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Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions

A Report of 17 cases

Skálová, Alena, MD, PhD*; Vanecek, Tomas, PhD*,†; Uro-Coste, Emmanuelle, MD, PhD‡,§; Bishop, Justin A., MD, PhD; Weinreb, Ilan, MD; Thompson, Lester D.R., MD#; de Sanctis, Stefano, MD, PhD**; Schiavo-Lena, Marco, MD††; Laco, Jan, MD, PhD‡‡; Badoual, Cécile, MD, PhD§§; Santana Conceiçao, Thalita, DDS, MSc, PhD∥∥; Ptáková, Nikola, MSc; Baněčkova, Martina, MD*; Miesbauerová, Marketa, MD*; Michal, Michal, MD*

The American Journal of Surgical Pathology: November 2018 - Volume 42 - Issue 11 - p 1445–1455
doi: 10.1097/PAS.0000000000001133
Original Articles

Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called “low-grade cribriform cystadenocarcinoma” and “low-grade salivary duct carcinoma.” The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

*Department of Pathology, Charles University, Faculty of Medicine in Plzen

Molecular and Genetic Laboratory, Biopticka Laboratory Ltd, Plzen

‡‡The Fingerland Department of Pathology, Charles University, Faculty of Medicine and University Hospital, Hradec Kralove, Czech Republic

Department of Pathology, Toulouse University Hospital

§INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse

§§Department of Pathology, G. Pompidou Hospital, Paris, APHP, Paris Descartes University, Paris, France

Department of Pathology, UT Southwestern Medical Center, Dallas, TX

Department of Pathology, University Health Network, Toronto, ON, Canada

#Southern California Permanente Medical Group, Woodland Hills, CA

**Histopathology Department, Addenbrooke Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK

††Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy

∥∥Department of Oral Pathology, Faculty of Dentistry, University of São Paulo, São Paulo, Brazil

The preliminary results of the study were presented as a platform presentation at USCAP Meeting 2018, Vancouver, Canada, March 17-22, 2018 (A.S.).

Conflicts of Interest and Source of Funding: Supported in parts by the grant SVV–2018 No. 260 391 provided by the Ministry of Education Youth and Sports of the Czech Republic. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Alena Skálová, MD, PhD, Sikl’s Department of Pathology, Medical Faculty of Charles University, Faculty Hospital, E. Benese 13, Plzen 305 99, Czech Republic (e-mail: skalova@fnplzen.cz).

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