Rare case of round cell sarcoma of bone with EWSR1-NFATC2 fusion

A rare diagnostically challenging case of CIC-DUX4 sarcoma arising in the neck

The present study describes a new case of EWSR1-negative undifferentiated sarcoma with CIC/DUX4 gene fusion. This case is similar to tumors described as primitive undifferentiated round cell sarcomas that occur mainly in the trunk and display an aggressive behavior. To our knowledge, this is the first report of such a tumor presenting locoregional lymph node metastasis. In view of previous studies that prove the existence of a particular variant of undifferentiated sarcoma with Ewing-like morphology and CIC/DUX-4 gene fusion, a search for this gene fusion in all undifferentiated round cell sarcomas should be considered if a conclusive diagnosis cannot be reached following other conventional studies. Although additional cases with more extensive follow-up studies are needed, we believe that EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion should be added to the list of new sarcoma variants with the possibility of lymph node metastasis.

Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion

The latest WHO (World Health Organization) Classification of Bone and Soft Tissue Tumours (5th edition) has recently defined undifferentiated round cell sarcomas (URCSs) with EWSR1/FUS::NFATC2 (EWS RNA binding protein 1 or FUS RNA binding protein fused with nuclear factor of activated T cells 2) fusions. Given the rarity of this fusion, cytologic findings remain unreported, and information regarding clinical presentation, biological behavior, diagnostic markers, and molecular characteristics is scarce. To provide a review of the clinicopathologic, molecular, and prognostic features of URCSs with EWSR1/FUS::NFATC2 fusions. Classic histopathologic findings, uncommon variations, and diagnostic pitfalls are addressed, along with the utility of recently developed immunohistochemical and molecular markers. Bringing together our institutional expertise and a thorough evaluation of the literature, this review captures key findings and trends through an extensive PubMed search. By integrating our own practical insights with evidence-based data, we offer a well-rounded perspective that sheds light on both foundational concepts and new advancements in the field. This review underscores the importance of integrating clinicopathologic features and immunohistochemical results with EWSR1/FUS testing to effectively identify sarcomas with rare gene fusions via next-generation sequencing, which carry prognostic significance. Additionally, URCS-harboring EWSR/FUS::NFATC2 fusions exhibit notable differences from Ewing sarcoma and other URCSs, including a limited response to neoadjuvant chemotherapy; unique morphologic characteristics; and distinct genomic, transcriptomic, and epigenetic (methylation) profiles. Given the potential differences in biological behavior, accurate subclassification of EWSR1/FUS fusion variants is essential.

Ewing sarcoma (ES) is an undifferentiated round cell sarcoma affecting children and young adults. It is characterized by gene fusions involving one of the gene members of FET family ( EWSR1 ) and ETS transcription family members. Recent studies have observed certain undifferentiated round cell sarcomas with EWSR1 -non-ETS fusions, particularly EWSR1::NFATC2 fusion. We identified 5 cases of EWSR1::NFATC2 fusion sarcomas. There was male preponderance and all the patients had a history of trivial trauma. It affected the distal femur and proximal tibia with destructive osteolytic lesions. There was morphologic heterogeneity ranging from round cells in a myxo hyaline stroma to sheets of round-to-spindle cells in a fibrotic stroma. All the cases showed immunopositivity for MIC2, NKX2.2, and NKX3.1, and one showed focal positivity for AE1/AE3 (dot-like) and SATB2. Fluorescence in situ hybridization showed EWSR1 gene rearrangement and amplification (red signals) at 5' end in all the cases classic of EWSR1::NFATC2 sarcoma. Two of the cases showed multiple relapses despite chemotherapy. Though there is morphologic and immunohistochemical overlap with Ewing sarcoma, this entity has been listed separately within the group of undifferentiated small round cell sarcomas.

Undifferentiated small round cell sarcoma is an extremely rare and highly aggressive tumor touching the soft tissues and bones. Here, we report the case of a 7-month-old girl who presented to our department with respiratory distress due to a hypopharyngeal mass causing airway obstruction. The patient underwent a tracheotomy and had a direct laryngoscopy. Histological examination confirmed the diagnosis of an undifferentiated small round cell sarcoma. The patient received chemotherapy and radiotherapy and underwent neck dissection. One year later, the patient was diagnosed with local recurrence as well as metastatic cervical nodes and liver and pulmonary metastases. The case is original by the tumor's location and the age of onset. To the best of our knowledge, this could be the first case in English and French literature reporting an undifferentiated small round cell sarcoma affecting the hypopharynx among infants. The purpose of this article is to report our case and discuss its clinical and anatomopathological features as well as its prognosis and treatment options.

Objective: To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma. Methods: The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen. The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AE). The patients were grouped according to the diagnosis: osteosarcoma, soft tissue sarcoma and undifferentiated small round cell sarcoma. And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy, lines of chemotherapy received, best response and PFS of original chemotherapy. Results: A total of 30 patients were included in this study, including 20 males and 10 females. The mean age was (25.6±14.7) years. There were 9 cases of osteosarcoma, 11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma. No patient achieved complete response, 8 patients (26.7%) achieved partial response, 19 patients (63.3%) achieved disease stability, the ORR was 26.7%(8/30), and the DCR was 90.0%(27/30). The median PFS and OS were 4.1 and 13.1 months respectively. Among the three different subtypes of sarcoma, the ORR of osteosarcoma was 44.4% (4/9), the median PFS was 4.1 months, and the median OS was not yet achieved; the ORR of undifferentiated small round cell sarcoma was 40% (4/10), the median PFS was 6.4 months, and the median OS was 10.9 months; No response was observed in soft tissue sarcoma, and the median PFS and median OS was 3.5 and 7.3 months respectively. Patients who achieved objective response had better PFS than patients with stable disease (12.8 vs 3.8 months, P=0.015), and patients with PFS≥ 6 months of original chemotherapy had better PFS benefits (12.7 vs 2.7 months, P<0.001). However, the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen. In terms of safety, the related toxicity of apatinib was no more than grade 2, and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity, of which 2 patients interrupted treatment because of febrile neutropenia. Conclusion: Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.

BackgroundBCOR-CCNB3 sarcoma (BCS) is a group of undifferentiated small round cell sarcomas harboring the BCOR gene rearrangement which shares morphology with the Ewing sarcoma family as well as other malignant round blue cell tumors, thus making them difficult to diagnose. The aim of this study was to explore the role of molecular techniques in the diagnosis of BCS.MethodsTwenty-three cases of EWSR1 rearrangement-negative undifferentiated small round cell sarcomas (Ewing-like sarcoma) were analyzed for the presence of BCOR gene rearrangement by Fluorescence in situ hybridization (FISH) and Reverse Transcription -Polymerase Chain Reaction (RT-PCR). The clinicopathological features of the positive cases were also reviewed. Fifteen additional cases were used as negative controls.ResultsEight cases were found with BCOR gene rearrangement by FISH and reappraised as BCS. The patients ranged in age from 8 to 20 years old, with a male predominance (M:F = 6:2). All tumors were located in the lower extremities. The tumor locations were more common in bone (n = 6) than deep soft tissue (n = 2). Histologically, 7 of 8 tumors were predominately composed of spindle or ovoid cells. The tumor cells were usually arranged in solid hypercellular sheets without a distinct architectural pattern. IHC showed expression of TLE1 (100%), CCNB3 (88%), BCOR (71%). RT-PCR for BCOR-CCNB3 fusion transcript was positive in 7 of 8 cases. Pre-operative chemotherapy resulted in eradication of tumors in 5 patients after a follow-up of 7 to 42 months.ConclusionsEfficient diagnosis of BCOR rearranged sarcomas is achieved by the using a combination of FISH and RT-PCR assays.

Proteomic Characterization of Undifferentiated Small Round Cell Sarcomas With EWSR1 and CIC::DUX4 Translocations Reveals Diverging Tumor Biology and Distinct Diagnostic Markers

Patient: Female, 36Final Diagnosis: Small cell sarcomaSymptoms: Mass to right upper thighMedication: —Clinical Procedure: Surgical resectionSpecialty: OncologyObjective:Rare diseaseBackground:A subset of undifferentiated small round cell sarcomas (USRCSs) is currently being recognized as emerging entities with unique gene fusions: CIC-DUX4 (the area of focus in this article), BCOR-CCNB3, or CIC-FOXO4 gene fusions. CIC-DUX4 and CIC-FOXO4 fusions have been reported in soft tissue tumors, while BCOR-CCNB3 fusion with an X chromosomal inversion was described in both bone and soft tissue tumors. CIC-DUX4 fusion can either harbor t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13), while t(4;19)(q35;q13.1) is reported more commonly.Case Report:The aim of this study is to share a new case report of a 36-year-old woman who had a rapidly growing mass in her right upper thigh, which was found to be an undifferentiated small round cell sarcoma with t(4;19) (q35;q13.1) CIC-DUX4 fusion was confirmed by cytogenetic testing. Combined modality treatment with surgery, radiation, and chemotherapy was used and achieved a good response. A review of the literature of the reported cases with CIC-DUX4 fusions including both t(4;19) and t(10;19) translocations revealed a total of 44 cases reported. Out of these 44 cases, 33 showed t(4;19)(q35;q13.1) translocation compared to 11 cases with t(10;19)(q26.3;q13).Conclusions:Undifferentiated small round cell sarcomas are aggressive tumors. Their treatment includes surgery, chemo-therapy, and radiation. Resistance to chemotherapy is common. Lung and brain are common sites of metastasis, with associated poor prognosis. Generally, median survival is less than 2 years. Newer techniques have been developed recently which helped identify a subset of previously unclassifiable sarcomas, with promising prognostic value.

Ewing’s sarcoma is a highly malignant small round cell tumor with a unique rearrangement of the EWSR1 (FUS) gene with partners genes of ETS family. Tumors with Ewing's sarcoma morphological features lacking without specific EWSR1 rear-rangement called undifferentiated small round cell sarcomas of bone and soft tissue. This group includes: sarcomas with СIC gene rearrangement, sarcomas with BCOR gene rearrangement and sarcomas with EWSR1 (FUS) gene rearrangement with non-ETS gene-partner. Clinical, morphological and molecular genetic characteristics of these groups of tumors will be described below

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

Undifferentiated Small Round Cell Sarcomas of Bone

Undifferentiated Small Round Cell Sarcomas of Bone.

CIC-rearranged undifferentiated small round cell sarcoma (CIC-rearranged USRCS) is a recently established type of Ewing-like small round cell sarcomas, characterized by CIC gene rearrangement, most commonly CIC-DUX4 fusion. This report presents the second case of CIC-rearranged USRCS arising primarily in the cerebrum. A 64-year-old otherwise healthy woman presented with a 1 × 1 cm sized hemorrhagic subcortical tumor in the left temporo-parietal lobe. The tumor repeatedly recurred, and the patient underwent three surgeries, chemotherapy with doxorubicin and ifosfamide, and radiotherapy, as well as gamma knife surgery. Systemic examination revealed no other extracranial masses. Imprint cytology revealed small to moderate-sized round-to-ovoid tumor cells with mild pleomorphism and variations in size and shape. The nuclei contained finely granular chromatin, and some had easily-recognizable nucleoli. The tumor exhibited a mainly cytoplasmic pattern of CD99 immunostaining, rather than a diffuse membranous pattern. The tumor also exhibited diffuse positivity for calretinin and p16, as well as partial positivity for WT1 (nuclear and cytoplasmic staining pattern) and D2-40. FISH assessment showed CIC split signals. In conclusion, CIC-rearranged USRCSs can occur primarily in the cerebrum. It would be impossible to diagnose them through cytology alone, but cytology would be useful to rule out other small round cell brain tumors including gliomas, lymphomas, carcinomas, and germinoma. Immunohistochemical analysis including tests for CD99, calretinin, and WT1 would help to suggest CIC-rearranged USRCSs and distinguish them from Ewing sarcomas. Additionally, immunohistochemistry for p16 might be useful in the diagnosis. Diagn. Cytopathol. 2016;44:828-832. © 2016 Wiley Periodicals, Inc.