Pathogenesis of Warthin's Tumor: Neoplastic or Non-Neoplastic?

Warthin's tumor is the second most frequent neoplasm next to pleomorphic adenoma in the salivary gland, mostly in the parotid gland. The epithelial cells constituting a tumor are characterized by the presence of mitochondria that undergo structural and functional changes, resulting in the development of oncocytes. In addition to containing epithelial cells, Warthin's tumors contain abundant lymphocytes with lymph follicles (germinal centers) that are surrounded by epithelial cells. The pathogenesis of Warthin's tumor is not fully understood, and several hypotheses have been proposed. The risk factors for the development of Warthin's tumor, which predominantly occurs in males, include aging, smoking, and radiation exposure. Recently, it has been reported that chronic inflammation and aging cells promote the growth of Warthin's tumor. Several reports regarding the origin of the tumor have suggested that (1) Warthin's tumor is an IgG4-related disease, (2) epithelial cells that compose Warthin's tumor accumulate mitochondria, and (3) Warthin's tumor is a metaplastic lesion in the lymph nodes. It is possible that the pathogenesis of Warthin's tumor includes mitochondrial metabolic abnormalities, accumulation of aged cells, chronic inflammation, and senescence-associated secretory phenotype (SASP). In this short review, we propose that DNA damage, metabolic dysfunction of mitochondria, senescent cells, SASP, human papillomavirus, and IgG4 may be involved in the development of Warthin's tumor.