title: Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma.
abstract: Ewing sarcoma shows considerable histologic overlap with other round cell tumors. NKX2-2, a homeodomain transcription factor involved in neuroendocrine/glial differentiation and a downstream target of EWSR1-FLI1, has been reported as an immunohistochemical marker for Ewing sarcoma. We assessed the specificity of NKX2-2 for Ewing sarcoma compared with other round cell malignant neoplasms and other soft tissue tumors with EWSR1 translocations. We evaluated whole-tissue sections from 270 cases: 40 Ewing sarcomas (4 with atypical/large cell features), 20 CIC-DUX4 sarcomas, 5 BCOR-CCNB3 sarcomas, 9 unclassified round cell sarcomas, 10 poorly differentiated synovial sarcomas, 10 lymphoblastic lymphomas, 10 alveolar rhabdomyosarcomas, 10 embryonal rhabdomyosarcomas, 10 Merkel cell carcinomas, 10 small cell carcinomas, 20 melanomas, 5 NUT midline carcinomas, 10 Wilms tumors, 10 neuroblastomas, 10 olfactory neuroblastomas, 12 mesenchymal chondrosarcomas, 10 angiomatoid fibrous histiocytomas, 10 clear cell sarcomas, 5 gastrointestinal clear cell sarcoma-like tumors, 5 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas, 10 soft tissue and cutaneous myoepitheliomas, and 19 myoepithelial carcinomas. NKX2-2 positivity was defined as moderate-to-strong nuclear immunoreactivity in at least 5% of cells. NKX2-2 was positive in 37/40 (93%) Ewing sarcomas, including all atypical Ewing sarcomas and cases with known EWSR1-FLI1 or EWSR1-ERG fusion; 85% of Ewing sarcomas showed diffuse (>50%) staining. NKX2-2 was positive in 9 (75%) mesenchymal chondrosarcomas, 8 (80%) olfactory neuroblastomas, 1 CIC-DUX4 sarcoma, 1 poorly differentiated synovial sarcoma, 1 neuroblastoma, 2 unclassified round cell sarcomas, and 3 small cell carcinomas; all other EWSR1-associated tumors were negative for NKX2-2, apart from 1 desmoplastic small round cell tumor, 1 myoepithelioma, and 1 myoepithelial carcinoma. In summary, NKX2-2 is a sensitive but imperfectly specific marker for Ewing sarcoma. Nonetheless, NKX2-2 may be helpful to distinguish Ewing sarcoma from some histologic mimics including CIC-DUX4 and BCOR-CCNB3 sarcomas. Most other EWSR1-associated soft tissue tumors are negative for NKX2-2.
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Yin P
authors: YP
authors: Hung
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Christopher D M
authors: CD
authors: Fletcher
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Jason L
authors: JL
authors: Hornick
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000175:diagnosis* / Q000235:genetics; D012512:Sarcoma, Ewing / Q000175:diagnosis* / Q000235:genetics; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis*; D055815:Young Adult; D029961:Zebrafish Proteins
chemical_list: D014408:Biomarkers, Tumor; D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish