Hypoxia Contributes to the Early-Stage Progression of Necrotizing Sialometaplasia

Necrotizing sialometaplasia (NSM) is a nonneoplastic lesion listed in the World Health Organization Classification of Tumours-Head and Neck Tumours. In early NSM lesion, there is infarction and necrosis of the acinar cells, and squamous metaplasia of the salivary ducts occurs as the lesion matures. Differentiation from squamous cell carcinoma and other malignancies is sometimes required clinically and histopathologically. Local hypoxia caused by trauma and vascular compromise is a proposed etiology of NSM. However, the mechanisms underlying the pathogenesis are unclear. This study focused on the early stages of NSM. Histopathologic observations revealed that the region showing acinar necrosis contained myoepithelial cells with reticular arrangement. Hypoxic in vitro experiments using mouse salivary gland organoids revealed that myoepithelial and basal cells were more tolerant to hypoxia than acinar cells. Moreover, the residual myoepithelial cells in NSM and hypoxia-tolerant cells in organoids expressed transforming growth factor-β3 (TGFB3), which plays a critical role in cell proliferation and squamous metaplasia. Organoid experiments have also replicated the process of squamous metaplasia in NSM during hypoxia and the resolution of hypoxia. Thus, this study demonstrated that hypoxia is a possible etiology of NSM based on the results of histopathologic and in vitro experimental observations.