The most common primary renal malignant tumor is renal cell carcinoma of epithelial origin, while the mesenchymal and neuroendocrine originated tumors are extremely rare. In this case, the histologic morphology and IHC stainings that AE1/AE3 weakly positive, and CK7, PAX8 and Syn negative, suggested that the diagnosis of epithelial and neuroendocrine tumors was not valid. Because of the tumor cells were mostly small round cells and expressed CD99, WT1 and BRG1, and negative for Vimentin, the diagnosis of sarcomatoid carcinoma was excluded. The dilemma lies in Ewing or Ewing-like sarcomas. The absence of specific EWSR1-ETS fusion for the former, and existence of a CIC-LEUTX gene fusion leaded to the diagnosis of CRS.

CRS is the most common type of Ewing like sarcomas, represents a new entity that has morphological similarity but differs in IHC, genetic and clinical manifestation while comparing to Ewing sarcoma (EWS) [7]. Currently, there are about 200 cases reported around the world [8,9,10,11,12,13,14,15,16,17,18,19,20,21]. Generally speaking, it mostly occurs in young adults and children, but the olders can also be affected, with a slight male predominance. According to our study, 84% of the cases occurred in the deep soft tissue of the limbs and trunk, and most of them were in the deep muscle. About 14% occurred in the viscera, including the kidney, gastrointestinal tract, lung and brain. Very few cases occurred in the bone, mostly in the pelvis. Among them, the kidney and digestive tract are the primary sites with relatively high incidence, about 2/3 of the visceral CRS occurs in these two sites, and the lung and brain are the most frequent sites of metastasis. Interestingly, from the 8 cases of renal CRS (Table 1) that we can get detailed information, we found that the majority of tumors originated in the right kidney. Previously, only Mangray et al. [15] reported a primary renal case of left side in an 82-year-old woman.

Morphologically, CRS exhibit a more heterogeneous appearance when compared with EWS. The tumor cells usually organized in solid sheets or a lobulated growth pattern in sclerotic stroma, with scant cytoplasm and prominent nucleoli, and may contain focal spindle cells, epithelioid cells and myxoid stromal changes. Geographic areas of necrosis and hemorrhage are commonly seen, and mitotic count is usually high. In our case, the growth pattern and cell morphology of tumor are basically consistent with those reported in previous literatures. The expression of CD99, a hallmark of EWS, can be observed in approximately 85% of the CRS cases. However, it is often patchy with a cytoplasmic diffuse expression pattern, lacking the strong, diffuse membranous staining observed in EWS [22]. The expression of WT1 and ETV4 is consistently present, which is useful for the differential diagnosis of CRS, although not entirely specific. According to Hung et al. [12], the sensitivity and specificity of diffuse ETV4 expression for CRS are 90% and 95%, respectively, whereas the sensitivity and specificity of WT1 are 95% and 81%, respectively. CRS can also express Keratin, S100, Fli1, ERG, Calretinin, etc. in varying degrees, but they are not specific. The expression of other markers in our case is basically the same as that in the literature, while GATA3 is diffuse nuclear strong positive, which has not been reported before. GATA3 can be a useful tool in various tumors in kidney [23], however, whether it has differential diagnostic value for CRS needs to be confirmed by more cases. In the 8 reported cases of renal CRS, CD99 and WT1 were all positive, while ETV4 was only positive in 1 case, so it is not recommended to be a good auxiliary diagnostic indicator.

The identification of molecular features is now the standard to confirm the diagnosis of CRS. In clinic, FISH dual-color break-apart probes can be used to detect the rearrangement of CIC gene, but the negative result cannot completely rule out CRS. Yoshida et al. [20] demonstrated that the detection of FISH probe has a false negative rate of 14%, thus RT-PCR, tri-color FISH detection or second-generation sequencing can be added if necessary. By far the most frequent fusion partner is DUX4 (95% of cases), followed by FOXO4, LEUTX, NUTM1, and NUTM2A. The type of the chimeras may be relevant to their biological characteristics since, for example, CIC-NUTM1 sarcomas show distinct anatomic tropism for the axial skeleton and unfavorable behavior compared with classic CRS [24].

Among the other 7 cases of renal CRS reported so far, 5 were CIC-DUX4, 1 was CIC-NUTM1, and the other 1 case was unsequenced due to lack of materials. However, with its break-apart probe test positive, DUX4 staining positive, it tended to be a CIC-DUX4 fusion. Our case indicated a rare fusion of CIC-LEUTX by NGS sequencing. This fusion located in exon 20 of CIC gene and exon 3 of LEUTX gene, and the breakpoints were at chr19: 42799274 and chr19: 40276608, respectively. LEUTX is a member of the paired homeobox genes, which plays an important role in human embryonic development and is silenced postnatally. CIC-LEUTX cases seemed to have a preference for the central nervous system (CNS), and its onset age is very young. Of the 5 reported cases (Table 2) of CIC-LEUTX rearrangement, 4 occurred in the CNS and were younger than 19 years old, and only 1 case of 26-year-old female occurred in the soft tissue of the lower limb. In our case, no CNS lesion was found when searching for the primary tumor, combined with the manifestation of solitary renal mass, positive GATA3 staining, it was considered primary renal malignancy. But soon it developed brain metastasis 2 months after diagnosis.

Currently, patients with CRS are routinely treated in the same way as EWS, with a neoadjuvant and adjuvant anthracycline-based polychemotherapy regimen, surgery, and radiotherapy [1]. The CRS generally has a dismal prognosis. The 5-year overall survival is around 50%, which is significantly lower than the 80% 5-year overall survival of EWS patients [8]. This may also be related to the metastatic rate of about 50% at the time of initial diagnosis [8]. Limited Data indicate that CRS are less chemo-sensitive than EWS [1], and the challenging aspect remains to design more specific novel therapies. Yoshimoto et al. [25] found that palbociclib and trabectedin can block the growth of CIC-DUX4 sarcomas in an ex vivo mouse model. Carrabotta et al. [26] provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to combat CIC-DUX4 sarcomas in the experimental models of patient-derived xenografts (PDX) and PDX-derived cell lines. These studies provide us with encouraging possibilities for the treatment of CRS, but optimal treatment remains to be further clarified, and more clinical data and experimental results are required.

To the best of our knowledge, this is the first case of CIC-LEUTX rearranged sarcoma that occurred in the kidney. Although the primary site is extremely rare, its histomorphology and immunophenotype are similar to those of other common sites. The unreported positive staining of GATA3 may be one of the diagnostic indicators for the kidney origin. The final diagnosis depends on FISH detection or sequencing of CIC gene rearrangement. This tumor showed a poor outcome and overall survival was dismal with no effective treatment. More clinical data and laboratory results are need to clarify the biological characteristics, and develop more targeted treatment accordingly.