Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.

Algarve Biomedical Center Research Institute Faro Portugal

Bioptic Laboratory Ltd Pilsen Czech Republic

Coordinator of the International Head and Neck Scientific Group Padua Italy

Department of Anatomical Pathology University of Calgary Calgary Alberta Canada

Department of Cellular Pathology Northern Lincolnshire and Goole NHS Foundation Trust Lincoln UK

Department of Otolaryngology Head and Neck Surgery Nottingham University Hospitals Queens Centre Campus Nottingham UK

Department of Pathology Hospital Clinic Barcelona Department of Basic Clinical Practice School of Medicine Universitat de Barcelona Barcelona Spain

Department of Pathology Kilimanjaro Christian Medical University College Moshi Tanzania

Department of Pathology Nijmegen Medical Centre Radboud University Nijmegen The Netherlands

Department of Pathology Sahlgrenska Center for Cancer Research University of Gothenburg Sahlgrenska University Hospital Gothenburg Sweden

Department of Pathology The University of Texas M D Anderson Cancer Center Houston TX USA

Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa 56126 Pisa Italy

Faculty of Medicine and Biomedical Sciences University of Algarve Campus de Gambelas Ala Norte 8005 139 Faro Portugal

Head and Neck Pathology Consultations Woodlands Hills CA 91364 USA

Institute of Biomedicine Pathology University of Turku Turku Finland

Institute of Pathology Faculty of Medicine University of Ljubljana 1000 Ljubljana Slovenia

Institute of Pathology University Hospital Erlangen Friedrich Alexander University Erlangen Nürnberg Erlangen EMN Erlangen Germany

Sikl's Department of Pathology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

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