The Role of Laryngopharyngeal Reflux Disease in Laryngeal and Hypopharyngeal Squamous Cell Carcinoma: A Systematic Review.

Background: Laryngeal and hypopharyngeal squamous cell carcinomas (L/HSCC) are common head and neck cancers with rising incidence globally. Laryngopharyngeal reflux disease (LPRD) is suspected to play a role in carcinogenesis through unknown mechanisms. The aim of this review was to summarize the literature findings about the potential carcinogenesis mechanisms associated with LPRD in L/HSCC.

Methods: A PubMed, Embase, and Web of Science database search was carried out by two independent investigators for studies investigating laryngeal and hypopharyngeal mucosa injuries and premalignancy modifications related to LPRD refluxate. The authors considered clinical and experimental studies using human biopsies, animal models, and cell lines that investigated potential mechanistic associations between LPRD and L/HSCC progression. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements were followed.

Results: Of the 689 identified papers, 34 studies were included. There were human tumor tissue studies (n = 8), human cell line studies (n = 19), and animal models (n = 12). Across methodologies, consistent evidence supported reflux-induced NF-κB pathway activation, oncogenic miRNA dysregulation, epithelial-mesenchymal transition, abnormal cell proliferation and differentiation, increased DNA damage, imbalance in the expression of tumor-promoting and tumor-suppressing genes, and altered cellular stress responses. Both pepsin and bile acids demonstrated carcinogenic potential through multiple molecular pathways, despite significant methodological heterogeneity across studies.

Conclusion: LPRD-refluxed pepsin and bile acids may substantially contribute to the carcinogenesis of laryngeal and hypopharyngeal cells through several pathways. Future translational studies documenting refluxed gastroduodenal enzymes in tumor samples are needed to better determine their role in the development of L/HSCC through understanding the underlying biomolecular cellular mechanisms.