Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach

After the publication of the 2017 World Health Organization Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an...

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Bibliographic Details
Published in:	Human pathology 2021-08, Vol.114, p.74-89
Main Authors:	Fisch, Adam S., Laklouk, Israa, Nakaguro, Masato, Nosé, Vânia, Wirth, Lori J., Deschler, Daniel G., Faquin, William C., Dias-Santagata, Dora, Sadow, Peter M.
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Algorithms Archives & records Biomarkers, Tumor - analysis Biomarkers, Tumor - genetics Cancer Carcinoma, Intraductal, Noninfiltrating - chemistry Carcinoma, Intraductal, Noninfiltrating - genetics Carcinoma, Intraductal, Noninfiltrating - pathology Classification Cloning Databases, Factual ETS Translocation Variant 6 Protein ETV6-RET Exocrine glands Female Gene Fusion Gene Rearrangement High-Throughput Nucleotide Sequencing Humans Immunohistochemistry Intraductal carcinoma Lymphatic system Male Middle Aged Morphology NCOA4-RET Nuclear Receptor Coactivators - genetics Oral cancer Pathology Predictive Value of Tests Proto-Oncogene Proteins c-ets - genetics Proto-Oncogene Proteins c-ret - genetics Repressor Proteins - genetics Salivary gland carcinoma Salivary Gland Neoplasms - chemistry Salivary Gland Neoplasms - genetics Salivary Gland Neoplasms - pathology Secretory carcinoma Tumors
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Summary:	After the publication of the 2017 World Health Organization Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an intact myoepithelial layer and a cystic, papillary, often cribriform architecture. Early studies of IC identified a heterogeneous group of molecular alterations driving neoplasia, and recent studies have defined three primary morphological/immunohistochemical variants, subsequently linking these morphologic variants with defined molecular signatures. Although studies to date have pointed toward distinct molecular alterations after histological classification, this study used a novel approach, focusing primarily on six cases of IC with NCOA4-RET gene rearrangement as determined by next-generation sequencing and describing the spectrum of clinicopathologic findings within that molecularly-defined group, among them a unique association between the NCOA4-RET fusion and hybrid variant IC and the first case of IC arising in association with a pleomorphic adenoma. RET-rearranged IC show histological and immunohistochemical overlap with the more widely recognized secretory carcinoma, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly leading to misdiagnosis. Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of six NCOA4-RET fusion-positive IC compared with four cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.
ISSN:	0046-8177 1532-8392