The patient was a 20-year-old man of Chinese descent presenting with a painful nodule in the left plantar of the second toe for 1 month. For past history, the patient had surgery twice on the same site of the toe 6 years ago and relapsed 1 month later, and there was no other treatment except surgery. Unfortunately, the pathological data were not available, and the operating margin was not known. For this time, the nodule was subcutaneous and palpable. The third surgical resection was performed, and a diagnosis of "low-grade fibromyxoid sarcoma" was made in a local hospital. For further medical attention, the pathological materials were referred to our department for consultation. The clinical follow-up period was 9 months since the last surgery. The timeline is summarized in  Figure 1 .
Grossly, the lesion was pale solid, and well-defined measuring 9 x 8 x 9 mm in size. Histological examination revealed a relatively well-defined and nodular tumor without a capsule ( Figure 2A ). The tumor was composed of short fascicles of uniform spindle cells in a collagenous to myxoid stroma. The tumor cells had pale eosinophilic cytoplasm and elongated nuclei with finely dispersed chromatin and small inconspicuous nucleoli ( Figures 2B, C ). Mitotic figures were rare.
Immunohistochemical staining was performed on 4-microm formalin-fixed, paraffin-embedded sections, which were immersed in a 10-mM sodium citrate buffer (pH 6) for 20 min at 97 C for antigen retrieval. The following antibodies were used: pankeratin (AE1/AE3, 1:50; Dako, Glostrup, Denmark), epithelial membrane antigen (EMA) (E29, 1:200; Dako), bcl-2 (clone 124, 1:100; Dako), CD34 (QB End 10, 1:100; Dako), alpha-smooth muscle actin (alpha-SMA) (1A4, 1:200; Dako), desmin (clone D33, 1:200; Dako), S100 protein (polyclonal, 1:800; Dako), SOX10 (polyclonal, 1:200; Santa Cruz Biotechnology, Dallas, TX, USA), H3K27me3 (RM175, 1:2,000, RevMAb, South San Francisco, CA, USA), MUC4 (8G7, 1:100; Abcam, Cambridge, UK), ERG (EPR3864, prediluted; Roche, Basel, Switzerland), SATB2 (SATBA4B10, 1:100, ZSGB), and Ki67 (MIB1, 1:150; Dako).The positive, blank, and negative controls were also performed in parallel.
By immunohistochemistry, the spindle tumor cells showed diffusely and strongly nuclear positive for ERG ( Figure 2D ), while S100, alpha-SMA, CD34, desmin, SATB2, EMA, MUC4, and other spindle cell tumor and vascular markers were negative. Ki67 index was about 15% in tumors.
According to the manufacturer's instructions, fluorescence in situ hybridization (FISH) was performed on formalin-fixed, paraffin-embedded tissue sections. Unstained 4-microm sections were placed on electrostatically charged slides and then evaluated using an EWSR1 (22q12) rearrangement in a dual-color, break-apart probe and an EWSR1 (22q12, green) and SMAD3 (15q22, red) fusion probe (LBP, Guangzhou, China). Under fluorescence microscopy, signals from 200 non-overlapping nuclei were counted. The cutoff level for the score as positive was when at least 20% of the nuclei showed a break-apart signal and/or loss of telomeric part or fusion signal (yellow).
The FISH assessment demonstrated an unbalanced rearrangement of EWSR1 with loss of the telomeric part ( Figure 3A ), combined with tumor cells, diffuse nuclear staining for ERG the diagnosis of EWSR1::SMAD3-rearranged fibroblastic tumor was considered. To identify the fusion partner, EWSR1 and SMAD3 fusion was detected by FISH ( Figure 3B ), and the fusion was confirmed by RT-PCR and Sanger sequencing between exon 7 of EWSR1 and exon 6 of SMAD3 ( Figure 3C ).
Based on the morphology, immunohistochemistry, and gene analysis, the final diagnosis was EWSR1::SMAD3-rearranged fibroblastic tumor. Treatment of the tumor was wide excision. To date, the patient is disease-free without relapse and metastasis for 9 months after the last surgery.