NKX2.2 is a new immunohistochemical marker that has been
reported to be sensitive and specific for Ewing sarcoma (ES). It has not, however, been investigated specifically in the sinonasal small round blue cell tumor (SRBCT) differential diagnosis which includes many tumors specific to that site. It has also not been investigated in the newly recognized “adamantinoma-like” variant of ES. Immunohistochemistry for NKX2.2 was performed on 170 poorly differentiated sinonasal neoplasms: 73 squamous cell carcinomas (67 poorly differentiated, non-keratinizing, or basaloid types and 6 nasopharyngeal carcinomas), 46 olfactory neuroblastomas, 8 sinonasal undifferentiated carcinomas (SNUCs), 6 melanomas, 7 Ewing sarcomas, 6 SMARCB1-deficient carcinomas, 6 teratocarcinosarcomas, 5 alveolar rhabdomyosarcomas, 4 solid adenoid cystic carcinomas, 4 NK/T cell lymphomas, 3 NUT carcinomas, and 2 small cell carcinomas. NKX2.2 was positive in 7 of 7 (100%) Ewing sarcomas, including 3 adamantinoma-like variant (all diffuse, 5 strong and 2 weak). It was also positive in 5 of 6 (83%) teratocarcinosarcomas (strong, but focal), 12 of 46 (26%) olfactory neuroblastomas (diffuse, 2 strong and 10 weak), 4 of 6 melanomas (2 diffuse, 2 focal, all weak), and 1 of 2 small cell carcinomas (diffuse and strong). All squamous cell carcinomas, NUT carcinomas, SMARCB1-deficient carcinomas, SNUCs, solid adenoid cystic carcinomas, NK/T cell lymphomas, and alveolar rhabdomyosarcomas were negative. In the sinonasal SRBCT differential diagnosis, NKX2.2 is a useful and very sensitive marker for Ewing sarcoma, including the treacherous adamantinoma-like variant. At the same time, it is not entirely specific, as it will be positive in a subset of other neuroendocrine/neuroectodermal tumors. As a result, NKX2.2 must be utilized as part of an immunohistochemical panel with other markers, especially cytokeratins, melanoma markers, and CD99.
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This article does not contain any studies with human participants or animals performed by any of the authors.
Weiss SW, Goldblum JR. Enzinger and Weiss’s soft tissue tumors. 5th ed. Philadelphia: Mosby Elsevier; 2008.Google Scholar
Qi Y, Cai J, Wu Y, Wu R, Lee J, Fu H, et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development. 2001;128:2723–33.PubMedGoogle Scholar
Briscoe J, Sussel L, Serup P, Hartigan-O’Connor D, Jessell TM, Rubenstein JLR, et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature. 1999;398:622–7.CrossRefPubMedGoogle Scholar
Wang Y-C, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo S-P, et al. Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors. Endocr Relat Cancer. 2009;16:267–79.CrossRefPubMedGoogle Scholar
Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 1998;125:2213–21.PubMedGoogle Scholar
Hung YP, Fletcher CDM, Hornick JL. Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma. Mod Pathol. 2016;29:370–80.CrossRefPubMedGoogle Scholar
Yoshida A, Sekine S, Tsuta K, Fukayama M, Furuta K, Tsuda H. NKX2.2 is a Useful Immunohistochemical Marker for Ewing Sarcoma. Am J Surg Pathol. 2012;36:993–9.CrossRefPubMedGoogle Scholar
Fadul J, Bell R, Hoffman LM, Beckerle MC, Engel ME, Lessnick SL. EWS/FLI utilizes NKX2-2 to repress mesenchymal features of Ewing sarcoma. Genes Cancer. 2015;6:129–43.PubMedPubMedCentralGoogle Scholar
Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell. 2006;9:405–16.CrossRefPubMedGoogle Scholar
Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma. PLoS ONE. 2008;3:e1965.CrossRefPubMedPubMedCentralGoogle Scholar
Shibuya R, Matsuyama A, Nakamoto M, Shiba E, Kasai T, Hisaoka M. The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma. Virchows Arch. 2014;465:599–605.CrossRefPubMedGoogle Scholar
Simons SA, Bridge JA, Leon ME. Sinonasal small round blue cell tumors: an approach to diagnosis. Semin Diagn Pathol. 2016;33:91–103.CrossRefPubMedGoogle Scholar
Bishop JA, Alaggio R, Zhang L, Seethala RR, Antonescu CR. Adamantinoma-like Ewing family tumors of the head and neck: a pitfall in the differential diagnosis of basaloid and myoepithelial carcinomas. Am J Surg Pathol. 2015;39:1267–74.CrossRefPubMedPubMedCentralGoogle Scholar
Folpe AL, Goldblum JR, Rubin BP, Shehata BM, Liu W, Dei Tos AP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005;29:1025–33.PubMedGoogle Scholar
Tilson MP, Gallia GL, Bishop JA. Among sinonasal tumors, CDX-2 immunoexpression is not restricted to intestinal-type adenocarcinomas. Head Neck Pathol. 2013;8:59–65.CrossRefPubMedPubMedCentralGoogle Scholar
Chapman-Fredricks J, Jorda M, Gomez-Fernandez C. A limited immunohistochemical panel helps differentiate small cell epithelial malignancies of the sinonasal cavity and nasopharynx. Appl Immunohistochem Mol Morphol AIMM. 2009;17:207–10.CrossRefPubMedGoogle Scholar
Rodriguez-Galindo C, Spunt SL, Pappo AS. Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol. 2003;40:276–87.CrossRefPubMedGoogle Scholar
Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A. Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors. Mod Pathol. 2006;19:1–8.CrossRefPubMedGoogle Scholar
Weidner N, Tjoe J. Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing’s sarcoma and peripheral neuroepithelioma. Am J Surg Pathol. 1994;18:486–94.CrossRefPubMedGoogle Scholar
Llombart-Bosch A, Machado I, Navarro S, Bertoni F, Bacchini P, Alberghini M, et al. Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009;455:397–411.CrossRefPubMedGoogle Scholar
Fatima SS, Minhas K, Din NU, Fatima S, Ahmed A, Ahmad Z. Sinonasal teratocarcinosarcoma: a clinicopathologic and immunohistochemical study of 6 cases. Ann Diagn Pathol. 2013;17:313–8.CrossRefPubMedGoogle Scholar
Pai SA, Naresh KN, Masih K, Ramarao C, Borges AM. Teratocarcinosarcoma of the paranasal sinuses: a clinicopathologic and immunohistochemical study. Hum Pathol. 1998;29:718–22.CrossRefPubMedGoogle Scholar
Yang S, Sun R, Liang J, Zhou Z, Zhou J, Rui J. Sinonasal teratocarcinosarcoma: a clinical and pathological analysis. Int J Surg Pathol. 2013;21:37–43.CrossRefPubMedGoogle Scholar