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Introduction: Lacrimal sac squamous cell carcinoma (SCC) is a rare tumor. Only 241 cases of lacrimal sac SCC have been reported in the literature. However, the detailed molecular profile of this tumor is unknown. Case Presentation: Fifty-seven-year-old Caucasian male presented with a 6-month history of epiphora. Multimodal examination revealed a unilateral lacrimal sac SCC T4aN0M0. The patient underwent primary surgery with subsequent chemoradiotherapy. The patient was alive 18 months after the end of the treatment, with no signs of local or distant relapse. Complex molecular profiling revealed the FGFR p.G388R variant, HER2 amplification, and progression phenotype. Conclusion: Here, we describe a clinical case of a male patient with lacrimal sac SCC with a careful description of the disease history, treatment, and molecular-genetic patterns of the tumor. This is the first report of HER2-positive lacrimal sac SCC. [ABSTRACT FROM AUTHOR]