Review ArticlesCystic Salivary Gland Neoplasms: Diagnostic Approach With a Focus on Ancillary StudiesRibeiro, Efrain A. MD, PhD; Maleki, Zahra MD, FCAP, MIAC Author Information Department of Pathology, The Johns Hopkins University School of Medicine and The Johns Hopkins Hospital, Baltimore, MD E.A.R.: helped in data curation, formal analysis, investigation, software, validation, visualization, writing—original draft, and writing—review and editing. Z.M.: helped in conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing—original draft, and writing—review and editing. The authors have no funding or conflicts of interest to disclose. Reprints: Zahra Maleki, MD, FCAP, MIAC, Division of Cytopathology, Johns Hopkins Hospital, Department of Pathology, 600 North Wolfe Street, Pathology 304B, Baltimore, MD 21287 (e-mail: [email protected]). All figures can be viewed online in color at www.anatomicpathology.com. Advances In Anatomic Pathology: November 2022 - Volume 29 - Issue 6 - p 365-372 doi: 10.1097/PAP.0000000000000361 Buy Metrics Abstract Cystic salivary gland cytology can be challenging due to the fact that a cystic mass can be the clinical presentation of both non-neoplastic and neoplastic conditions. Neoplastic lesions consist of both benign and malignant neoplasms. The cytomorphologic features of these entities can overlap and the cystic background may additionally contribute to the complexity of these lesions and their interpretation. Ancillary studies have been reported in several studies to be beneficial in further characterization of the cellular components and subsequent diagnosis of the cystic lesions of the salivary gland. Fluorescence in situ hybridization, real-time polymerase chain reaction, and next-generation sequencing are now being utilized to detect molecular alterations in salivary gland neoplasms. MALM2 rearrangement is the most common gene fusion in mucoepidermoid carcinoma. PLAG1 rearrangement is present in more than half of pleomorphic adenomas. AKT1:E17K mutation is the key diagnostic feature of the mucinous adenocarcinoma. NR4A3 overexpression is highly sensitive and specific for the diagnosis of acinic cell carcinoma. MYB fusion is noted in adenoid cystic carcinoma. ETV6:NTRK3 fusion is helpful in diagnosis of secretory carcinoma. p16 and human papillomavirus (HPV) studies differentiate HPV-related squamous cell carcinoma from non–HPV-related neoplasms with overlapping features. NCOA4:RET fusion protein is the main fusion in intraductal carcinoma. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.