Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma

• Published in: Modern pathology Vol. 29; no. 4; pp. 370 - 380
• Main Authors: Hung, Yin P, Fletcher, Christopher D M, Hornick, Jason L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2016; Elsevier Limited
• Subjects: 692/420/755; 692/53/2421; Adolescent; Adult; Aged; Biomarkers, Tumor - analysis; Calmodulin-Binding Proteins - genetics; Cancer; Child; Diagnosis, Differential; Ewings sarcoma; Female; Homeobox Protein Nkx-2.2; Homeodomain Proteins - analysis; Homeodomain Proteins - biosynthesis; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Laboratory Medicine; Lymphoma; Male; Medicine; Medicine & Public Health; Melanoma; Middle Aged; Neuroblastoma; Nuclear Proteins; original-article; Pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Protein EWS; RNA-Binding Proteins - genetics; Sarcoma - diagnosis; Sarcoma - genetics; Sarcoma, Ewing - diagnosis; Sarcoma, Ewing - genetics; Sensitivity and Specificity; Transcription factors; Transcription Factors - analysis; Transcription Factors - biosynthesis; Tumors; Young Adult; Zebrafish Proteins; United States > US
• ISSN: 0893-3952; 1530-0285; 1530-0285
• DOI: 10.1038/modpathol.2016.31

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.