NR4A3 Immunohistochemistry Reliably Discriminates Acinic Cell Carcinoma from Mimics
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ORIGINAL PAPER
NR4A3 Immunohistochemistry Reliably Discriminates Acinic Cell Carcinoma from Mimics Kristine S. Wong1 · Adrian Mariño‑Enriquez1 · Jason L. Hornick1 · Vickie Y. Jo1 Received: 13 July 2020 / Accepted: 17 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Acinic cell carcinoma (AciCC) harbors a recurrent t(4;9)(q13;q31) translocation, which leads to upregulation of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3). Previous work on tissue microarrays suggests that NR4A3 immunohistochemistry (IHC) may be useful in the diagnosis of AciCC. Thus far, only a single study has evaluated the utility of NR4A3 immunohistochemistry (IHC) in the diagnosis of AciCC, using a tissue microarray to assess most non-AciCC tumor types. Herein we evaluate the diagnostic performance of NR4A3 IHC for AciCC in a large cohort of 157 salivary gland tumors, using whole tissue sections. The cohort consisted of 37 AciCC (6 of them (16%) with high grade transformation), 30 secretory carcinomas (SC), and 90 additional salivary gland tumors, including mucoepidermoid carcinomas (MEC), polymorphous adenocarcinomas (PAC), pleomorphic adenomas (PA), salivary duct carcinomas (SDC), and adenoid cystic carcinomas (AdCC). NR4A3 nuclear staining by IHC was considered positive if present in more than 5% of tumor cells. Overall, 92% of AciCC (34/37) expressed NR4A3 by IHC, with strong (89%) or moderate (3%) nuclear staining, yielding a sensitivity of 92%. IHC detected NR4A3 expression in all cases of recurrent/metastatic AciCC and tumors with high grade transformation. Importantly, all SC were negative for NR4A3 IHC, with no staining in 28/30 cases and weak focal staining, in 97% of AciCC [8, 9]. In this latter study, NR4A3 IHC was performed on AciCC, SC, and a tissue microarray containing other salivary tumors. The goal of this study was to further evaluate the performance of NR4A3 IHC in AciCC and to broaden the scope of other salivary tumors evaluated using whole tissue sections.
Interphase FISH analysis was performed according to standard protocols on 4-µm-thick FFPE tissue sections from 5 cases of AciCC (including 2 cases showing high grade transformation) which stained positively for NR4A3. The presence of NR4A3 rearrangement was evaluated using a commercially available dual-color break-apart probe set (ZytoLight SPEC NR4A3 Dual Color Break Apart Probe, Z-2145–50, ZytoVision GmbH, Bremerhaven, Germany) as described in the literature [8]. Signals separated by > 3 signal diameters were considered split signals. The slides were reviewed manually by a pathologist (A.M.E.) and at least 50 tumor nuclei were evaluated for each case. One case was technically unsuccessful. Tumors with more than 30% nuclei showing isolated signals or split signals were considered positive for NR4A3 rearrangement.
Methods
Results
Study Population and Data Acquisition
Clinicopathologic Characteristics
Approval was obtained from the Brigham and Women’s Hospital Institutional Review Board. Cases of AciCC and secretory
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