NR4A3 Immunohistochemistry Lacks Sensitivity for the Diagnosis of Extraskeletal Myxoid Chondrosarcoma.

To the Editor: We were very interested to read the recent paper by Haller and colleagues published in the journal entitled “Nuclear NR4A3 Immunostaining is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands.”1 The authors had previously demonstrated that the recurrent genomic rearrangement [t(4;9)(q13; q31)] is characteristic of salivary gland acinic cell carcinoma.2 This rearrangement brings the secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 to the region upstream of the Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) gene at 9q31. Although most recurrent gene rearrangements associated with malignancy result in the generation of a fusion oncogene, the t(4;9)(q13;q31) translocation leads to upregulation of the transcription factor NR4A3 by the process of enhancer hijacking whereby the chromatin enhancer properties of the SCPP gene region cause overexpression of the downstream NR4A3 gene, even when the site of fusion is located up to several hundred kbps away. Most importantly, the authors were able to elegantly translate this new molecular knowledge into clinical practice by demonstrating that NR4A3 immunohistochemistry was positive in