 2006, doi: 10.1093/hmg/ddl136.
  5. Le Loarer F et al., "Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas," The American journal of surgical pathology, vol. 43, no. 2, 2019 Feb 2019, doi: 10.1097/PAS.0000000000001187.
  6. Sugita S et al., "A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma," The American journal of surgical pathology, vol. 38, no. 11, 2014 Nov 2014, doi: 10.1097/PAS.0000000000000286.
  7. Sugita S et al., "NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma," Human pathology, vol. 65, 2017 Jul 2017, doi: 10.1016/j.humpath.2017.01.012.
  8. Hung YP et al., "Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics," Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, vol. 29, no. 11, 2016 Nov 2016, doi: 10.1038/modpathol.2016.140.
  9. Kao YC et al., "ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements." Genes Chromosomes Cancer. 2017 Jun;56(6):501-510. doi: 10.1002/gcc.22454. Epub 2017 Mar 31. PMID: 28233365; PMCID: PMC5643042.


Contributed by Pooria Khoshnoodi, MD, and Ivy John, MD




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