Diagnostic Value of Nuclear Receptor Subfamily 4 Group A Member 3 in Salivary Gland Carcinomas


  • Asmaa S. Algharyani Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Tripoli University, Tripoli, Libya
  • Marwa M. Maghrabi Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Tripoli University, Tripoli, Libya
  • Samah K. Ezzat Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
  • Marwa M. Shakweer Department of General Pathology, Ain Shams University, Cairo, Egypt; Department of Pathology, Badr University in Cairo (BUC), Badr City, Egypt
  • Doaa Esmaeil Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt https://orcid.org/0000-0001-9054-8333




Salivary gland carcinomas, Nuclear receptor subfamily 4 Group A member 3, Immunohistochemistry, Acinic cell carcinoma


Salivary gland carcinomas are diagnostically challenging lesions in heterogeneous groups. However, recently described genomic alterations may be helpful and have future therapeutic implications. The molecular investigation is becoming useful tool to help diagnosis and provide prognostic information. Diagnosis of acinic cell carcinoma (AcCC) is challenging due to its rarity and similarity with other SGCs or normal acinar cells.

Herein, the diagnostic performance of transcription factor nuclear receptor subfamily 4 group A member3 (NR4A3) was analysed immunohistochemically. This study was done on 68 cases of SCCs, including 32 of AcCC, 14 of adenoid cystic carcinoma (AdCC), 8 of mucoepidermoid carcinoma (MEC), 7 of epithelial myoepithelial carcinoma (EMC), 4 of salivary duct carcinoma (SDC), and only one case from each of carcinoma ex pleomorphic adenoma (CXPA), polymorphous adenocarcinoma (PAC) and secretory carcinoma (SC) for detecting NR4A3.

All stained samples of AcCC (100%) responded positively to the NR4A3 antibody. However, only one case of AdCC and MEC demonstrated NR4A3 immunostaining in less than 10% of cells. On the other hand, the different types of SGCs, including EMC, SDC, CXPA, PAC, and SC, revealed negative expressions. Therefore, we can conclude that NR4A3 can be used as a potential marker for AcCC rather than other SGCs.


Download data is not yet available.


Metrics Loading ...

Plum Analytics Artifact Widget Block


Speight PM, Barrett AW. Salivary gland tumors: Diagnostic challenges and an update on the latest WHO classification. Diagn Histopathol. 2020;26:147-158. DOI: https://doi.org/10.1016/j.mpdhp.2020.01.001

Robinson M, Hunter K, Pemberton M, Sloan P, editors. Soames’ and Southam’s Oral Pathology. Oxford University Press, UK. Oxford, United Kingdom; 2018. p. 105. https://doi.org/10.1111/ jop.12778 DOI: https://doi.org/10.1093/oso/9780199697786.001.0001

Freiberger SN, Brada M, Fritz C, Höller S, Vogetseder A, Horcic M, et al. SalvGlandDx a comprehensive salivary gland neoplasm specific next generation sequencing panel to facilitate diagnosis and identify therapeutic targets. Neoplasia. 2021;23(5):473-87 https://doi.org/10.1016/j.neo.2021.03.008 PMid:33878706 DOI: https://doi.org/10.1016/j.neo.2021.03.008

Babu SS, Sunil S, Prathap A, Mathew AL. Acinic cell carcinoma of the posterior buccal mucosa: A rare case report. J Can Res Ther. 2020;16(3):675-9. https://doi.org/10.4103/jcrt.JCRT_399_18 PMid:32719290 DOI: https://doi.org/10.4103/jcrt.JCRT_399_18

El-Naggar AK, Chan JK, Grandis JR, Takata TS. WHO Classification of Head and Neck Tumours. 4th ed. Lyon, France: IARC Press; 2017.

Poorten VV, Triantafyllou A, Thompson LD, Bishop J, Hauben E, Hunt J, et al. Salivary acinic cell carcinoma: Reappraisal and update. Eur Arch Otorhinolaryngol. 2016;273(11):3511-31. https://doi.org/10.1007/s00405-015-3855-7 PMid:26685679 DOI: https://doi.org/10.1007/s00405-015-3855-7

Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, et al. Mammary analog secretory carcinoma of salivary glands, containing the Etv6-Ntrk3 fusion gene: A hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34(5):599-608. https://doi.org/10.1097/PAS.0b013e3181d9efcc PMid:20410810 DOI: https://doi.org/10.1097/PAS.0b013e3181d9efcc

Inaki R, Abe M, Zong L, Abe T, Shinozaki-Ushiku A, Ushiku T, et al. Secretory carcinoma impacts translocation and gene fusions on salivary gland tumors. Chin J Cancer Res. 2017;29(5):379-84. https://doi.org/10.21147/j.issn.1000-9604.2017.05.01 PMid:29142456 DOI: https://doi.org/10.21147/j.issn.1000-9604.2017.05.01

Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003;33(2):208-13. https://doi.org/10.1038/ng1083 PMid:12539049 DOI: https://doi.org/10.1038/ng1083

Luk PP, Wykes J, Selinger CI, Ekmejian R, Tay J, Gao T, et al. Diagnostic and prognostic utility of mastermind-like 2 (MAML2) gene rearrangement detection by fluorescent in situ hybridization (FISH) in mucoepidermoid carcinoma of the salivary glands. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(5):530-41. https://doi.org/10.1016/j.oooo.2016.01.003 PMid:27068311 DOI: https://doi.org/10.1016/j.oooo.2016.01.003

Saade RE, Bell D, Garcia J, Roberts D, Weber R. Role of CRTC1/ MAML2 translocation in mucoepidermoid carcinoma prognosis and clinical outcomes. JAMA Otolaryngol Head Neck Surg. 2016;142(3):234-40. https://doi.org/10.1001/jamaoto.2015.3270 PMid:26796488 DOI: https://doi.org/10.1001/jamaoto.2015.3270

Fehr A, Röser K, Heidorn K, Hallas C, Löning T, Bullerdiek J. A new type of MAML2 fusion in mucoepidermoid carcinoma. Genes Chromosomes Cancer. 2008;47(3):203-6. https://doi.org/10.1002/gcc.20522 PMid:18050304 DOI: https://doi.org/10.1002/gcc.20522

Nakayama T, Miyabe S, Okabe M, Sakuma H, Ijichi K, Hasegawa Y, et al. Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma. Mod Pathol. 2009;22(12):1575-81. https://doi.org/10.1038/modpathol.2009.126 PMid:19749740 DOI: https://doi.org/10.1038/modpathol.2009.126

Mitani Y, Li J, Rao PH, Zhao YJ, Bell D, Lippman SM, et al. Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. Clin Cancer Res. 2010;16(19):4722-31. https://doi.org/10.1158/1078-0432.CCR-10-0463 PMid:20702610 DOI: https://doi.org/10.1158/1078-0432.CCR-10-0463

Allen S, Ho Ochoa A, Jayakumaran G, Zehir A, Mayor CV, Tepe J, et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J Clin Invest. 2019;129(10):4276-89. https://doi.org/10.1172/JCI128227 PMid:31483290 DOI: https://doi.org/10.1172/JCI128227

Xu LH, Zhao F, Yang WW, Chen CW, Du ZH, Fu M, et al. MYB promotes salivary adenoid cystic carcinoma growth and metastasis. Int J Oncol. 2019;54(5):1579-90. https://doi.org/10.3892/ijo.2019.4754 PMid:30896785 DOI: https://doi.org/10.3892/ijo.2019.4754

Weinreb I, Zhang L, Tirunagari LM, Sung YS, Chen CL, Perez- Ordonez B, et al. Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin. Genes Chromosomes Cancer. 2014;53(10):845-56. https://doi.org/10.1002/gcc.22195 PMid:24942367 DOI: https://doi.org/10.1002/gcc.22195

Fedorova O, Petukhov A, Daks A, Shuvalov O, Leonova T, Vasileva E, et al. Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene. 2019;38(12):2108-22. https://doi.org/10.1038/s41388-018-0566-8 PMid:30455429 DOI: https://doi.org/10.1038/s41388-018-0566-8

Kurakula K, Koenis DS, van Tiel CM, de Vries CJ. NR4A nuclear receptors are orphans but not lonesome. Biochim Biophys Acta. 2014;1843(11):2543-55. https://doi.org/10.1016/j.bbamcr.2014.06.010 PMid:24975497 DOI: https://doi.org/10.1016/j.bbamcr.2014.06.010

Haller F, Bieg M, Will R, Körner C, Weichenhan D, Bott A, et al. Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun. 2019;10(1):368. https://doi.org/10.1038/s41467-018-08069-x PMid:30664630 DOI: https://doi.org/10.1038/s41467-018-08069-x

Martin TA, Ye L, Sanders AJ, Lane J, Jiang WG. Cancer invasion and metastasis: Molecular and cellular perspective. In: Madame Curie Bioscience Database. Austin, TX: Landes Bioscience; 2000-2013.

Ada C, Soares NF, Santos DA, Vieira FK, Teresinha OS. Novel non-coding transcript in NR4A3 locus, LncNR4A3, regulates RNA processing machinery proteins and NR4A3 expression. Front Oncol. 2020;10:569668. https://doi.org/10.3389/fonc.2020.569668 PMid:33330042 DOI: https://doi.org/10.3389/fonc.2020.569668

Wong KS, Mariño-Enriquez A, Hornick JL, Jo VY. NR4A3 immunohistochemistry reliably discriminates acinic cell carcinoma from mimics. Head Neck Pathol. 2021;15(2):425-32. https://doi.org/10.1007/s12105-020-01213-4 PMid:32910350 DOI: https://doi.org/10.1007/s12105-020-01213-4

Cheng K, Wang X, Wei X, Ma J, Xia QY, Shi QL, et al. Expression of NR4A3/NOR-1 in acinic cell carcinoma of the salivary gland. Zhonghua Bing Li Xue Za Zhi. 2020;49(11):1142-6. https://doi.org/10.3760/cma.j.cn112151-20200224-00127 PMid:33152819

Haller F, Moskalev EA, Kuck S, Bieg M, Winkelmann C, Müller SK, et al. Nuclear NR4A2 (Nurr1) immunostaining is a novel marker for acinic cell carcinoma of the salivary glands lacking the classic NR4A3 (NOR-1) Upregulation. Am J Surg Pathol. 2020;44(9):1290-2. https://doi.org/10.1097/PAS.0000000000001494 PMid:32341238 DOI: https://doi.org/10.1097/PAS.0000000000001494




How to Cite

Algharyani AS, Maghrabi MM, Ezzat SK, Shakweer MM, Esmaeil D. Diagnostic Value of Nuclear Receptor Subfamily 4 Group A Member 3 in Salivary Gland Carcinomas. Open Access Maced J Med Sci [Internet]. 2022 Jun. 2 [cited 2023 Mar. 28];10(A):1082-8. Available from: https://oamjms.eu/index.php/mjms/article/view/9831