INTRODUCTION

Ewing sarcoma (ES) and Ewing-like sarcoma are highly aggressive round-cell mesenchymal neoplasms [1]. Ewing-like sarcoma refers to tumors that histologically resemble ES but lack the characteristic fusion between the EWSR1 gene and various members of the ETS family of transcription factors [1]. Recent advances in molecular techniques have revealed new entities in addition to ES, including round-cell sarcomas with EWSR1 gene fusion with non-ETS family members, CIC-rearranged sarcomas, and BCOR-rearranged sarcomas [1].

BCOR::CCNB3 fusion is the most common BCOR gene abnormality and was first identified by Pierron et al. in 2012 [2] through RNA sequencing and subsequent reverse transcription polymerase chain reaction (RT-PCR) confirmation in a large series of sarcoma cases. BCOR::CCNB3 fusion arises from a paracentric inversion on the X chromosome between exon 15 (Xp11.4) of BCOR and exon 5 (Xp11.22) of CCNB3 [3]. This fusion alters the complex associated with chromatin remodeling and histone modifications, impacting downstream gene regulation and contributing to sarcomatogenesis [3,4]. The 5-year survival rate for patients with BCOR::CCNB3 sarcoma is similar to that of ES patients (72%–80%) and superior to that of CIC-rearranged sarcoma [3]. It is currently considered responsive to conventional ES therapy, although treatment guidelines are not firmly established due to the limited number of cases [3].

There have been few reports of primary renal BCOR::CCNB3 sarcoma, with only 11 cases documented worldwide, all of which involved male patients [5]. Here, we present the first case of primary renal BCOR::CCNB3 sarcoma in a 22-year-old woman, which posed diagnostic challenges.

CASE REPORT

A 22-year-old female patient with an unremarkable medical history visited the hospital complaining of lower back and lower abdominal pain that had persisted for several days. Physical examination revealed tenderness in the lower abdomen and percussion pain in the left flank. Abdominal pelvic computed tomography showed a large cystic lesion measuring 8 cm in diameter with peripheral and septal enhancement in the left kidney (Fig. 1A). Initially, a needle biopsy was attempted to rule out malignancy, but it was unsuccessful. Therefore, a laparoscopic radical nephrectomy was subsequently performed for both diagnostic and therapeutic purposes.

Macroscopic examination revealed that the kidney measured 12.5 cm × 9.0 cm × 7.5 cm and weighed 412 g. A well-demarcated, lobulated, solid, and firm tumor measuring 9.5 cm × 7.5 cm × 5.0 cm was identified in the renal pelvis (Fig. 1B). This tumor was closely adjacent to the renal capsule and extended into the perinephric fat tissue. The cut surface of the tumor displayed a predominantly tan and ivory color with multifocal areas of hemorrhage and necrosis.

Microscopic examination revealed that the mass was composed of solid sheets of small round to oval or spindle cells, interspersed with fibrous septa (Fig. 2A). The mass exhibited focal cystic change, hemorrhage, necrosis, and focal hyalinization (Fig. 2B, C). A delicate vascular network was observed with extravasated red blood cells (Fig. 2D). At high-power magnification, the tumor cells exhibited vesicular nuclei, pale chromatin, and inconspicuous nucleoli (Fig. 2E). The nuclear membranes were indistinct and irregular, and the cytoplasm appeared clear to mildly eosinophilic. Frequent mitotic figures were identified, with up to 23 mitoses per 10 high-power fields (Fig. 2F).

Immunohistochemistry revealed diffusely strong nuclear positivity for TLE1 and focal nuclear positivity for cyclin D1 (Fig. 2G, H), diffuse cytoplasmic and membranous positivity for BCL2 (Fig. 2I), and membranous positivity for CD56 (Fig. 2J). The tumor cells were negative for CD99 (Fig. 2K). CD34 immunostaining showed extensive vascular proliferation within the tumor (Fig. 2L).

For more accurate diagnosis and treatment planning, next generation sequencing (NGS)–based molecular test was conducted using CancerScan V3.1 (Twist Biosciences, South San Francisco, CA, USA), a hybrid capture panel containing 407 genes along with introns of three genes for fusion hotspots. The panel also incorporates approximately 4,000 additional single-nucleotide polymorphisms distributed evenly across chromosomes for copy number variation purity correction and specific regions for microsatellite instability detection [6]. The quality of the NGS test was excellent, with a 98.86% on-target rate, mean depth = 612.45×, uniformity = 96.68%, and Q30 = 91.51%. In addition to detecting 15 single nucleotide variants and indels that were not clinically significant, the test identified a BCOR::CCNB3 fusion, which was critical for diagnostic confirmation.

Although the tumor was completely removed with negative resection margins, the patient underwent postoperative chemotherapy using vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, and etoposide (VAC/IE) to reduce recurrence potential. The patient remained stable for 10 months after postoperative chemotherapy, but the tumor recurred in the pelvis and left lower back skin. Subsequently, the patient underwent wide excisions for the recurrent tumors. Despite these procedures, the tumor metastasized to retroperitoneum and the lung. High-dose ifosfamide chemotherapy was administered, but metastatic tumors recurred five months later. Additional chemotherapy using irinotecan, gemcitabine, and docetaxel was attempted, but the patient expired 3 years after the initial diagnosis. The clinical course following nephrectomy is depicted in Fig. 3.

DISCUSSION

BCOR-rearranged sarcoma is a rare tumor, particularly in the kidney [5]. It was first described by Pierron et al. in 2012 [2]. This newly recognized entity encompasses several variants, including BCOR::CCNB3 sarcoma, sarcoma with BCOR variant fusions with a non-CCNB3 partner, and sarcomas with internal tandem duplication of BCOR exon 15 (BCOR ITD) [5]. BCOR ITD is predominantly associated with clear-cell sarcomas of the kidney (CCSK), while BCOR::CCNB3 fusion is identified in rare cases of renal sarcomas [5].

BCOR::CCNB3 sarcoma is relatively more common in bone than soft tissue, with a ratio of 1.5:1, and it tends to preferentially affect the pelvis, lower extremities, and paraspinal area. This type of sarcoma is most frequently seen in adolescents and young adults, with a male predominance; over 90% of patients are under 20 years old [4,7]. Only a small fraction (7.6%) of cases involve adults over 20 years old [8]. In contrast, sarcoma with BCOR-ITD mainly occurs in the soft tissues of the trunk, retroperitoneum, and head and neck, typically sparing the extremities [7]. Additionally, BCOR-ITD tumors often present within the first of year of life or even at birth, with 41% of cases diagnosed before the age of one [7,8].

To date, all 11 reported cases of primary renal BCOR::CCNB3 sarcoma have occurred in male patients, with a mean age of 18 years (Table 1) [3,5,8-13]. The marked male predominance is thought to result from the BCOR::CCNB3 fusion occurring during pericentric inversion of the X chromosome [13]. Clinical manifestations are nonspecific, with most patients presenting with abdominal pain. At the time of diagnosis, these tumors are usually large (3.2–27 cm), solid, and variably cystic [5]. The clinical manifestations in this case were similar to those reported in previously documented cases, aside from the sex. However, due to its rarity and nonspecific clinical findings, accurate preoperative diagnosis was not achieved [5].

Histopathological diagnosis is challenging even for experienced renal pathologists because BCOR::CCNB3 sarcoma exhibits considerable morphological diversity and overlaps significantly with CCSK and synovial sarcoma in its histological and immunohistochemical features [5]. Key histological features include a uniform proliferation of primitive small round to ovoid and plump spindle cells arranged in solid sheets, surrounded by abundant capillary networks [5]. Immunohistochemical markers such as SATB2, cyclin D1, TLE-1, BCOR, and CCNB3 can be helpful for diagnosis [5]. In previous studies, BCOR::CCNB3 sarcoma showed positivity for CCNB3 (97%), BCOR (90%), TLE1 (84%), and SATB2 (84%). However, due to the insufficient sensitivity and specificity of these markers, molecular genetic analyses such as fluorescence in situ hybridization, RT-PCR, or RNA sequencing are currently the diagnostic gold standard for confirming the presence of BCOR::CCNB3 fusion [4,5,7,9].

BCOR::CCNB3 sarcoma prognosis remains uncertain due to its rarity. However, some reports suggest a 5-year survival rate and a disease-free survival rate of approximately 72% and 68%, respectively, similar to those of CCSK and better than those of ES [5]. Other reports suggest the 5-year survival rate is comparable to that of ES [14,15]. A significant proportion of patients with BCOR::CCNB3 sarcoma experiences metastases, most commonly to the lungs, followed by bone, soft tissue, and visceral sites [14,15]. Poor prognostic factors include axial location, local recurrence, and metastasis [14,15].

The optimal therapeutic regimen for BCOR::CCNB3 sarcoma has not been established [5]. Since BCOR::CCNB3 sarcoma was initially classified within the ES family of tumors, most patients have been treated according to ES-related chemotherapy protocols [14,15]. BCOR::CCNB3 sarcoma has shown a histologic response to ES-based treatment, resulting in better outcomes [14,15]. Given the overlapping morphology and transcriptional profile of BCOR::CCNB3 sarcoma and CCSK and the known sensitivity of CCSK to doxorubicin-based chemotherapy, there is a possibility that BCOR::CCNB3 sarcoma may respond to similar treatments. However, it remains unclear whether these patients would benefit from a less toxic treatment protocol compared with current ES-based regimens [9,15]. Further studies on renal BCOR::CCNB3 sarcoma are essential to define optimal treatment strategies and accurately predict prognosis for these patients.

Fig. 1.

Computed tomography image and gross findings. (A) Computed tomography scan reveals a well-defined, huge, solid-cystic tumor with focal enhancement (arrow). (B) A well-demarcated large solid tumor with cystic change in the renal pelvis.

Fig. 2.

Microscopic and immunohistochemistry findings of the tumor. (A) Solid growth pattern separated by fibrous septa. (B) Cystic change. (C) Necrosis. (D) Vascular networks with extravasated red blood cells. (E) Round to oval tumor cells with vesicular nuclei, irregular nuclear membrane, inconspicuous nucleoli, and clear to eosinophilic cytoplasm. (F) Increased mitotic activity (circles) up to 23/10 high-power field. (G) Diffuse strong nuclear positivity for TLE1. (H) Focal nuclear positivity for cyclin D1. (I) Diffuse cytoplasmic and membranous positivity for BCL2. (J) Diffuse membranous positivity for CD56. (K) No immunopositivity for CD99. (L) CD34 highlighted vascular networks.

Fig. 3.

Patient clinical course after left radical nephrectomy. VAC/IE, vincristine, adriamycin, cyclophosphamide alternating with ifosfamide and etoposide; HD-IF, high-dose ifosfamide.

REFERENCES

• 1. Sbaraglia M, Righi A, Gambarotti M, Dei Tos AP. Ewing sarcoma and Ewing-like tumors. Virchows Arch 2020; 476: 109-19. ArticlePubMedPDF
• 2. Pierron G, Tirode F, Lucchesi C, et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 2012; 44: 461-6. ArticlePubMedPDF
• 3. Hagoel TJ, Cortes Gomez E, Gupta A, et al. Clinicopathologic and molecular analysis of a BCOR-CCNB3 undifferentiated sarcoma of the kidney reveals significant epigenetic alterations. Cold Spring Harb Mol Case Stud 2022; 8: a005942.ArticlePubMedPMC
• 4. Rekhi B, Kosemehmetoglu K, Ergen FB, et al. Spectrum of histopathological, immunohistochemical, molecular and radiological features in 12 cases of BCOR::CCNB3-positive sarcomas with literature review. Int J Surg Pathol 2023; 31: 1244-64. ArticlePubMedPDF
• 5. Zhao M, Zhang Q, He X, Zhang D. Primary renal BCOR-CCNB3 fusion sarcoma: a case report and review of the literature. Urol Int 2022; 106: 644-8. ArticlePubMedPDF
• 6. Park S, Lee C, Ku BM, et al. Paired analysis of tumor mutation burden calculated by targeted deep sequencing panel and whole exome sequencing in non-small cell lung cancer. BMB Rep 2021; 54: 386-91. ArticlePubMedPMC
• 7. Choi JH, Ro JY. The 2020 WHO classification of tumors of soft tissue: selected changes and new entities. Adv Anat Pathol 2021; 28: 44-58. ArticlePubMed
• 8. Yoshida A, Arai Y, Hama N, et al. Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults. Histopathology 2020; 76: 509-20. ArticlePubMedPDF
• 9. Argani P, Kao YC, Zhang L, et al. Primary renal sarcomas with BCOR-CCNB3 gene fusion: a report of 2 cases showing histologic overlap with clear cell sarcoma of kidney, suggesting further link between BCOR-related sarcomas of the kidney and soft tissues. Am J Surg Pathol 2017; 41: 1702-12. ArticlePubMedPMC
• 10. Setoodeh S, Palsgrove DN, Park JY, Pedrosa I, Kapur P, Jia L. Primary renal sarcoma with BCOR-CCNB3 gene fusion in an 18-year-old male: a rare lesion with a diagnostic quandary. Int J Surg Pathol 2021; 29: 194-7. ArticlePubMedPMCPDF
• 11. Wong MK, Ng CCY, Kuick CH, et al. Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion. Histopathology 2018; 72: 320-9. ArticlePubMed
• 12. Han H, Bertrand KC, Patel KR, et al. BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney. Pediatr Blood Cancer 2020; 67: e28151.ArticlePubMedPDF
• 13. Dorwal P, Abou-Seif C, Ng J, Super L, Chan Y, Rathi V. Clear cell sarcoma of the kidney (CCSK) with BCOR-CCNB3 fusion: a rare case report with a brief review of the literature. Pediatr Dev Pathol 2023; 26: 149-52. ArticlePubMedPDF
• 14. Cohen-Gogo S, Cellier C, Coindre JM, et al. Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Societe Francaise des Cancers de L'Enfant. Pediatr Blood Cancer 2014; 61: 2191-8. ArticlePubMed
• 15. Kao YC, Owosho AA, Sung YS, et al. BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am J Surg Pathol 2018; 42: 604-15. ArticlePubMedPMC

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References

Citations

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• Update on the management of BCOR::CCNB3 sarcoma
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  Japanese Journal of Clinical Oncology.2025;[Epub]     CrossRef