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Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands

Haller, Florian MD*; Skálová, Alena MD, PhD; Ihrler, Stephan MD; Märkl, Bruno MD§; Bieg, Matthias; Moskalev, Evgeny A. PhD*; Erber, Ramona MD*; Blank, Susanne*; Winkelmann, Christa*; Hebele, Simone*; Baněčková, Martina MD; Wiemann, Stefan PhD; Müller, Sarina MD#; Zenk, Johannes MD**; Eils, Roland PhD; Iro, Heinrich MD#; Hartmann, Arndt MD*; Agaimy, Abbas MD*

The American Journal of Surgical Pathology: September 2019 - Volume 43 - Issue 9 - p 1264–1272
doi: 10.1097/PAS.0000000000001279
Original Articles
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Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in “zymogen granule”-poor examples within the differential diagnostic spectrum of AciCC and MASC.

*Institute of Pathology

#Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

Dermpath Munich, Munich

§Institute of Pathology, Klinikum Augsburg

**Department of Otorhinolaryngology, Head and Neck Surgery, Augsburg Clinic Center, Augsburg

Center for Digital Health, Berlin Institute of Health and Charité—Universitätsmedizin Berlin, Berlin

Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany

Department of Pathology, Charles University, Faculty of Medicine in Plzen, Plzen, Czech Republic

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Abbas Agaimy, MD, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, Erlangen 91054, Germany (e-mail: abbas.agaimy@uk-erlangen.de).

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