Diagnosing salivary gland tumors remains challenging due to their clinical and biological complexity, histopathologic diversity, and overlapping morphology. Over the last few years, molecular profiling has emerged as a key tool for improving tumor classification, shedding light on the cellular and molecular mechanisms underlying tumors pathogenesis. This review provides a comprehensive exploration of the clinical application of molecular profiling in the decision to indicate targeted therapy for salivary gland neoplasm. The increasing adoption of innovative biological markers associated with Next-Generation Sequencing highlights the potential of molecular diagnostic approaches as well as the prediction of therapeutic response. While immunohistochemistry remains a reliable and widely accessible ancillary tool for characterizing specific salivary gland tumors subtypes, additional validation using in situ hybridization, reverse transcription polymerase chain reaction or Next-Generation Sequencing may enhance diagnostic accuracy and facilitate the identification of actionable molecular alterations in the appropriate clinical and morphological context. This integrated diagnostic approach strengthens clinical decision-making and opens new avenues for precision-targeted therapy in the management of salivary gland tumors. As molecular insights continue to expand, the integration of traditional and modern tools will be critical to improving diagnostic accuracy, prognostic stratification, and treatment outcomes for patients with salivary gland tumors.

Bioptic Laboratory Ltd Plzen Czech Republic

Cancer Institute of the State of São Paulo São Paulo State of São Paulo Brazil

Coordinator of the International Head and Neck Scientific Group Padua Italy

Department of Head and Neck Surgery and Otorhinolaryngology A C Camargo Cancer Center São Paulo Brazil

Department of Oncology Section Head and Neck Oncology KU Leuven Louvain Belgium

Department of Oral Diagnosis Faculdade de Odontologia de Piracicaba Universidade Estadual de Campinas Piracicaba São Paulo Brazil

Department of Pathology Faculdade de Ciências Médicas University of Campinas Campinas São Paulo Brazil

Department of Pathology Faculty of Medicine Charles University Pilsen Czech Republic

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

Department of Pathology University of Calgary Calgary AB Canada

Department of Thoracic Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA

Head and Neck Surgery Department and LIM 28 University of São Paulo Medical School São Paulo Brazil

Hospital Israelita Albert Einstein São Paulo Brazil

Institute of Pathology University Hospital Erlangen Erlangen Germany

Otorhinolaryngology Head and Neck Surgery Leuven Cancer Institute University Hospitals Leuven Louvain Belgium

Unit of Otorhinolaryngology Head and Neck Surgery ASST Spedali Civili of Brescia Department of Surgical and Medical Specialties Radiological Sciences and Public Health University of Brescia School of Medicine Brescia Italy

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