Epithelial tumors of the lacrimal drainage system: A narrative review

In this review, we aimed to provide a comprehensive and up-to-date overview of epithelial tumors of the lacrimal drainage system (LDS)-rare but clinically significant entities that are often misdiagnosed as benign obstructions-by integrating recent evidence regarding epidemiology, clinical manifestations, diagnostic approaches, histopathological and molecular diversity as well as warning signs and imaging and biopsy strategies. According to the available data, squamous cell carcinoma is the predominant subtype, including both human papillomavirus (HPV)-positive non-keratinizing (transitional-type) variants with p16 overexpression and phosphatidylinositol 3-kinase, catalytic subunit alpha (PIK3CA)/fibroblast growth factor receptor 3 (FGFR3) alterations and HPV-negative keratinizing forms with tumor protein p53 (TP53) mutations. Management emphasizes complete en bloc resection aiming for negative margins supported by adjuvant radiotherapy. Organ-preserving chemoradiotherapy may be feasible in p16-positive cases, whereas proton or carbon-ion therapy has been shown to allow for precise dosing at anatomically constrained sites. Prognosis depends mainly on extent, margin status, perineural invasion, nodal involvement, histological subtype, and HPV status. Earlier recognition through awareness of "red flags" and standardized work-ups can significantly improve outcomes by reducing resection extent and morbidity risk. The integration of HPV status assessment and molecular profiling now allows biologically informed risk stratification and opens up new avenues for targeted and immune therapies, and proton and carbon-ion radiotherapies extend curative options to anatomically constrained regions. Important future research directions include designing molecularly informed therapeutic trials and prioritizing the development and establishment of standardized diagnostic frameworks and multicenter registries.