Rare Case of BCOR::CCNB3 Sarcoma of Bone

Background

BCOR (BCL-6 interacting corepressor)::CCNB3 (Cyclin B3) sarcoma has been described as one of the subtypes of undifferentiated/unclassified sarcomas, sharing a small round cell feature like Ewing sarcoma together with spindle cell proliferation [1]. In the WHO Classification of Bone and Soft Tissue Tumours (5th edition, 2020), Ewing sarcoma and part of un-differentiated/unclassified sarcoma (small round cell sarcoma except Ewing sarcoma) were integrated into a new independent chapter of “undifferentiated small round cell sarcomas of bone and soft tissue” [2]. While Ewing sarcoma is characterized by the EWSR1/FET::ETS fusion gene, there are 3 categories of non-Ewing sarcomas, based on each specific histopathological and genetic feature, such as round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations [2]. The last type has been further subdivided into 2 subtypes: BCOR::CCNB3 sarcoma and sarcomas with BCOR::ITD [3]. Although BCOR::CCNB3 sarcoma is the most frequent type in the BCOR gene alterations category, it comprises only 4% of cases of Ewing sarcoma-mimicking tumor of the bone, and whether it shares consistent clinical features as a unique entity is still not well known [4].

Case Report

A 15-year-old boy had right thigh pain for more than 6 months with no notable cause. He consulted a local orthopedic clinic, and a radiograph was taken, which showed an expansion of the right proximal femoral shaft along with irregular cortical thickening (Figure 1). Although he had been on analgesics for another 6 months, he still experienced occasional severe pain. Because the pain worsened during the last week, he consulted a local clinic again, and the radiographic image taken at that time showed significant progression of the femoral lesion. Then, he consulted our hospital. He had a past history of pathologically confirmed schwannoma in his right forearm.

A physical examination revealed an elastic-hard mass in his proximal thigh, measuring about 10×12×5 cm. It was tender on palpation, and local inflammation with heat were also prominent.

Plain radiographic images of the right femur showed a fracture line, together with cortical erosion over the proximal metaphysis and the diaphysis (Figure 2). The results of a computed tomography (CT) scan revealed similar irregular cortical erosion and expansion of the femoral shaft (Figure 3). Magnetic resonance imaging (MRI) showed a solid mass extending both inside and outside of the femur, exhibiting relatively homogenous iso-intensity on T1-weighted images and high-intensity on short-T1 inversion recovery (STIR) images (Figure 4). It revealed high accumulation on 18F-fluorodeoxyglucose positron emission tomography/CT scanning, and no other neoplastic lesion was observed (Figure 5).

With a tentative diagnosis of malignant bone tumor, a biopsy of the right femur was conducted. Histologically, the biopsy specimen demonstrated a proliferation of small round and short spindle cells, showing round to oval nuclei on hematoxylin-eosin staining (Figure 6A), which is a typical histological appearance of BCOR::CCNB3 sarcoma. Immunohistochemical analysis revealed that the tumor cell nuclei were diffusely positive for BCOR, CCNB3, and PAX7 and negative for NKX2.2 (Figure 6B, 6C). Neither EWSR1 nor SS18 gene rearrangement were detected by fluorescence in situ hybridization (FISH) study. As those features are commonly recognized diagnostic features of BCOR::CCNB3 sarcoma, we consequently diagnosed this tumor as a BCOR::CCNB3 sarcoma arising in the femur (G4, T2, N0, M0, Stage IIB: UICC version 6).

While we stabilized the pathologic fracture with direct femoral traction, the patient was on 3 courses of alternative chemotherapy using vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC/IE), based on the JESS04 protocol [5], which brought a marked improvement of the femoral lesion (Figure 7). Because of a pathologic fracture that might have extended tumor invasion further than estimated and a traction pin that was inserted at the distal femur, a total fem-oral-wide resection was chosen for the definitive surgery, followed by total femoral prosthetic replacement (Figure 8). The surgical specimen also showed no viable tumor histologically. After 2 courses of postoperative chemotherapy, local heat of his right knee was recognized and became persistent. With a suspicion of surgical site infection due to chemotherapy myelosuppression, antibiotic treatment was commenced. Local tissue biopsy was not conducted because the heat subsided within a few weeks. However, additional adjuvant chemotherapy was not adapted because the patient was not willing to have a high risk of prosthetic infection that could lead to subsequent amputation surgery. At the latest follow-up at 3 years after surgery, the patient was doing well, showing no evidence of recurrence, with an ISOLS limb functional score of 53%.

Discussion

In 2012, BCOR::CCNB3 sarcoma, which is now acknowledged as a definite histological category, was first reported by Pierron et al as a Ewing-like tumor in the bones of adolescents. Both the BCOR and CCNB3 genes exist in the short arm of the X chromosome, fusion by reverse chromosome inv(X) (p11.4: p11.22) [4]. The BCOR gene was originally reported as an individual interacting corepressor of BCL6 in diffuse large B-cell lymphoma in 2000 [6]. It was also identified in renal tumors and NK/T cell malignant lymphoma as one of the frequently observed function-acquiring mutations [7,8]. CCNB3 encodes testis-specific cyclin B gene, functions in mitosis, and connects CDK2 for spermatic production [9]. The precise function of BCOR::CCNB3 is still under investigation. However, when it was detected in NIH3T3 cells, high expression of the hedgehog or Wnt pathways was noted [4].

BCOR::CCNB3 sarcoma occurs predominantly in the young and adolescent population, which is similar to Ewing sarcoma. It occurs slightly more often in the bone than in the soft tissue (ratio: 1.5: 1) with a predilection for the pelvis, lower extremity, and paraspinal region. The 5-year-survival rate is approximately 72% to 80% [3].

Histologically, it is typically observed as a uniform and diffuse proliferation of small round to short spindle cells showing oval nuclei without pleomorphism. The nuclei show fine chromatin and inconspicuous nuclei [3]. The histological appearance of our case was typical for BCOR::CCNB3 sarcoma: the tumor cells were predominately round cells with oval to short spindle-shaped nuclei. Immunohistologically, they showed positivity for BCOR and CCNB3, whereas they were negative for NKX2-2 (a reliable positive marker of Ewing sarcoma), which supported the diagnosis of BCOR::CCNB3 sarcoma. We thought further molecular sequencing was not necessary, because cyclin B3 expression is not seen in other BCOR family tumors [3].

In addition, NKX2.2 negativity also ensures the diagnosis of BCOR::CCNB3 sarcoma more than of Ewing sarcoma [10].

Chemotherapy and wide resection of the tumor is a current mainstay for BOR::CCNB3 sarcoma [2]. Optional treatment for this case might be a surgical procedure. Amputation, femoral rotationplasty, proximal or total femoral resection with prosthetic or allograft replacement would be considerable choices of surgery. The first reason we chose total femoral replacement is that we were worried about local tumor spread caused by pathologic fracture. The second reason was risk of infection if the distal part of the femur, in which the traction pin was inserted during chemotherapy. were preserved,

The tumor responded favorably to the chemotherapy based on a protocol for Ewing sarcoma. A similar result of Ewing sarcoma-oriented chemotherapy for BCOR::CCNB3 sarcoma was already reported [11].

In contrast to distinct pathological features with the evidence of a tumor-specific fusion gene, clinical manifestations of BCOR::CCNB3 sarcoma have still not been sufficiently documented in the literature. One of the characteristic features of our case was that the symptomatic period lasted for almost 1 year, which seems rather longer than that of usual Ewing sarcoma cases. Nevertheless, appropriate literature discussing the symptomatic period could not be found, and whether this should be a common clinical character of BCOR::CCNB3 sarcoma is not determined yet.

Regarding imaging studies, Sirisena et al reviewed 14 articles and highlighted 148 cases of BCOR::CCNB3 sarcoma, with images of 96 cases. Most of them showed a clear margin in the X-ray, and only a small number of cases showed a poor tumor margin [12]. The rate of occurrence of lytic lesion was 60%, that of sclerotic lesion was 15%, and a mixture of sclerotic and lytic lesions was 5% out of the total samples. In a small number of patients, 2-mm cortical thickening was also observed. MRI results for most of the cases showed heterogenous intensity and septa on T2-weighted images, which showed marked enhancement with contrast medium, and central necrosis was recognized as well. Brady et al also reported X-ray and CT images in which 2 cases showed lytic lesions and 3 showed sclerotic lesions [13]. They noted a marked effect of enhancement of images in the imaging study; of all the cases, 33% showed flow void and 66% showed necrosis. Our case probably should be included in the sclerotic type. However, there was a slight inconsistency in the characteristics shown on MRI, because our case showed a homogenous appearance. Another possibility is that we should conclude that the appearance of BCOR::CCNB3 sarcoma on MRI is variable and that there may be a type that shows homogenous appearance on MRI, like our case.

Conclusions

We reported a rare tumor of BCOR::CCNB3 sarcoma of the fem-oral bone. Notable characteristics of this case were an almost 1-year symptomatic period and the specific imaging feature of a homogenous appearance on MRI. The diversity of clinical manifestations and imaging characteristics of BCOR::CCNB3 sarcoma are still not well known and should be further discussed in future reports.