Confirmation of NKX3-1 Expression in EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma Using Monoclonal Antibody Immunohistochemistry, RT-PCR, and RNA In Situ Hybridization

Yoshida, Akihiko; Hashimoto, Taiki; Ryo, Eijitsu; Motoi, Toru; Yatabe, Yasushi; Mori, Taisuke

doi:10.1097/pas.0000000000001627

Cited by 12 publications

(13 citation statements)

References 3 publications

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“…Yoshida et al first reported NKX3.1 expression in 9/11 (82%) of EWSR1-NFATC2 sarcomas using a polyclonal antibody, consistent with transcriptomic analyses, as well as 9/9 mesenchymal chondrosarcomas [96]. After two other studies could not replicate these findings [97,98], a follow-up study by Yoshida et al confirmed NKX3.1 expression in both tumor types using a monoclonal antibody, as well as RT-PCR and in situ hybridization [99]. The reasons for these discrepant findings remain somewhat uncertain.…”

Section: Nkx22 In Ewing Sarcoma and Nkx31mentioning

confidence: 77%

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

Anderson

2021

Diagnostics

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The diagnosis of benign and malignant soft tissue and bone neoplasms is a challenging area of surgical pathology, due to the large number, rarity, and histologic diversity of tumor types. In recent years, diagnosis and classification has been aided substantially by our growing understanding of recurrent molecular alterations in these neoplasms. Concurrently, the role of diagnostic immunohistochemistry has also expanded, with the development of numerous biomarkers based on underlying molecular events. Such biomarkers allow us to infer the presence of these events and can therefore substitute for other ancillary molecular genetic techniques (e.g., fluorescence in situ hybridization, polymerase chain reaction, and next-generation sequencing). In this review, we discuss a range of biomarkers currently available for these neoplasms, highlighting the accuracy, staining characteristics, and interpretation pitfalls of each antibody. These include immunohistochemical antibodies that represent reliable surrogates for the detection of gene fusions (e.g., STAT6, CAMTA1, FOSB, DDIT3) and more recently described breakpoint-specific antibodies (e.g., SS18-SSX, PAX3/7-FOXO1). Additionally, discussed are markers that correlate with the presence of gene amplifications (e.g., MDM2, CDK4), deletions (e.g., SMARCB1, SMARCA4), single nucleotide variants (e.g., G34W, K36M), aberrant methylation (H3K27me3), and increased expression as discovered through gene expression profiling (e.g., MUC4, DOG1, ETV4, NKX2.2, NKX3.1).

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Section: Nkx22 In Ewing Sarcoma and Nkx31mentioning

confidence: 77%

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

Anderson

2021

Diagnostics

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“…Focal dot‐like keratin expression is common, which may lead to misinterpretation as metastatic carcinoma. RNA expression profiling identified differential NKX3‐1 overexpression in EWSR1::NFATC2 sarcoma, 70 which was later confirmed by RNA in situ hybridization and immunohistochemistry 76,79 . NKX3.1 is immunohistochemically expressed in ~80% of EWSR1::NFATC2 sarcomas (Figure 5f), whereas it is not expressed in many other round cell mimics, including Ewing sarcoma, CIC ‐rearranged sarcoma, and BCOR ‐associated sarcoma 76 .…”

Section: Ewsr1::nfatc2 Sarcomamentioning

confidence: 86%

“…NKX3.1 has been widely used as a prostatic adenocarcinoma marker in surgical pathology in the context of carcinoma of unknown origin 80 . One caveat is that NKX3.1 is also commonly expressed in mesenchymal chondrosarcoma in the primitive noncartilaginous component but not in the well‐differentiated cartilaginous component, and its ancillary diagnostic role is emerging 76,79,81,82 . In mice, Nkx3‐1 and Nkx3‐2 play important roles in chondrogenesis 83 .…”

Section: Ewsr1::nfatc2 Sarcomamentioning

confidence: 99%

Ewing and Ewing‐like sarcomas: A morphological guide through genetically‐defined entities

Yoshida

2022

Pathology International

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The fifth edition of the World Health Organization classification of soft tissue and bone tumors redefined Ewing sarcoma by fusions between EWSR1/FUS and ETS family of transcription factors, and recognized three tumor groups among Ewing‐like sarcoma: CIC‐rearranged sarcoma, sarcoma with BCOR genetic alterations, and round cell sarcoma with EWSR1::non‐ETS fusions. Although this classification underscores the critical role of molecular genetics in the diagnosis of small round cell sarcoma, each entry is recognized as a specific entity not only because they have different genetics but because their phenotypes are distinct and reasonably robust to support the diagnosis. This review focuses on the morphological aspects of Ewing sarcoma and a subset of Ewing‐like sarcomas (CIC‐rearranged sarcoma, BCOR‐associated sarcoma, and EWSR1::NFATC2 sarcoma) for which phenotypic characteristics have been well established. Classic histological findings, uncommon variations, and recurrent diagnostic pitfalls are addressed, along with the utility of recently developed immunohistochemical markers (NKX2.2, PAX7, ETV4, BCOR, CCNB3, and NKX3.1). Phenotypic expertise would significantly expedite the diagnostic process and complement (or sometimes outperform) genetic testing, even in well‐resourced settings. Morphological knowledge plays an even more substantial role in facilities that do not have easy access to molecular testing.

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“…NKX3.1 has been found to be up‐regulated in the transcriptome of sarcomas with NFATc2 rearrangements 17 . Its overexpression has been confirmed by immunohistochemistry; this is present in 82% of cases, with nuclear and diffuse staining in the majority of cases, with both monoclonal and polyclonal antibodies 59,60 . It is also overexpressed in mesenchymal chondrosarcomas.…”

Section: Recent Advances In the Immunohistochemical Panel Of Round Cell Sarcomasmentioning

confidence: 88%

“…AGGRECAN is positive in almost all cases but not in ES 57 . NK3 homeobox 1 (NKX3.1) may also be expressed consistently, 59 but the reproducibility of this finding is still under investigation 57,60,61 . Focal expression of cytokeratins AE1 and AE3 can occasionally be seen, as well as expression of EMA and markers of other round cell sarcomas (ETV4, WT1, and BCOR) 56,57,62 .…”

Section: Sarcomas With Nfatc2 Rearrangementsmentioning

confidence: 99%

Advances in the classification of round cell sarcomas

Loarer

Baud

Azmani³

et al. 2021

Histopathology

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Round cell sarcomas represent a diagnostic challenge for pathologists, owing to the poorly differentiated features of these high‐grade tumours. The diagnosis of round cell sarcoma requires large immunohistochemical panels and molecular testing in many cases. This spectrum of malignancies is largely dominated by Ewing sarcomas (ESs), which represent the most common family of these tumours. Nonetheless, new families have been delineated in the past few years, with the addition of two additional families in the 2020 World Health Organization classification of bone and soft tissue tumours, namely sarcomas with CIC rearrangements and sarcomas with BCOR alterations. EWSR1, one of the genes involved in the driver fusion of ESs, is also implicated in the translocation of many other tumours with heterogeneous lineages and variable levels of aggressiveness. Round cell sarcomas associated with fusions inwhichEWSR1is partnered with genes encoding transcription factors distinct from those of the ‘Ewing family’ represent a heterogeneous group of rare tumours that require further study to determine whether their fusions may or not define a specific subgroup. They include mainly sarcomas with NFATc2 rearrangements and sarcomas with PATZ1 rearrangements. At this point, PATZ1 fusions seem to be associated with tumours of high clinical and morphological heterogeneity. Molecular studies have also helped in the identification of more consistent biomarkers that give tremendous help to pathologists in triaging, if not diagnosing, these tumours in practice. This review compiles the latest accumulated evidence regarding round cell sarcomas, and discusses the areas that are still under investigation.

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Confirmation of NKX3-1 Expression in EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma Using Monoclonal Antibody Immunohistochemistry, RT-PCR, and RNA In Situ Hybridization

Cited by 12 publications

References 3 publications

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

Ewing and Ewing‐like sarcomas: A morphological guide through genetically‐defined entities

Advances in the classification of round cell sarcomas

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