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      Ewing Sarcoma and Ewing-Like Sarcoma and the Role of NKX2.2 Immunoreactivity

      case-report
      Author(s): 1 , 2 , , 3 , 4 , 1
      Editor(s): ,
      Publication date (Electronic, pub):
      Publication date (Electronic, collection):
      Journal: Cureus
      Publisher: Cureus
      Keywords: ewing sarcoma, small round blue cell, immunostaining, ewing-like sarcoma, nkx2.2

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          Abstract

          Ewing sarcoma (ES) belongs to the family of “small round blue cell” tumors and its diagnosis currently involves a combination of immunostaining and molecular analysis. However, due to significant histological overlap with other tumors of the same family, accurate diagnosis has historically involved combining these results with clinical correlation. Recently, multiple studies have analyzed the role of NKX2.2 immunopositivity in the diagnosis of ES. NKX2.2, a downstream target of the Ewing sarcoma breakpoint region-Friend leukemia integration 1 (EWSR1-FLI1) fusion, has been identified as a potential stain to differentiate ES and Ewing-like sarcoma from other small round blue cell tumors. In this study, we examine the histopathological interpretation of five patients. Four cases showed fluorescent in situ hybridization (FISH)-identified EWSR1 rearrangement. In one case, rearrangements of EWSR1 or FUS could not be detected, and a diagnosis of Ewing-like sarcoma was rendered. NKX2.2 was immunopositive in all five cases. Based on this limited dataset, NKX2.2 immunopositivity can significantly support the diagnosis of ES and has the potential to support the diagnosis of fusion-undetected Ewing-like sarcoma in appropriate clinical and histologic settings.

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          Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.

          M Kawamura, N Kawaguchi, Hiroyuki Aburatani … (2006)
          Ewing's family tumors (EFTs) are highly malignant tumors arising from bone and soft tissues that exhibit EWS-FLI1 or variant EWS-ETS gene fusions in more than 85% of the cases. Here we show that CIC, a human homolog of Drosophila capicua which encodes a high mobility group box transcription factor, is fused to a double homeodomain gene DUX4 as a result of a recurrent chromosomal translocation t(4;19)(q35;q13). This translocation was seen in two cases of soft tissue sarcoma diagnosed as Ewing-like sarcoma. CIC-DUX4 exhibits a transforming potential for NIH 3T3 fibroblasts, and as a consequence of fusion with a C-terminal fragment of DUX4, CIC acquires an enhanced transcriptional activity, suggesting that expression of its downstream targets might be deregulated. Gene expression analysis identified the ETS family genes, ERM/ETV5 and ETV1, as potential targets for the gene product of CIC-DUX4. Indeed, CIC-DUX4 directly binds the ERM promoter by recognizing a novel target sequence and significantly up-regulates its expression. This study clarifies the function of CIC and its role in tumorigenesis, as well as the importance of the PEA3 subclass of ETS family proteins in the development of EFTs arising through mechanisms different from those involving EWS-ETS chimeras. Moreover, the study identifies the role of DUX4 that is closely linked to facioscapulohumeral muscular dystrophy in transcriptional regulation.
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            Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor.

            Y Qi, J. Rubenstein, Y. Wu … (2001)
            Oligodendrocytes are derived from glial precursors that arise from the ventral neural tube early in development. In the developing chicken CNS, oligodendrocyte progenitors selectively express Nkx2.2 homeodomain transcription factor, raising the possibility that Nkx2.2 may directly regulate oligogliogenesis. In this study, we have examined Nkx2.2 expression in rodent glial precursors and studied the effect of a loss of Nkx2.2 on oligodendrocyte and astrocyte differentiation. We show that Nkx2.2 is also expressed in mammalian oligodendrocyte progenitors and that the differentiation of MBP-positive and PLP-DM20-positive oligodendrocytes is dramatically retarded in Nkx2.2-null mutants along the entire rostrocaudal axis. In contrast, no effect is seen on astrocytic differentiation. Interestingly, absence of Nkx2.2 expression leads to a ventral expansion of the Olig1/Olig2 expression in neuroepithelial cells into the Nkx2.2 domain and a consequent increase in the production of Olig1/Olig2-positive and platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitors. These results strongly suggest that Nkx2.2 regulates the differentiation and/or maturation, but not the initial specification, of oligodendrocyte progenitors. Consistent with this suggestion, overproduction of Nkx2.2 protein in fibroblast cells can induce gene expression from the proteolipid protein promoter.
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              NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.

              Akihiko Yoshida, Koji Tsuta, Koh Furuta … (2012)
              Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain-containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array-based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cureus
                Journal ID (iso-abbrev): Cureus
                Journal ID (issn): 2168-8184
                Title: Cureus
                Publisher: Cureus (Palo Alto (CA) )
                ISSN (Electronic): 2168-8184
                Publication date (Electronic, pub): 23 August 2021
                Publication date (Electronic, collection): August 2021
                Volume: 13
                Issue: 8
                Electronic Location Identifier: e17391
                Affiliations
                [1 ] Pathology, Medical College of Georgia - Augusta University, Augusta, USA
                [2 ] Orthopedic Surgery, Medical College of Georgia - Augusta University, Augusta, USA
                [3 ] Pathology, University of Texas Medical Branch, Galveston, USA
                [4 ] Pathology, Medical University of South Carolina, Charleston, USA
                Author notes
                Margaret A. Sinkler msinkler@ 123456augusta.edu
                Article
                DOI: 10.7759/cureus.17391
                PMC ID: 8457536
                PubMed ID: 34584801
                SO-VID: b802aa58-28b8-42d5-b4ac-34159350b47a
                Copyright © Copyright © 2021, Ullah et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date accepted : 23 August 2021
                Categories
                Subject: Pathology
                Subject: Oncology
                Subject: Orthopedics

                Keywords: ewing sarcoma,small round blue cell,immunostaining,ewing-like sarcoma,nkx2.2
                Data availability:
                Keywords: ewing sarcoma, small round blue cell, immunostaining, ewing-like sarcoma, nkx2.2

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