Introduction: Capicua transcriptional repressor (CIC)-DUX4 rearranged sarcoma is a subtype of CIC-rearranged sarcomas composed of undifferentiated Wilms’ tumor 1 (WT1)+, CD99+ round cells with recurrent CIC gene rearrangement. The diagnosis of CIC-rearranged sarcoma remains challenging, and the prognosis of CIC-rearranged sarcomas is poor. Case Presentation: In this report, we described a case of CIC-DUX4 rearranged sarcoma presenting in the skin, expressing WT1 and CD99 in a dot-like pattern. In addition, the assessment of genomic alterations using genome panel testing was useful to confirm the accurate diagnosis. Conclusion: Our present case suggests that widespread use of genomic panel testing in the future may lead to early treatment and improve the prognosis of CIC-rearranged sarcomas.

Capicua transcriptional repressor (CIC)-rearranged sarcoma is a subgroup of the Ewing-like sarcoma family that represents an undifferentiated round cell malignancy with recurrent CIC gene rearrangement [1]. The most common fusion partner is DUX4, located on the long arm of chromosomes 4q35 or 10q26.3. CIC-DUX4 predominantly affects children and young adults, with a median age in the second decade. Most tumors arise in the deep soft tissue of the trunk, limbs, or head and neck region, occasionally involving adjacent bone. In this report, we described a case of CIC-DUX4 rearranged sarcoma presenting in the skin.

A 24-year-old Japanese woman visited our outpatient clinic with a 2-year history of an asymptomatic subcutaneous nodule on the abdomen. One week prior to her visit, the nodule developed a traumatic blister due to bruising (Fig. 1). The tumor was marginally, incompletely resected in a private surgery 3 months before her visit, and a pathologist histologically diagnosed it as epidermoid angiosarcoma. On her initial visit, a physical examination revealed only a surgical scar. In addition, there were no signs of local recurrence and distant metastasis of the tumor, using positron emission tomography-computed tomography and MRI. The specimen from the primary tumor revealed a predominantly necrotic lesion, with scattered active lesions composed of a massive proliferation of atypical clear, balloon-like cells (Fig. 2). Immunohistochemical staining showed that these balloon-like cells were positive for Wilms’ tumor 1 (WT1) (Fig. 3a), CD99 (Fig. 3b), vimentin, BCL2, and p53 and negative for AE1/AE3, CK20, CD3, CD5, CD10, CD20, CD68, CD163, CD79a, TdT, MPO, TTF1, SALL4, CD31, CD34, D2-40, melan A, EMA, desmin, S-100, a-SMA, MyoD1, chromogranin A, synaptophysin, HHF35, and NKX3.1. No translocations of EWSR1 or FKHR were detected by fluorescence in situ hybridization. The assessment of genomic alterations using FoundationOne® CDx detected the CIC-DUX4 fusion gene.

Fig. 1.

Physical examination at the initial treatment during private surgery.

Fig. 1.

Physical examination at the initial treatment during private surgery.

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Fig. 2.

Specimen from the primary tumor: most of the tumor was necrotic lesion with scattered active lesions composed of a massive proliferation of atypical clear, balloon-like cells.

Fig. 2.

Specimen from the primary tumor: most of the tumor was necrotic lesion with scattered active lesions composed of a massive proliferation of atypical clear, balloon-like cells.

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Fig. 3.

Immunohistochemical staining at tumor sites: balloon-like tumor cells were positive for WT1 and CD99.

Fig. 3.

Immunohistochemical staining at tumor sites: balloon-like tumor cells were positive for WT1 and CD99.

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Based on these findings, our diagnosis was CIC-DUX4 rearranged sarcoma presenting in the skin. The patient was treated with vincristine (2 mg/body on day 1), doxorubicin (37.5 mg/kg on days 1 and 2), cyclophosphamide (1,200 mg/kg on day 1), ifosfamide (1,800 mg/kg on days 15–19), and etoposide (100 mg/kg on days 15–19) in the neoadjuvant setting for 3 cycles, followed by vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide or VC-IE therapy for 4 cycles before undergoing radical resection. There was no recurrence 14 months after the completion of intensive therapy. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539501).

The histological diagnosis of soft tissue sarcomas presenting in the skin is occasionally challenging since such sarcomas can manifest differently between superficial and deep dermal lesions [2]. Therefore, in general, an appropriate immunohistochemical staining set is essential for accurate diagnosis. In our present case, since most of the tumor is composed of necrotic tissues, we first determined the appropriate tumor lesion for immunohistochemical staining evaluation using a comprehensive panel of antibodies, which revealed that tumor lesion was positive for WT1 and CD99 in a dot-like pattern.

CD99 staining is observed in approximately 85% of cases of CIC rearranged sarcoma, but it is often patchy, lacking the strong, diffuse membranous pattern observed in Ewing sarcoma [3]. In our present case, contrary to previous reports, we observed CD99 expression in dot-like patterns, which has been reported in Merkel cell carcinoma, small cell lung cancer, Ewing sarcoma, lymphoblastic lymphoma/leukemia, and rhabdomyosarcoma [4]. Since such CD99 staining pattern has not been reported in CIC-rearranged sarcomas, our initial diagnosis was anaplastic small round cell sarcoma. CD99 is a transmembrane protein located in the pseudoautosomal region of the short arm of the XY chromosome, and it is assumed that the dot-like pattern may be due to a mixed reaction with intermediate diameter filaments or related to a fusion gene [5]. Further cases are needed to elucidate why our present case exhibited CD99 expression in a dot-like shape.

In addition to CD99 expression, WT1 expression is useful for differentiating CIC-rearranged sarcomas from Ewing sarcoma and other Ewing-like sarcomas [6]. WT1 is a transcription factor with a zinc finger structure, expressed in tissues of mesodermal origin, and it interacts with the tumor suppressor gene p53. WT1 was classically discovered as a cancer-suppressor gene in association with Wilms’ tumors but has recently been considered to have an oncogene function. Since WT1 was strongly positive in small round tumor cells in both cytoplasm and nucleus in our present case as previously reported [7], we further suspected that our present case might be a CIC-DUX4 rearranged sarcoma. We then employed genomic alteration assessment using FoundationOne® CDx, which confirmed our final diagnosis.

Since CIC-rearranged sarcomas are highly aggressive and their diagnosis remains challenging [8, 9], the prognosis of CIC-rearranged sarcomas is poor. Indeed, approximately 40% are associated with multiple metastases at the initial diagnosis [8]. Due to the diagnostic challenges described above, CIC-rearranged sarcoma used to be a fatal disease, but the widespread use of genomic panel testing such as FoundationOne® CDx has improved diagnosis. Indeed, there has been a case report definitively diagnosed by FoundationOne® CDx [9]. In our present case, FoundationOne® CDx was also useful to confirm our final diagnosis for CIC-DUX4 rearranged sarcoma. Although reported cases are still limited, further cases may confirm that the widespread use of genomic panel testing in the future leads to early treatment and improved prognosis of CIC-rearranged sarcomas.

Written informed consent was obtained from the patient for publication of the details of her medical case and any accompanying images. The protocol for this human study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan (permit No. 2021-1–1213).

The authors have no conflicting interests to declare.

There is no funding source to declare for this study.

R.A., T.F., A.H., S.Y. and Y.A. treated the patient and acquired the clinical data. R.A. and T.F. wrote the manuscript. T.F. and Y.A. supervised the study.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

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