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Head and Neck Pathology

, Volume 12, Issue 1, pp 89–94 | Cite as

Usefulness of NKX2.2 Immunohistochemistry for Distinguishing Ewing Sarcoma from Other Sinonasal Small Round Blue Cell Tumors

  • Austin McCuiston
  • Justin A. Bishop
Original Paper

Abstract

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.

Keywords

NKX2.2 CD99 Ewing sarcoma Primitive neuroectodermal tumor EWSR1-FLI1 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Weiss SW, Goldblum JR. Enzinger and Weiss’s soft tissue tumors. 5th ed. Philadelphia: Mosby Elsevier; 2008.Google Scholar
  2. 2.
    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
  3. 3.
    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
  4. 4.
    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
  5. 5.
    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
  6. 6.
    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
  7. 7.
    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
  8. 8.
    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
  9. 9.
    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
  10. 10.
    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
  11. 11.
    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
  12. 12.
    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
  13. 13.
    Bridge JA, Bowen JM, Smith RB. The small round blue cell tumors of the sinonasal area. Head Neck Pathol. 2010;4:84–93.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bishop JA. Recently described neoplasms of the sinonasal tract. Semin Diagn Pathol. 2016;33:62–70.CrossRefPubMedGoogle Scholar
  15. 15.
    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
  16. 16.
    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
  17. 17.
    Bishop JA, Guo TW, Smith DF, Wang H, Ogawa T, Pai SI, et al. Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol. 2013;37:185–92.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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
  19. 19.
    Bishop JA, Westra WH. NUT midline carcinomas of the sinonasal tract. Am J Surg Pathol. 2012;36:1216–21.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Alexiev BA, Tumer Y, Bishop JA. Sinonasal adamantinoma-like Ewing sarcoma: a case report. Pathol Res Pract. 2017;213:422–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Iezzoni JC, Mills SE. “Undifferentiated” small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol. 2005;124(Suppl):S110–21.PubMedGoogle Scholar
  22. 22.
    Tilson MP, Bishop JA. Utility of p40 in the differential diagnosis of small round blue cell tumors of the sinonasal tract. Head Neck Pathol. 2013;8:141–5.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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
  24. 24.
    Bishop JA, Antonescu CR, Westra WH. SMARCB1 (INI-1)-deficient carcinomas of the sinonasal tract. Am J Surg Pathol. 2014;38:1282–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hafezi S, Seethala RR, Stelow EB, Mills SE, Leong IT, MacDuff E, et al. Ewing’s family of tumors of the sinonasal tract and maxillary bone. Head Neck Pathol. 2011;5:8–16.CrossRefPubMedGoogle Scholar
  26. 26.
    Vaccani JP, Forte V, de Jong AL, Taylor G. Ewing’s sarcoma of the head and neck in children. Int J Pediatr Otorhinolaryngol. 1999;48:209–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Huang M, Lucas K. Current therapeutic approaches in metastatic and recurrent Ewing sarcoma. Sarcoma (internet) (2011). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995926/. Accessed 5 June 2016.
  28. 28.
    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
  29. 29.
    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
  30. 30.
    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
  31. 31.
    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
  32. 32.
    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
  33. 33.
    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
  34. 34.
    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

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of PathologyThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Departments of Otolaryngology/Head and Neck SurgeryThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA

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