CIC–NUTM1 sarcoma in an 8‐year‐old female patient with a new fusion: A case report

Small blue round cell sarcomas in children usually include congenital/infantile fibrosarcoma, Ewing sarcoma, rhabdomyosarcoma, malignant rhabdoid tumor, desmoplastic small round cell tumor, and undifferentiated sarcoma such as sarcoma with BCOR genetic alterations and CIC rearranged sarcoma. CIC–NUTM1 sarcoma (C-NS) as a distinct subtype of CIC rearranged sarcoma is very rare in children.1 It has an aggressive clinical course, distinct histopathology and genetic features, and poor prognosis. An 8-year-old female patient was admitted to our hospital with a mass and intermittent pain at the back for 3 weeks. Magnetic resonance imaging detected an intramuscular mass at the back measuring about 7.4 × 6.4 × 6.3 cm with hypointensity at T1-weighted image and mixed intensity at T2-weighted image and inhomogeneous enhancement by contrast medium (Figure 1A). The tumor extended to the right thoracic cavity and canalis vertebralis, compressing the thoracic spinal cord and destroyed the surrounding vertebra. Plain computed tomography revealed the mixed density mass and multiple metastases in both lungs. The child was clinically diagnosed with a neurogenic tumor. Tumor biopsy was conducted. The resected tumor was sent for pathological investigation. Grossly, the resected mass measured 2.7 × 2.7 × 2.7 cm. The cut surface was gray-white. Morphologically, many sheets of round cells were embedded in a myxoid background with necrosis and mitoses (Figure 1B). The tumor cells had large vesicular nuclei, prominent nucleoli, and abundant cytoplasm (Figure 1B). Scattered rhabdoid tumor cells and pseudoinclusions were noticed (Figure 1C). Immunohistochemically, the tumor cells were positive for NUTM1 (Figure 1D), WT-1 (Figure 1E), CR, INI-1, BRG1, and vimentin, paranuclear dot-like expression for CD99 and pan-TRK, and negative for CK, PHOX2B, S-100, GFAP, desmin, CD34, p63, SYN, NKX2.2, SALL4, and Brachyury. Ki-67 proliferation index was approximately 30%. Fluorescence in situ hybridization (FISH) revealed positivity of the CIC rearrangement (Figure 1F). Next-generation sequencing detected CIC (NM_01386298.1 intron19)–NUTM1 (NM_001284292.2 intron5) fusion in the tumor cells. Other genetic alterations included mutations of TSC2 (exon41:c.A5237T:p.H1746L), CIC (exon10: c.G2396T:p.G799V; exon14: c.G3316A:p.A1106T; exon15: c.G3488A:p.S1163N), and TBX22 (exon8:c. T1555C:p.Y519H) genes and low-level microsatellite instability. The tumor mutational burden was 0.7 muts/Mb. The final diagnosis was CIC–NUTM1 sarcoma. AVCP (adriamycin, vincristine,cyclophosphamide,and cisplatin) chemotherapy regimen was administered. The patient was still in her treatment course at the second month’ follow-up after surgery. Written informed consent was taken from her parents. CIC rearranged sarcoma was first discovered by Richkind et al. in 1996 and designated by Kawamura-Saito et al. in 2006.2, 3 It was adopted as a unique subset of undifferentiated sarcoma in the fifth edition of the WHO classification of soft tissue and bone tumors in 2020.1 It includes CIC-DUX4 (the most common subtype), CIC-DUX10, CIC-FOXO4, CIC–NUTM1, CIC–NUTM2A, and CIC-LEUTX sarcomas.1, 4-6 CIC–NUTM1 sarcoma was first reported by Watson et al. in 20184 and is characterized by aggressive biological behaviors, round to epithelioid cell microscopic appearance with scattered rhabdoid morphology, and a unique immunohistochemical and genetic phenotype. Thirteen CIC–NUTM1 sarcomas (including our case) have been reported, with only seven pediatric cases.4, 7-11 The male to female sex ratio was 7:6, and the age range was 2–61 (average 24.3) years.7-11 Maximum tumor diameter ranged 2.0–12.5 (average 6.8) cm.7-11 The primary tumor locations were the deep soft tissue (n = 3), vertebra (n = 3), cranial bone (n = 2), extradural spinal cord (n = 2), brain (n = 1), kidney (n = 1), and lung (n = 1).7-11 Nine cases were derived from bone or had the neighborhood cranial bone or vertebra erosion. Rounded and epitheloid pattern is the most common histological feature of C-NS (13/13).5-10 Rabdoid cells were only highlighted in four cases.7-11 It usually has a positive immunoprofile for NUTM1 and CD99 (membrane or dot-like pattern). FISH tests for CIC or NUTM1 rearrangement are useful for the diagnosis.7 Next-generation sequencing detecting the CIC–NUTM1 fusion can verify the diagnosis of C-NS. The gene breakpoints were located in CIC (exons 16 to 20) and NUTM1 (exons 2 to 6 or intron 4).7-11 We report a new fusion of CIC intron 19–NUTM1 intron 5, which has never been reported. Treatment protocols for C-NS are still ill-defined. Combination of surgery,chemotherapy, and radiation therapy was the most common treatment strategies in those reported cases. Different chemotherapy schemes including VIDE (vincristin, dactinomycin, cyclophosphamide, uromitexan,and methylprednisolone), BEP (bleomycin, etoposide and platin), IVADO (ifosfamide, vincristine, actinomycin D), AI (doxorubicin and ifosfamide), IVA (ifosfamide, vincristine, and actinomycin D), or AVCP regimens had been used in different patients.7-11 Nine cases of the total 13 patients were observed tumor progression or metastatses in the treatment course, which showed C-NS tumor cells were resistant to the adopted adjuvant therapies to some extent. Pembrolizumab was administered as a maintenance immunotherapy in one patient.8 The prognosis of C-NS is very poor. Twelve cases with follow-up data showed an overall survival of 2−40 months. Eight patients died of disease, with an overall survival of 7−37 (mean: 15.6; median: 14.5) months. Targeted therapy may be promising for C-NS. The combination of dactolisib with trabectedin12 or iP300w13 had been demonstrated to strongly inhibit the tumor growth and metastasis for CIC-DUX4 sarcoma cell lines in vitro and in vivo. More specific therapies are urgently needed for this rare tumor to improve its prognosis. The authors declare no conflicts of interest.